World Health Organization (WHO) · Publications

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach

June 26, 2013 World Health Organization

The full text is hosted by the publishing organisation. lawenc.com indexes the metadata and links to the official source.

Full text

1. Introduction

1 Introduction

HIV/AIDS Programme

guidelines the use of ANTIRETROVIRAL DRUGS FOR TREATING AND PREVENTING HIV INFECTION CONSOLIDATED GUIDELINES on

recommendations for a public health approach June 2013

HIV/AIDS Programme

CONSOLIDATED GUIDELINES ON

the use of ANTIRETROVIRAL DRUGS FOR TREATING AND PREVENTING HIV INFECTION recommendations for a public health approach

JUNe 2013

WHO Library Cataloguing-in-Publication Data Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 1. Antiretroviral agents – supply and distribution. 2. HIV infection – therapy. 3. Drug industry – trends. 4. Intersectoral cooperation. I.World Health Organization. II.UNAIDS. ISBN 978 92 4 150572 7 (NLM classification: WC 503.2)

© World Health Organization 2013 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press through the WHO web site (www.who.about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the name or proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.

Design and layout by ACW, London Printed in Kuala Lumpur, Malaysia

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

contents Abbreviations and acronyms Definition of key terms Acknowledgements Foreword Executive summary Summary of new recommendations 12 14 18 24 26 28 37 38 38 39 39 40 40 40 40 41 41 43 44 44 44 45 45 45 47 48 48 49 49

1. Introduction 1.1 1.2 Background and context Rationale for consolidated guidelines

1.3 Objectives 1.4 Target audience 1.5 Scope and components

1.5.1 Introductory chapters 1.5.2 Clinical guidance 1.5.3 Operational and service delivery guidance 1.5.4 Guidance for programme managers 1.5.5 Monitoring and evaluation

2. Guiding principles 3. 2.1 2.2 2.3 2.4 2.5 2.6 Contribution to global health goals Public health approach Strengthening health systems through innovation and learning Increasing the effectiveness and efficiency of programmes Promoting human rights and health equity Implementation based on local context

Methods and process for developing the guidelines 3.1 Overview 3.2 Information sources 3.3 External participation 3.3.1 Guideline Development Groups and peer review process

Contents

3.3.2 Conflicts of interest

49 50 53 53 55 56 58 58 59 59 61 63 65

Contents

3.4 Process of formulating recommendations 3.5 Other methods 3.6 Dissemination Organization of the guidelines 4.1 Structure of presentation for new recommendations

Continuum of care 4.2 Structure of presentation of selected recommendations from existing guidelines 4.3 How to use the guidelines for specific populations 4.3.1 Pregnant and breastfeeding women

4.3.2 Adolescents 4.3.3 Children 4.3.4 Key populations

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention 5.1 HIV testing and counselling 5.1.2 HIV testing and counselling in health facilities 5.1.3 Community-based HIV testing and counselling 5.1.1 Introduction

67 68 68 69 70 72

5.1.4 HIV testing and counselling in specific populations 5.2 HIV prevention based on ARV drugs 5.2.1 Oral pre-exposure oral prophylaxis

82 82 83 83 84

5.2.2 ART for prevention among serodiscordant couples 5.2.3 Post-exposure prophylaxis for occupational and non-occupational exposure to HIV 5.2.4 Combination HIV prevention

6. Clinical guidelines across the continuum of care: linking people diagnosed with HIV infection to HIV care and treatment 6.1 Introduction 6.2 6.3 Good practices for linkage to care General care for people living with HIV

85 86 86 86

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

6.4 6.5

Preparing people living with HIV for ART What to expect in the first months of ART

89 90

Clinical guidance across the continuum of care: antiretroviral therapy 91 7.1 When to start ART 7.1.1 When to start ART in adults and adolescents 7.1.2 When to start ART in pregnant and breastfeeding women 7.1.3 ARV drugs and duration of breastfeeding 7.1.4 When to start ART in children 7.2.1 First-line ART for adults What ART regimen to start with (first-line ART) 7.2.2 First-line ART for pregnant and breastfeeding women and ARV drugs for their infants 7.2.3 First-line ART for children younger than three years of age 7.2.4 First-line ART for children three years and older (including adolescents) 7.2.5 TB co-treatment in children 92 93 100 104 112

7.2

108 113 116 122 126 130 132 132 133 138 138 138 142 143 143 146 146 150 153

7.3 Monitoring response to ART and the diagnosis of treatment failure 7.3.1 Laboratory monitoring before and after initiating ART 7.3.2 Monitoring the response to ART and the diagnosis of treatment failure Monitoring and substitutions for ARV drug toxicities 7.4.2 Major types of ARV toxicities 7.4.4 Toxicity monitoring for other ARV drugs 7.4.5 Drug substitutions for ARV drug toxicity What ART regimen to switch to (second-line ART) 7.5.1 Second-line ART for adults and adolescents 7.5.2 Second-line ART for children (including adolescents) Third-line ART

7.4

7.4.1 Guiding principles 7.5

7.4.3 Monitoring TDF toxicity 141

7.4.6 Drug interactions 7.6

Contents

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities 8.1 Prevention, screening and management of common coinfections 8.1.1 Co-trimoxazole preventive therapy 8.1.3 Cryptococcal infection 8.1.4 Hepatitis B and C 8.1.6 Sexually transmitted infections and cervical cancer 8.1.7 Vaccines for people living with HIV

Contents

155 156 156 158 165 166 167 168 169 170 170 171 171 172 173 173 175 176 176 176 178 183 182 182 182 185 185 185 190 192 192 192

8.1.2 Tuberculosis

8.1.5 Malaria

8.2 Preventing and managing other comorbidities and chronic care for people living with HIV 8.2.1 Screening for and care of noncommunicable diseases 8.2.3 Drug use and drug use disorders 8.2.4 Nutritional care and support 8.2.5 Palliative care: symptom management and end-of-life care 8.2.6 Other relevant general guidance on care

8.2.2 Mental health

Guidance on operations and service delivery 9.1 Introduction 9.2 Adherence to ART 9.2.1 Barriers to adherence 9.2.2 Interventions to optimize adherence to ART 9.2.3 Monitoring adherence to ART in routine programme and care settings Retention across the continuum of care

9.3

9.3.1 Background

9.3.2 Good practices for retention across the continuum of care 9.4 Service delivery 9.4.1 Good practices in providing chronic care 9.4.2 Integrating and linking services 9.4.3 Decentralizing HIV treatment and care 9.5.1 Building human resource capacity 9.5.2 Task shifting for HIV treatment and care

9.5 Human resources

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.6

Laboratory and diagnostic services 9.6.2 Implementation considerations and good practices 9.6.3 Strengthening and expanding laboratory and diagnostic services 9.6.4 Supporting a dedicated specimen referral system 9.6.5 Increasing access to HIV viral load testing 9.6.6 Expanding diagnostic services to point-of-care settings 9.6.7 Providing guidance for developing health workers’ capacity, including staff training and certification 9.6.8 Implementing comprehensive quality management systems Procurement and supply management systems 9.7.2 Rationale and supporting evidence 9.7.3 Implementation considerations and good practices

194 194 194 194 195 195 195 197 197 197 197 197 198 201 202 203 203 203 204 204 204 207 207 207 208 209 211

9.6.1 Overview 9.7

9.7.1 Overview 10.

Guidance for programme managers 10.1 Introduction 10.2 Decision-making process 10.3 Data to support decision-making 10.3.2 National and local HIV epidemiology 10.3.3 Programme performance and response analysis 10.3.4 Socioeconomic, policy and legal context 10.4.1 Ethics, equity and human rights 10.4.2 Impact and cost–effectiveness 10.4.3 Opportunities and risks

10.3.1 Overview

10.4 Key parameters for decision-making

10.5 Implementation considerations across the health system 10.6 Implementation considerations for key recommendations

Contents

10.7 Implementing recommendations in different contexts 10.7.2 Implementing recommendations in different epidemic settings

217 217 217 218 219 220 221 222 225 225 225 225 227 229 230 232 234 236 237 238 242 251

Contents

10.7.1 Overview 11. 10.8 Useful tools for costing and planning Monitoring and evaluation 11.1 Introduction 11.2 Monitoring implications of new recommendations 11.3 Monitoring the outputs and outcomes of scaling up access to ARV drugs 11.4 Other monitoring considerations 11.4.1 HIV drug resistance 11.4.2 Sentinel surveillance for ARV toxicity monitoring 11.4.3 Evaluation, including impact and programme performance, and implementation research

11.5 Reviewing and strengthening monitoring and evaluation systems

12. Annexes Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children Annex 2. Algorithm for the 2013 recommendations for adults and adolescents Annex 3. Algorithm for the 2013 recommendations for pregnant and breastfeeding women Annex 5. Algorithm for early infant diagnosis

Annex 4. Algorithm for the 2013 recommendations for children Annex 6. Readiness assessment checklist: moving towards ART for pregnant and breastfeeding women Annex 7. Dosages of recommended antiretroviral drugs

13. References

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Abbreviations and acronyms 3TC AIDS ART ARV lamivudine acquired immunodeficiency syndrome antiretroviral therapy antiretroviral (drug) ABC abacavir

ATV atazanavir ATV/r atazanavir/ritonavir AZT BMI CD4 CDC CNS DALYs DBS DNA zidovudine (also known as ZDV) body mass index T–lymphocyte cell bearing CD4 receptor United States Centers for Disease Control and Prevention central nervous system death- and disability-adjusted life-years dried blood spot deoxyribonucleic acid

d4T stavudine

ddI didanosine DRV darunavir DRV/r darunavir/ritonavir EFV efavirenz eGFR ELISA ETV estimated glomerular filtration rate enzyme-linked immunosorbent assay etravirine

FPV fosamprenavir FPV/r fosamprenavir/ritonavir FTC GNP+ HBsAg HBV HCV HIV emtricitabine Global Network of People Living with HIV hepatitis B surface antigen hepatitis B virus hepatitis C virus human immunodeficiency virus

GRADE Grading of Recommendations Assessment, Development and Evaluation

Abbreviationa and acronyms

HPTN HSV IPT IRIS

HIV Prevention Trials Network herpes simplex virus isoniazid preventive therapy immune reconstitution inflammatory syndrome

Abbreviations and acronyms

INH isoniazid

LPV lopinavir LPV/r lopinavir/ritonavir MDR MTCT NNRTI NRTI OST PCR PI PICO PMTCT PrEP RBV RNA sd-NVP TAM TB TDF multidrug-resistant TB, resistant to at least isoniazid and rifampicin mother-to-child transmission (of HIV) non-nucleoside reverse-transcriptase inhibitor nucleoside reverse-transcriptase inhibitor opioid substitution therapy polymerase chain reaction protease inhibitor Population, Intervention, Comparison and Outcomes prevention of mother-to-child transmission of HIV pre-exposure prophylaxis of HIV ribavirin ribonucleic acid single-dose nevirapine thymidine analogue mutation tuberculosis tenofovir disoproxil fumarate

NFV nelfinavir

NVP nevirapine

PCP/PJP Pneumocystis ( jirovecii ) pneumonia

RAL raltegravir RIF rifampicin RTV ritonavir

TPV tipranavir UNAIDS Joint United Nations Programme on HIV/AIDS UNICEF WHO United Nations Children’s Fund World Health Organization UNODC United Nations Office on Drugs and Crime

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

definition of key terms GENERAL HIV refers to human immunodeficiency virus. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of HIV infections globally. Within these guidelines, HIV refers to both HIV-1 and HIV-2 unless otherwise specified.

AGE GROUPS AND POPULATIONS The following definitions for adults, adolescents, children and infants are used to ensure consistency within these consolidated guidelines, as well as with other WHO guidelines. It is recognized that other agencies may use different definitions. An adult is a person older than 19 years of age unless national law defines a person as being an adult at an earlier age. An adolescent is a person aged 10 to 19 years inclusive. A child is a person 19 years or younger unless national law defines a person to be an adult at an earlier age. However, in these guidelines when a person falls into the 10 to 19 age category they are referred to as an adolescent (see adolescent definition). An infant is a child younger than one year of age. These guidelines define key populations to include both vulnerable and most-at-risk populations. They are important to the dynamics of HIV transmission in a given setting and are essential partners in an effective response to the epidemic. People living with HIV are considered a key population in all epidemic contexts. These guidelines define most-at-risk populations as men who have sex with men, transgender people, people who inject drugs and sex workers. Most-at-risk populations are disproportionately affected by HIV in most, if not all, epidemic contexts. Vulnerable populations are groups of people who are particularly vulnerable to HIV infection in certain situations or contexts, such as adolescents (particularly adolescent girls), orphans, street children, people in closed settings (such as prisons or detention centres), people with disabilities and migrant and mobile workers. Each country should define the specific populations that are particularly vulnerable and key to their epidemic and response based on the epidemiological and social context. Serodiscordant couples are couples in which one partner is living with HIV and the other is HIV-negative. A couple refers to two people in an ongoing sexual relationship; each of these is referred to as a partner in the relationship. How individuals define their relationships varies considerably according to cultural and social context.

HEALTH CARE SERVICES Continuum of HIV care refers to a comprehensive package of HIV prevention, diagnostic, treatment and support services provided for people living with HIV and their families ranging across: initial HIV diagnosis and linkage to care; management of opportunistic infections and other comorbid conditions; initiating, maintaining and monitoring ART; switching to secondline and third-line ART; and palliative care.

Definition of key terms

A public health approach addresses the health needs of a population or the collective health status of the people rather than just individuals. A public health approach involves a collaborative effort by all parts of the health sector, working to ensure the well-being of society through comprehensive prevention, treatment, care and support. For HIV, this involves: simplified limited formularies; large-scale use of fixed-dose combinations for first-line treatment for adults and children; care and drugs given free at the point of service delivery, decentralization; and integration of services, including task shifting and simplified clinical and toxicity monitoring.

Definition of key terms

HIV TESTING AND PREVENTION Voluntary counselling and testing (also referred to as client-initiated testing and counselling) describes a process initiated by an individual who wants to learn his or her HIV status. Since there are now many different community approaches to providing HIV testing and counselling and people often have mixed motivations for seeking testing (both recommended by a provider and sought by a client), WHO prefers to use the term HIV testing and counselling. All forms of HIV testing and counselling should be voluntary and adhere to the five C’s: consent, confidentiality, counselling, correct test results and connections to care, treatment and prevention services. Quality assurance of both testing and counselling is essential in all approaches to HIV testing and counselling. Provider-initiated testing and counselling is HIV testing and counselling recommended by a health-care provider in a clinical setting. Provider-initiated testing and counselling, as with all forms of HIV testing and counselling, should be voluntary and adhere to the five C’s. Combination prevention refers to a combination of behavioural, biomedical and structural approaches to HIV prevention to achieve maximum impact on reducing HIV transmission and acquisition.

ART (ANTIRETROVIRAL THERAPY) ARV (antiretroviral) drugs refer to the medicines themselves and not to their use. ART refers to the use of a combination of three or more ARV drugs to achieve viral suppression. This generally refers to lifelong treatment. Synonyms are combination ART and highly active ART. ART for prevention is used to describe the HIV prevention benefits of ART. Eligible for ART refers to people living with HIV for whom ART is indicated according to the definitions of clinical and immunological eligibility in WHO treatment guidelines. The term is often used interchangeably with “needing treatment”, although this implies an immediate risk or an obligation to initiate treatment. Viral suppression refers to the aim of ART to maintain viral load below the level of detection of available assays, generally less than 50 copies per ml. The current WHO virological criterion for treatment failure is 1000 copies per ml or more. Universal access to ART is defined broadly as a move to a high level of access ( ≥80% of the eligible population) for the most effective interventions that are equitable, accessible, affordable, comprehensive and sustainable over the long term; this does not necessarily mean 100% coverage.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

HEALTH WORKFORCE Community health workers are health workers who have received standardized and nationally endorsed training outside the nursing, midwifery or medical curricula. Midwives are people trained to assist in childbirth, including registered and enrolled midwives. Non-physician clinicians are professional health workers capable of many of the diagnostic and clinical functions of a physician but who are not trained as physicians. These types of health workers are often known as health officers, clinical officers, physician assistants, nurse practitioners or nurse clinicians. Nurses include professional nurses, enrolled nurses, auxiliary nurses and other nurses such as dental or primary care nurses.

EPIDEMIOLOGY Concentrated HIV epidemic : HIV has spread rapidly in one or more defined subpopulation but is not well established in the general population. Numerical proxy: HIV prevalence is consistently over 5% in at least one defined subpopulation but is less than 1% among pregnant women in urban areas. Generalized HIV epidemic : HIV is firmly established in the general population. Numerical proxy: HIV prevalence consistently exceeding 1% among pregnant women. Most generalized HIV epidemics are mixed in nature, in which certain (key) subpopulations are disproportionately affected. Mixed epidemics : people are acquiring HIV infection in one or more subpopulations and in the general population. Mixed epidemics are therefore one or more concentrated epidemics within a generalized epidemic. Low-level epidemic : epidemics in which the prevalence of HIV infection has not consistently exceeded 1% in the general population nationally or 5% in any subpopulation. Low-, moderate- and high-uptake ART settings refer to settings in which the uptake of ART among those eligible for ART is less than 50%, 50–80% and greater than 80%, respectively.

Definition of key terms

A setting with a high burden of TB and HIV refers to settings with adult HIV prevalence ≥1% or HIV prevalence among people with TB ≥ 5%. HIV incidence is the number of new people acquiring HIV infection in a given period in a specified population. HIV prevalence refers to the number of people living with HIV at a specific point in time and is expressed as a percentage of the population.

Definition of key terms

PMTCT (PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HIV) In these guidelines, WHO is moving away from the previous terms “Options A, B and B+”. Instead, these guidelines recommend two options: (i) providing lifelong ART to all pregnant and breastfeeding women living with HIV regardless of CD4 count or clinical stage or (ii) providing ART (ARV drugs) for pregnant and breastfeeding women with HIV during the mother-to-child transmission risk period and then continuing lifelong ART for those women eligible for treatment for their own health. In settings that are not implementing lifelong ART for all pregnant and breastfeeding women living with HIV, the distinction between prophylaxis (ARV drugs given for a limited time during the risk period for transmitting HIV from mother to child to prevent this) and treatment (ART given both for the mother’s health, based on current adult eligibility and to prevent vertical transmission) is still important. ARV drugs for women living with HIV during pregnancy and breastfeeding refers to a triple-drug ARV drug regimen provided to mothers living with HIV primarily as prophylaxis during pregnancy and throughout breastfeeding (when there is breastfeeding) to prevent mother-to-child transmission of HIV. In this option, the mother’s regimen is continued lifelong after delivery or after the breastfeeding ends only if she meets the ART eligibility criteria for her own health based on CD4 count or clinical stage. Previous WHO guidance referred to this as option B. Lifelong ART for all pregnant and breastfeeding women living with HIV refers to the approach in which all pregnant women living with HIV receive a triple-drug ART regimen regardless of CD4 count or clinical stage, both for their own health and to prevent vertical HIV transmission and for additional HIV prevention benefits. Previous WHO guidance referred to this as option B+.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

acknowledgements Anthony Harries (International Union against Tuberculosis and Lung Disease, United Kingdom) and Gottfried Hirnschall (Department of HIV, World Health Organization) co-chaired the guidelines process.

Adult Guideline Development Group Co-chairs: Serge Eholie (ANEPA/Treichville Hospital, Abidjan, Côte d’Ivoire) and Stefano Vella (Istituto Superiore di Sanità, Italy). GRADE methodologist: Elie Akl (American University of Beirut, Lebanon). Pedro Cahn (Fundación Huesped, Argentina), Alexandra Calmy (University of Geneva, Switzerland), Frank Chimbwandira (Ministry of Health, Malawi), David Cooper (University of New South Wales and St Vincent’s Hospital, Australia), Judith Currier (UCLA Clinical AIDS Research & Education Center, USA), François Dabis (School of Public Health (ISPED), University Bordeaux Segalen, France), Charles Flexner (Johns Hopkins University, USA), Beatriz Grinsztejn (Fundação Oswaldo Cruz (FIOCRUZ), Brazil), Diane Havlir (University of California at San Francisco, USA), Charles Holmes (Centre for Infectious Disease Research in Zambia, Zambia), John Idoko (National Agency for the Control of AIDS, Nigeria), Kebba Jobarteh (Centers for Disease Control and Prevention, Mozambique), Nagalingeswaran Kumarasamy (Y.R. Gaitonde Centre for AIDS Research and Education, India), Volodymyr Kurpita (AllUkrainian Network of People Living with HIV, Ukraine), Karine Lacombe (Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), France), Albert Mwango (Ministry of Health, Zambia), Leonardo Palombi (DREAM Program, Community of Sant’Egidio, Rome, Italy), Anton Pozniak (Chelsea and Westminster Hospital, United Kingdom), Luis Adrián Quiroz (Derechohabientes Viviendo con VIH del IMSS (DVIMSS), Mexico), Kiat Ruxrungtham (Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thailand), Michael Saag (University of Alabama at Birmingham, USA), Gisela Schneider (German Institute for Medical Mission, Germany), Yanri Subronto (Universitas Gadjah Mada, Indonesia) and Francois Venter (University of the Witwatersrand, South Africa).

Maternal and Child Health Guideline Development Group Co-chairs: Elaine Abrams (International Center for AIDS Care and Treatment Programs (ICAP), Columbia University, USA) and Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Uganda). GRADE methodologist: Joerg Meerpohl (German Cochrane Centre, University Medical Center, Freiburg, Germany). Renaud Becquet (Internationale Institut de Santé Publique d’Epidémiologie et de Développement, Université Bordeaux Segalen, France), Deborah Birx (United States Centers for Disease Control and Prevention, USA), Benjamin Chi (Centre for Infectious Disease Research in Zambia, Zambia), Mark Cotton (Stellenbosch University, South Africa), Nonhlanhla Dlamini (National Department of Health, South Africa), René Ekpini (United Nations Children’s Fund, New York), Carlo Giaquinto (Paedatric Infectious Disease Unit and Clinical Trials Unit of Azienda Ospedaliera di Padua, Italy), Diana Gibb (Medical Research Council Clinical Trials Unit, United Kingdom), Sabrina Bakeera-Kitaka (Makerere University and Mulago National Referral Hospital, Uganda), Louise Kuhn (Columbia University, USA), Evgenia Maron (Charitable Women’s Foundation Astra, Russian Federation), Babalwa Mbono (mothers2mothers, South Africa), James McIntyre (University of Cape

Acknowledgements

Town, South Africa), Lynne Mofenson (National Institutes of Health, USA), Angela Mushavi (Ministry of Health and Child Welfare, Zimbabwe), Ryan Phelps (United States Agency for International Development, USA), Jorge Pinto (Federal University of Minas Gerais, Brazil), Andrew Prendergast (Queen Mary University of London, United Kingdom), Thanyawee Puthanakit (Chulalongkorn University, Thailand), Atiene Sagay (Unversity of Jos, Nigeria), Roger Shapiro (Harvard School of Public Health, USA), George Siberry (National Institutes of Health, USA), Landry Tsague (United Nations Children’s Fund, Zambia), Thorkild Tylleskar (University of Bergen, Norway), Paula Vaz (Fundação Ariel Glaser contra o SIDA Pediátrico, Mozambique), Evgeny Voronin (Russian AIDS Pediatric Center, Russian Federation) and Linhong Wang (Chinese Center for Disease Control and Prevention, China).

Acknowledgements

Operational and Service Delivery Guideline Development Group Co-chairs: Kevin De Cock (United States Centers for Disease Control and Prevention, USA) and Yogan Pillay (National Department of Health, South Africa). GRADE methodologist: Holger Schünemann (Faculty of Health Sciences, McMaster University, Canada). Tsitsi Mutasa Apollo (Ministry of Health and Child Welfare, Zimbabwe), Yibletal Assefa (Ministry of Health, Ethiopia), Paula Braitstein (Indiana University School of Medicine, USA), Zengani Chirwa (Ministry of Health, Malawi), Bui Duc Duong (Ministry of Health, Viet Nam), Ade Fakoya (Global Fund to Fight AIDS, Tuberculosis and Malaria, Switzerland), Robert Ferris (United States Agency for International Development, USA), Ronaldo Hallal (Departamento de DST, Aids e Hepatites Virais, Brazil), Eihab Ali Hassan (Federal Ministry of Health, Sudan), David Hoos (International Centre for AIDS Care and Treatment Programs, Columbia University, USA), Barbara Milani (Médecins Sans Frontières (MSF), Switzerland), Christine Nabiryo (The AIDS Support Organization (TASO), Uganda), Natalia Nizova (Ministry of Health, Ukraine), Anupam Pathni (International Planned Parenthood Federation South Asia, India), Elliot Raizes (United States Centers for Disease Control and Prevention, USA), Kenly Sekwese (Treatment Advocacy Literacy Campaign, Zambia), Larissa Stabinski (Office of the United States Global AIDS Coordinator, USA), Miriam Taegtmeyer (Liverpool School of Tropical Medicine, United Kingdom), Wim Van Damme (Institute of Tropical Medicine, Belgium), Eric van Praag (Family Health International (FHI), United Republic of Tanzania), Mean Chhi Vun (Ministry of Health, Cambodia), Larry Westerman (United States Centers for Disease Control and Prevention, USA), Steve Wignall (Clinton Health Access Initiative (CHAI), Indonesia) and Anna Zakowicz (Global Network of People Living with HIV (GNP+), Europe).

Programmatic Guideline Development Group Co-chairs: Tsitsi Apollo (Ministry of Health and Child Welfare, Zimbabwe) and Adeeba Kamarulzaman (University of Malaya, Malaysia). Ihab Abdelrahman (Ministry of Health and Population, Egypt), John Aberle-Grasse (United States Centers for Disease Control and Prevention, USA), Yibeltal Assefa (Ministry of Health, Ethiopia), Rob Baltussen (Radboud University Nijmegen, Netherlands), Anton Best (Ministry of Health, Barbados), John Blandford (United States Centers for Disease Control and Prevention, USA), Sergiy Filippovych (International HIV/AIDS Alliance in Ukraine, Ukraine), Eric Goemaere (Médecins Sans Frontières (MSF), South Africa), Dirceu Greco (Ministry of Health, Brazil), Timothy Hallett (Imperial College London, United Kingdom), Priscilla Idele (United Nations Children’s Fund, New York), Ushma Mehta (Independent Consultant, South Africa), Irene Mukui (National AIDS & STI Control Programme, Kenya), Jean Paul Moatti (French National Institute of Health and Medical Research (INSERM), Université de la Méditerranée, France), Natalia Nizova (Ministry of Health, Ukraine), Ole Frithjof Norheim

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

(University of Bergen, Norway), Asia Russell (Health GAP, USA), Kenly Sikwese (Positive Health Outcomes, Zambia), Jerome Singh (Centre for the AIDS Programme of Research in South Africa, South Africa), Petchsri Sirinirund (Ministry of Public Health, Thailand), John Stover (Futures Institute, USA), Aliou Sylla (Ministry of Health, Mali), Wim Van Damme (Institute of Tropical Medicine, Belgium), Stefan Weinmann (Deutsche Gessellschaft für Internationale Zusammenarbeit (GIZ) GmbH, Germany) and Annemarie M. J. Wensing (University Medical Centre Utrecht, Netherlands). Observer at the Programmatic Guideline Development Group meeting: Bernhard Schwartländer (UNAIDS).

External peer reviewers Michelle Adler (United States Centers for Disease Control and Prevention, USA), Isabelle Andrieux-Meyer (Médecins Sans Frontières, Switzerland), Xavier Anglaret (Programme PACCI du site ANRS de Côte d’Ivoire, Côte d’Ivoire), Marcelo Araujo de Freitas (Ministry of Health, Brazil), Pamela Bachanas (United States Centers for Disease Control and Prevention, USA), Shaiful Bahari Ismail (Universiti Sains Malaysia, Malaysia), Pierre Barker (University of North Carolina at Chapel Hill, USA), David Barr (HIV Collaborative Fund at Tides Center, USA), Jose Gerard Belimac (National AIDS and STI Prevention and Control Program, Philippines), Soumia Benchekroun (Centre Hospitalier Universaitaire Ibn Sina de Rabat, Morocco), Marc Bulterys (Chinese Centers for Disease Control and Prevention, China), Helen Bygrave (Médecins Sans Frontières, South Africa), Carlos F. Cáceres (Universidad Peruana Cayetano Heredia, Peru), Georgina Caswell (Global Network of People Living with HIV, South Africa), Alexander Chuykov (AIDS Healthcare Foundation, Russian Federation), Polly Clayden (HIV i-base, United Kingdom), Suzanne Crowe (Burnet Institute, USA), Margarett Davis (United States Centers for Disease Control and Prevention, USA), Chris Duncombe (Bill & Melinda Gates Foundation, USA), Marhoum El Filali (Ibn Rochd University Hospital, Morocco), Wafaa El-Sadr (International Center for AIDS Care and Treatment Programs, USA), Carlos Falistocco (SIDA y ETS del Ministerio de Salud de la Nación, Argentina), Donna Futterman (Children’s Hospital at Montefiore, USA), Elvin Geng (University of California at San Francisco, USA), Charles Gilks (University of Queensland, Australia), Giovanni Guidotti (DREAM Program, Community of Sant’Egidio, Italy), Bertrand Kampoer (Health consultant, Cameroon), Jonathan Kaplan (United States Centers for Disease Control and Prevention, USA), Sairankul Kassymbekova (National AIDS Center, Kazakhstan), Tamil Kendall (Trudeau Fondation, Mexico), Karusa Kiragu (UNAIDS), Emily Koumans (United States Centers for Disease Control and Prevention, USA), Richard Lester (University of British Columbia, Canada), Oyun Lkhagvasuren (Geneva Foundation for Medical Education and Research, Switzerland), Rangsima Lolekha (Ministry of Public Health, Thailand), Yolisa Mashologu (Human Sciences Research Council, South Africa), Edward Mills (University of Ottawa, Canada), Thomas Minior (United States Agency for International Development, USA), Julio Montaner (University of British Columbia, Canada), Lydia Mungherera (The AIDS Support Organization, Uganda), Joseph Murungu (Ministry of Health, Zimbabwe), Anthony Mutiti (Kitwe Central Hospital, Zambia), Jean Nachega (Johns Hopkins Bloomberg School of Public Health, USA), Steave Nemande (Alternatives-Cameroun, Cameroon), John Nkengasong (United States Centers for Disease Control and Prevention, USA), Siobhan O’Connor (United States Centers for Disease Control and Prevention, USA), Sylvia Ojoo (University of Maryland, USA), Nittaya Phanuphak (AIDS Research Centre, Thailand), Christian Pitter (Elizabeth Glaser Pediatric AIDS Foundation, USA), Praphan Pranuphak (Thai Red Cross AIDS Research Centre, Thailand), Helena Rabie (University of Cape Town and Stellenbosch University, South Africa), Gilles Raguin (GIP Esther, France), Peter Saranchuk (Médecins Sans

Acknowledgements

Frontières, South Africa), Erik Schouten (Management Sciences for Health, Malawi), Jason Sigurdson (UNAIDS), Mariângela Simao (UNAIDS), Annette Sohn (TREAT Asia/ amfAR – Foundation for AIDS Research, Thailand), Luis Soto-Ramirez (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico), Wendy Stevens (National Health Laboratory Service, South Africa), Omar Sued (Fundacion Huésped, Argentina), Fatiha Terki (World Food Programme, Switzerland), Tengiz Tsertsvadze (Tbilisi State University, Georgia), Emilia Valadas (Clínica Universitária de Doenças Infecciosas e Parasitárias, Portugal), Helena Walkowiak (Management Sciences for Health, USA), Alice Welbourn (Salamander Trust, United Kingdom), Robin Wood (University of Cape Town, South Africa), Zhao Yan (Chinese Center for Disease Control and Prevention, China), Yazdan Yazdanpanah (Université Paris Diderot, France), José M. Zuniga (The International Association of Providers of AIDS Care, USA) and Sheryl Zwerski (National Institutes of Health, USA).

Acknowledgements

Contributors to the GRADE systematic reviews and supporting evidence GRADE and evidence reviews: Isabelle Andrieux-Meyer (Médecins Sans Frontières, Switzerland), Andrew Anglemyer (University of California at San Francisco, USA), Till Barnighausen (Harvard School of Public Health, USA), Heiner Bucher (University Hospital Basel, Switzerland), Krista Chaivachati (Yale School of Medicine, USA), Larry Chang (Johns Hopkins University, USA), Tamara Credo (Medical Research Council, South Africa), Andrea De Luca (Azienda Ospedaliera Universitaria Senese, Italy), Didier Koumavi Ekouevi (PACCI Programme, France), Elvin Geng (University of California at San Francisco, USA), Tara Hovarth (University of California at San Francisco, USA), Andreas Jahn (Ministry of Health, Malawi), Alexander Kay (Stanford University, USA), Gail Kennedy (University of California at San Francisco, USA), Joy Oliver (South African Cochrane Centre, South Africa), Rosanna Peeling (London School of Hygiene and Tropical Medicine, United Kingdom), Martina Penazzato (WHO consultant, Switzerland), Heike Raatz (University Hospital Basel, Switzerland), George Rutherford (University of California at San Francisco, USA), Nandi Siegfried (University of California at San Francisco, USA), Alicen Spaulding (University of Minnesota, USA), Amitabh Suthar (WHO Consultant, Switzerland), Joseph Tucker (University of North Carolina School of Medicine, China), Gavrilah Wells (University of California at San Francisco, USA) and Zara Shubber (Imperial College London, United Kingdom). Modelling work: Andrea Ciaranello (Massachusetts General Hospital, USA), Anne Cori (Imperial College London, United Kingdom), Mary-Ann Davies (University of Cape Town, South Africa), Jeffrey Eaton (Imperial College London, United Kingdom), Matthias Egger (University of Berne, Switzerland), Christophe Fraser (Imperial College London, United Kingdom), Timothy Hallett (Imperial College London, United Kingdom), Daniel Keebler (South African DST/NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, South Africa), Nicolas Menzies (Harvard School of Public Health, USA), Paul Revill (University of York, United Kingdom), Michael Schomaker (University of Cape Town, South Africa), John Stover (Futures Institute, USA) and Peter Vickerman (London School of Hygiene and Tropical Medicine, United Kingdom). Community values and preferences: Alice Kate Armstrong (Children’s HIV Association, South Africa), Laura Ferguson (Institute for Global Health, University of Southern California, USA), Adam Garner (Global Network of People Living with HIV, USA), Carolyn Green (International HIV/AIDS Alliance Associated Consultant, United Kingdom), Amy Hsieh (Global Network of People Living with HIV, USA), Nick Keeble (International HIV/AIDS Alliance, United Kingdom), Gitau Mburu (International HIV/

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

AIDS Alliance, United Kingdom), Florence Ngobeni (Children’s HIV Association, South Africa), Mala Ram (International HIV/AIDS Alliance, United Kingdom), Anja Teltschik (International HIV/AIDS Alliance, United Kingdom) Robert Worthington (Kwantu, United Kingdom), and the WHO Civil Society Reference Group.i Christoforos Mallouris (WHO consultant) provided coordination support for the community consultation work with the International HIV/AIDS Alliance and the Global Network of People Living with HIV.

WHO staff and consultants Andrew Ball and Philippa Easterbrook (Department of HIV) coordinated the overall guideline development process with support from Cadi Irvine (Consultant, Department of HIV). The clinical and service delivery components of the guideline were supervised by Meg Doherty (Department of HIV), and the four Guideline Development Group work streams were facilitated by Eyerusalem Kebede Negussie (Operational and Service Delivery Guideline Development Group facilitator, Department of HIV), Lulu Muhe and Nathan Shaffer (Maternal and Child Health Guideline Development Group facilitators, Department of Maternal, Child and Adolescent Health and Department of HIV), Marco Vitoria (Adult Guideline Development Group facilitator, Department of HIV) and Joseph Perriëns (Programmatic Guideline Development Group facilitator, Department of HIV). The above group constitutes the WHO Guideline Steering Group. A special thanks to the following WHO consultants who made major contributions to the writing and research for the guidelines: Jhoney Barcarolo (Guidance for Programme Managers), Shaffiq Essajee (Maternal and Child Health), Martina Penazzato (Maternal and Child Health) and Amitabh Suthar (Adult and Operational and Service Delivery). Ian Grubb provided overarching writing support and coordination of writing activities. David Breuer technically edited the text. The following WHO consultants were also involved in developing these guidelines: April Baller, Sally Girvin , Kathi Fox , Elizabeth Marum , Priya Shetty and Michelle Williams. The following WHO staff members contributed to developing these guidelines: Rachel Baggaley (Department of HIV), Silvia Bertagnolio (Department of HIV), Jesus García Calleja (Department of HIV), Agnes Chetty (WHO Regional Office for the Eastern Mediterranean), Irina Eramova (WHO Regional Office for Europe), Nathan Ford

WHO Civil Society Reference Group: Eddie Banda (Malawi Network of People Living with HIV/AIDS (MANET+), Malawi), Mabel Bianco (Fundación para el Estudio e Investigación de la Mujer (FEIM), Argentina), Tung Bui (Youth Voices Count, Thailand), Michaela Clayton (AIDS and Rights for Southern Africa, Namibia), Lee Hertel (International Network of People Who Use Drugs, USA), Ruth Mery Linares Hidalgo (Ciudad Quesada, Costa Rica), Noreen Huni (Regional Psychosocial Support Initiative (REPSSI), South Africa), Matthew Kavanagh (Health Gap, USA), JoAnne Keatley (University of California at San Francisco, USA), Sharonann Lynch (Doctors without Borders, USA), Babalwa Mbono (Mothers to Mothers (M2M), South Africa), Gitau Mburu (International HIV/AIDS Alliance, United Kingdom), Othoman Mellouk (orum on MSM and HIV, Morocco), Luís Mendão (European AIDS Treatment Group, Portugal), Noah Metheny (Global Forum on MSM and HIV, USA), Carlo Oliveras (Caribbean Treatment Action Group, Puerto Rico), Rachel Ong (Communities Delegation to the Board of the Global Fund to Fight AIDS, Tuberculosis and Malaria, Singapore), Asia Russell (Health Gap, USA), Leickness Simbayi (Human Sciences Research Council, South Africa), Felly Nkweto Simmonds (Population Council, Zambia), Lucy Stackpool-Moore (International Planned Parenthood Federation, United Kingdom), Ruth Morgan Thomas (Global Network of Sex Workers Projects, United Kingdom) and Mary Ann Torres (International Council of AIDS Service Organizations, Canada).

Acknowledgements

(Department of HIV), Masami Fujita (WHO Regional Office for the Western Pacific), Haileyesus Getahun (Stop TB Department), Vincent Habiyambere (Department of HIV), Chika Hayashi (Department of HIV), Lali Khotenashvili, (WHO Regional Office for Europe), Ying-Ru Lo (WHO Regional Office for the Western Pacific), Frank Lule (WHO Regional Office for Africa), Viviana Mangiaterra (Department of Reproductive Health and Research), Hernan Julio Montenegro (Department of Health Policy, Development and Services), Lisa Nelson (Department of HIV), Morkor Newman (WHO Regional Office for Africa), Boniface Dongmo Nguimfack (Department of HIV), Linh Nguyen (Stop TB Department), Kevin O’Reilly (Department of HIV), Brian Pazvakavambwa (WHO Regional Office for Africa), Razia Pendse (WHO Regional Office for South-East Asia), Françoise Renaud-Théry (Department of HIV), Bharat B. Rewari (WHO Regional Office for South-East Asia), Nigel Rollins (Department of Maternal, Child and Adolescent Health), Anita Sands (Department of Essential Medicines and Health Products), Yves Souteyrand (WHO Regional Office for the Eastern Mediterranean), Isseu Diop Toure (WHO Regional Office for Africa), Annette Verster (Department of HIV), Gundo Weiler (Department of HIV) and Stefan Wiktor (Department of Pandemic and Epidemic Diseases). Supporting WHO interns include: Grace Akol, Hanna Yemane Berhane and Jayne Ellis. WHO administrative support was led by Hayet Souissi and Jasmin Leuterio. Communication support was provided by Oyuntungalag Namjilsuren , Sarah Russell and Glenn Thomas. Maryann-Nnenkai Akpama , Afrah Al-Doori, Adriana De Putter, Lydia Mirembe Kawanguzi and Ophelia Riano provided additional administrative and management support.

Acknowledgements

Funders Funding to support this work come from the United States Centers for Disease Control and Prevention, Bill & Melinda Gates Foundation, Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ), UNAIDS Unified Budget, Results and Accountability Framework, United States Agency for International Development and specific funds through WHO staff time. In addition, WHO is extremely thankful to the institutions that contributed staff time and other in-kind contributions to the guideline development process.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

FOREW0RD With this publication, WHO issues its first consolidated guidelines for the use of antiretroviral drugs to treat and prevent HIV infection. The guidelines are ambitious in their expected impact, yet simplified in their approach, and firmly rooted in evidence. They take advantage of several recent trends, including a preferred treatment regimen that has been simplified to a single fixed-dose combination pill taken once per day, which is safer and affordable. The guidelines also take advantage of evidence demonstrating the multiple benefits of antiretroviral therapy. With the right therapy, started at the right time, people with HIV can now expect to live long and healthy lives. They are also able to protect their sexual partners and infants as the risk of transmitting the virus is greatly reduced. The guidelines represent another leap ahead in a trend of ever-higher goals and evergreater achievements. In Africa, the region that bears the brunt of the HIV epidemic, an estimated 7.5 million people were receiving treatment at the end of 2012, compared with only 50,000 a decade earlier. Worldwide, some 9.7 million people were receiving treatment, indicating that the global target of providing antiretroviral therapy to 15 million people by 2015 is within reach. The present achievement represents the fastest scale-up of a life-saving public health intervention in history. A key way to accelerate progress is to start treatment earlier, as recommended in the guidelines. As the evidence now shows, earlier treatment brings the dual advantage of keeping people healthier longer and dramatically reducing the risk of virus transmission to others. Earlier treatment has the further advantage of simplifying the operational demands on programmes. The guidelines recommend that pregnant women and children under the age of five years start treatment immediately after diagnosis. The same once-per-day combination pill is now recommended for all adults living with HIV, including those with tuberculosis, hepatitis, and other co-infections. Additional recommendations in the guidelines aim to help programmes get services closer to people’s homes; expedite test results; integrate HIV treatment more closely with antenatal, tuberculosis, drug dependence and other services; and use a wider range of health workers to administer treatment and follow-up care.

Foreword

Countries asked WHO for simplified guidance on the use of antiretroviral drugs. I believe these consolidated guidelines go a long way towards meeting that request. They offer recommendations for all age groups and populations. They bring clinical recommendations together with operational and programmatic guidance on critical dimensions of treatment and care, from testing through enrollment and retention, and from general HIV care to the management of co-morbidities. The new guidelines ask programmes to make some significant changes. They also require increased investments. I am personally convinced that the future of the HIV response will follow the pattern of the recent past: that is, a constant willingness to build on success and rise to new challenges. WHO estimates that doing so will have an unprecedented impact: global implementation of the guidelines could avert an additional 3 million deaths between now and 2025, over and above those averted using 2010 guidelines, and prevent around 3.5 million new infections. Such prospects – unthinkable just a few years ago – can now fuel the momentum needed to push the HIV epidemic into irreversible decline. I strongly encourage countries and their development partners to seize this unparalleled opportunity that takes us one more leap ahead.

Dr Margaret Chan Director-General, WHO

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

EXECUTIVE SUMMARY These consolidated guidelines provide guidance on the diagnosis of human immunodeficiency virus (HIV) infection, the care of people living with HIV and the use of antiretroviral (ARV) drugs for treating and preventing HIV infection. They are structured along the continuum of HIV testing, care and treatment. Behavioural, structural and biomedical interventions that do not involve the use of ARV drugs are not covered in these guidelines. The 2013 consolidation process combines and harmonizes recommendations from a range of WHO guidelines and other documents, including the following 2010 guidelines on using antiretroviral therapy (ART) for HIV infection in adults and adolescents, in infants and children and for treating pregnant women living with HIV and preventing HIV infection in infants. Comprehensive guidance is now provided on using ARV drugs across age groups and populations of adults, pregnant and breastfeeding women, adolescents, children and key populations. The guidelines also aim to consolidate and update clinical, service delivery and programmatic guidance. The 2013 guidelines reflect important advances in HIV responses during the past three years. Since 2010, new technologies, including CD4 point-of-care testing, and new service delivery approaches allow HIV testing and treatment monitoring to be diversified and decentralized. Simple, safer, once-daily, single-pill ARV regimens that are suitable for use in most populations and age groups have become more affordable and more widely available in low- and middle-income countries. Countries are moving towards earlier initiation of triple-drug regimens and simplified programming for the prevention of mother-to-child transmission of HIV (PMTCT) that emphasizes the long-term health of pregnant women and mothers living with HIV and preventing HIV infection among their children. The broader HIV prevention benefits of ARV drugs are being recognized: in addition to improving health and prolonging lives, ART prevents the sexual transmission of HIV, while pre-exposure prophylaxis of HIV with ARV drugs expands HIV prevention options and post-exposure prophylaxis of HIV continues to play an important role in managing HIV exposure in certain populations and settings, including for those who have been sexually assaulted. Although countries are at different stages of ART coverage and implementing the 2010 WHO guidelines, there is a consistent global trend towards initiating HIV treatment earlier. Consistent with previous WHO guidelines, the 2013 guidelines are based on a public health approach to the further scaling up of ARV drugs for treatment and prevention that considers feasibility and effectiveness across a variety of resource-limited settings. The new clinical recommendations in these guidelines promote expanded eligibility for ART with a CD4 threshold for treatment initiation of 500 cells/mm 3 or less for adults, adolescents and older children. Priority should be given to individuals with severe or advanced HIV disease and those with CD4 count of 350 cells/mm 3 or less. ART is recommended to be initiated regardless of CD4 count for certain populations, including people with active tuberculosis (TB) disease who are living with HIV, people with both HIV and hepatitis B virus (HBV) infection with severe chronic liver disease, HIV-positive partners in serodiscordant couples, pregnant and breastfeeding women and children younger than five years of age. Harmonization of ART regimens for adults and children is recommended whenever possible, with a new, preferred first-line ART regimen. The need to phase out d4T in first-line ART regimens for adults and adolescents is being reinforced.

Executive summary

Viral load testing is now recommended as the preferred approach to monitoring ART success and diagnosing treatment failure, complementing clinical and immunological monitoring of people receiving ART. The guidelines emphasize that ARV drugs should be used within a broad continuum of HIV care. Additional new recommendations provide guidance on community-based HIV testing and counselling and HIV testing of adolescents. Apart from new recommendations, summaries of and links to existing WHO guidance are provided for HIV testing and counselling, HIV prevention, general care for people living with HIV, the management of common coinfections and other comorbidities and monitoring and managing drug toxicities. Some existing recommendations need to be updated, and new recommendations will need to be reviewed in the next few years, as new evidence emerges. Expanded eligibility for ART and a wider range of options for using ARV drugs provide new opportunities to save lives, improve clinical outcomes and reduce HIV incidence but also pose challenges to policy-makers and implementers in many countries. New operational guidance in 2013 provides recommendations for strengthening key aspects of the continuum of HIV care and improving linkages across the health system. This guidance focuses on strategies to improve retention in care and adherence to ART and on decentralizing the provision of ART to primary care, maternal and child health clinics, TB clinics and services to treat drug dependence. The operational guidance also addresses the implications of new clinical recommendations for laboratory services and supply systems for ARV drugs and other commodities. Guidance specifically developed for HIV programme managers addresses decision-making and planning for the strategic use of ARV drugs in the context of national governance processes, HIV epidemiology, health systems capacity, available financial resources and ethical and human rights considerations. Implementation considerations especially relevant to programme managers are provided for major new recommendations. A concluding chapter on monitoring and evaluation provides preliminary guidance on monitoring the implementation of new recommendations. The revision process for the 2013 guidelines was conducted in accordance with procedures established by the WHO Guidelines Review Committee. New clinical and operational recommendations in the guidelines are based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to reviewing evidence and decision-making. Modelling, expert consultations and country case studies have informed clinical, operational and programmatic guidance. The process has identified key gaps in knowledge that will guide the future research agenda. In addition to new recommendations based on the GRADE system, the guidelines summarize existing recommendations from other WHO guidelines. Most of these recommendations were developed using the GRADE system or a modification of the GRADE rating of the strength and quality of the evidence. The primary audience for these guidelines is national HIV programme managers, especially in low- and middle-income countries. The guidelines are anticipated to guide country policy decisions and planning the scaling up of ART. They will also be a valuable resource for clinicians and informing the priorities of development agencies, international organizations, nongovernmental organizations and other implementing partners during the next few years. The 2013 guidelines represent an important step towards achieving universal access to ARV drugs for treating and preventing HIV, increasing the efficiency, impact and long-term sustainability of ARV programmes and realizing the ultimate goal of ending the HIV epidemic.

Executive summary

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

SUMMARY of new recommendations The following table summarizes the new WHO recommendations formulated for the 2013 guidelines on HIV testing and counselling, antiretroviral therapy (ART) and HIV service delivery. It also summarizes the guidance provided in Chapter 10 for programme managers. Where the recommendations remain unchanged from 2010 ART guidelines, this is clearly stated in the table. The table is not comprehensive and does not include all WHO recommendations referred to in these guidelines, specifically recommendations that have been drawn from other, already existing WHO guidelines. The existing WHO recommendations referred to can be found in: Chapter 5 on HIV testing and counselling and HIV prevention, Chapter 6 on general care for people living with HIV, Chapter 8 on the management of common coinfections and other comorbidities and in section 7.4 on monitoring and management of drug toxicities.

HIV testing and counselling Topic and population Community-based testing Recommendations

In generalized HIV epidemics, community-based HIV testing and counselling with linkage to prevention, care and treatment services is recommended, in addition to provider-initiated testing and counselling (strong recommendation, low-quality evidence).

In all HIV epidemic settings, community-based HIV testing and counselling for key populations, with linkage to prevention, care and treatment services is recommended, in addition to providerinitiated testing and counselling (strong recommendation, lowquality evidence). HIV testing and counselling of adolescentsa

HIV testing and counselling, with linkages to prevention, treatment and care, is recommended for adolescents from key populations in all settings (generalized, low and concentrated epidemics) (strong recommendation, very-low-quality evidence).

HIV testing and counselling with linkage to prevention, treatment and care is recommended for all adolescents in generalized epidemics (strong recommendation, very-low-quality evidence).

We suggest that HIV testing and counselling with linkage to prevention, treatment and care be accessible to all adolescents in low and concentrated epidemics (conditional recommendation, very-low-quality evidence).

We suggest that adolescents be counselled about the potential benefits and risks of disclosure of their HIV status and empowered and supported to determine if, when, how and to whom to disclose (conditional recommendation, very-lowquality evidence).

Summary of new recommendations

When to start ART in people living with HIV Topic and population When to start ART in adults and adolescentsa Recommendations

As a priority, ART should be initiated in all individuals with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and individuals with CD4 count ≤350 cells/mm3 (strong recommendation, moderate-quality evidence).

ART should be initiated in all individuals with HIV with CD4 count >350 cells/mm³ and ≤ 500 cells/mm3 regardless of WHO clinical stage (strong recommendation, moderate-quality evidence).

ART should be initiated in all individuals with HIV regardless of WHO clinical stage or CD4 cell count in the following situations: • Individuals with HIV and active TB disease (strong

recommendation, low-quality evidence). • Individuals coinfected with HIV and HBV with evidence of

severe chronic liver disease (strong recommendation, low-quality evidence). • Partners with HIV in serodiscordant couples should be offered

ART to reduce HIV transmission to uninfected partners (strong recommendation, high-quality evidence). When to start ART in pregnant and breastfeeding women

For programmatic and operational reasons, particularly in generalized epidemics, all pregnant and breastfeeding women with HIV should initiate ART as lifelong treatment (conditional recommendation, low-quality evidence).

In some countries, for women who are not eligible for ART for their own health, consideration can be given to stopping the ARV regimen after the period of mother-to-child transmission risk has ceased (conditional recommendation, low-quality evidence) . a

An adolescent is a person aged 10 to 19 years inclusive.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

When to start ART in people living with HIV (continued) Topic and population Recommendations

ARVs and duration of breastfeeding

The key principles and recommendations established in 2010 remain, including: National or subnational health authorities should decide whether health services will mainly counsel and support mothers known to be infected with HIV to either breastfeed and receive ARV interventions or avoid all breastfeeding given their particular context. In settings where national authorities have decided that maternal and child health services will mainly promote and support breastfeeding and ARV interventions as the strategy that will most likely give infants born to mothers known to be infected with HIV the greatest chance of HIV-free survival:

Mothers known to be infected with HIV (and whose infants are HIV uninfected or of unknown HIV status) should exclusively breastfeed their infants for the first 6 months of life, introducing appropriate complementary foods thereafter, and continue breastfeeding for the first 12 months of life. Breastfeeding should then only stop once a nutritionally adequate and safe diet without breast-milk can be provided (strong recommendation, highquality evidence for the first 6 months; low-quality evidence for the recommendation of 12 months) . When to start ART in children

A RT should be initiated in all children infected with HIV below five years of age, regardless of WHO clinical stage or CD4 cell count. • I nfants diagnosed in the first year of life (strong recommendation, moderate-quality evidence) • Children infected with HIV one year to less than five years of age (conditional recommendation, very-low-quality evidence).

A RT should be initiated in all children infected with HIV five years of age and older with CD4 cell count ≤500 cells/mm 3, regardless of WHO clinical stage. • C D4 count ≤350 cells/mm 3 (strong recommendation, moderate-quality evidence) • C D4 count between 350 and 500 cells/mm 3 (conditional recommendation, very-low-quality evidence).

A RT should be initiated in all children infected with HIV with severe or advanced symptomatic disease (WHO clinical stage 3 or 4) regardless of age and CD4 cell count (strong recommendation, moderate-quality evidence).

A RT should be initiated in any child younger than 18 months of age who has been given a presumptive clinical diagnosis of HIV infection (strong recommendation, low-quality evidence)

Summary of new recommendations

What ART regimens to start Topic and population First-line ART regimens for adults Recommendations

F irst-line ART should consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse-transcriptase inhibitor (NNRTI). • TDF + 3TC (or FTC) + EFV as a fixed-dose combination is

recommended as the preferred option to initiate ART (strong recommendation, moderate-quality evidence). • If TDF + 3TC (or FTC) + EFV is contraindicated or not

available, one of the following options is recommended: • AZT + 3TC + EFV • AZT + 3TC + NVP • TDF + 3TC (or FTC) + NVP

(strong recommendation, moderate-quality evidence).

Countries should discontinue d4T use in first-line regimens because of its well-recognized metabolic toxicities (strong recommendation, moderate-quality evidence). First-line ART for pregnant and breastfeeding women and their infants

Infants of mothers who are receiving ART and are breastfeeding should receive six weeks of infant prophylaxis with daily NVP. If infants are receiving replacement feeding, they should be given four to six weeks of infant prophylaxis with daily NVP (or twice-daily AZT). Infant prophylaxis should begin at birth or when HIV exposure is recognized postpartum (strong recommendation, moderate-quality evidence for breastfeeding infants; strong recommendation, low-quality evidence for infants receiving only replacement feeding).

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

What ART regimens to start (continued) Topic and population First-line ART for children younger than 3 years of age Recommendations

W here viral load monitoring is available, consideration can be given to substituting LPV/r with an NNRTI after virological suppression is sustained (conditional recommendation, lowquality evidence).

For infants and children infected with HIV younger than three years, the NRTI backbone for an ART regimen should be ABC + 3TC or AZT + 3TC (strong recommendation, low-quality evidence). First-line ART for children 3 years of age and older

For children infected with HIV three years of age and older

(including adolescents)

(including adolescents), EFV is the preferred NNRTI for first-line treatment and NVP is the alternative (strong recommendation, low-quality evidence). old (and adolescents weighing less than 35 kg), the NRTI backbone for an ART regimen should be one of the following, in preferential order: • ABC + 3TC • AZT or TDF + 3TC (or FTC) (conditional recommendation, low-quality evidence).

For children infected with HIV three years to less than 10 years

Summary of new recommendations

Monitoring ART response and diagnosis of treatment failure Topic and population All populations Recommendations

V iral load is recommended as the preferred monitoring approach to diagnose and confirm ARV treatment failure (strong recommendation, low-quality evidence).

If viral load is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure (strong recommendation, moderate-quality evidence).

Second-line ART: what ARV regimen to switch to Topic and population What ARV regimen to switch to in adults and adolescents Recommendations

S econd-line ART for adults should consist of two nucleoside reverse-transcriptase inhibitors (NRTIs) + a ritonavir-boosted protease inhibitor (PI).

(includes pregnant and breastfeeding women)

T he following sequence of second-line NRTI options is recommended: • After failure on a TDF + 3TC (or FTC)-based first-line

regimen, use AZT + 3TC as the NRTI backbone in second-line regimens. • After failure on an AZT or d4T + 3TC-based first-line

regimen, use TDF + 3TC (or FTC) as the NRTI backbone in second-line regimens.

Use of NRTI backbones as a fixed-dose combination is recommended as the preferred approach (strong recommendation, moderate-quality evidence). H eat-stable fixed-dose combinations ATV/r and LPV/r are the preferred boosted PI options for second-line ART (strong recommendation, moderate-quality evidence).

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Second-line ART: what ARV regimen to switch to (continued) Topic and population What ARV regimen to switch to in children Recommendations

A fter failure of a first-line NNRTI-based regimen, a boosted PI plus two NRTIs are recommended for second-line ART; LPV/r is the preferred boosted PI (strong recommendation, moderate-quality evidence).

(including adolescents)

A fter failure of a first-line LPV/r-based regimen, children younger than 3 years should remain on their first-line regimen, and measures to improve adherence should be undertaken (conditional recommendation, very-low-quality evidence).

A fter failure of a first-line LPV/r-based regimen, children 3 years or older should switch to a second-line regimen containing an NNRTI plus two NRTIs; EFV is the preferred NNRTI (conditional recommendation, low-quality evidence).

A fter failure of a first-line regimen of ABC or TDF + 3TC (or FTC), the preferred NRTI backbone option for secondline ART is AZT + 3TC (strong recommendation, low-quality evidence).

A fter failure of a first-line regimen containing AZT or d4T + 3TC (or FTC) the preferred NRTI backbone option for second-line ART is ABC or TDF + 3TC (or FTC) (strong recommendation, low-quality evidence).

Third-line ART Topic and population All populations Recommendations

N ational programmes should develop policies for third-line ART (conditional recommendation, low-quality evidence). T hird-line regimens should include new drugs with minimal risk of cross-resistance to previously used regimens, such as integrase inhibitors and second-generation NNRTIs and PIs (conditional recommendation, low-quality evidence).

Patients on a failing second-line regimen with no new ARV options should continue with a tolerated regimen (conditional recommendation, very low-quality evidence). Special considerations for children

Strategies that balance the benefits and risks for children need to be explored when second-line treatment fails. For older children and adolescents who have more therapeutic options available to them, constructing third-line ARV regimens with novel drugs used in treating adults such as ETV, DRV and RAL may be possible. Children on a second-line regimen that is failing with no new ARV drug options should continue with a tolerated regimen. If ART is stopped, opportunistic infections still need to be prevented, symptoms relieved and pain managed.

Summary of new recommendations

Operations and service delivery Topic Interventions to optimize adherence to ART Recommendations

M obile phone text messages could be considered as a reminder tool for promoting adherence to ART as part of a package of adherence interventions (strong recommendation, moderate-quality evidence).

Service integration and linkage

I n generalized epidemic settings, ART should be initiated and maintained in eligible pregnant and postpartum women and in infants at maternal and child health care settings, with linkage and referral to ongoing HIV care and ART, where appropriate (strong recommendation, very-low-quality evidence).

I n settings with a high burden of HIV and TB, ART should be initiated for an individual living with HIV in TB treatment settings, with linkage to ongoing HIV care and ART (strong recommendation, very-low-quality evidence).

I n settings with a high burden of HIV and TB, TB treatment may be provided for an individual living with HIV in HIV care settings where TB diagnosis has also been made (strong recommendation, very-low-quality evidence).

A RT should be initiated and maintained in eligible people living with HIV at care settings where opioid substitution therapy (OST) is provided (strong recommendation, very-lowquality evidence). Decentralization of treatment and care

The following options should be considered for decentralization of ART initiation and maintenance.

I nitiation of ART in hospitals with maintenance of ART in peripheral health facilities (strong recommendation, low-quality evidence).

I nitiation and maintenance of ART in peripheral health facilities (strong recommendation, low-quality evidence). I nitiation of ART at peripheral health facilities with maintenance at the community level (that is, outside health facilities in settings such as outreach sites, health posts, home-based services or community-based organizations) between regular clinical visits (strong recommendation, moderate-quality evidence).

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Operations and service delivery (continued) Topic Task-shifting Recommendations

Trained non-physician clinicians, midwives and nurses can initiate first-line ART (strong recommendation, moderate-quality evidence).

Trained non-physician clinicians, midwives and nurses can maintain ART (strong recommendation, moderate-quality evidence).

Trained and supervised community health workers can dispense ART between regular clinical visits (strong recommendation, moderate-quality evidence).

Guidance for programme managers Topic Guidance for programme managers Guidance

For deciding on the implementation of the clinical and operational recommendations, it is recommended that: T he national authorities do so using a transparent, open and informed process. This process should have broad stakeholder engagement, including meaningful participation from the affected communities, and take into account the specifics of the recommendations under discussion. T he decision-making process take into account data on the national and local HIV epidemiology, current ART programme performance and the socioeconomic, policy and legal context, including the budgetary, human resource requirements and other health system implications. The latter would identify which inputs and systems are currently available and which areas require additional investment. T he decision-making process take into account the ethics, equity and human rights, the impact and cost-effectiveness and the opportunity and risk dimensions of alternative implementation options.

INTRODUCTION

1.1 Background and context 36 1.2 Rationale for consolidated guidelines 36 1.3 Objectives 37 1.4 Target audience 37 1.5 Scope and components 38 1.5.1 Introductory chapters 38 1.5.2 Clinical guidance 38 1.5.3 Operational and service delivery guidance 38 1.5.4 Guidance for programme managers 39 1.5.5 Monitoring and evaluation 39

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

1. Introduction 1.1 Background and context WHO first published guidelines on the use of ART for HIV infection among adults and adolescents in 2002 (1) and on the use of ARV drugs for PMTCT in 2004 (2). The 2006 updates of the guidelines (3–5) introduced the concept of a public health approach, with simplified and harmonized ART regimens (6). These publications and their updates, most recently in 2010 (7–9) , have provided important guidance to countries that have scaled up national ARV programmes during the past decade. In 2013, for the first time, WHO has revised and combined these and other ARV-related guidance documents into one set of consolidated guidelines that addresses the use of ARV drugs for HIV treatment and prevention across all age groups and populations, based on the broad continuum of HIV care. These guidelines were updated in late 2012 and early 2013. The ARV regimens now available, even in the poorest countries, are safer, simpler, more efficacious and more affordable than ever before. New testing strategies and approaches are enabling earlier diagnosis of HIV in a wider range of settings, and new, more affordable technologies for monitoring people receiving ART are becoming available. Countries are moving towards triple-drug regimens and simplified programming for PMTCT that emphasizes the long-term health of pregnant women and mothers living with HIV as well as their children. Important new evidence has shown that ARV drugs offer significant benefits in preventing HIV transmission (10). Although countries are at different stages of ART coverage and implementation of the 2010 guidelines (7–9) and there are still important gaps in research, there is a consistent global trend towards expanding access and the earlier initiation of treatment. Expanding the eligibility criteria for ART and the options for using ARV drugs creates opportunities to save lives and reduce HIV transmission but can pose significant technical, operational, programmatic and ethical challenges to policy-makers and implementers in many low- and middle-income countries. These include implementing a strategic mix of approaches to ensure more timely diagnosis of HIV infection in both health facility and community settings. Effective linkage and referrals between care settings, innovative, decentralized approaches to delivering ART services and effective adherence support and interventions are also needed to ensure that people are retained in long-term care. Reliable, quality-assured and affordable laboratory monitoring tools, adequate health workforce capacity and uninterrupted drug supplies are also essential. At the programmatic level, countries often encounter difficulties in reaching the people who need ARV drugs the most. They may face difficult choices in allocating limited resources and determining programme priorities to make the best use of ARV drugs for treatment and prevention in combination with other HIV prevention methods. National HIV programmes may need to justify increased investment in ARV programmes by assessing the costs and benefits and demonstrating how they impact on HIV morbidity, mortality and incidence.

1.2 Rationale for consolidated guidelines The consolidated guidelines offer the following anticipated benefits. Guidance on using ARV drugs is presented within the context of the continuum of HIVrelated prevention, treatment and care. In addition to providing recommendations on the clinical use of ARV drugs for treatment, the guidelines address other major aspects of HIV-related care.

1. Introduction

The guidelines address the use of ARV drugs for all age groups and populations. Previously separate WHO guidelines on using ART among adults and adolescents have been combined with those for children and for PMTCT, harmonizing ARV regimens and treatment approaches to the extent possible across age groups and populations. New and existing guidance is harmonized. Consolidation has allowed for new recommendations to be harmonized with relevant, existing WHO guidance. Consolidation promotes the consistency of approaches and linkage between settings. Consolidated recommendations help to facilitate linkage and promote consistency of approaches across the various settings in which ARV drugs and related services may be provided, including specialized HIV care, primary care, community-based care, maternal and child health services, TB services and services for people who use drugs. Updates will be more timely and comprehensive. Consolidated guidelines enable key clinical, operational and programmatic implications of new science and emerging practice in the use of ARV drugs to be comprehensively reviewed every two years across populations, age groups and settings.

1 Introduction

1.3 Objectives The objectives of the consolidated guidelines are: to provide updated, evidence-based clinical recommendations outlining a public health approach to providing ARV drugs for HIV treatment and prevention in the context of the continuum of HIV care, with a focus on settings with limited capacity and resources in the health system; to provide guidance on key operational and service delivery issues that need to be addressed to increase access to HIV services, strengthen the continuum of HIV care and further integrate the provision of ARV drugs into health systems; and to provide programmatic guidance for decision-makers and planners at the national level on adapting, setting priorities for and implementing the clinical and operational recommendations and monitoring their implementation and impact.

1.4 Target audience The guidelines are intended primarily for use by national HIV programme managers. They will also be of interest to the following audiences: national HIV treatment and prevention advisory boards; national TB programme managers; managers of maternal, newborn and child health and reproductive health programmes; clinicians and other health service providers; managers of national laboratory services; people living with HIV and community-based organizations; and international and bilateral agencies and organizations that provide financial and technical support to HIV programmes in resource-limited settings.

Consolidated guidelines on general HIV care and the use of antiretroviral drugs for treating and preventing hiv infection

1.5 Scope and components The guidelines address clinical, operational and programmatic aspects of using ARV drugs for HIV treatment and prevention (Fig. 1.1).

1.5.1 Introductory chapters The guidelines include several introductory chapters. Chapter 1: Describes the background, context, rationale and objectives of the guidelines and the target audience. Chapter 2: Outlines the guiding principles that underpin the guidelines. Chapter 3: Describes the methods and process for developing the guidelines. Chapter 4: Presents the format used to present new recommendations.

1.5.2 Clinical guidance The recommendations in Chapters 5, 6 and 7 address key aspects of using ARV drugs for HIV treatment and prevention for all age groups and populations along the continuum of care from HIV-related diagnosis to care and treatment. Chapter 5: Summarizes HIV testing and counselling approaches, with links to existing WHO guidance. In addition, it summarizes approaches to using ARV drugs for preventing HIV transmission (pre-exposure prophylaxis and post-exposure prophylaxis of HIV and ARV drugs for prevention in serodiscordant couples) within the context of comprehensive combination HIV prevention, with links to existing WHO guidance. Note that the guidelines do not address behavioural, structural and biomedical prevention interventions that do not involve the use of ARV drugs. Chapter 6: Summarizes general HIV care for individuals from the time that they are diagnosed with HIV infection to the time that they are initiated on ART, including practices for linking people diagnosed with HIV infection to HIV care and treatment, the components of a general care package and preparing individuals for starting ART. Chapter 7: Includes recommendations on ART for adults (including pregnant and breastfeeding women), adolescents and children, including updated recommendations applicable to the majority of populations regarding the optimal timing for initiating ART (when to start); updated recommendations on the most effective and feasible first- and second-line treatment regimens (what to start and what to switch to); updated recommendations for monitoring the response to and toxicity of ART; and a discussion of third-line ART. Chapter 8: Includes a summary of approaches to preventing and managing common HIVrelated opportunistic infections, other coinfections and other comorbidities, with links to existing WHO guidance.

1.5.3 Operational and service delivery guidance Chapter 9: Includes recommendations in six major operational and service delivery areas in which action is essential to further scaling up ARV programmes and ensuring their effectiveness and sustainability across the health system. These areas are: retention in care; adherence to ART; human resources; models of service delivery, focusing on decentralizing ART to primary health care services and integrating ART with TB treatment, antenatal care and maternal and child health programmes and drug dependence services; laboratory services; and drug supply management.

1. Introduction

1.5.4 Guidance for programme managers Chapter 10: Aims to assist countries in decision-making and programme planning. Implementation will involve various policy mixes based on local context, including the prevalence and dynamics of HIV infection; modes of transmission; the organization and capacity of health systems; relative income; and the current coverage of interventions. The chapter proposes steps to ensure fair, inclusive and transparent decision-making processes at the country level; discusses parameters to consider in assessing and adapting the global recommendations in countries; and suggests tools for costing and planning. Considerations for implementation across the health system and for specific, key recommendations in the guidelines are also discussed.

1.5 Scope and components

1.5.5 Monitoring and evaluation Chapter 11: Provides guidance on the implications for monitoring of key new recommendations in these guidelines. It proposes a range of indicators that may be used to track the implementation of new recommendations and indicators to monitor the performance of programmes across the continuum of care. Chapter 11 also highlights opportunities provided by new recommendations to review and strengthen monitoring and evaluation systems.

Fig. 1.1 Components of the consolidated guidelines What to do • HIV testing and counseling • Prevention based on ARV drugs • General HIV care • When to start ART (first-line ART) • What ART to start with • How to monitor (ART response and toxicity) • What ART to switch to (second-line ART) • Management of coinfections and comorbidities Programmatic Clinical Operational

How to do it • Adherence to ART • Retention in care • Innovative models of service delivery (integration, decentralization and task shifting) • Human resources • Laboratory and diagnostic services • Procurement and supply management systems

How to decide what to do, where and when • Decision-making (process, data required and key parameters) • Implementation considerations • Useful tools for costing and planning

Monitoring and evaluation • Monitoring implications of new recommendations • Monitoring outputs and outcomes of scaling up ARV access • Other monitoring considerations (HIV drug resistance and ARV toxicity monitoring) • Strengthening monitoring and evaluation systems

2. Guiding principles

1 Introduction

GUIDING PRINCIPLES

2.1 Contribution to global health goals 42 2.2 Public health approach 42 2.3 Strengthening health systems through innovation and learning 42 2.4 Increasing the effectiveness and efficiency of programmes 43 2.5 Promoting human rights and health equity 43 2.6 Implementation based on local context 43

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

2. Guiding principles 2.1 Contribution to global health goals Implementing these guidelines will contribute to achieving universal access to HIV prevention, treatment, care and support in accordance with the goals and targets articulated in the 2006 Political Declaration on HIV/AIDS (1) and the 2011 Political Declaration on HIV and AIDS: Intensifying Our Efforts to Eliminate HIV and AIDS (2). These guidelines will also contribute to attaining specific health sector goals in the Global Health Sector Strategy on HIV/AIDS 2011–2015 (3) and the Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive (4). Major targets for 2015 include reducing by half the percentage of young people 15–25 years who are infected with HIV compared with 2009; reducing the number of children newly infected with HIV by 90% compared with 2009; reducing the number of people dying from HIV-related causes by 25% compared with 2009; reducing by half the number of HIV-related maternal deaths compared with 2009; reducing by half the number of people dying from TB compared with 2004; and having 15 million people on ART in low- and middle-income countries. In the longer term, the guidelines will contribute to and inform efforts to achieve universal health coverage, a key pillar of the post-2015 development agenda.

2.2 Public health approach In accordance with WHO guidance on HIV since 2002, these guidelines are based on a public health approach to scaling up the use of ARV drugs for HIV treatment and prevention (5). The public health approach seeks to ensure the widest possible access to high-quality services at the population level, based on simplified and standardized approaches, and to strike a balance between implementing the best-proven standard of care and what is feasible on a large scale in resource-limited settings.

2.3 S trengthening health systems through innovation and learning The recommendations and innovations in service delivery described in these guidelines should be implemented with a view to strengthening the continuum of HIV care and broader health systems, especially primary care and chronic care. HIV services are already being integrated at lower-level health facilities in many settings with a high burden of HIV infection, while services for PMTCT are increasingly becoming core elements of maternal and child health services. HIV, TB, hepatitis, drug dependence and harm reduction services are being integrated to varying degrees. As people receiving ART begin to age and HIV infection becomes a chronic, manageable condition, improving the integration of HIV services with care for noncommunicable diseases will also become more important. In accordance with these trends, the guidelines promote the adaptation of service delivery models that strengthen the continuum of HIV care and enable the timely initiation of ART in a variety of settings, ensuring that people are appropriately referred to services and are retained in and adhere to lifelong treatment. National HIV programmes should consider undertaking implementation research to determine how best to adopt and adapt these guidelines to their local context and bringing to scale more efficient and effective services.

2. Guiding principles

2 Guiding principles

2.4 Increasing the effectiveness and efficiency of programmes In the context of limited financial resources, competing priorities and health system constraints, countries may face difficult choices among an expanding range of options for using ARV drugs to reduce HIV morbidity, mortality and transmission. These guidelines are based on the principle that countries should further scale up and optimize the effectiveness and efficiency of HIV programmes through a strategic approach to using ARV drugs that involves: Giving priority to providing ARV drugs to people living with HIV who are eligible for treatment and most in need; E xploring opportunities to enhance the impact of ARV drugs on HIV prevention by starting treatment earlier in certain populations; Increasing the effectiveness and reach of ARV programmes across the continuum of care

through a strategic mix of quality-assured HIV testing approaches, improving adherence and retention, innovative service delivery, integrating ART in a wider range of settings and strengthening links between services; and Engaging in both short- and longer-term efforts to optimize and harmonize drug regimens and increase their affordability and to develop and implement simpler and more affordable point-of-care diagnostics and laboratory services.

2.5 Promoting human rights and health equity Access to HIV prevention, treatment, care and support should be recognized as fundamental to realizing the universal right to health, and these guidelines should be implemented based on core human rights and ethical principles. In general, HIV programmes need to ensure that ARV drugs and related interventions are accessible to the people who need them most, including pregnant women, children and key populations, and that they are provided in an environment that minimizes stigma and discrimination. Informed consent – notably for HIV testing but also for initiating ART – should always be obtained. Adequate safeguards must be in place to ensure confidentiality. Some countries may face significant ethical challenges as they seek to implement these guidelines in the context of constraints on resources and health systems. A key challenge may involve the need to give priority to ensuring ART for the people who are most ill and those already receiving treatment, while also striving to implement expanded eligibility criteria. Each country will need to plan its own approach to ensuring that current ARV programmes are not disrupted and that expanded access is fair and equitable.

2.6 Implementation based on local context Implementation of the recommendations in these guidelines should be informed by local context, including HIV epidemiology, availability of resources, the organization and capacity of the health system and anticipated cost-effectiveness. A strong recommendation for a specific approach to service delivery should not necessarily be viewed as an endorsement of that model over an effective service delivery model already in place in a country.

3. Methods and process for developing the guidelines

1 Introduction

Methods and process for developing the guidelines

3.1 Overview 46 3.2 Information sources 46 3.3 External participation 47 3.3.1 Guideline Development Groups and peer review process 47 3.3.2 Conflicts of interest 47 3.4 Process of formulating recommendations 48 3.5 Other methods 51 3.6 Dissemination 51

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

3. Methods and process for developing the guidelines The 2013 consolidated guidelines compile new recommendations, existing recommendations and other guidance across the continuum of HIV care. This includes guidance on HIV diagnosis, general HIV care and the strategic use of ARV drugs for treating and preventing HIV infection, based on a public health approach. New clinical and operational recommendations were developed in accordance with procedures outlined by the WHO Guidelines Review Committee (1) and are based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system (2–11). Most recommendations cited from existing guidance were developed using the GRADE system. In a few cases where GRADE was not used, the text notes this. Chapter 10 did not use the GRADE approach, since the programmatic guidance does not contain any formal recommendations.

3.1 Overview

3.2 Information sources The following sources of information were used in developing new recommendations. Intervention, Comparison and Outcome (PICO) format by the WHO Guideline Steering Group (3) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The 41 topics covered the continuum of HIV care (9 on when to start; 11 on what to start; 4 on monitoring the response to treatment; 6 on monitoring toxicity; 11 on various aspects of service delivery; and 5 on adherence interventions). The WHO Guideline Steering Group established the critical outcomes for the reviews of clinical evidence (mortality, morbidity, transmission and severe adverse reactions) and for the reviews of operational service delivery (mortality, morbidity, transmission, access, retention in care, viral suppression and adherence) in consultation with the Guidelines Development Groups. Systematic reviews were outsourced to researchers who developed search protocols and conducted reviews of the available scientific evidence. Searches of electronic databases (MEDLINE/PubMed, Embase, CENTRAL), conference databases (Aegis, AIDSearch, NLM Gateway and hand searches) and clinical trial registers (http://clinicaltrials.gov, www.controlled-trials.com and www.pactr.org) used relevant keywords and search strings. The Web Annex (www. who.int/hiv/pub/guidelines/arv2013/annexes) includes the search protocols, the full list of review questions and the GRADE tables and evidence summaries for each topic. of the evidence and assessment of its quality for each PICO question by outcome. The GRADE system was used to rate the quality of evidence (4–10) and the strength of the recommendations (11) (Box 3.1; Web Annex www.who.int/hiv/pub/guidelines/ arv2013/annexes). C ommunity consultations on values and preferences in priority areas for the A standardized GRADE evidence table was used to present quantitative summaries Systematic reviews were commissioned on 41 topics framed using Population,

guidelines were conducted through an online e-survey and moderated e-forum discussions with civil society networks and coordinated by the International HIV/ AIDS Alliance and the Global Network of People Living with HIV (GNP+). Focus group discussions were also held in Uganda and Malawi on the experiences of pregnant women with lifelong ART, and on PMTCT and paediatric ART in South Africa (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).

3. Methods and process for developing the guidelines

Two global community and civil society consultations on service delivery across the continuum of care in generalized and concentrated epidemic settings. Consultations with health workers working with adults and with children on the values and preferences related to priority areas in the guidelines were conducted through an e-survey (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The sixth annual survey in 2012 of the WHO AIDS Medicines and Diagnostics Service on the use of ARV drugs and diagnostics in 80 low- and low-middle-income countries (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). Mathematical modelling on the impact and cost–effectiveness of earlier ART in

3 Methods and process for developing the guidelines

various populations and settings, based on data from countries with both generalized and concentrated epidemics (India, Kenya, South Africa, Viet Nam and Zambia), together with modelling of various treatment monitoring strategies were undertaken by the HIV Modelling Consortium (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). A n impact assessment using the Spectrum model to estimate the increased number of adults and children eligible for ART based on various eligibility criteria (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).

Reports on country implementation experiences were provided on using option

B+ for PMTCT in Malawi; introducing TDF in first-line ART regimens in Zambia; phasing out d4T in Zimbabwe; and scaling up viral load monitoring in Médecins Sans Frontières programmes in southern Africa. A n electronic e-survey of country-level end-users was undertaken of WHO guidelines on ARV drugs to identify areas for improvement in format, presentation and dissemination (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).

3.3 External participation 3.3.1 Guideline Development Groups and peer review process The process was supported by four, separate, external Guideline Development Groups (Adult; Maternal and Child Health; Operational and Service Delivery; and Programmatic, comprising 108 individuals) and an external peer review group of over 100 individuals. The acknowledgements list the members of these Groups. The composition of the Groups was in accordance with WHO procedures for developing guidelines (1) and included HIV experts, researchers, programme managers, guideline methodologists, epidemiologists, human rights experts, development agencies, United Nations partners, civil society representatives and representatives from networks of people living with HIV. Appropriate representation by geography and sex was considered. Community group members were selected following an open call for nominations. A full draft of the guidelines was circulated for comment to members of the Guideline Development Groups and the external peer review group.

3.3.2 Conflicts of interest All members of the Guideline Development Groups and peer review group completed WHO declaration of interest forms (including participation in consulting and advisory panels, research support and financial investment). A total of 21 Guideline Development Group members and 12 peer reviewers declared membership of pharmaceutical industry or other advisory panels or receipt of consulting fees, and 23 Guideline Development Group members and 13 peer reviewers declared pharmaceutical industry financial support through grants for research.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

The focus of the 2013 guidelines was on the development of new or updated recommendations on the use of ARV drugs in adults, adolescents, children and pregnant women. The WHO secretariat and co-chairs of each Guideline Development Group considered that important areas for potential conflict of interest would be evidence for exclusive engagement with one pharmaceutical company, or a major role within completed, ongoing or planned trials on either the timing of ART, or evaluation of specific ART regimens. The WHO Guideline Steering Group reviewed all declarations, and found no case where there was exclusive membership of an advisory group panel, receipt of consulting fees or financial support through research grants from only one pharmaceutical company. There was also a further declaration at the Guideline Development Group meeting of the involvement of members as investigators in key trials and studies. Overall, the WHO Guideline Steering Group and co-chairs of each Guideline Development Group were satisfied that there had been a transparent declaration of interests, and that no case necessitated exclusion from the deliberations. The broad range of constituencies represented on the different Guideline Development Group panels was also noted, and that the majority of members had no declared interests. All individuals with declared interests therefore proceeded to participate fully in the Guideline Development Group meetings or to act as peer reviewers.

3.4 P rocess of formulating recommendations Four Guideline Development Group meetings were held in Geneva, Switzerland between November 2012 and January 2013 (Operational and Service Delivery Guideline Development Group, November 2012; Adult Guideline Development Group and Maternal and Child Health Guideline Development Group, December 2012; and Programmatic Guideline Development Group, January 2013). The systematic reviews, evidence tables prepared in accordance with GRADE and other relevant information described in section 3.2 were presented and discussed at these meetings and made available through a password-protected web site. The proposed recommendations were then considered, informed by a standardized decision-making table for each topic (Box 3.1) encompassing the following elements: existing and proposed recommendations; summary of the evidence; benefits and risks; community and health care worker values and preferences; costs and resource implications; cost-effectiveness; feasibility and barriers to implementation; equity, ethics and human rights implications; the suggested rating of the strength of recommendations (strong or conditional) and quality of the evidence; research gaps and needs; and the overall rationale for the recommendations. The Guideline Development Groups discussed both the proposed wording of the recommendations and the rating of its strength (strong or conditional). All decisions were reached by discussion and consensus on the recommendations, including their strength and, where appropriate, the conditions to be attached to the recommendations. Disagreements were resolved through e-mail discussions, teleconferences and redrafting recommendations and rationale. Early drafts of sections of the guidelines were circulated to Guideline Development Group members, and a full draft of the guidelines was circulated to Guideline Development Group members and peer reviewers for comment. The extensive comments from more than 100 reviewers were addressed where possible and incorporated into the revised guidelines.

3. Methods and process for developing the guidelines

3.4 Process of formulating recommendations

Box 3.1 Approach to rating the quality of evidence and strength of recommendations using the GRADE system Since 2008, WHO has followed the GRADE system. GRADE separates the rating of the quality of evidence from the rating of the strength of the recommendation. The quality of evidence is defined as the confidence that the reported estimates of effect are adequate to support a specific recommendation. The GRADE system classifies the quality of evidence as high, moderate, low and very low (Table 3.1) (4–10) . Randomized controlled trials are initially rated as high-quality evidence but may be downgraded for several reasons, including the risk of bias, inconsistency of results across studies, indirectness of evidence, imprecision and publication bias. Observational studies are initially rated as low-quality evidence but may be upgraded if the magnitude of the treatment effect is very large, if multiple studies show the same effect, if evidence indicates a dose–response relationship or if all plausible biases would underestimate the effect (10) . The higher the quality of evidence, the more likely a strong recommendation can be made. The strength of a recommendation reflects the extent to which the Guideline Development Group was confident that the desirable effects of following a recommendation outweigh the potential undesirable effects. The strength is influenced by the following factors: the quality of the evidence, the balance of benefits and harms, values and preferences, resource use and the feasibility of the intervention (Table 3.2). The GRADE system classifies the strength of a recommendation in two ways: “strong” and “conditional” (11) . A strong recommendation is one for which the Guideline Development Group was confident that the desirable effects of adhering to the recommendation outweigh the undesirable effects. A conditional recommendation is one for which the Guideline Development Group concluded that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects but the Guideline Development Group is not confident about these trade-offs. Table 3.3 summarizes the implications of a strong or conditional recommendation for individuals, clinicians and policy-makers. The reasons for making a conditional recommendation include the absence of highquality evidence; imprecision in outcome estimates; variability in the values and preferences of individuals regarding the outcomes of interventions; small benefits; applicability in all settings versus specific settings; and benefits that may not be worth the costs (including the costs of implementing the recommendation).

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 3.1 GRADE classification of the level of evidence Level of evidence High Moderate Low Very low Rationale Further research is very unlikely to change our confidence in the estimate of effect Further research is likely to have an important impact on our confidence in the effect Further research is very likely to have an estimate of effect and is likely to change the estimate Any estimate of effect is very uncertain

Table 3.2 Key domains considered in determining the strength of recommendations Domain Benefits and risks Rationale Desirable effects (benefits) need to be weighed against undesirable effects (risks). The more that the benefits outweigh the risks, the more likely that a strong recommendation will be made. If the recommendation is likely to be widely accepted or highly valued, a strong recommendation will probably be made. If there are strong reasons that the recommended course of action is unlikely to be accepted, a conditional recommendation is more likely to be made. Lower costs (monetary, infrastructure, equipment or human resources) or greater cost–effectiveness will more likely result in a strong recommendation. If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is more probable.

Values and preferences (acceptability) Costs and financial implications (resource use) Feasibility

Table 3.3 Implications for strong and conditional recommendations for individuals, clinicians and policy-makers Strong recommendation Individual Most people in your situation would want the recommended course of action and only a small proportion would not Most individuals should receive the recommended course of action The recommendation can be adapted as a policy in most situations Conditional recommendation The majority of people in your situation would want the recommended course of action, but many would not Be prepared to help individuals to make a decision that is consistent with their own values There is a need for substantial debate and involvement of stakeholders

Clinician

Policy-maker

3. Methods and process for developing the guidelines

3.5 Other methods Recommendations from existing guidelines. In addition to new recommendations based on the GRADE system, the guidelines summarize existing relevant recommendations from other WHO guidelines). Most of these recommendations were developed using the GRADE system or an alternative grading used prior to 2008 (A (strongly recommended) to C (optional)) and I–IV (level of evidence) (Web Annex www.who.int/hiv/pub/guidelines/ arv2013/annexes). For these existing recommendations, no new evidence reviews were undertaken. Recommendations that require updating are noted, and it is clearly stated where updated guidelines are planned. Where systematic reviews and GRADE assessment of quality of evidence to support new recommendations were not possible or appropriate, qualitative reviews of the literature were undertaken and presented. This applies to specific topics in Chapter 9, including retention across the continuum of care, but this did not lead to formal recommendations. Guidance for programme managers on programmatic decision-making. Chapter 10 and Chapter 11 did not involve formulating recommendations or rating of the quality of evidence and therefore did not follow the GRADE system. The process involved a narrative review of literature on both the process and criteria for evidence-based ethical decisionmaking, a review of relevant WHO policies and World Health Assembly resolutions, and results from mathematical modelling on the impact and cost–effectiveness of earlier ART in various populations and settings. Structured discussions were held among Guideline Development Group members regarding setting priorities for key clinical recommendations in various epidemic scenarios (settings with generalized and concentrated epidemics and with low, moderate and high ART coverage).

3.6 Dissemination

3.6 Dissemination The guidelines will be disseminated as a printed publication and electronically on the WHO web site in the six official United Nations languages. The web version will include all annexes. A short version will summarize key new and existing recommendations for easy reference. A library of all supporting documentation and evidence will also be made available on the web site. WHO headquarters will work closely with regional and country offices and implementing partners to ensure their wide dissemination through regional and subregional meetings. Assistance will be provided to Member States to adapt the guidelines to their national contexts. An evaluation of how users have implemented the guidelines has been developed to assess the uptake of the recommendations and the barriers to effective implementation. A review of the guidelines is planned for 2015. Interim technical and programmatic updates may be developed if important new evidence becomes available.

4. Organization of the guidelines

1 Introduction

ORGANIZATION OF THE GUIDELINES

4 Continuum of care 54 4.1 Structure of presentation for new recommendations 56 4.2 Structure of presentation of selected recommendations from existing guidelines 56 4.3 How to use the guidelines for specific populations 57 4.3.1 Pregnant and breastfeeding women 57 4.3.2 Adolescents 59 4.3.3 Children 61 4.3.4 Key populations 62

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

4. Organization of the guidelines Continuum of care

Section 6.2

Section 9.3

■■ ■■

RETENTION HIV PREVENTION GENERAL HIV CARE PREPARING PEOPLE FOR ART MANAGING COINFECTIONS AND COMORBIDITIES

HIV TESTING AND counselling

■■

INKAGE L TO CARE

Enrolment in care

■■ ■■

■■

Section 5.1

Section 5.2 Section 6.1 Section 6.4 Sections 8.1 and 8.2

4. Organization of the guidelines

Continuum of care

SectionS 9.2 and 9.3

■■

R ETENTION AND ADHERENCE second and third line art

ART initiation (FIRST LINE ART)

■■

MONITORING ART RESPONSE MONITORING ARV TOXICITY

Sections 7.1 and 7.2

Sections 7.3 and 7.4

Section 7.5

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

4.1 Structure of presentation for new recommendations New recommendations in these guidelines are flagged by a symbol New . These include existing recommendations that have been updated, where a new evidence review was undertaken as part of this guidelines process. When the original recommendation remained unchanged, this is clearly indicated. They are presented in the following format to reflect the full evidence review and discussion held within the Guideline Development Group for new recommendations. Recommendation . The new recommendation and the strength and quality of evidence assessed using the GRADE method are stated. B ackground . Previous WHO guidance in this area and key developments since

recommendations were last published are described. When the recommendation relates to a specific population, the key issues for that population may be briefly summarized. R ationale for recommendation and supporting evidence. The new evidence on which the recommendation is based and other key operational and programmatic considerations that informed the development of the recommendation are summarized. Clinical or implementation considerations. In some cases, key clinical implementation issues specific to the recommendation are listed. For several key recommendations, discussion of implementation considerations relevant to programme managers is presented in Chapter 10. Key research gaps. In some cases, critical issues requiring further research are briefly described or listed, where these are integral to the recommendations. chapter number. T he references relating to each section are listed at the end of the guidelines by

4.2 S tructure of presentation of selected recommendations from existing guidelines Two chapters summarize recommendations from existing WHO guidelines: Chapter 5 on HIV testing and counselling as well as the use of ARV drugs for prevention; and Chapter 8 on general HIV care, including prevention and management of coinfections and comorbidities. In general, these are presented in the following format: B ackground ; S ource(s) for recommendation(s) ; A dditional guidance (where appropriate) ; and E xisting recommendation(s) . The new recommendations and the strength and quality of the evidence assessed using the GRADE method (or an alternative method) are stated.

4. Organization of the guidelines

4.3 How to use the guidelines for specific populations These guidelines include recommendations for adults, pregnant and breastfeeding women, adolescents, children, and key populations. The population relevant to each recommendation is clearly specified and also marked by an appropriate symbol for quick reference. Adults Pregnant women Adolescents Children Key populations

4 Organization of the guidelines

Tables 4.1–4.4 also summarize the chapter and section number of key recommendations and guidance for specific populations:- pregnant and breastfeeding women, adolescents, children and infants, and key populations. The tables highlight selected topics that are particularly relevant to the respective populations. However, the topics listed are not exhaustive and many of the recommendations and other guidance are relevant across different populations.

4.3.1 Pregnant and breastfeeding women Table 4.1 summarizes the location of key guidance and recommendations specific to pregnant and breastfeeding women.

Table 4.1. Key recommendations and guidance for pregnant and breastfeeding women Chapter Chapter 5: HIV diagnosis and ARV drugs for HIV prevention Topic HIV testing in health facilities Community-based HIV testing and counselling HIV testing and counselling in specific populations: couples HIV testing and counselling in specific populations: pregnant and postpartum women HIV testing and counselling in specific populations: early infant diagnosis ART for prevention among serodiscordant couples Chapter 6: Linking people diagnosed with HIV infection to HIV care and treatment General care for people living with HIV Preparing people living with HIV for ART What to expect in the first months of ART Chapter subsections Section 5.1.2 Section 5.1.3 Section 5.1.4.1 Section 5.1.4.2 Section 5.1.4.3 Section 5.2.2 Section 6.3 Section 6.4 Section 6.5

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 4.1 (continued) Chapter Chapter 7: Antiretroviral therapy Topic When to start ART in pregnant and breastfeeding women ARV drugs and duration of breastfeeding Special considerations for the care and management of pregnant women First-line ART for pregnant and breastfeeding women and ARV drugs for their infants Monitoring response to ART and diagnosis of treatment failure (includes pregnant and breastfeeding women) Monitoring and substitutions for ARV drug toxicities (includes pregnant and breastfeeding women) Second-line ART for adults and adolescents (includes pregnant and breastfeeding women) Third-line ART (includes pregnant and breastfeeding women) Chapter 8: Managing common coinfections and comorbidities Chapter 9: Guidance on operations and service delivery Prevention, screening and management of coinfections Preventing and managing other comorbidities and chronic care for people living with HIV Chapter subsections Section 7.1.2 Section 7.1.3 Section 7.1.3; Box 7.1 Section 7.2.2 Section 7.3 Section 7.4 Section 7.5.1 Section 7.6 Section 8.1 Section 8.2

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues. Adherence to ART: pregnant and postpartum women Section 9.2.1 Delivering ART in antenatal care and maternal and child health settings Decentralization and task shifting Section 9.4.2.1 Sections 9.4.3 and 9.5.2

Chapter 10: Guidance for programme managers Chapter 11: Monitoring and evaluation Annexes

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues. Implementation considerations for key recommendations: Section 10. 6 moving to lifelong ART for all pregnant and breastfeeding Box 10.4 women Monitoring implications of new recommendations Section 11.2

Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children Annex 3. Algorithms for the 2013 recommendations for pregnant and breastfeeding women Annex 6. Readiness assessment checklist: moving towards ART for pregnant and breastfeeding women Annex 7. Dosages of recommended ARV drugs for adults and adolescents (includes pregnant and breastfeeding women)

Chapter 12

4. Organization of the guidelines

4.3.2 Adolescents WHO defines adolescence as 10–19 years old. Adolescents with HIV include those surviving perinatal infection and those newly acquiring infection as they become sexually active or are exposed through injecting drug use, other unsafe injections and blood transfusions. Adolescents may access care in a variety of settings, including paediatric and antenatal care clinics, as well as adult clinics. Since few health systems provide adolescent-specific services it can be challenging for adolescents to access health care and maintain adherence to treatment regimens. In general, in these guidelines, clinical and general care recommendations for adults apply to adolescents. Where guidance for adolescents is addressed in recommendations for children, this is clearly indicated. There are four specific recommendations on testing and counselling taken from additional recent adolescent-specific guidance. The 2013 Guidance on HIV testing and counselling for adolescents and care for adolescents living with HIV contains recommendations on HIV testing and counselling and delivery of services for adolescents (Table 4.2).

4.3 How to use the guidelines for specific populations

Table 4.2. Key recommendations and guidance for adolescents Chapter Chapter 5: HIV diagnosis and ARV drugs for HIV prevention Chapter 6: Linking people diagnosed with HIV infection to HIV care and treatment Chapter 7: Antiretroviral therapy Topic HIV testing in health facilities Community-based HIV testing and counselling HIV testing and counselling in specific populations: adolescents General care for people living with HIV Preparing people living with HIV for ART What to expect in the first months of ART When to start ART in adults and adolescents First-line ART for children three years and older (includes adolescents) TB co-treatment in children with HIV Monitoring response to ART and the diagnosis of treatment failure (includes adolescents) Monitoring and substitutions for ARV drug toxicities (includes adolescents) Key ARV drug interactions (includes adolescents) Second-line ART for adults and adolescents Second-line ART for children includes adolescents Third-line ART (includes adolescents) Chapter subsections Section 5.1.2 Section 5.1.3 Section 5.1.4.4 Section 6.3 Section 6.4 Section 6.5 Section 7.1.1 Section 7.2.4 Section 7.2.5 Section 7.3 Section 7.4 Table 7.17 Section 7.5.1 Section 7.5.2 Section 7.6

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 4.2 (continued) Chapter Chapter 8: Managing common coinfections and comorbidities Topic Prevention, screening and management of coinfections Preventing and managing other comorbidities and chronic care for people living with HIV Nutritional care and support among adolescents and adults living with HIV Chapter 9: Guidance on operations and service delivery Chapter subsections Section 8.1 Section 8.2 Section 8.2.4.1

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues. Adherence to ART: adolescents Decentralization and task shifting Section 9.2 Sections 9.4.3 and 9.5.2

Chapter 10: Guidance for programme managers

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues. Implementation considerations for key recommendations for programme managers: raising the CD4 threshold for initiating ART in adults and adolescents from 350 to 500 cells/mm3 Monitoring implications of new recommendations Section 10.6; Box 10.2

Chapter 11: Monitoring and evaluation Annexes

Section 11.2

Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children Annex 2. Algorithm for the 2013 recommendations for adults and adolescents Annex 7. Dosages of recommended ARV drugs for adults and adolescents

Chapter 12

4. Organization of the guidelines

4.3 How to use the guidelines for specific populations

4.3.3 Children The location of the most important guidance and recommendations specific to children (younger than 10 years) is summarized in Table 4.3.

Table 4.3. Key recommendations and guidance for children Chapter Chapter 5: HIV diagnosis and ARV drugs for HIV prevention Chapter 6: Linking people diagnosed with HIV infection to HIV care and treatment Chapter 7: Antiretroviral therapy Topic HIV testing and counselling in health facilities Community-based HIV testing and counselling HIV testing and counselling in specific populations: infants and children General care for people living with HIV Preparing people living with HIV for ART What to expect in the first months of ART When to start ART in children First-line ART for children younger than 3 years of age First-line ART for children 3 years of age and older TB co-treatment in children with HIV Monitoring response to ART and the diagnosis of treatment failure (includes children) Monitoring and substitutions for ARV drug toxicities (includes children) Key ARV drug interactions (includes chidren) Third-line ART (includes children) Chapter 8: Managing common coinfections and comorbidities Prevention, screening and management of coinfections (includes children) Immunizations Preventing and managing other comorbidities and chronic care for people living with HIV Nutritional care and support among children living with HIV Chapter 9: Guidance on operations and service delivery Chapter subsections Section 5.1.2 Section 5.1.3 Section 5.1.4.3 Section 6.3 Section 6.4 Section 6.5 Section 7.1.4 Section 7.2.3 Section 7.2.4 Section 7.2.5 Section 7.3 Section 7.4 Table 7.17 Section 7.6 Section 8.1 Section 8.1.8

Section 8.2.4.2

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues. Adherence to ART: infants and children Decentralization and task shifting Section 9.2.1 Sections 9.4.3 and 9.5.2

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 4.3 (continued) Chapter Chapter 10: Guidance for programme managers Topic Chapter subsections

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues. Implementation considerations of key recommendations: scaling up treatment for children Implementation considerations of key recommendations: phasing out d4T Section 10.6; Box 10.6 Section 10.7; Box 10.7. Section 11.2

Chapter 11: Monitoring and evaluation Annexes

Monitoring implications of new recommendations

Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children Annex 4. Algorithm for the 2013 recommendations for children Annex 5. Algorithm for early infant diagnosis Annex 7. Weight-based dosing for ARV formulations for children

Chapter 12

4.3.4 Key populations In these guidelines, key populations include both vulnerable and most-at-risk populations. Most-at-risk populations include men who have sex with men, transgender people, people who inject drugs and sex workers. The use of ART in key populations should follow the same general principles and recommendations as for adults. There is one recommendation on community-based HIV testing, that is specific to key populations. The location of the most important guidance and recommendations specific to key populations is summarized in Table 4.4.

Table 4.4 Key recommendations and guidance for key populations Chapter Chapter 2: Guiding principles Chapter 5: HIV diagnosis and ARV drugs for HIV prevention Topic Promoting human rights and health equity HIV testing and counselling in health facilities Community-based HIV testing and counselling HIV testing and counselling in specific populations: key populations Chapter subsections Section 2.5 Section 5.1.2 Section 5.1.3 Section 5.1.4.5

4. Organization of the guidelines

Table 4.4 (continued) Chapter Chapter 6: Linking people diagnosed with HIV infection to HIV care and treatment Chapter 7: Antiretroviral therapy Topic General care for people living with HIV Preparing people living with HIV for ART What to expect in the first months of ART When to start ART in adults and adolescents (includes key populations) First-line ART for adults (includes key populations) Monitoring response to ART and the diagnosis of treatment failure (includes key populations) Monitoring and substitutions for ARV drug toxicities (includes key populations) Second-line ART for adults and adolescents (includes key populations) Third-line ART (includes key populations) Chapter 8: Managing common coinfections and comorbidities Chapter 9: Guidance on operations and service delivery Prevention, screening and co-management of coinfections Preventing and managing common coinfections and comorbidities Drug use and drug use disorders Adherence to ART: most-at-risk populations (including sex workers, men who have sex with men, transgender people and people who inject drugs) ART in settings providing opioid substitution therapy, integrating and linking services Decentralization and Task shifting Chapter 10: Guidance for programme managers Chapter subsections Section 6.3 Section 6.4 Section 6.5.1 Section 7.1.1 Section 7.2.1 Section 7.3 Section 7.4 Section 7.5.1 Section 7.5.3 Section 8.1 Section 8.2 Section 8.2.3 Section 9.2.1

4.3 How to use the guidelines for specific populations

Section 9.4.2.3 Sections 9.4.3 and 9.5.2

Guidance throughout this chapter is relevant across populations. The topics listed here are indicative of some of the specific issues Socioeconomic, policy and legal context Ethics, equity and human rights Implementation considerations for key recommendations: raising the CD4 threshold for initiating ART in adults from 350 to 500 cells/mm3 Section 10.3.4 Section 10.4.1 Section 10.6; Box 10.2

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 4.4 (continued) Chapter Chapter 11: Monitoring and evaluation Annexes Topic Monitoring implications of new recommendations Chapter subsections Section 11.2

Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children Annex 7: Dosages of recommended antiretroviral drugs

Chapter 12

HIV diagnosis and ARV drugs for HIV prevention

clinical guidelines across the continuum of care:

5.1 HIV testing and counselling 66 5.1.1 Introduction 66 5.1.2. HIV testing and counselling in health facilities 67 5.1.3 Community-based HIV testing and counselling 68 5.1.4 HIV testing and counselling in specific populations 70 5.2 HIV prevention based on ARV drugs 80 5.2.1 Oral pre-exposure prophylaxis 80 5.2.2 ART for prevention among serodiscordant couples 81 5.2.3 Post-exposure prophylaxis for occupational and non-occupational exposure to HIV 81 5.2.4 Combination HIV prevention 82

Goal of this chapter To provide a summary of existing and new evidence-based clinical recommendations outlining a public health approach to diagnosing HIV infection and providing ARV drugs for prevention in the context of the broad continuum of HIV care, with a focus on settings with limited health system capacity and resources.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

5. C linical GUIDELINES across the continuum of care: HIV DIAGNOSIS AND ARV DRUGS FOR HIV PREVENTION 5.1 HIV testing and counselling 5.1.1 Introduction People access HIV treatment, care and prevention through the gateway of HIV testing and counselling. It is currently estimated globally that about half of the people living with HIV do not know their HIV status. The people who do know often test late, and poor linkages from HIV testing and counselling to care – including failure to assess rapidly for ART eligibility – mean that many people start treatment when they are already significantly immunocompromised, resulting in poor health outcomes and ongoing HIV transmission. The overall HIV testing and counselling goal for a national HIV programme should be to identify as many people living with HIV as early as possible after acquiring HIV infection, and link them appropriately and in a timely manner to prevention, care and treatment services. The people tested who are not infected should be linked to appropriate prevention services, such as voluntary male medical circumcision in the priority countries in sub-Saharan Africa, or harm reduction services for those who use drugs, and encouraged to retest at a later time. Diverse models of HIV testing and counselling services are available to increase access to HIV diagnosis, including testing services in health care facilities, freestanding sites and a wide range of community-based approaches. These are described in detail in the WHO 2012 strategic HIV testing and counselling framework (1) . The use of rapid HIV diagnostic tests that can be used at point of care has become an important strategy to expand access, increase the return of same-day results and enable appropriate referral and follow-up. Countries should choose a strategic mix of service delivery models to achieve equitable access to HIV testing and counselling, based on the local context, the nature of the epidemic, cost–effectiveness and available resources. The mix should facilitate diagnosing as many people living with HIV as early as possible to enable timely linkage to ART. Strategies should be able to reach the people who are most vulnerable, most-at-risk and marginalized (Box 5.1). The use of a single HIV test to diagnose HIV infection is not sufficient; it must be confirmed by following the steps outlined in the updated WHO 2012 HIV testing strategies (algorithms) (1) . Quality assurance systems should be put in place to minimize false-positive and false-negative results. Failure to do this will lead to people being given incorrect test results, with potential serious adverse long-term consequences. Quality assurance and quality improvement measures are also important for the counselling process to ensure that HIV testing and counselling is always conducted in an acceptable and effective manner.

5. HIV testing and counselling

1 Introduction 5.1 HIV testing and counselling

Box 5.1 HIV testing and counselling: guiding principles All forms of HIV testing and counselling should be voluntary and adhere to the five C’s: consent, confidentiality, counselling, correct test results and connections to care, treatment and prevention services. Mandatory or coerced testing is never appropriate, whether that coercion comes from a health care provider or from a partner or family member. The following key principles apply to all models of HIV testing and counselling and in all circumstances. People receiving HIV testing and counselling must give informed consent (verbal consent is sufficient and written consent is not required) to be tested and counselled. They should be informed of the process for HIV testing and counselling and their right to decline testing. HIV testing and counselling services are confidential, meaning that what the HIV testing and counselling provider and the person discuss will not be disclosed to anyone else without the expressed consent of the person being tested. Although confidentiality should be respected, it should not be allowed to reinforce secrecy, stigma or shame. Counsellors should raise, among other issues, whom else the person may wish to inform and how they would like this to be done. Shared confidentiality with a partner or family members and trusted others and with health care providers is often highly beneficial. HIV testing and counselling services must be accompanied by appropriate and high quality pre-test information (which can be provided as group pre-test information in some settings) and post-test counselling. Quality assurance mechanisms and supportive supervision and mentoring systems should be in place to ensure the provision of high-quality counselling. HIV testing and counselling providers should strive to provide high-quality testing

services, and quality assurance mechanisms should be in place to ensure the provision of correct test results. Quality assurance may include both internal and external measures and should include support from the national reference laboratory as needed. Connections to prevention, care and treatment services should include the provision of effective referral to appropriate follow-up services as indicated, including longterm prevention and treatment support. Quality assurance of both testing and counselling is essential in all approaches used.

5.1.2 H IV testing and counselling in health facilities Background WHO recommends routinely offering HIV testing and counselling in clinical settings (known as provider-initiated testing and counselling) as an efficient and effective way to identify people with HIV who could benefit from treatment.

Source for recommendations: G uidance on provider-initiated HIV testing and counselling in health facilities. Geneva, World Health Organization, 2007 (http://whqlibdoc.who.int/ publications/2007/9789241595568_eng.pdf) (2) .

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Existing recommendations (2) In generalized epidemics, provider-initiated testing and counselling should be recommended to everyone (adults, adolescents and children) attending all health facilities, including medical and surgical services; sexually transmitted infection, hepatitis and TB clinics; public and private facilities; inpatient and outpatient settings; mobile or outreach medical services; services for pregnant women (antenatal care, family planning and maternal and child health settings); services for key populations; services for infants and children; and reproductive health services. In concentrated and low-level epidemics, provider-initiated testing and counselling should be recommended in all health facilities for: adults, adolescents or children who present in clinical settings with signs and symptoms or medical conditions that could indicate HIV infection, including TB; and HIV-exposed children, children born to women living with HIV and symptomatic infants and children. Provider-initiated testing and counselling should be considered in sexually transmitted infection, hepatitis and TB services, antenatal care settings and services for key populations (notably men who have sex with men, transgender people, sex workers and people who inject drugs).

5.1.3 Community-based HIV testing and counselling In addition to providing HIV testing and counselling in clinical settings, HIV testing and counselling can be offered in a variety of settings in the community. New

New recommendations (2013)

linkage to prevention, care and treatment services is recommended, in addition to provider-initiated testing and counselling (strong recommendation, low-quality evidence). In all HIV epidemic settings, community-based HIV testing and counselling for key populations, with linkage to prevention, care and treatment services is recommended, in addition to provider-initiated testing and counselling ( strong recommendation, low-quality evidence).

In generalized HIV epidemics, community-based HIV testing and counselling with

Background These guidelines include expanded criteria for eligibility for ART for children, adolescents, adults and pregnant and breastfeeding women living with HIV. To maximize the individual and public health benefits of these recommendations, people living with HIV must be diagnosed and linked to care early in the course of HIV infection. Although facility-based testing is a key approach, people living with HIV are often identified late in the course of HIV disease in clinical settings, and some populations, including men and adolescents, and especially key populations, have low utilization of health care services. Community-based

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

testing approaches may reach people with HIV earlier in the course of HIV disease than provider-initiated testing and counselling, as well as reaching populations that may not normally attend health services. The use of rapid HIV diagnostic tests using blood from a finger-prick sample taken by trained lay counsellors and community health workers has facilitated the expansion of HIV testing and counselling in community settings including homes, transport stations, religious facilities, schools, universities, workplaces and venues frequented by key populations. Continued expansion of community-based testing to complement facilitybased testing is an important consideration in achieving universal knowledge of HIV status and earlier diagnosis linked to care and treatment. Community-based HIV testing and counselling includes using mobile, door-to-door, index, campaign, workplace and schoolbased HIV testing and counselling approaches (1) .

5.1 HIV testing and counselling

Rationale and supporting evidence The recommendations are based on evidence and on operational and programmatic considerations. The systematic review identified four randomized studies (3,4) and eight observational studies (5–10) comparing community-based testing to facility-based testing in generalized epidemics (Web Annex: www.who.int/hiv/pub/guidelines/arv2013/ annexes). Overall, community-based approaches had increased rates of people testing for the first time and adults diagnosed with CD4 counts exceeding 350 cells/mm 3. However, the frequency of positive test results was higher in health facility–based testing than in many community settings. The systematic review found that HIV testing and counselling coverage at the district level increased as a result of offering community-based HIV testing and counselling (using either door-to-door or mobile approaches) in combination with facility-based HIV testing and counselling. An additional review covering key populations identified three studies comparing community-based testing to facility-based testing in key populations (11–13) . Although increased uptake was observed in community-based approaches, the rate of participants receiving their first HIV test was comparable in both the community- and facility-based approaches. Fifteen studies examined potential negative consequences of community-based testing (10,14–25) . These studies discussed both the clients’ positive testing experiences and their fears. Eight articles reported that a minority of participants refused HIV testing and counselling because of fear of status disclosure or stigma (10,14–17,21,23,25) . The studies did not demonstrate that community-based approaches either reduced stigma or fear or increased them or other harms. The few studies comparing the cost per person tested using facility- and community-based testing found that the cost per person tested was similar in both approaches (Web Annex: www.who.int/hiv/pub/guidelines/arv2013/annexes). Although the review provided low-quality evidence overall, there was consensus that the critical programmatic advantages of community-based HIV testing and counselling and an assessment of values, preferences, costs and feasibilities provided sufficient basis for the Guideline Development Group to propose strong recommendations. Community-based testing should be implemented in addition to provider-initiated testing and counselling. Multiple approaches are needed, which may include standalone sites, home-based testing, mobile outreach (including in workplaces, schools, universities, special testing campaigns and events) and multi-disease campaigns tailored to epidemiological and social contexts.

New

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

5.1.4 HIV testing and counselling in specific populations 5.1.4.1 Couples Background Studies in several countries have shown that couples HIV testing and counselling is acceptable, feasible and effective. It can identify seroconcordant positive couples who can be linked to treatment and receive treatment adherence support. It also identifies couples with serodiscordant HIV test results who can benefit from HIV prevention interventions. Services should be offered to married and cohabiting couples, premarital couples, polygamous unions and any other partnerships. As with all HIV testing and counselling approaches, couples HIV testing and counselling should be voluntary. Health providers must be aware of the potential for intimate partner–based violence and should support individuals when they do not want to test with their partners. Couples HIV testing and counselling can be offered in all settings where HIV testing and counselling is provided, including antenatal care and TB services. Support to encourage the testing of the partners of people living with HIV is also an efficient and effective way of identifying additional people living with HIV, who then can benefit from treatment. Further, couples HIV testing and counselling can be an important intervention to increase access to earlier ART and reach more men with treatment. Offering family counselling and testing to couples where one or both are living with HIV can identify children, adolescents and other household members who have not previously been diagnosed.

Source for recommendations: Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/publications/2012/9789241501972_eng.pdf) (26).

Existing recommendations (26) Couples and partners should be offered voluntary HIV testing and counselling with support for mutual disclosure (strong recommendation, low-quality evidence) . Couples and partners in antenatal care settings should be offered voluntary HIV testing and counselling with support for mutual disclosure (strong recommendation, low-quality evidence) . Couples and partner voluntary HIV testing and counselling with support for mutual disclosure should be offered to individuals with known HIV status and their partners (strong recommendation, low-quality evidence for all people with HIV in all epidemic settings; conditional recommendation, low-quality evidence for HIV-negative people depending on the country-specific HIV prevalence) .

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

5.1.4.2 Pregnant and postpartum women Background Provider-initiated testing and counselling for pregnant women and linkage to prevention and care are needed to promote the mother’s health and prevent new paediatric infections and can contribute to a strategy for couples testing.

5.1.4 HIV testing and counselling in specific populations

Source for recommendations: Guidance on provider-initiated HIV testing and counselling in health facilities. Geneva, World Health Organization, 2007 (http://www.who.int/hiv/pub/vct/pitc2007/en) (2).

Existing recommendations (2) Generalized epidemics Provider-initiated testing and counselling is recommended for women as a routine component of the package of care in all antenatal, childbirth, postpartum and paediatric care settings. delivery, because of the high risk of acquiring HIV infection during pregnancy.

Re-testing is recommended in the third trimester, or during labour or shortly after

Low-level and concentrated epidemics Provider-initiated testing and counselling should be considered for pregnant women. Many countries prioritize provider-initiated testing and counselling in antenatal care as a key component of their effort to eliminate the mother-to-child transmission of HIV and are effectively bundling HIV testing with syphilis screening, hepatitis testing or other key tests relevant to the setting as well as strengthening the underlying maternal and child health system.

5.1.4.3 Infants and children Background HIV-exposed infants and children younger than 18 months should be tested within four to six weeks of birth so that those already infected with HIV can start ART. Mortality is very high among untreated infants infected with HIV in the first year of life, making early HIV testing, prompt return of results and rapid initiation of treatment essential. In this population, HIV infection can only be definitively confirmed using virological tests because of the presence of persisting maternal HIV antibody in the child up to 15–18 months of age. Virological tests include assays to detect viral nucleic acid (HIV DNA, RNA or total nucleic acid) or p24 antigen. Currently, virological testing is most commonly performed on dried blood spot (DBS) specimens, with collection at local sites and transport and testing at centralized laboratories. While early testing is increasing, there are ongoing challenges of access, return of results and initiation of early treatment in infants testing positive. Point-of-care virological testing, in development, is expected to greatly improve early diagnosis and treatment. Because some infants are not identified as HIV-exposed or are lost to postpartum follow-up, provider-initiated

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

testing and counselling should be implemented in infant care settings for additional casefinding. Final diagnosis (or definitive diagnosis) at the end of the risk period for motherto-child transmission (breastfeeding period) should be ensured. A negative HIV antibody test in a known HIV-exposed infant can be useful to exclude HIV infection if there is no ongoing exposure. (See Annex 5 for the algorithm on HIV diagnosis in children less than 18 months of age.) For children 18 months of age and older (who are not breastfeeding or who stopped breastfeeding at least six weeks earlier), standard HIV serological tests such as rapid diagnostic tests can be used to reliably determine HIV infection status. WHO recommends provider-initiated testing and counselling for all children who are malnourished, have TB, are admitted to hospital or have other signs or symptoms of HIV infection. Other approaches such as testing all children in childhood vaccination programmes have been implemented in some settings to increase chances of finding HIV-infected children. The recommendations on diagnosis of HIV infection in infants and children will be reviewed in the coming year.

Table 5.1 Summary of recommended testing approaches for infants (27) Category Well, HIVexposed infant Infant – unknown HIV exposure Well, HIVexposed infant at 9 months Test required Virological testing at 4–6 weeks of age Maternal HIV serological test or infant HIV serological test HIV serological test (at last immunization, usually 9 months) Purpose To diagnose HIV To identify or confirm HIV exposure To identify infants who have persisting HIV antibody or have seroreverted Action Start ART if HIVinfected Need virological test if HIV-exposed Those HIV seropositive need virological test and continued follow up; those HIV negative, assume uninfected, repeat testing required if still breastfeeding Perform virological test if <18 months of age

Infant or child with signs and symptoms suggestive of HIV infection Well or sick child seropositive >9 months and <18 months Infant or child who has completely discontinued breastfeeding

HIV serological test

To confirm exposure

Virological testing

To diagnose HIV

Reactive – start HIV care and ART

Repeat testing six weeks or more after breastfeeding cessation – usually initial HIV serological testing followed by virological testing for HIV-positive child and <18 months of age

To exclude HIV infection after exposure ceases

Infected infants and children <5 years of age, need to start HIV care, including ART

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

Source for recommendations: WHO recommendations on the diagnosis of HIV infection in infants and children. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599085_eng.pdf) (27)

5.1 HIV testing and counselling in specific populations

Guideline on HIV disclosure counselling for children up to 12 years of age, Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502863_ eng.pdf) (28).

Existing recommendations (27) It is strongly recommended that all infants with unknown or uncertain HIV exposure being seen in health care facilities at or around birth or at the first postnatal visit (usually 4–6 weeks), or other child health visit, have their HIV exposure status ascertained (strong recommendation – high-quality evidence). It is strongly recommended that all HIV-exposed infants have HIV virological

testing at four to six weeks of age or at the earliest opportunity thereafter (strong recommendation, high-quality evidence). For infants with an initial positive virological test result, it is strongly recommended that ART be started without delay and, at the same time, a second specimen be collected to confirm the initial positive virological test result. Do not delay ART. Immediate initiation of ART saves lives and should not be delayed while waiting for the results of the confirmatory test (strong recommendation, high-quality evidence). It is strongly recommended that infants with signs or symptoms suggestive of HIV infection undergo HIV serological testing and, if positive (reactive), virological testing (strong recommendation – low-quality evidence). testing at around nine months of age (or at the time of the last immunization visit). Infants who have reactive serological assays at nine months should have a virological test to identify HIV-infected infants who need ART (strong recommendation, low-quality evidence).

It is strongly recommended that well, HIV-exposed infants undergo HIV serological

HIV infection or HIV exposure, have HIV serological testing performed according to the standard diagnostic HIV serological testing algorithm used in adults (strong recommendation, high-quality evidence).

It is strongly recommended that children 18 months of age or older with suspected

Existing recommendation (28) Children of school age should be told their HIV-positive status and their parents or caregiver’s status; younger children should be told their status incrementally to accommodate their cognitive skills and emotional maturity, in preparation for full disclosure (strong recommendation, low-quality evidence).

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

5.1.4.4 Adolescents Background Adolescents are often underserved and given insufficient priority in many HIV programmes, with poor access to and uptake of HIV testing and counselling and linkage to prevention and care. Adolescents with HIV include those surviving perinatal infection and those newly acquiring infection as they become sexually active or are exposed through injecting drug use, other unsafe injections and blood transfusions. In generalized epidemic settings, many vertically infected infants are not diagnosed through programmes for PMTCT and would benefit from earlier HIV diagnosis and treatment. In many settings, adolescent girls and adolescents from key populations are also vulnerable to HIV infection and would benefit from access to acceptable and effective HIV services, including HIV testing and counselling. Consent issues may pose a barrier to access for adolescents in some settings and are discussed in detail in the WHO 2013 guidelines for adolescents (29).

Source for recommendations: Guidance on HIV testing and counselling for adolescents and care for adolescents living with HIV. Geneva, World Health Organization, 2013, in press (29).

New recommendations (2013) (29)

New

recommended for adolescents from key populations in all settings (generalized, low and concentrated epidemics) (strong recommendation, very-low-quality evidence) . HIV testing and counselling with linkage to prevention, treatment and care is recommended for all adolescents in generalized epidemics (strong recommendation, very-low-quality evidence) . We suggest that HIV testing and counselling with linkage to prevention, treatment and care be accessible to all adolescents in low and concentrated epidemics (conditional recommendation, very-low-quality evidence). of disclosure of their HIV status and empowered and supported to determine if, when, how and to whom to disclose (conditional recommendation, very-lowquality evidence). We suggest that adolescents be counselled about the potential benefits and risks

HIV testing and counselling, with linkages to prevention, treatment and care, is

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

Rationale and supporting evidence These recommendations were developed as part of new HIV guidelines for adolescents from WHO, UNESCO, UNFPA, UNICEF and GNP+ published in 2013 and are based on systematic reviews of the evidence, community consultations to assess values and preferences of adolescents and health providers and consideration by the respective Guideline Development Group. For the most part, published evidence for adolescent-specific recommendations is lacking; for these guidelines, considerable weight is given to expert opinion, values and preferences of adolescents and their health care providers, and to the field experience of practitioners. Further details are provided in the summary of evidence in the full Guidance on HIV testing and counselling for adolescents and care for adolescents living with HIV (29).

5.1.4 HIV testing and counselling in specific populations

5.1.4.5 Key populations Background HIV testing and counselling has been provided to key populations since HIV tests were first developed. WHO produced guidance for testing people who inject drugs in 2006, for prisoners and refugees in 2009, for men who have sex with men and for transgender people in 2011 and for sex workers in 2012. For key populations, especially those who are criminalized, HIV testing and counselling services are sometimes used in punitive or coercive ways. Both existing and new recommendations for HIV testing and counselling for these most-at-risk and vulnerable groups therefore emphasize consent and confidentiality as well as ensuring that HIV testing and counselling is part of a comprehensive prevention, care and treatment programme. The 2012 WHO HIV testing and counselling strategic framework (1) summarizes HIV testing and counselling for all of these groups and populations (Tables 5.2 and 5.3).

Additional guidance: Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/77745/1/9789241504744_eng.pdf) (33) . Prevention and treatment of HIV and other sexually transmitted infections among men who have sex with men and transgender people: recommendations for a public health approach. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/ publications/2011/9789241501750_eng.pdf) (34) .

New

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 5.2 Summary of HIV testing and counselling recommendations for generalized epidemics Who to test Everyone attending health facilities When to test Integrate in all health care encounters Where to test All settings, including primary health care, outpatient medical and surgical wards, antenatal care and maternal and child health, TB, family planning and sexually transmitted infection clinics Primary health care settings, voluntary counselling and testing sites, ART clinics, antenatal care, family planning clinics, sexually transmitted infection clinics, community and mobile outreach, home Primary health care settings, ART clinics, maternal and child health and antenatal care settings, homes and community and mobile outreach Primary health care settings, sexually transmitted infections clinics and outreach services, including harm reduction and other sites providing services to key populations Relevant WHO guidance

Guidance on provider-initiated HIV testing and counselling in health facilities (2)

Partners and couples

Premarital, pregnancy, after separations, new partnerships and at the start of care and ART For the HIV-negative person in serodiscordant couples, offer re-testing every 6–12 months

Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26) Delivering HIV test results and messages for re-testing and counselling in adults (30) Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Planning, implementing and monitoring home-based HIV testing (31) Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach (32) Prevention and treatment of HIV and other sexually transmitted infections among men who have sex with men and transgender people: recommendations for a public health approach (33) Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Delivering HIV test results and messages for re-testing and counselling in adults (30)

Families of index cases

As soon as possible after the family member is diagnosed

Key populations: people who inject drugs, men who have sex with men, transgender people, sex workers, prisoners, and partners of people who inject drugs

Every 6–12 months

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

Table 5.2 (continued) Who to test Pregnant women and male partners When to test At first antenatal care visit Re-test in third trimester or peripartum Offer partner testing Where to test Antenatal care, delivery, postpartum Relevant WHO guidance

5.1 HIV testing and counselling in specific populations

Guidance on provider-initiated HIV testing and counselling in health facilities (2) Delivering HIV test results and messages for re-testing and counselling in adults (30) Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26)

Infants and children <18 months old

Early infant diagnosis at 4–6 weeks for all infants whose mothers are living with HIV or if maternal HIV status is unknown; determine the final infant HIV infection status after 18 months and/or when breastfeeding ends Establish HIV status for all health contacts Integrate into all health care encounters Annually if sexually active; with new sexual partners

Maternal and child health services Paediatric clinics Immunization clinics

WHO recommendations on the diagnosis of HIV infection in infants and children (27)

Children

Child inpatients and outpatients, immunization clinics Primary health care, outpatients, inpatients, voluntary counselling and testing sites, youthfriendly services, family planning and sexually transmitted infections clinics

Guidance on provider-initiated HIV testing and counselling in health facilities (2) Delivering HIV test results and messages for re-testing and counselling in adults (30) Guidelines on HIV testing and counselling for adolescents and care and treatment for adolescents living with HIV (29)

Adolescents

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 5.3 Summary of HIV testing and counselling recommendations for lowlevel and concentrated epidemics Who to test People with signs or symptoms of HIV infection Partners of people with HIV When to test Integrate in health care encounter Where to test Sexually transmitted infection clinics, TB clinics, medical wards, other clinics Clinical settings including primary health care settings, ART, TB, sexually transmitted infection clinics, voluntary counselling and testing Relevant WHO guidance

Guidance on provider-initiated HIV testing and counselling in health facilities (2) Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26) Delivering HIV test results and messages for re-testing and counselling in adults (30) Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Planning, implementing and monitoring home-based HIV testing (32) Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26)

As soon after partner diagnosis as possible For the negative person in serodiscordant couples, offer retesting every 6–12 months As soon as possible after the family member is diagnosed

Families of index cases

ART clinics, maternal and child health and antenatal care settings, homes, community outreach

Key populations: people who inject drugs, men who have sex with men, transgender people and sex workers

Every 6–12 months

Sexually transmitted infection clinics, outreach services for key populations and harm-reduction services

Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach (32) Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Delivering HIV test results and messages for re-testing and counselling in adults (30)

Pregnant women

At the first antenatal care visit

Antenatal care

Guidance on provider-initiated HIV testing and counselling in health facilities (2)

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

Table 5.3 (continued) Who to test Infants and children <18 months old When to test Early infant diagnosis at 4-6 weeks for all infants whose mothers are living with HIV or if maternal HIV status is unknown; determine the final infant HIV infection status after 18 months and/or when breastfeeding ends Integrate in health care encounter Where to test Maternal and child health services Paediatric clinics Immunization clinics Relevant WHO guidance

5.1 HIV testing and counselling in specific populations

WHO recommendations on the diagnosis of HIV infection in infants and children (27)

Children with signs or symptoms of HIV infection or who have a family member living with HIV

In all health settings

Guidance on provider-initiated HIV testing and counselling in health facilities (2)

Adolescents from key populations

Every 6–12 months

Youth-friendly services, sexually transmitted infection clinics, outreach

Delivering HIV test results and messages for re-testing and counselling in adults (30) Guidelines on HIV testing and counselling for adolescents and care and treatment for adolescents living with HIV (29)

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

5.2 HIV prevention based on ARV drugs1 5.2.1 Oral pre-exposure prophylaxis Background Oral pre-exposure prophylaxis of HIV (PrEP) is the daily use of ARV drugs by HIV-uninfected people to block the acquisition of HIV. Clinical trials of daily oral PrEP have shown evidence of effectiveness with serodiscordant heterosexual couples (35) , men and transgender women who have sex with men (36) , high risk heterosexual couples (37) , people who inject drugs (38).

Source for recommendations: Guidance on oral pre-exposure prophylaxis (PrEP) for serodiscordant couples, men and transgender women who have sex with men at high risk of HIV: recommendations for use in the context of demonstration projects. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75188/1/9789241503884_eng.pdf) (39).

Existing recommendations (39) Existing WHO recommendations (39) are for the use of oral PrEP in demonstration projects for serodiscordant couples and men and transgender women who have sex with men.

S erodiscordant couples. When serodiscordant couples are identified and where additional HIV prevention choices for them are needed, daily oral pre-exposure prophylaxis (either TDF or the combination of TDF + FTC) may be considered as a possible additional intervention for the uninfected partner (conditional recommendation, high-quality evidence). If oral pre-exposure prophylaxis is to be provided for the HIV-negative partner in same-sex, male serodiscordant couples, the combination of TDF + FTC should be used, as evidence of effectiveness and safety in male-to-male penetrative sex is available for this regimen only.

Men and transgender women . Where HIV transmission occurs among men and transgender women who have sex with men and additional HIV prevention choices for them are needed, daily oral pre-exposure prophylaxis (specifically the combination of TDF + FTC) may be considered as a possible additional intervention (conditional recommendation, high-quality evidence).

Chapter 7 covers other aspects of ARV drugs as prevention, including PMTCT.

5. Clinical guidelines across the continuum of care: HIV diagnosis and ARV drugs for HIV prevention

5.2.2 ART for prevention among serodiscordant couples Source for recommendations: Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples. Geneva, World Health Organization, 2012 (http:// whqlibdoc.who.int/publications/2012/9789241501972_eng.pdf) (26).

5.2 HIV prevention based on ARV drugs

Existing recommendations (26) People with HIV in serodiscordant couples who start ART for their own health should be advised that ART is also recommended to reduce HIV transmission to the uninfected partner (strong recommendation, high-quality evidence) . H IV-positive partners with a CD4 count ≥ 350 cells/mm 3 in serodiscordant couples should be offered ART to reduce HIV transmission to uninfected partners (strong recommendation, high-quality evidence) .

5.2.3 P ost-exposure prophylaxis for occupational and non-occupational exposure to HIV Background Post-exposure prophylaxis is short-term ART to reduce the likelihood of acquiring HIV infection after potential exposure either occupationally or through sexual intercourse. Within the health sector, post-exposure prophylaxis should be provided as part of a comprehensive package of universal precautions that reduces the exposure of personnel to infectious hazards at work. WHO post-exposure prophylaxis guidelines for occupational exposure have not been reviewed since 2006 and will be updated by 2014. The current recommended duration of post-exposure prophylaxis for HIV infection is 28 days, and the first dose should be offered as soon as possible within 72 hours after exposure. The choice of post-exposure prophylaxis drugs should be based on the country’s first-line ART regimen for HIV. A recent recommendation (40) relates specifically to post-exposure prophylaxis in the case of sexual assault.

Source for recommendation: Responding to intimate partner violence and sexual violence against women: clinical and policy guidelines. Geneva, World Health Organization, in press (40).

Existing recommendation (2013) (40) Consider HIV post-exposure prophylaxis for women presenting within 72 hours of a sexual assault. Use shared decision-making with the survivor to determine whether HIV post-exposure prophylaxis is appropriate (strong recommendation, very-low-quality evidence).

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

5.2.4 Combination HIV prevention Background People’s HIV prevention needs change during their lifetime, and a combination approach helps people to access the types of interventions that best suit their needs at different times. Combining approaches may also result in synergies that have greater impact than single interventions alone. Although ARV drugs play a key role in HIV prevention, they should be used in combination with an appropriate mix of the following. Other biomedical interventions that reduce HIV risk practices and/or the probability of HIV transmission per contact event, including the following. •

M ale and female condoms. Male condoms reduce heterosexual transmission by at least 80% and offer 64% protection in anal sex among men who have sex with men (41) , if used consistently and correctly. Fewer data are available for the efficacy of female condoms, but evidence suggests they can have a similar prevention effect (42). N eedle and syringe programmes are highly associated with a reduction in HIV transmission through injecting drug use (43). O pioid substitution therapy with methadone or buprenorphine is the most effective form of treatment for opioid dependence and has the additional benefit of effectively reducing HIV risk behaviour and transmission through injecting drug use. Opioid substitution therapy also provides adherence support to people on ART (44-45). V oluntary medical male circumcision reduces acquisition of infection and the risk of acquisition for men by up to 66% and offers significant lifelong protection (4).

• •

•

Behavioural interventions reduce the frequency of potential transmission events, including the following. •

T argeted information and education. Programmes that use various communication approaches – for example, school-based sex education, peer counselling and community-level and interpersonal counselling – to disseminate behavioural messages designed to encourage people to reduce behaviour that increases the risk of HIV and increase the behaviour that is protective (such as safer drug use, delaying sexual debut, reducing the frequency of unprotected sex with multiple partners, using male and female condoms correctly and consistently and knowing your and your partner’s HIV status).

Structural and supportive interventions affect access to, uptake of and adherence to behavioural and biomedical interventions. Such interventions address the critical social, legal, political and environmental enablers that contribute to HIV transmission, including legal and policy reform, measures to reduce stigma and discrimination, the promotion of gender equality and prevention of gender-based violence, economic empowerment, access to schooling and supportive interventions designed to enhance referrals, adherence, retention and community mobilization.

Clinical guidelines across THE CONTINuUM OF CARE:

LINKING PEOPLE DIAGNOSEd WiTH hiv infection to hiv care and treatment

6.1 Introduction 84 6.2 Good practices for linkage to care 84 6.3 General care for people living with HIV 84 6.4 Preparing people living with HIV for ART 87 6.5 What to expect in the first months of ART 88

Goal of this chapter To provide an overview of issues and interventions related to general HIV care for individuals from the time that they are diagnosed with HIV infection to the time that they are initiated on ART, including practices for linking people diagnosed with HIV infection to HIV care and treatment, the components of a general care package, and preparing individuals for starting ART.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

6. Th e continuum of care: linking people diagnosed with HIV infection to HIV care and treatment 6.1 Introduction It is critical for people living with HIV to enrol in care as early as possible. This enables both early assessment of their eligibility for ART and timely initiation of ART as well as access to interventions to prevent the further transmission of HIV, prevent other infections and comorbidities and thereby to minimize loss to follow-up. The 2012 WHO strategic HIV testing and counselling programme framework (1) especially emphasizes the importance of ensuring linkage between HIV testing and counselling programmes and prevention, treatment, care and support services.

6.2 Good practices for linkage to care Interventions to improve linkage to care need to be more rigorously evaluated. However, several systematic reviews and observational studies suggest that several good practices can improve linkage to care (2–4). These include integrating HIV testing and counselling and care services; providing on-site or immediate CD4 testing with same-day results; assisting with transport if the ART site is far from the HIV testing and counselling site; involving community outreach workers to identify the people lost to follow-up; ensuring support from peers or expert patients; and using new technologies, such as mobile phone text messaging.

6.3 General care for people living with HIV Countries should establish a package of general HIV care interventions, in addition to ART, for people living with HIV to reduce HIV transmission, prevent illness and improve their quality of life. Not all people living with HIV are eligible for ART and, of those eligible, not all will be able to access ART immediately. Others may choose to defer ART to later. Enrolment in care provides an opportunity for close clinical and laboratory monitoring and early assessment of eligibility for ART and timely initiation, and aims to minimize loss to follow-up. Many care interventions are relevant across the full continuum of care, including HIV-exposed individuals and people living with HIV before initiating, and during ART. General care includes basic HIV prevention, promoting the health of people living with HIV and the screening, prophylaxis and management of HIV-related coinfections and comorbidities. WHO has produced summary guidance on general care and prevention interventions (5–7) , and in 2008, recommended a package of 13 prevention interventions for adults and adolescents living with HIV in resource-limited settings (5). These include (1) psychosocial counselling and support; (2) disclosure and partner notification; (3) co-trimoxazole prophylaxis; (4) TB counselling, screening and preventive therapy; (5) preventing common fungal infections; (6) preventing sexually transmitted infections and supporting reproductive health needs, including prevention of and screening for cervical cancer; (7) malaria (co-trimoxazole, bed-nets and preventing malaria among pregnant women); (8) selected vaccine-preventable diseases; (9) nutrition; (10) family planning; (11) PMTCT; (12) needle and syringe programmes for people

6. The continuum of care: linking people diagnosed with HIV infection to HIV care and treatment

who inject drugs; and (13) water, sanitation and hygiene. A general care package will vary according to the epidemic type, populations affected and prevalence of coinfections, other comorbidities and health conditions. Table 6.1 provides an overview of elements of a general care package for people living with HIV. Section 8.1 summarizes key recommendations from existing WHO guidelines on the screening, prophylaxis and timing of ART with the most common coinfections, comorbid conditions and other health conditions.

6. The continuum of care: linking people diagnosed with HIV infection to HIV care and treatment

Table 6.1 Overview of key elements of general care over the continuum of HIV care for people living with HIV Service At HIV diagnosis At At Stable enrolment initiation while into care of ART receiving ART At treatment failure and switching ART regimen Comment and crossreferences

General care WHO clinical staging Past and current HIVrelated conditions Pregnancy status Family planning and Contraception PMTCT Support for disclosure and partner notification Risk reduction counselling and combination HIV prevention approaches Screening for, preventing and managing comorbidities and noncommunicable diseases Screening for and managing mental health problems and substance use Psychosocial counselling and support ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Section 8.2.6.1 Sections 7.1.2 and 7.2.2 Section 5.1.4 ✓ ✓ ✓ Annex 1

✓

Section 5.2.4

✓

Section 8.2.1

✓

Sections 8.2.2 and 8.2.3

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 6.1 (continued) Service At HIV diagnosis At At Stable enrolment initiation while into care of ART receiving ART At treatment failure and switching ART regimen Comment and crossreferences

General care Managing pain and symptoms Nutritional assessment and counselling Nutritional, growth and development assessment in children and adolescents Infant and child feeding Preventing and treating coinfections Co-trimoxazole preventive therapy Intensified TB casefinding Isoniazid preventive therapy Screening for cryptococcal infection and fungal prophylaxis Screening for hepatitis B and C Malaria prevention (insecticide-treated bed-nets and prophylaxis) Screening for sexually transmitted infections Prevention of and screening for cervical cancer ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Section 8.1.1 Section 8.1.2 Section 8.1.2 Section 8.1.3 ✓ ✓ ✓ ✓ ✓ ✓ Section 8.2.5 Section 8.2.4

✓

Sections 7.1.3 and 8.2.4

✓

Section 8.1.4

✓

Section 8.1.5

✓

✓ ✓

Section 8.1.6 Section 8.1.7

6. The continuum of care: linking people diagnosed with HIV infection to HIV care and treatment

Table 6.1 (continued) Service At HIV diagnosis At At Stable enrolment initiation while into care of ART receiving ART At treatment failure and switching ART regimen ✓ Comment and crossreferences

6.4 Preparing people living with HIV for ART

Assessing for vaccine-preventable diseases Preparing people for ART Preparing, assessing and supporting adherence Current medications

✓

Section 8.1.7

✓

✓ ✓ ✓ ✓

Section 6.4 Sections 6.4 and 9.2 See section 7.4.6

✓

6.4 Preparing people living with HIV for ART Before people start ART, it is important to have a detailed discussion with them about their willingness and readiness to initiate ART, the ARV regimen, dosage and scheduling, the likely benefits and possible adverse effects and the required follow-up and monitoring visits. For children with HIV, this conversation should directly involve the carer and include discussion about disclosing their HIV status (see Chapter 5). Retesting all people living with HIV before initiating ART is good practice to ensure correct diagnosis of HIV infection. Initiation of ART should always consider nutritional status, any comorbidities and potentially interacting medications for possible contraindications or dose adjustment. The choice to accept or decline ART ultimately lies with the individual person or his or her caretaker, and if they choose to defer initiation, ART can be offered again at subsequent visits. If there are mental health, substance use or other problems that are major barriers to adherence, appropriate support should be provided, and readiness to initiate ART should be reassessed at regular intervals. A wide range of patient information materials as well as community and peer support can help the person’s readiness and decision to start therapy. People starting treatment and carers should understand that the first ART regimen offers the best opportunity for effective viral suppression and immune recovery, and that successful ART requires them to take the medications exactly as prescribed. They should be advised that many adverse effects are temporary or may be treated, or that substitutions can often be made for problematic ARV drugs. (See section 9.2 for strategies to support adherence to an ART regimen.) People receiving ART and carers should also be asked regularly about any other medications they take, including herbal remedies and nutritional supplements. People receiving ART should understand that, while the ARV drugs reduce the risk of HIV transmission, they cannot be relied on to prevent other people from acquiring infection. They should be given advice on safer sex (including condom use) and avoidance of other high-risk activities, such as sharing of injecting equipment, to prevent transmitting HIV to other people.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

6.5 What to expect in the first months of ART Although taking ART is a lifelong commitment, the first six months of therapy are especially important. Clinical and immunological improvement and viral suppression are expected when individuals adhere to ART, but opportunistic infections and/or immune reconstitution inflammatory syndrome (IRIS) may develop, as well as early adverse drug reactions, such as drug hypersensitivity, especially in the first three months of ART. ART significantly decreases mortality overall, but death rates are also highest in the first three months of ART. These complications are commonest when the people starting ART already have advanced HIV disease with severe immunodeficiency and existing coinfections and/or comorbidities, severely low haemoglobin, low body mass index and very low CD4 counts or are severely malnourished (8,9) .

CD4 recovery In most adults and children, CD4 cell counts rise when ART is initiated and immune recovery starts. Generally, this increase occurs during the first year of treatment, plateaus, and then continues to rise further during the second year (10) . However, severe immunosuppression may persist in some individuals who do not experience a significant rise in CD4 cell count with treatment, especially those with a very low CD4 cell count when initiating ART. Failure to achieve some CD4 recovery should alert the health care provider to potential adherence problems or primary non-response to ART, and consideration should be given to continue prophylaxis for opportunistic infections such as co-trimoxazole preventive therapy.

Immune reconstitution inflammatory syndrome (IRIS) IRIS is a spectrum of clinical signs and symptoms thought to be associated with immune recovery brought about by a response to ART. It is a widely recognized phenomenon that occurs among 10–30% of the people initiating ART, usually within the first 4–8 weeks after initiating therapy (11,12). It may present in two different ways: paradoxical IRIS, when an opportunistic infection or tumour diagnosed before ART initially responds to treatment but then deteriorates after ART starts; or unmasking IRIS, in which initiating ART triggers disease that is not clinically apparent before ART. It should be considered only when the presentation cannot be explained by a new infection, expected course of a known infection or drug toxicity. The clinical spectrum is diverse, and IRIS has been reported for many different infections, tumours and non-infectious conditions (11,12). The most serious and life-threatening forms of paradoxical IRIS are for TB, cryptococcosis, Kaposi’s sarcoma and herpes zoster. BCG vaccine–associated IRIS (localized and systemic) may occur in infants infected with HIV in settings where BCG immunization is routine. A low CD4 + cell count (<50 cells/mm3 ) at ART initiation, disseminated opportunistic infections or tumours and a shorter duration of therapy for opportunistic infections before ART starts are the main risk factors (11,12). IRIS is generally self-limiting, and interruption of ART is rarely indicated, but people may need to be reassured in the face of protracted symptoms to prevent discontinuation of or poor adherence to ART. The most important steps to reduce the development of IRIS include: earlier HIV diagnosis and initiation of ART before a decline to below 200 CD4 cells/mm3 ; improved screening for opportunistic infections before ART, especially TB and Cryptococcus ; and optimal management of opportunistic infections before initiating ART. Timing of ART in people with opportunistic infections requires balancing a greater risk of IRIS after early initiation against continuing high mortality if ART is delayed. Chapter 8 summarizes existing WHO recommendations for the optimal timing of ART among people with TB (see section 8.1.2) and cryptococcal disease (see section 8.1.3) based on evidence from randomized clinical trials.

CLINICAL GUIDANCE ACROSS the continuum of care:

antiretroviral therapy

7.1 When to start ART 90 7.1.1 When to start ART in adults and adolescents 91 7.1.2 When to start ART in pregnant and breastfeeding women 98 7.1.3 ARV drugs and duration of breastfeeding 102 7.1.4 When to start ART in children 106 7.2 What ART regimen to start with (first-line ART) 110 7.2.1 First-line ART for adults 111 7.2.2 First-line ART for pregnant and breastfeeding women and ARV drugs for their infants 114 7.2.3 First-line ART for children younger than three years of age (including adolescents) 120 7.2.4 First-line ART for children three years and older (including adolescents) 124 7.2.5 TB co-treatment in children with HIV 128 7.3 Monitoring response to ART and the diagnosis of treatment failure 130 7.3.1 Laboratory monitoring before and after initiating ART 130 7.3.2 M onitoring the response to ART and the diagnosis of treatment failure 131 7.4 Monitoring and substitutions for ARV drug toxicities 136 7.4.1 Guiding principles 136 7.4.2 Major types of ARV toxicities 136 7.4.3 Monitoring TDF toxicity 139 7.4.4 Toxicity monitoring for other ARV drugs 140 7.4.5 Drug substitutions for ARV drug toxicity 141 7.4.6 Drug interactions 141 7.5 What ART regimen to switch to (second- and third-line ART) 144 7.5.1 Second-line ART for adults and adolescents 144 7.5.2 Second-line ART for children (including adolescents) 148 7.6 Third-line ART 151

Goal of this chapter To provide updated, evidence-based clinical recommendations outlining a public health approach to ART in the context of the continuum of HIV care, with a focus on resource and capacity limited settings.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7. C linical guidance across the continuum of care: antiretroviral therapy 7.1 When to start ART Early treatment initiation is associated with clinical and HIV prevention benefits, improving survival and reducing the incidence of HIV infection at the community level. The 2013 Guidelines Development Group recommends that national HIV programmes provide ART to all people with a confirmed HIV diagnosis with a CD4 count of 500 cells/mm3 or less, giving priority to initiating ART among those with severe/advanced HIV disease (see Annex 1) or a CD4 count of 350 cells/mm3 or less. It is also recommended to initiate ART in people with active TB disease and HBV coinfection with severe liver disease, all pregnant and breastfeeding women with HIV, all children younger than five years living with HIV and all individuals with HIV in serodiscordant relationships, regardless of CD4 cell count (Table 7.1).

Table 7.1 Summary of recommendations on when to start ART in adults, adolescents, pregnant and breastfeeding women and children Population Recommendation Initiate ART if CD4 cell count ≤500 cells/mm3 • A s a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤350 cells/mm3 Adults and adolescents ( ≥10 years) Initiate ART regardless of WHO clinical stage and CD4 cell count • Active TB disease • HBV coinfection with severe chronic liver disease • Pregnant and breastfeeding women with HIV • HIV-positive individual in a serodiscordant partnership (to reduce HIV transmission risk) Initiate ART if CD4 cell count ≤500 cells/mm3 • A s a priority, initiate ART in all children with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤350 cells/mm3 Initiate ART regardless of CD4 cell count • WHO clinical stage 3 or 4 • Active TB disease Initiate ART in all regardless of WHO clinical stage and CD4 cell count • A s a priority, initiate ART in all HIV-infected children 1–2 years old or with severe/advanced HIV disease (WHO clinical stage 3 or 4) or with CD4 count ≤750 cells/mm3 or <25%, whichever is lower Initiate ART in all infants regardless of WHO clinical stage and CD4 cell count

Children ≥5 years old

Children 1–5 years olda Infants <1 year olda a

Initiate ART in all HIV-infected children below 18 months of age with presumptive clinical diagnosis of HIV infection.

7. Clinical guidance across the continuum of care: antiretroviral therapy

7.1 When to start ART

7.1.1 When to start ART in adults and adolescents New recommendations As a priority, ART should be initiated in all individuals with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and individuals with CD4 count ≤ 350 cells/mm 3 (strong recommendation, moderatequality evidence) . ART should be initiated in all individuals with HIV with a CD4 count >350 cells and ≤ 500/mm 3 regardless of WHO clinical stage (strong recommendation, moderate-quality evidence ). a ART should be initiated in all individuals with HIV regardless of WHO clinical stage or CD4 cell count in the following situations: • I ndividuals with HIV and active TB disease (strong recommendation, low-quality evidence) . • I ndividuals coinfected with HIV and HBV with evidence of severe chronic

New

liver disease b (strong recommendation, low-quality evidence).

New

• Partners with HIV in serodiscordant couples should be offered ART to

reduce HIV transmission to uninfected partners (strong recommendation, high-quality evidence) . New

• P regnant and breastfeeding women with HIV (see section 7.1.2 for recommendations).

There is insufficient evidence and /or favourable risk–benefit profile to support initiating ART at a CD4 cell count >500 cells/mm 3 or regardless of CD4 cell count or WHO clinical stage in the following situations: individuals with HIV older than 50 years, individuals with HIV-1 infected or coinfected with HIV-2, individuals with HIV coinfected with HCV and key populations with HIV with a high risk of transmission (such as people who inject drugs, men who have sex with men, transgender people and sex workers). ART initiation in these populations should therefore follow the same principles and recommendations as for other adults with HIV. b There is insufficient evidence and /or favourable risk-benefit profile to support initiating ART in everyone coinfected with HIV and HBV with a CD4 count >500 cells/mm 3 or regardless of CD4 cell count or WHO clinical stage. Initiating ART regardless of CD4 count is therefore recommended among people with evidence of severe chronic liver disease, who are at greatest risk of progression and mortality from liver disease. For people without evidence of severe chronic liver disease, ART initiation should follow the same principles and recommendations as for other adults. a

New

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 7.2. Summary of when to initiate ART in adults and adolescents When to start ART in adults and adolescents Target population Severe/advanced HIV infection (WHO clinical stage 3 or 4) HIV infection (WHO clinical stage 1 or 2) TB disease Recommendation Initiate ART in all individuals regardless of CD4 cell count Initiate ART if CD4 ≤500 cells/mm3 (CD4 ≤350 cells/mm3 as a priority) Initiate ART in all individuals with active TB disease regardless of CD4 cell count a (Unchanged from 2010 recommendations (2)) Initiate in all individuals with CD4 ≤500 cells/mm3 and regardless of CD4 cell count in the presence of severe chronic liver diseaseb Provide ART to all partners infected with HIV regardless of CD4 cell count (to reduce the risk of HIV transmission to the negative partner) (Existing 2012 recommendation (49))

Hepatitis B coinfection

HIV-serodiscordant couples

TB treatment should be initiated first, followed by ART as soon as possible afterwards (and within the first eight weeks of initiating TB treatment). For those with a CD4 count less than 50 cells/mm 3, ART should be provided within two weeks of starting TB treatment (see section 8.1.2) . b Severe chronic liver disease includes cirrhosis and end-stage liver disease and is categorized into compensated and decompensated stages. Decompensated cirrhosis is defined by the development of clinically evident complications of portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy) or liver insufficiency (jaundice). a

Background Since 2002, WHO guidelines on ART have evolved as the body of evidence to support the earlier initiation of ART has progressively increased (1) . The 2010 WHO guidelines for adults and adolescents (2) recommended initiating ART for all individuals (including pregnant women) with a CD4 count ≤ 350 cells/mm 3 regardless of WHO clinical stage and for those with severe or advanced HIV disease (WHO clinical stages 3 or 4) regardless of CD4 count. This strong recommendation was based on moderate-quality evidence from randomized controlled trials (3,4) and observational studies (5–8) showing that initiating ART at or below this CD4 threshold reduced mortality, disease progression (including TB), vertical HIV transmission and serious adverse events. Mathematical modelling simulations also suggested that initiating ART earlier could impact on both sexual and vertical HIV transmission if there is high treatment coverage and full adherence (9) . For people with active TB disease or HBV coinfection requiring HBV treatment, the 2010 guidelines (2) recommended initiating ART regardless of CD4 cell count. Global ART coverage for those eligible according to the 2010 recommendations (CD4 ≤ 350 cells/mm 3 ) had reached 54% – or more than 8 million people – by the end of 2011 (10) , but coverage varies across regions, ranging from 15% to 68% (11) . Only 9 lowand middle-income countries have reported coverage exceeding 80%, and 68 countries have reported coverage of less than 50%. Nevertheless, policy changes in countries have been significant. A recent survey in 92 countries (Web Annex www.who.int/hiv/

7. Clinical guidance across the continuum of care: antiretroviral therapy

pub/guidelines/arv2013/annexes) showed that more than 90% had adopted the CD4 threshold for initiating ART of 350 cells/mm 3 or less, and several other countries have moved their CD4 threshold above 350 cells/mm 3. The median CD4 count at the time ART is initiated, although increasing, has been far lower than 350 cells/mm 3 in almost all settings, including high-income countries (12,13) , and late presentation for treatment is associated with high early mortality rates and poor retention in care (6,14) . Increasing knowledge of HIV status, strengthening links between testing and care and ensuring optimal long-term retention and adherence remain significant challenges in many settings.

7.1 When to start ART

Rationale and supporting evidence Since 2010, evidence and programmatic experience have continued to shift the riskbenefit ratio towards initiating ART earlier. Increasing evidence also indicates that untreated HIV may be associated with the development of several non-AIDS-defining conditions (including cardiovascular disease, kidney disease, liver disease, several types of cancer and neurocognitive disorders) (15–17) and that initiating ART earlier reduces such events and improves survival. Recent evidence (18) also show that ART substantially reduces sexual transmission in HIV-serodiscordant couples, but not all studies have reported survival benefits. At the same time, more convenient and less toxic regimens have become more widely available, and ARV costs have continued to fall. How early ART should be started is still debated, and the Guidelines Development Group paid close attention to evaluating the potential benefits and harms to the individual and community in developing these new recommendations. Initiating ART in individuals with symptomatic and asymptomatic HIV disease at a CD4 count ≤ 350 cells/mm 3 as a priority The benefits of initiating ART are greatest among individuals with symptomatic HIV disease or those with lower CD4 counts. The 2013 Guidelines Development Group did not change the strength and quality of evidence for this recommendation established in the 2010 ART guidelines (2) . Moderate-quality evidence from two randomized controlled trials and several observational studies shows that initiating ART at CD4 ≤ 350 cells/mm 3 significantly reduces mortality, disease progression and the incidence of opportunistic diseases, especially TB and non-AIDS-defining conditions (2) . Initiating ART at a CD4 count between 350 and 500 cells/mm 3 The risk-benefit analysis of the rationale for ART initiation between 350 and 500 CD4 cells/mm 3 in these guidelines was debated. The Guidelines Development Group agreed that impact on HIV transmission is strongly supported by the evidence. The quality of evidence for clinical benefit of earlier ART initiation was rated as moderate using the GRADE system, as it mostly relies on observational data mainly from high-income countries. The Guidelines Development Group strongly recommended earlier ART as a public health approach. In settings where feasibility of implementation is a concern, the Guidelines Development Group suggested conducting operational research during implementation to assess context-specific factors such as feasibility, linkage to and retention in care, adherence and resource allocation.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

The recommendation for initiating ART at CD4 counts between 350 and 500 cells/mm 3 is based on a systematic review with GRADE evidence profiles (Web Annex www.who. int/hiv/pub/guidelines/arv2013/annexes) that assessed the quality and strength of the evidence from 21 observational studies (8,19–39) and three randomized controlled trials (3,18,40) reporting morbidity, mortality and immunological and virological outcomes. They showed that initiating ART at a CD4 count >350 cells/mm 3 compared with treatment at a CD4 count ≤ 350 cells/mm 3 reduced the risk of progression to AIDS and/or death, TB, development of a non-AIDS-defining illness and increased the likelihood of immune recovery. Although no studies suggest that earlier ART causes individual harm, these studies were of limited duration. The pooled analysis of the observational studies found a consistent decreased risk of death with earlier initiation of ART in 13 studies (21–23,26,29–31,34–39) and a decreased risk of progression to AIDS or death in 9 studies (21,23,26,27,30,33,34,36,39) and 3 randomized controlled trials (3,18,40) , with a low level of heterogeneity, supporting moderate-quality evidence for earlier treatment. A further subgroup analysis showed a reduced risk of mortality with a CD4 threshold for initiating ART of 500 cell/mm 3. The impact on immune recovery was inconsistent and rated as low- to very-low-quality evidence (20,24,28) . Two studies found no significant difference in the likelihood of viral suppression (<500 copies/ ml), risk of virological failure and viral rebound when treatment is initiated at higher or lower CD4 cell counts (20,36) . In the pooled analysis of two randomized controlled trials (3,18) there was low-quality evidence supporting ART initiation at higher CD4 thresholds for reducing mortality, disease progression or the combined outcome of death and/or progression and, in one trial, the risk of non-AIDS-defining illnesses. The risk of severe adverse events did not differ significantly, but the risk of Grade 3 or 4 laboratory abnormalitiesii was increased in one randomized controlled trial (40) . Since treatment in the delayed arm of the SMART trial (3) was initiated when the CD4 count fell below 250 cells/mm 3 (rather than 350 cells/mm 3 ), the quality of the evidence for clinical benefit was graded as low because of imprecision and indirectness. A separate systematic review (41) identified one randomized clinical trial (18) and two observational studies (42,43) reporting a decreased risk of TB when individuals initiated ART with CD4 counts exceeding 350 cells/mm 3. ART also reduces recurrent TB by about 50% (44) . Dynamic models have suggested ART initiation above 350 cells/mm 3 could lead to a more substantial reduction in population tuberculosis incidence (45) . Finally, there is high-quality evidence from one randomized controlled trial (18) indicating that earlier ART can markedly reduce the risk of sexual transmission to HIV-negative sexual partners. This is supported by the secondary outcomes of a trial that also found a 92% reduction in HIV sexual transmission from partners with HIV taking ART (46) . Cost and cost–effectiveness The Guidelines Development Group reviewed mathematical simulations of the costs and epidemiological benefits of initiating ART at a CD4 count ≤ 350 cells/mm 3, CD4 count ≤ 500 cells/mm 3 and for all adults with HIV regardless of CD4 cell count. These models suggest that expanding the ART eligibility criteria to ≤ 500 cells/mm 3 could lead to substantial health benefits and be cost-effective in both generalized and concentrated epidemic settings; the increased cost of earlier ART would be partly offset by subsequent reduced costs (such as decreased hospitalization and increased productivity) and preventing ii

Grade 3 and 4 laboratory abnormalities are considered as severe drug adverse reactions and usually requires discontinuation of ARV drugs until the patient is stabilized and substitution for an alternative drug (See Web Annex www.who.int/hiv/pub/ guidelines/arv2013/annexes)

7. Clinical guidance across the continuum of care: antiretroviral therapy

new HIV infections (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). However, these benefits depend on a high testing uptake, high treatment coverage, sustained adherence and high rates of retention in care. The models also show that, because the greatest costs are associated with full implementation of the 2010 ART guidelines (2) (initiating ART at CD4 count ≤ 350 cells/mm 3 ), the incremental cost of moving the ART initiation criterion from a CD4 count ≤ 350 cells/mm 3 to ≤ 500 cells/ mm 3 is relatively small, especially if countries already have a substantial number of people with HIV with a CD4 cell count less than 350 cells/mm 3 already receiving ART. These modelling findings support the recommendation to initiate ART in adults and adolescents with HIV with a CD4 count ≤ 350 cells/mm 3 as a priority. However, the cost implications at the regional and country levels should be explored further, since countries have different levels of treatment coverage and local cost considerations depending on their context and resources. Potential harms Not all observational studies have consistently demonstrated the beneficial impact of initiating ART earlier on mortality and the incidence of non-AIDS events associated with chronic inflammation and ongoing viral replication, and longer follow-up is needed to evaluate potential harms and benefits. The long-term safety profile of ART and the implications of earlier initiation on drug resistance and toxicity will also need to be closely monitored. Feasibility According to cohort and national programme data, the number of people needing treatment could increase by up to 25% if eligibility is based on CD4 counts increasing from ≤ 350 cells/mm 3 to ≤ 500 cells/mm 3 (47,48) (Web Annex www.who.int/hiv/pub/ guidelines/arv2013/annexes). However, country experience has also shown that moving to a higher CD4 threshold for ART initiation may not necessarily lead to a significant immediate increase in the numbers of people who actually access treatment in the absence of increased uptake of HIV testing and counselling, stronger linkages to care, adequate treatment monitoring and sustained adherence support. Implementing the recommendation to initiate ART in individuals with HIV with CD4 counts between 350 and 500 cells/mm 3 may involve additional human, infrastructure and financial resources. Chapter 10 discusses these issues in further detail.

7.1 When to start ART

Initiating ART regardless of CD4 cell count

HIV-positive partners in HIV-serodiscordant couples iii The results of the HPTN052 study (18) strongly support the use of ART to prevent HIV transmission among HIV-serodiscordant couples. The Guidelines Development Group therefore endorsed the recommendations established in the 2012 WHO guidance on HIV testing and counselling including ART for treatment and prevention in serodiscordant couples (49) that the sexual partner with HIV in such a couple should be offered ART regardless of CD4 count.

iii

An HIV-serodiscordant couple is a couple in which one of the sexual partners is HIV-positive and one is HIV-negative. Although one partner is currently HIV-negative, this does not mean that this partner is immunized or protected against getting HIV in the future.

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Treating active TB disease iv In 2010, WHO recommended starting ART in all people with HIV and active TB regardless of CD4 cell count, and that TB treatment should be started first, followed by ART, as soon as possible afterwards (and within the first eight weeks). The Guidelines Development Group reviewed evidence from three randomized clinical trials that showed for people with TB and severe immunodeficiency (CD4 count ≤50 cells/mm3 ), starting ART before eight weeks has a clinical benefit compared with deferring treatment to later than eight weeks (50–52) , and endorsed the 2010 recommendations. Implementation of the recommendations on HIV and TB management may be facilitated by integration of services (Chapter 9). HIV and HBV coinfection with evidence of severe chronic liver diseasev HIV coinfection affects almost every aspect of the natural history of HBV infection. The consequences include higher rates of chronicity; less spontaneous HBV clearance; accelerated liver fibrosis progression with increased risk of cirrhosis and hepatocellular carcinoma; higher liver-related mortality and decreased ARV response (53–56) . Liver disease has emerged as a leading cause of death in people coinfected with HIV and HBV (57,58) . The 2010 WHO ART guidelines (2) recommended initiating ART among all individuals coinfected with HIV and HBV who require treatment for their HBV infection (defined as chronic active hepatitis), regardless of CD4 cell count or WHO clinical stage. However, in the absence of routine screening for HBV, most people are unaware of their HBV status. In addition, there is limited access to costly diagnostic tools for staging liver disease (liver biopsy, transient elastography, HBV-DNA and serum biomarkers) needed to establish the presence of chronic active liver disease and eligibility for HBV treatment. A meta-analysis (59) and a subgroup analysis of a randomized controlled trial (60) provide low-quality evidence of the overall impact of ART on liver-related morbidity and mortality among individuals coinfected with HIV and HBV, but these studies did not examine the benefit of initiating ART at higher CD4 counts. Overall, the Guidelines Development Group considered that there was not sufficient evidence and/or a favourable risk–benefit profile to support initiating ART among all people coinfected with HIV and HBV with a CD4 count >500 cells/mm3 or regardless of CD4 count or stage of liver disease. There are also risks associated with initiating ART earlier (hepatotoxicity, immune reconstitution inflammatory syndrome and hepatic flares). However, the Guidelines Development Group does recommend providing ART to all people coinfected with HIV and HBV regardless of CD4 count in people with evidence of severe chronic liver disease, who are at greatest risk of liver disease progression and mortality. The term severe chronic liver disease was used instead of chronic active hepatitis (as in the 2010 guidelines), as this is a term that is more widely understood and applicable using clinical criteria alone. In settings where ART cannot be provided to all individuals with HIV with CD4 counts ≤500 cells/mm3, giving priority to diagnosing and treating individuals coinfected with HIV and HBV should be considered. As reported in the 2010 WHO ART guidelines (2) , data from one randomized controlled trial support the use of at least two agents with activity against HBV (TDF + 3TC or FTC) in terms of improved viral load response and reduced development of HBV drug resistance (61,62) .

Active TB disease refers to TB infection where the person has symptoms and clinical disease. Latent TB infection refers to TB infection where the person does not have symptoms or clinical disease. Not all persons with latent TB infection will develop TB disease, but the risk of progressing to disease is very high in people with HIV. v S evere chronic liver disease includes cirrhosis and end-stage liver disease and is categorized into compensated and decompensated stages. Decompensated cirrhosis is defined by the development of clinically evident complications of portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy) or liver insufficiency (jaundice). iv

7. Clinical guidance across the continuum of care: antiretroviral therapy

Critical research gaps in this area include the need for more data on the impact of ART on liver-related outcomes in HBV-coinfected people in resource-limited settings and on the relative impact of ART in people with CD4 cell counts >500 cells/mm3 and early-stage liver disease. Populations for which no specific new recommendation is made The Guidelines Development Group did not find evidence and/or favourable risk–benefit profiles to support recommendations for initiating ART at CD4 cell count >500 cells/mm3 or regardless of CD4 cell count or WHO clinical stage in the following populations.

7.1 When to start ART

Individuals with HIV who are 50 years of age and older A pooled analysis of data from 13 cohorts from Europe and North America showed increased risk of death and disease progression in people with HIV older than 50 years of age (26) . However, these data were not stratified by CD4 cell count and do not support initiating ART at CD4 counts > 500 cells/mm3 for this group. Individuals with HIV-2 The lack of randomized treatment studies in individuals with HIV-2 makes it difficult to determine the optimal timing of ART initiation in this population. A systematic review (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes) evaluated observational data from 15 studies and showed no significant differences between initiating ART at a CD4 count ≤ 350 cells/mm3 and >350 cells/mm3, considering the outcomes of mortality, disease progression, increase in CD4 cell count, virological response and risk of drug resistance. The quality of evidence was rated as low to very low, with serious risk of bias and imprecision (few events) for all these outcomes. Individuals coinfected with HIV and HCV Observational studies have shown that coinfection with HIV and HCV accelerates HCVrelated progression of liver fibrosis and leads to a higher rate of end-stage liver disease (63) and mortality (63–65) . There is consistent but low-quality observational data about the overall benefit of ART on mortality and progression of liver disease in individuals coinfected with HIV and HCV based on evidence from a meta-analysis (66) , and a review of nine cohort studies that examined the relationship between ART and hepatic fibrosis showing that ART was associated with a decreased rate of liver fibrosis progression, although this was not evaluated by the level of CD4 count (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The Guidelines Development Group endorsed the special note in the 2010 guidelines (2) that initiating ART among people coinfected with HCV should follow the same principles as in HIV monoinfection. Initiating ART regardless of CD4 cell count was not recommended because of lack of evidence. There are challenges in diagnosing and treating active HCV infection in settings with limited access to HCV antibody and RNA assays, diagnostic tools for staging of liver disease (such as biopsy) and HCV therapy and in certain populations such as people who inject drugs. However, limited access to HCV testing or treatment and/or high rates of HCV infection should not be barriers to initiating ART. WHO hepatitis guidelines forthcoming in 2014 will provide detailed guidance on HCV screening, treatment and care. People coinfected with HIV and HCV receiving ART and HCV drugs require close monitoring because of potential drug interactions and increased risk for drug toxicity between HCV drugs (such as interferon, ribavirin and newer directly acting agents) and ARV drugs.

100

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Key populations The scale-up of ARV drugs for preventing HIV infection or reducing HIV incidence in key populations has been evaluated in community-wide and ecological studies and mathematical models (67–79) . Some of these studies showed a reduction in the community viral load, with and without an associated decline in HIV incidence, invariably where ART coverage is high or access to ART is expanding rapidly. However, the Guidelines Development Group concluded that there is insufficient evidence to recommend earlier initiation of ART in key populations regardless of CD4 cell count. The initiation of ART in key populations should follow the same general principles and recommendations as in other adults and adolescents with HIV.

Clinical considerations Section 10.6 (Checklist 10.3) discusses implementation considerations for moving the CD4 threshold from 350 cells/mm 3 to 500 cells/mm 3 of relevance to programme managers.

Key research gaps Further research is required to determine more fully the clinical benefits and disadvantages of earlier ART initiation. Two large randomized trials are examining the optimal timing for initiating ART, with results expected in 2014 to 2015. The Strategic Timing of Antiretroviral Therapy (START) trial in ARV-naive adults aged 18 years and older is comparing immediate ART in those with CD4 cell counts above 500 cells/mm 3 to ART deferred until the CD4 count falls below 350 cells/mm 3 or an AIDS event develops (80) . The TEMPRANO trial (Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis against Tuberculosis in HIV-infected Adults – ANRS 12136) is comparing the benefits and risks of initiating ART according to the 2010 WHO guidelines ( ≤ 350 cells/mm 3 ) (2) to the benefits and risks of initiating ART immediately among adults with CD4 counts >350 cells/mm 3 in Côte d’Ivoire (81) . These studies will inform future WHO recommendations. Other research priorities include assessing the incidence of severe adverse events as a result of increased exposure to ART and assessing ART acceptability, uptake, adherence and long-term retention in care for people who initiate ART at higher CD4 counts, and the magnitude of the prevention benefit of immediately initiating ART in key populations.

7.1.2 When to start ART in pregnant and breastfeeding women New recommendations New

All pregnant and breastfeeding women with HIV should initiate triple ARVs (ART), which should be maintained at least for the duration of mother-to-child transmission risk. Women meeting treatment eligibility criteria should continue lifelong ART (strong recommendation, moderate-quality evidence). For programmatic and operational reasons, particularly in generalized epidemics, all pregnant and breastfeeding women with HIV should initiate ART as lifelong treatment (conditional recommendation, low-quality evidence). In some countries, for women who are not eligible for ART for their own health, consideration can be given to stopping the ARV regimen after the period of mother-to-child transmission risk has ceased (conditional recommendation, low-quality evidence).

7. Clinical guidance across the continuum of care: antiretroviral therapy

101

Table 7.3 Programme options for ART for PMTCT National PMTCT programme option Pregnant and breastfeeding women with HIV Regardless of WHO clinical stage or CD4 cell count Initiate ART and maintain after delivery and cessation of breastfeeding Eligible for treatmenta Initiate ART and maintain after delivery and cessation of breastfeeding b Not eligible for treatmenta Initiate ART and stop after delivery and cessation of breastfeeding b c HIV-exposed infant

7.1 When to start ART

Use lifelong ART for all pregnant and breastfeeding women (“Option B+”)

Breastfeeding 6 weeks of infant prophylaxis with once-daily NVP

Replacement feeding 4–6 weeks of infant prophylaxis with once-daily NVP (or twice-daily AZT)

Use lifelong ART only for pregnant and breastfeeding women eligible for treatment (“Option B”)

CD4 count ≤ 500 cells/mm3 or clinical stage 3 or 4 disease at the time of ART initiation or in accordance with national guidelines. Patients who develop clinical or laboratory criteria indicating failure during pregnancy or the breastfeeding period should be assessed for second-line therapy. c In the case of breastfeeding stop ART one week after breastfeeding ends. In the case of replacement feeding stop ART after delivery. a b

Background ARV drugs are used for pregnant and breastfeeding women with HIV primarily for the mother’s health and to prevent the exposed child from becoming infected. It may also offer benefits for preventing the sexual transmission of HIV. The 2010 WHO PMTCT guidelines (82) recommended lifelong ART for women eligible for treatment (based on the 2010 eligibility criteria of CD4 counts ≤ 350 cells/mm 3 or presence of WHO clinical stage 3 or 4 disease) and ARV prophylaxis for PMTCT for women with HIV not eligible for treatment. For those not eligible for treatment, two prophylaxis regimens were recommended: “Option A”, AZT for the mother during pregnancy, single-dose NVP (sd-NVP) plus AZT and 3TC for the mother at delivery and continued for a week postpartum; and “Option B”, triple ARV drugs for the mother during pregnancy and throughout breastfeeding. Prophylaxis was recommended to start as early as 14 weeks of gestation, and both prophylaxis options included four to six weeks of peripartum NVP or AZT for the infant, regardless of whether the mother was breastfeeding. Countries were advised to choose a national approach for their ARV option for PMTCT based on operational considerations. To accelerate the rapid global scaling up of ART and PMTCT in resource-limited settings, ensure equitable access to ART for pregnant women and achieve the global goal of eliminating new paediatric infections and keeping mothers alive (83) , recommendations need to be further simplified, standardized and harmonized. In 2011, Malawi implemented a new approach of lifelong ART for all pregnant and breastfeeding women with HIV regardless of CD4 count or clinical status, commonly referred to as “Option B+” (84–86) . WHO issued a programmatic update in April 2012 (87) outlining some of the operational advantages of Option B and the emerging strategy of Option B+.

New

102

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

These 2013 guidelines recommend ART (one simplified triple regimen) for all pregnant and breastfeeding women with HIV during the period of risk of mother-to-child HIV transmission and continuing lifelong ART either for all women or for the women meeting eligibility criteria for their own health. Option A is no longer recommended.

Rationale and supporting evidence Advantages of a standardized ART regimen for all pregnant and breastfeeding women with HIV Although available data continue to show that the Option A and B prophylaxis regimens have similar efficacy in clinical trial settings (88–92) , the complexities of Option A have been an impediment to scaling up PMTCT in many countries. These complexities include different treatment and prophylaxis regimens; the requirement for CD4 measurement to determine treatment eligibility and type of regimen; changing antepartum-intrapartumpostpartum regimens; the need for an additional postpartum ARV “tail” in mothers; and extended NVP prophylaxis in infants. By contrast, providing an optimized, fixed-dose combination first-line ART regimen of TDF + 3TC (or FTC) + EFV (see section 7.2.2) to all pregnant and breastfeeding women with HIV provides important programmatic and clinical benefits, including the following. E ase of implementation. The same simplified ART regimen is administered to all pregnant women (regardless of “eligibility” for treatment) and continued during pregnancy and labour and postpartum. H armonized regimens. The optimized first-line fixed-dose combination regimen can be harmonized with guidelines for ART in non-pregnant adults. I ncreased coverage of ART. This ensures that immunocompromised women who do not have access to CD4 testing receive appropriate ART without delay. • Vertical transmission benefit. Provides coverage with ART to maximize the prevention of infant infections. • Maternal health benefit. Will delay disease progression over the course of treatment (93) . A cceptability. Reviews conducted for these guidelines generally indicated strong community preference and acceptability for this approach. S exual prevention benefit. ART will reduce sexual transmission of HIV to sexual partners (18) . The Guidelines Development Group also considered the overall evidence from the systematic review of 21 observational studies (19–39) and three randomized controlled trials (3,18,40) used in the evaluation of when to start ART in adults (Web Annex www. who.int/hiv/pub/guidelines/arv2013/annexes; see section 7.1.1). The recommendation to increase the use of ART in pregnant and breastfeeding women is made with the understanding that there are limited ARV drug options in resource-limited countries. It also recognizes the need to balance the benefits of starting ART in pregnant and breastfeeding women with the possible risks of ARV drug toxicity to the mother and fetus and infant during pregnancy and breastfeeding. Other issues the Guidelines Development Group considered included costs; cost–effectiveness and health system burden (94,95) ; issues related to adherence and retention (96) , HIV drug resistance, ART failure and the availability of future treatment options; and ensuring treatment access for all people who meet current guidelines on eligibility for treatment.

7. Clinical guidance across the continuum of care: antiretroviral therapy

103

Lifelong ART versus stopping ART after the risk of mother-to-child HIV transmission ends The recommendation to provide lifelong ART to all pregnant and breastfeeding women with HIV or to continue ART only for those meeting treatment eligibility criteria for the woman’s health is conditional, based on the epidemic setting and country programme, and because of the lack of conclusive evidence on the impact and efficacy of fully implementing lifelong ART. In generalized epidemic settings and in settings with limited access to CD4 testing, limited partner testing, long duration of breastfeeding or high rates of fertility, the benefits of lifelong ART for all pregnant and breastfeeding women with HIV are clear. It will assure maximum coverage for those needing treatment for their own health, avoid stopping and starting drugs with repeat pregnancies, provide early protection against mother-to-child transmission in future pregnancies, reduce the risk of HIV transmission to HIV-serodiscordant partners and improve maternal health. With the new treatment eligibility threshold of CD4 ≤500 cells/mm3, approximately 60% of HIV-infected pregnant women will meet treatment eligibility criteria for their own health (97) . Although not well quantified, it is likely that at least an additional 10–20% of women would become eligible for treatment over the subsequent two years after birth. In countries with concentrated epidemics that have high access to CD4 testing, adequate capacity to provide ART to the pregnant and breastfeeding women eligible for treatment, low fertility rates and/or where breastfeeding for mothers with HIV is not recommended, consideration can be given to stopping the ARV drugs in women not eligible for ART after the period of mother-to-child transmission risk has ended. Regardless of the approach, special effort and supportive initiatives are needed to optimize adherence, especially during breastfeeding, where many programmes currently have poor follow-up, and to assure effective linkages to long-term treatment. Chapter 10 provides additional guidance for national programmes on making the decision between lifelong ART and stopping ART (Box 10.4). Enhanced ARV toxicity surveillance for exposure throughout pregnancy and the breastfeeding period is critical to evaluate the safety of this approach for women, the fetus and the child. This is especially true as an increasing number of women already receiving ART become pregnant, resulting in much higher levels of ARV drug exposure during early gestation (see Sections 7.2.2 on “What ART regimen to start with” and 7.4 on “Monitoring and substitutions for ARV drug toxicities”). In addition, implementation research is important to ensure that the many gaps in knowledge associated with lifelong ART are addressed. Transition from the 2010 guidelines to the 2013 guidelines The new 2013 guidelines recommend that countries currently implementing Option A based on the 2010 guidelines (82) should transition, with appropriate planning, to initiating ART for all pregnant and breastfeeding women with HIV; the 2013 guidelines no longer recommend Option A. Countries moving towards Option B and those currently implementing Option B should consider the advantages and disadvantages of implementing lifelong ART for all pregnant and breastfeeding women in their setting.

7.1 When to start ART

Clinical considerations Section 10.6 (Implementation considerations for key recommendations, Box 10.4) discusses clinical and implementation considerations relevant to programme managers for moving towards lifelong ART for all pregnant and breastfeeding women. A toolkit for managing the transition to lifelong ART for pregnant and breastfeeding women has been developed (98) , including a readiness assessment checklist (Annex 6).

104

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Key research gaps The Guidelines Development Group emphasized the need for more research to support the new recommendations, to inform programmatic decisions and to promote optimal implementation. Key research gaps include the following. ARV toxicity surveillance. Additional research is needed on the safety and acceptability of lifelong ART for pregnant and breastfeeding women, and their infants, especially in lowresource settings, where malnutrition and comorbidities are more common than in resourcerich countries and monitoring capacity is limited. Better data are needed on mothers’ health outcomes, pregnancy outcomes (such as stillbirth, low birth weight and prematurity) birth defects and health outcomes for infants and young children (see Box 7.2). Maternal and child health outcomes. Research is needed to better define the long-term outcomes in terms of both mother-to-child transmission at the end of breastfeeding and maternal health. In addition to short-term outcomes (such as impact on early mother-tochild transmission rates, which are now commonly measured at six weeks), assessments of long-term outcomes with maternal ART are critical to measure final transmission rates at the end of breastfeeding and HIV-free survival; the health of the mother and children infected or uninfected with HIV; retention in care (for those with both low and high CD4 counts); the longterm success of first-line ART; and HIV drug resistance. Adherence and retention. Research is needed to determine how to optimize acceptability, adherence and retention on ART in pregnant and breastfeeding women, including among the women initiating lifelong ART who do not meet current eligibility criteria for their own health. Research is also needed on health systems and community interventions to optimize lifelong ART for pregnant and breastfeeding women with HIV, and the potential impact of different ART initiation strategies in different populations.

7.1.3 ARV drugs and duration of breastfeeding Recommendations The key principles and recommendations established in 2010 remain, including: National or subnational health authorities should decide whether health services will mainly counsel and support mothers known to be infected with HIV to either breastfeed and receive ARV interventions or avoid all breastfeeding given their particular context. In settings where national authorities have decided that maternal and child health services will mainly promote and support breastfeeding and ARV interventions as the strategy that will most likely give infants born to mothers known to be infected with HIV the greatest chance of HIV-free survival. Mothers known to be infected with HIV (and whose infants are HIV uninfected or of unknown HIV status) should exclusively breastfeed their infants for the first 6 months of life, introducing appropriate complementary foods thereafter, and continue breastfeeding for the first 12 months of life. Breastfeeding should then only stop once a nutritionally adequate and safe diet without breast-milk can be provided (strong recommendation, high-quality evidence for the first 6 months; low-quality evidence for the recommendation of 12 months).

7. Clinical guidance across the continuum of care: antiretroviral therapy

105

Background The primary aim of WHO recommendations regarding HIV and infant feeding is to improve the HIV-free survival of HIV-exposed infants. This includes reducing the risk of HIV transmission through breast-milk, primarily by providing ARV drugs, while avoiding malnutrition and the increased risk of serious infections in infants and children through unsafe feeding practices. In 2010, WHO recommended that ARV drugs be provided either to the mother or the infant throughout breastfeeding to reduce the risk of postnatal HIV transmission (82, 99) . In countries that recommended breastfeeding with ARV drugs, it was recommended that women with HIV should “continue breastfeeding for the first 12 months of life” and “only stop once a nutritionally adequate and safe diet without breast-milk can be provided” (99) . This recommendation was based on evidence that the maximum benefit of breastfeeding in preventing mortality from diarrhoea, pneumonia and malnutrition is in the first 12 months of life and that the risk of transmitting HIV to infants through breastfeeding is low in the presence of ARV drugs (100,101) . At that time, there was uncertainty about the mothers’ adherence to ARV drugs as prophylaxis and their ability to give ARV drugs to their breastfeeding infants over longer periods of time up to 18 or 24 months of age. Consequently, there was uncertainty about the level of protection against HIV transmission for children breastfeeding beyond 12 months. Finally, there were limited data on potential adverse events among infants exposed to prolonged – though low-dose – ARV drugs through breast-milk (102–104) . Since 2010, country-level recommendations on the appropriate duration of breastfeeding for women with HIV and their infants (where breastfeeding is recommended) have varied from 12 to 24 months; in some cases, the duration is not specified. Data on ARV drug coverage and adherence during breastfeeding and effective postpartum follow-up of mother–infant pairs remain limited. With increasing antenatal coverage of ARV drugs in PMTCT programmes, the relative proportion of infants infected during breastfeeding may be increasing because of inadequate ARV drug coverage during breastfeeding, emphasizing the importance of an effective postpartum prevention strategy. The option of providing lifelong ART to all pregnant women with HIV, regardless of CD4 count or clinical stage (section 7.1.2), raises the question of whether these mothers need to limit the duration of breastfeeding. The Guidelines Development Group therefore considered whether, in the context of pregnant women with HIV receiving lifelong ART regardless of CD4 count or clinical stage, to maintain the recommendation on the duration of breastfeeding as continued breastfeeding for the first 12 months of life or whether to recommend unrestricted duration of breastfeeding. The Guidelines Development Group considered a revision because of the potential operational advantages of extending the breastfeeding period, including: harmonizing and simplifying recommendations for mothers with HIV and their infants with those for mothers without HIV would likely simplify public health messaging and improve infant-feeding practices in the entire community; and decreasing stigma and possible increasing acceptability by mothers and communities. Ultimately, the Guidelines Development Group decided not to change the 2010 recommendations on HIV and infant feeding.

7.5.3 ARV drugs and duration of breastfeeding

106

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Rationale for not changing the 2010 WHO recommendations on HIV and infant feeding Overall, there is no new evidence to support changing the 2010 recommendation. The main concern about promoting unrestricted breastfeeding among mothers with HIV is that mothers may not adhere to ART throughout breastfeeding, placing their infants at risk of HIV transmission. Although this is important at any time when the infant is breastfeeding, it is of particular concern after the infant reaches 12 months of age. Before 12 months of age, breastfeeding provides major protection to the infant against death from diarrhoea, pneumonia and malnutrition. Although breastfeeding continues to provide a range of benefits to the child after 12 months of age, reductions in mortality from these conditions become less significant. WHO recommendations acknowledge that some mothers may not be able to provide a safe and adequate diet to children beyond 12 months of age without breastfeeding and, in these situations, suggest that breastfeeding should continue. However, evidence to support this as a general approach, including the additional risk of HIV transmission and ARV toxicity surveillance data to exclude possible ARV-related adverse health outcomes for the infant, is not currently available.

Clinical considerations for supporting mothers with HIV to breastfeed Key clinical and implementation considerations for using ARV drugs during breastfeeding include: p ostnatal prophylaxis for infants remains critical: infants of mothers who are receiving ART and are breastfeeding should receive six weeks of infant prophylaxis with daily NVP (section 7.2.2); specific interventions (such as integrated follow-up with immunization and other wellchild services) should be considered to improve postpartum follow-up of mother–infant pairs, which is often weak in most programmes; and c ommunicating clearly and effectively with the community and users the value of breastfeeding with ARV drugs and local considerations regarding the duration of breastfeeding. In addition, the Guidelines Development Group emphasized the need to support enhanced monitoring for potential toxicities from prolonged exposure to ARV drugs (such as sentinel site monitoring of infant cohorts during the first two years of life), for the next three to five years, and to continue monitoring as new drugs are introduced, to assess the effects of ARVs especially on neurodevelopmental outcomes and renal and bone health.

Key research gaps t he risk of postpartum transmission in the context of ART, with variable duration of breastfeeding and different programme settings; s hort- and long-term infant health outcomes related to prolonged, low-dose exposure to ARV drugs (especially EFV and TDF) through breast-milk, including neurodevelopmental outcomes, nutritional status (including micronutrients), bone metabolism and growth; and interventions to improve adherence to postnatal ARV drugs and breastfeeding and whether initiating lifelong ART in all pregnant and postpartum women enhances adherence to ARV drugs during breastfeeding, which would enable women with HIV to breastfeed without any time restriction.

7. Clinical guidance across the continuum of care: antiretroviral therapy

107

7.1 When to start ART

Box 7.1. Special considerations for the care and management of pregnant women (See also Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes)

Sources of guidance: P regnancy, childbirth, postpartum and newborn care: a guide for essential practice. Geneva, World Health Organization, 2006 (www.who.int/ reproductivehealth/publications/maternal_perinatal_health/924159084X/en/ index.html). G uidance on global scale-up of the prevention of mother-to-child transmission of HIV. Geneva, World Health Organization, 2007 (www.who.int/hiv/pub/mtct/ pmtct_scaleup2007/en/index.html). I MAI/IMPAC clinical training for integrated PMTCT services. Geneva, World Health Organization, 2013 (www.who.int/hiv/topics/mtct/training/en).

General guidance Pregnant women with HIV should receive at least the minimum package of recommended antenatal visits and pregnancy care, and additional interventions such as screening for sexually transmitted infections, nutritional support and infant feeding and family planning counselling should be considered. There is a high risk of HIV transmission during labour and delivery. This risk can be minimized by following several key principles and practices, including reinforcing recommended antenatal clinic visits, especially high-risk management in the late third trimester; promoting facility-based delivery by trained skilled birth attendants; avoiding unnecessary instrumentation and premature rupture of membranes by using a partograph to monitor stages of labour; and non-invasive suction of nasogastric secretions and washing away blood in the newborn.

Additional measures to reduce HIV transmission include the following: The early identification of mothers with HIV and providing ARV drugs to both the mother and the newborn baby are essential. For mothers presenting at labour with unknown HIV status, rapid HIV testing should be done during labour or immediately postpartum. For women testing positive, ARV drugs should be provided to both the mother and child in accordance with current treatment recommendations and with consideration of extended prophylaxis to the infant (see section 7.2.2). Health care workers should follow universal precautions for all deliveries, including those involving mothers with HIV. Special efforts should be made to ensure that delivery care is provided in a nonstigmatizing and supportive manner. Although Caesarean section has been shown to protect against HIV transmission, especially in the absence of ARV drugs or in the case of high viral load, WHO does not recommend it in resource-limited settings specifically for HIV infection; rather it is recommended for obstetric and other medical indications.

108

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Box 7.1 (continued) Women with HIV and women of unknown HIV status who deliver outside health facilities should be encouraged to be medically assessed at a maternal and child health facility as soon as possible after delivery and to begin or continue appropriate HIV interventions. Providing follow-up, linkages to care and treatment and postpartum care are especially important for women with HIV and their HIV-exposed infants. Initial care of the child is usually scheduled at the first immunization visit at four to six weeks, including reinforcement of safe feeding practices, review of ARV coverage and early infant diagnosis testing. Follow-up care for the mother should ideally be scheduled at the same time and should include a postpartum check, family planning counselling, review of ARV regimen and adherence support.

7.1.4 When to start ART in children New recommendations New

ART should be initiated in all children infected with HIV below five years of age, regardless of WHO clinical stage or CD4 cell count nfants diagnosed in the first year of life I (strong recommendation, moderate-quality evidence) • Children infected with HIV one year to less than five years of age (conditional recommendationa, very low-quality evidence). •

ART should be initiated in all HIV-infected children five years of age and older with CD4 cell count ≤500 cells/mm3, regardless of WHO clinical stage • CD4 count ≤350 cells/mm3 (strong recommendation, moderate-quality evidence) • CD4 count between 350 and 500 cells/mm3 (conditional recommendationb, very-low-quality evidence). ART should be initiated in all children infected with HIV with severe or advanced symptomatic disease (WHO clinical stage 3 or 4) regardless of age and CD4 cell count (strong recommendation, moderate-quality evidence). ART should be initiated in any child younger than 18 months of age who has been given a presumptive clinical diagnosis of HIV infection (strong recommendation, low-quality evidence).

This recommendation is conditional because of the lack of evidence supporting earlier initiation in this age group, but this approach is expected to provide significant programmatic advantages in settings with limited access to immunological testing, high burden of paediatric HIV disease and low ART coverage among children, since simplifying eligibility criteria for initiating ART is likely to increase ART coverage in children infected with HIV and improve their health outcomes. Priority for ART initiation should be given to children younger than two years of age, because of higher mortality risk, and to children between two and five years of age with advanced disease (WHO HIV clinical stages 3 and 4 or with CD4 count ≤750 cells/mm 3 or <25%, whichever is lower), regardless of WHO clinical stage (strong recommendation, very-low-quality evidence) (105). b This recommendation is conditional because of the lack of evidence in this population for individual benefit as a result of initiating ART earlier; however, this approach is expected to provide significant programmatic advantages in settings with high coverage of paediatric ART and a programmatic need to align with ARV drug recommendations for adults. If this recommendation is not adopted, ART should be initiated at WHO HIV clinical stages 3 and 4 or with CD4 count ≤ 350 cells/mm 3 regardless of WHO clinical stage (strong recommendation, very-low-quality evidence) (105). a

7. Clinical guidance across the continuum of care: antiretroviral therapy

109

Table 7.4. Summary of recommendations on when to start ART in children Age Infants (<1 year) 1 year to less than 5 years 5 years and above When you start Treat all individuals Treat all individuals (children ≤2 years or with WHO stage 3 or 4 or CD4 count ≤750 cells/mm³ or <25% as a priority) WHO stage 3 or 4 Or CD4 ≤500 cells/mm3 (CD4 ≤350 cells/ mm³ as a priority)

7.1 When to start ART

Background Infants and young children have an exceptionally high risk of poor outcomes from HIV infection. Up to 52% of children die before the age of two years in the absence of any intervention (106) . By five years of age, the risk of mortality and disease progression in the absence of treatment falls to rates similar to those of young adults (107,108) . The scaling up of early infant diagnosis programmes has increased the identification of infants infected with HIV, but initiating ART early for those who have been found to be infected remains poor. Most HIV-infected children who are eligible for ART are still not being treated, and ART coverage among children lags significantly behind that among adults (28% versus 57% globally in 2011) (11) . Diagnosing and retaining children exposed to HIV and children infected with HIV in care also presents unique challenges because of their dependence on a caregiver. Loss to follow-up has been particularly high along the continuum of care (109) , with retention especially challenging for children who are in HIV care but not yet eligible for ART. Some countries are already introducing immediate ART for children younger than five years based on operational and programmatic grounds (110,111) . The 2010 WHO guidelines aligned clinical and immunological criteria for ART eligibility for children older than five years with those for adults (that is, treat for WHO clinical stage 3 or 4 disease or CD4 ≤ 350 cells/mm 3 ) (105) . They also recommended treating all children infected with HIV younger than two years of age regardless of clinical or immunological status. For children between two and five years of age, it was recommended that those with WHO stage 3 or 4, clinical disease or CD4 <25% or ≤750 cells/mm 3 be treated (105) . The review of evidence in 2013, together with operational considerations and values and preferences expressed by care providers, has led to revised recommendations to simplify and expand treatment in children, including initiating ART in all children up to five years and to increase the CD4 count threshold for ART initiation to ≤ 500 cells/mm³ in children 5 years and older, aligning with the new threshold in adults. New

110

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Rationale and supporting evidence These recommendations are based on strong operational and programmatic advantages resulting from simplification of criteria for initiating ART, despite the lack of clinical benefits to support treatment regardless of CD4 or clinical stage beyond infancy. Similarly, for programmatic purposes and given that disease progression in children five years and older is comparable to that of young adults, alignment with ART initiation criteria for adults was considered of high value. Evidence for increasing the age threshold for early ART to five years CD4 count and WHO clinical stage can identify children at increased risk of disease progression and death. Previous recommendations were based on observational studies demonstrating that untreated children in the second year of life continue to experience high rates of death and illness compared with children without HIV (106). Child-survival curves suggest that the mortality for children older than two years of age and with CD4 exceeding 25% is about 1–2% per year (107,108). A systematic review identified only one randomized clinical trial, PREDICT (112) , informing this issue (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The trial enrolled 300 children (1–12 years old, median age 6.4 years) with CD4 counts above 15% and without CDC clinical stage C disease, randomizing them to either immediate treatment or deferred treatment until the CD4 count fell below 15%. AIDS-free survival, neurodevelopmental outcomes and growth parameters did not differ between groups (113). A causal modelling study was also undertaken using prospective data collected by the IeDEASouthern Africa network on 5732 ART-naive children 24–59 months old (median age 3.3 years) who had CD4 counts above the existing eligibility thresholds of 25% or 750 cells/mm3 (114) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). The study did not show any survival benefit from early treatment in this population, but a large proportion of children in this age range would rapidly become eligible under the existing criteria, since most children with CD4 count of 750 cells/mm3 or higher at enrolment into care reached the CD4 treatment threshold within three years. More specifically, 32% of this subset of the cohort fell below the thresholds for eligibility after one year and 60% after two years. Operational and programmatic advantages Despite the lower risk of progression in children 2–5 years old compared with children younger than two years and the low quality of evidence, the Guidelines Development Group emphasized the operational and programmatic advantages of removing the CD4 barrier to treatment for children under 5 years of age. Treating all children younger than five years of age is expected to simplify paediatric treatment and facilitate a significant expansion of ART coverage for young children. Although this has not been assessed as an outcome, programmatic data suggest that retention is better among children on ART than among those in care but not started on ART (109). Increasing ART coverage and targeting these children for HIV care may also facilitate the treatment of other preventable causes of under-five mortality. This approach will likely represent a small increased burden on current systems (115). Note that late diagnosis is still occurring, and a large proportion of the children identified as infected with HIV would already be eligible for ART based on the 2010 recommendations. Community values and preferences Expanding ART to every child younger than five years of age is expected to be well accepted. Assessment of the values and preferences of people living with HIV, caregivers and health care providers of children with HIV showed that earlier initiation is preferable because it is believed to facilitate family-based care, prevent loss to follow-up and improve adherence (116). Nevertheless, there is a risk of resistance if treatment is initiated early in young children and

7. Clinical guidance across the continuum of care: antiretroviral therapy

111

adherence is poor or drug supplies are suboptimal; this is particularly the case for the youngest children, among whom harmonizing the formulations for children and adults is most difficult. However, the benefits of treatment are likely to outweigh these risks. Where access to immunological testing is limited, the burden of paediatric HIV disease is high and paediatric ART coverage is low, simplifying the eligibility criteria for initiating ART may significantly improve the overall health outcomes for children with HIV (117). National programmes need to determine how best to implement this recommendation and whether to recommend universal treatment for all children younger than five years or to focus on universal treatment for infants younger than one year and apply clinical and immunological criteria for children one to five years old. When ART initiation is expanded regardless of clinical and immunological status beyond infancy to all children younger than five years, treatment of children younger than two years should be given priority because of their higher risk of death and rapid disease progression. In addition, expanding ART services will require ensuring retention in care and should be matched with concomitant expansion of interventions to support adherence. Evidence for increasing the CD4 threshold to 500 cells/mm3 The criteria for initiating ART in children five years of age and older are the same as for adults. Although there are limited data to assess the clinical impact of treating children with a CD4 count between 350 and 500 cells/mm3 and the benefits of ARV drugs in preventing sexual transmission are not a factor for this population, this approach has programmatic advantages resulting from harmonizing the criteria with those for adults. It may be most feasible in settings with high ART coverage. As in the case of adults, treating children with CD4 counts ≤350 cells/ mm3 should be a high priority since they have the highest risk of disease progression. Coinfection with HIV and HBV Small cohort studies in which both HIV and HBV are endemic report rates of chronic HBV among children with HIV between 1% and 49% (118). HBV is often acquired in infancy or early childhood and, unlike among adults, may have an immunotolerant phase that lasts throughout childhood and adolescence. Unfortunately, the natural history of the disease among children with HIV is still poorly known, and the benefits from initiating ART earlier in these children remain to be assessed. Clinical considerations for scaling up ART among children Section 10.6 discusses implementation considerations relevant to programme managers (see Box 10.6). An additional important implementation consideration for clinicians and other health care providers is that expanding the initiation of ART regardless of clinical and immunological status to children younger than five years eliminates the need for determining the CD4 count to initiate treatment in this age group and avoids delaying ART in settings without access to CD4 testing. However, the availability of CD4 testing, including determining the baseline CD4 count and percentage, remains important to ensure appropriate treatment monitoring in the absence of viral load monitoring.

7.1 When to start ART

Key research gaps More data are needed to define potential clinical benefits and the impact of initiating ART early on morbidity for children younger than five years as well as immunological response and virological response over time. The impact of initiating ART earlier on retention, adherence and potential HIV drug resistance among children with less advanced disease needs to be investigated further. Data are also needed to inform the optimal approach to initiating ART in children coinfected with HBV.

112

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.2 What ART regimen to start with (first-line ART) Using simplified, less toxic and more convenient regimens as fixed-dose combinations is recommended for first-line ART. Once-daily regimens comprising a non-thymidine NRTI backbone (TDF + FTC or TDF + 3TC) and one NNRTI (EFV) are maintained as the preferred choices in adults, adolescents and children older than three years. For children younger than three years, a PI-based regimen is the preferred approach (Table 7.5).

Table 7.5 Summary of first-line ART regimens for adults, adolescents, pregnant and breastfeeding women and children First-line ART Preferred first-line regimens Alternative first-line regimens a b AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + NVP TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV Adolescents (10 to 19 years) ≥35 kg AZT + 3TC + NVP TDF + 3TC (or FTC) + NVP ABC + 3TC + EFV (or NVP) ABC + 3TC + NVP AZT + 3TC + EFV Children 3 years to less than 10 years and adolescents <35 kg ABC + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP Children <3 years ABC or AZT + 3TC + LPV/r ABC + 3TC + NVP AZT + 3TC + NVP

Adults (including pregnant and breastfeeding women and adults with TB and HBV coinfection)

or adolescents, using d4T as an option in first-line treatment should be discontinued and restricted to special cases in which F other ARV drugs cannot be used and to the shortest time possible, with close monitoring. For children, d4T use should be restricted to the situations in which there is suspected or confirmed toxicity to AZT and lack of access to ABC or TDF. The duration of therapy with this drug should be limited to the shortest time possible. See Box 10.7 for guidance on phasing out d4T. b ABC or boosted PIs (ATV/r, DRV/r , LPV/r) can be used in special circumstances. a

7. Clinical guidance across the continuum of care: antiretroviral therapy

113

7.2 What ART regimen to start with (first-line ART)

7.2.1 First-line ART for adults New recommendations First-line ART should consist of two nucleoside reverse-transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse-transcriptase inhibitor (NNRTI) • TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART (strong recommendation, moderate-quality evidence). New

• If TDF + 3TC (or FTC) + EFV is contraindicated or not available, one of the following options is recommended: • AZT + 3TC + EFV • AZT + 3TC + NVP • TDF + 3TC (or FTC) + NVP (strong recommendation, moderate-quality evidence). Countries should discontinue d4T use in first-line regimens because of its wellrecognized metabolic toxicities (strong recommendation, moderate-quality evidence).

Table 7.6 Summary of first-line ART regimens for adultsa First-line ART for adults (including pregnant and breastfeeding women and people with TB and HBV coinfection) Preferred regimens Alternative regimens Special circumstancesc a

TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP) TDF + 3TC (or FTC) + NVP Regimens containing ABC, d4Tb and boosted PIs

For adolescents, see section 7.2.4 on first-line ART for children three years and older which includes adolescents infected with HIV (10 years and older). b Using d4T as an option in first-line treatment should be discontinued and restricted to special cases in which other ARV drugs cannot be used. The duration of therapy with this drug should be limited to the shortest time possible and include close monitoring. c S pecial circumstances may include situations where preferred or alternative regimens may not be available or suitable because of significant toxicities, anticipated drug-drug interactions, drug procurement and supply management issues, or for other reasons.

New

Background The 2010 WHO ART guidelines (2) recommended that ART in treatment-naive adults should initially consist of an NNRTI (either NVP or EFV) plus two NRTIs, one of which should be 3TC (or FTC) and the other AZT or TDF. The guidelines emphasized the importance of avoiding d4T as a preferred option in first-line regimens because of its well-known mitochondrial toxicity, using regimens that are potentially less toxic and more suitable for most people, preferably as fixed-dose combinations given the clinical, operational and programmatic benefits. The recommended regimens had better toxicity profiles than d4T but were considered comparable in terms of efficacy, since there was no evidence that AZT is virologically superior to d4T, AZT superior to TDF, TDF superior to d4T or ABC, or EFV superior to NVP.

114

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

The phasing out of d4T as a preferred option in first-line ART has been variable. Some countries have made rapid and substantial progress, whereas others have taken a gradual approach, such as avoiding d4T only for people starting ART or not using d4T in pregnant women (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). WHO (119,120) promotes a more affordable and efficient approach to treatment, including simpler, single-pill, once-daily ART regimens. The 2013 guidelines promote further simplification of ART delivery by reducing the number of preferred first-line regimens and focusing on regimens that may be used across a range of populations.

Rationale and supporting evidence The move to TDF + 3TC (or FTC) + EFV as the preferred first-line option A systematic review comparing six regimens showed moderate-quality evidence indicating that a once-daily combination of TDF + 3TC (or FTC) + EFV is less frequently associated with severe adverse events and has a better virological and treatment response compared with other once- or twice-daily regimens (Web Annex www.who.int/hiv/pub/guidelines/ arv2013/annexes). An additional systematic review showed people receiving NVP are twice as likely as those receiving EFV to discontinue treatment because of adverse events (121) . The Guideline Development Group also reviewed a published meta-analysis and a further updated analysis (122, 123) that showed no increased risk of birth defects with EFV compared with other ARV drugs used during the first trimester of pregnancy (122) . 3TC and FTC are pharmacologically comparable (123) . TDF + 3TC (or FTC) + EFV offers good potential for harmonizing treatment across different populations: TDF/FTC or TDF/3TC are the preferred NRTI backbone for people coinfected with HIV and HBV and can be used among people coinfected with TB and among pregnant women. EFV is the preferred NNRTI for people with HIV and TB (pharmacological compatibility with TB drugs) and HIV and HBV coinfection (less risk of hepatic toxicity) and can be used among pregnant women, including those in the first trimester. If TDF + 3TC (FTC) + EFV cannot be used, other once- or twice-daily NNRTI-containing regimens (AZT + 3TC + EFV, AZT + 3TC + NVP, and TDF + 3TC (or FTC) + NVP) can be used as alternative first-line regimens in ART-naive people. Despite being considered equivalent options, they have potential disadvantages compared with preferred regimens. Use of other drugs such as ABC and boosted PIs are acceptable as potential backup options in special situations but are not recommended as preferred alternatives, considering the principles of optimizing ARV drugs. NVP in pregnant women There are continued concerns about the higher risk of adverse events with NVP compared with EFV, and about the use of NVP in women with HIV with CD4 cell counts above 250 cells/mm3, with some studies showing an increased relative risk for severe hepatic and skin reactions in pregnant women using NVP at higher CD4 cell counts (124–126). A systematic review (127), updated in 2013 (134) of the risk of NVP-associated toxicity in pregnant women suggests that the frequency of adverse events is elevated but no higher than that observed in the general adult population. The evidence supporting the theory that pregnant women with HIV who have high CD4 counts are at increased risk of adverse events compared with the general population with HIV is weak. The need for lead-in dosing for initial use of NVP and the fact that it is not available as a fixed-dose combination with TDF + 3TC (or FTC) are important considerations. NVP should therefore be used with caution in pregnant women and women who might be pregnant and only after considering the risk and benefits and available alternatives (see section 7.3.2).

7. Clinical guidance across the continuum of care: antiretroviral therapy

115

Alternatives to NVP, such as ABC and boosted PIs, are acceptable but should only be used when NVP is not available. Using alternative regimens and phasing out d4T The currently recommended alternative regimens (such as AZT instead of TDF or NVP instead of EFV (Table 7.7) are comparable in therapeutic efficacy but have potential clinical and programmatic disadvantages compared with the preferred options. Individuals who are already clinically stable on an alternative regimen with no contraindications can consider continuing that regimen based on national guidance or switch to the preferred options to simplify treatment management, reduce cost, improve tolerability, enhance adherence and promote better regimen sequencing. In special circumstances, ABC and boosted PIs are acceptable but should only be used when other options are not available. Use of d4T-containing regimens should be discontinued and restricted to cases in which other ARV drugs cannot be used, and the duration of therapy with this drug should be limited to the shortest time possible and include close monitoring. In settings in which d4T regimens are still used as a preferred option for initiating ART, a plan for phasing out d4T should be implemented, preferably towards using TDF-based first-line regimens (2,128,129) . Section 10.6 (Box 10.7) further discusses the issue of phasing out d4T. TDF toxicity A systematic review on TDF toxicity (Web Annex www.who.int/hiv/pub/guidelines/ arv2013annexes) indicates that TDF has a low rate of renal toxicity in the short to medium term, especially among people with pre-existing, or risk factors for, renal disease. Prospective cohort data show that TDF is associated with modest reduction in renal function (measured by the decrease in the estimated glomerular filtration rate) (130,131) and reduction in bone mineral density, but the clinical significance and magnitude of these side effects, especially with prolonged therapy, need to be investigated further. Further research is also needed to determine whether laboratory screening and monitoring of TDF toxicity should be routine or undertaken only in high-risk populations, such as people with hypertension or diabetes or those using boosted PIs. Since TDF renal toxicity is usually tubular, glomerular function tests do not provide a direct measure, and no other simple test can detect renal tubular toxicity. Section 7.4 discusses this issue further. Evidence suggests that the overall improvement in renal function resulting from ART can offset the risk of TDF toxicity among people with HIV who do not have secondary renal disease. HIV-2 infection A systematic review of treatment options for individuals with HIV-2 (Web Annex www. who.int/hiv/pub/guidelines/arv2013/annexes) rated the evidence in all observational studies as being of very low quality, with serious risk of bias, inconsistency and imprecision. Since HIV-2 is naturally resistant to NNRTIs, treatment-naive people coinfected with HIV-1 and HIV-2 should be treated with a regimen containing three NRTIs (TDF + 3TC (or FTC) + AZT or AZT + 3TC + ABC or a ritonavir-boosted PI plus two NRTIs. If a PI-based regimen is used, the preferred option for first-line therapy should be LPV/r, since this will be procured in low-income settings for both second-line treatment for adults and for first-line treatment for children. SQV/r and DRV/r are alternative boosted-PI options, but they are not available as heat-stable fixed-dose combinations.

7.2 What ART regimen to start with (first-line ART)

116

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.2.2 First-line ART for pregnant and breastfeeding women and ARV drugs for their infants New recommendations New

A once-daily fixed-dose combination of TDF + 3TC (or FTC) + EFV is recommended as first-line ART in pregnant and breastfeeding women, including pregnant women in the first trimester of pregnancy and women of childbearing age. The recommendation applies both to lifelong treatment and to ART initiated for PMTCT and then stopped (strong recommendation, low- to moderate-quality evidence: moderate-quality evidence for adults in general but low-quality evidence for the specific population of pregnant and breastfeeding women and infants) . Infants of mothers who are receiving ART and are breastfeeding should receive six weeks of infant prophylaxis with daily NVP. If infants are receiving replacement feeding, they should be given four to six weeks of infant prophylaxis with daily NVP (or twice-daily AZT). Infant prophylaxis should begin at birth or when HIV exposure is recognized postpartum (strong recommendation, moderate-quality evidence for breastfeeding infants; strong recommendation, low-quality evidence for infants receiving only replacement feeding) . Note: For the recommendations on infant prophylaxis, the GRADE ratings and recommendations shown are from the 2010 guidelines and were not reviewed by the Guidelines Development Group for the current guidelines.

Background The 2010 WHO guidelines on PMTCT (82) recommended a choice of four different regimens for pregnant and breastfeeding women with HIV who required ART for their own health: AZT + 3TC or TDF + 3TC (or FTC) plus either NVP or EFV. Because of concerns about the increased risk of toxicity of NVP among pregnant women with higher CD4 counts (132–134) , the recommended regimens for pregnant women who did not require treatment for their own health and who were receiving triple ARV regimens for PMTCT were AZT + 3TC or TDF + 3TC (or FTC) + EFV as the preferred NNRTI regimens. Alternative regimens were AZT + 3TC plus either LPV/r or ABC, rather than NVP. Although TDF and EFV were recommended, there were limited safety data on their use during pregnancy and breastfeeding. The 2010 WHO guidelines (82) also recommended four to six weeks of infant NVP (or AZT) as post-exposure prophylaxis for all infants born to mothers who were receiving triple ARV regimens for treatment or prevention. Daily NVP infant prophylaxis throughout breastfeeding was recommended if the mother was not receiving a triple ARV regimen. In clinical trials, infant prophylaxis has been shown to be especially important for PMTCT when the mother has received limited or no antepartum ARV drugs and when viral suppression has not yet been achieved (135–137) . This continues to be a recommended component of PMTCT regimens in resource-rich countries as added protection against exposure to HIV during labour, even when mothers receive ART during pregnancy and when the mother is not breastfeeding (138) . The data informing this recommendation have not changed since 2010.

7. Clinical guidance across the continuum of care: antiretroviral therapy

117

Rationale and supporting evidence The 2013 guidelines emphasize simplifying and harmonizing first-line therapy. A once-daily fixed-dose combination regimen is recommended, with TDF as the preferred NRTI and EFV as the preferred NNRTI, in combination with 3TC or FTC for all adults – including pregnant and breastfeeding women – as the preferred regimen to improve health outcomes and facilitate adherence and drug procurement (see section 7.2.1 and Web Annex www.who. int/hiv/pub/guidelines/arv2013/annexes). The ideal first-line regimen for pregnant and breastfeeding women with HIV has low cost; is available as a fixed-dose combination; is safe for both pregnant and breastfeeding women and their infants; is well tolerated; has low monitoring requirements and a low drug-resistance profile; is compatible with other drugs used in clinical care; and is harmonized with the recommendations for non-pregnant adults. The regimen of TDF + 3TC (or FTC) + EFV is available as a once-daily fixed-dose combination and is the recommended first-line regimen for adults because of simplicity, affordability (the cost has declined significantly since 2010) and efficacy against HBV. Safety is a critical issue for pregnant and breastfeeding women and their infants as well as women who might become pregnant. Although data on EFV and TDF use in pregnant women remain limited, more data have become available since 2010 and provide increased reassurance for recommending TDF + 3TC (or FTC) + EFV as the first-line ARV regimen for pregnant and breastfeeding women (122,139,140). Sections 7.3.1 and 7.5.2 provide more detail on the overall rationale for the recommended first-line regimen, including toxicity and monitoring issues. Safety of EFV in pregnancy Early data suggesting birth defects, including anencephaly, microphthalmia and cleft palate among primates with EFV exposure in utero (141) and some isolated case reports and retrospective clinical data on neural tube defects among humans (142) have led to concern about using EFV in the first trimester of pregnancy or in non-pregnant women with childbearing potential. The United States Food and Drug Administration and European Medicines Agency advise against using EFV in the first trimester and in women of childbearing potential unless the potential benefits outweigh the potential risks; however, the British HIV Association recently changed its recommendation to allow EFV to be used in the first trimester (143) . Because the risk of neural tube defects is limited to the first five to six weeks of pregnancy and because pregnancy is rarely recognized this early, especially in resource-limited settings, any potential risk of neural tube defects with the use of EFV would be primarily in women who become pregnant while already receiving EFV. Evaluation of prospectively collected data in humans is reassuring; an updated systematic review and meta-analysis, including the Antiretroviral Pregnancy Registry (47,134) , reported outcomes for 1502 live births to women receiving EFV in the first trimester and found no increase in overall birth defects and no elevated signal for EFV compared with other ARV exposure in pregnancy (140) . With one identified neural tube defect, the estimated prevalence from the systematic review continues to be about 7 per 10 000 population (0.07%), which is comparable to the estimates of 0.02–0.2% in the general population in the USA (138) . Because neural tube defects are relatively rare events and there are limited exposures in the Antiretroviral Pregnancy Registry and in the meta-analyses, current available data are sufficient to rule out a potential increased risk greater than three-fold or up to 0.21% (the more limited data available for the 2010 guidelines were sufficient to rule out a 10-fold increased risk). Although the Guidelines Development Group emphasized that better data on birth defects are needed, it felt confident that this potential low risk should be balanced against the programmatic advantages and the clinical benefit of EFV in preventing HIV infection in infants and for the mother’s health.

New

7.2 What ART regimen to start with (first-line ART)

118

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Safety of NVP in pregnancy: (see section 7.2.1) Safety of TDF in pregnancy and during breastfeeding Potential concerns about the safety of TDF include renal toxicity (see section 7.4.3), adverse birth outcomes and effects on bone density. A systematic review assessed the toxicity of fetal exposure to TDF in pregnancy (Web Annex www.who.int/hiv/pub/ guidelines/arv2013/annexes). In the Antiretroviral Pregnancy Registry, the prevalence of overall birth defects with exposure to TDF in the first trimester was 2.4% of 1612 live births and did not differ from the background rate in the USA. A limited number of studies showed no difference in fetal growth between infants exposed or not exposed to TDF (144,145) . TDF has limited penetration into breast-milk, which would limit potential toxicity for the breastfeeding infant. However, there have been no studies of TDF among lactating women, who normally have bone loss during breastfeeding that stabilizes after lactation. More extensive studies are ongoing of TDF bone and renal safety in pregnancy and breastfeeding for both the mother and child. The once-daily TDF + 3TC (or FTC) + EFV fixed-dose regimen is simple and convenient, and harmonizing the recommendations for pregnant and non-pregnant women simplifies supply chain management. Based on available data and experience, the Guidelines Development Group felt that the clear benefits of this regimen for pregnant and breastfeeding women (and women of childbearing potential) outweigh the potential risks (see section 7.5.2). Infant prophylaxis

Table 7.8 Simplified infant prophylaxis dosing recommendations (adapted from (82) ) Simplified infant prophylaxis dosing recommendations: NVP Infant age Birtha to 6 weeksb • Birthweight 2000−2499 g • Birthweight ≥2500 g > 6 weeks to 6 monthsc > 6 months to 9 months > 9 months until breastfeeding ends a b

Daily dosing 10 mg once daily 15 mg once daily 20 mg once daily 30 mg once daily 40 mg once daily

Infants weighing <2000 g should receive mg/kg dosing; the suggested starting dose is 2 mg/kg once daily. Recommended for 6 weeks, but 4 weeks may be considered in settings with replacement feeding. c Dosing beyond 6 weeks of age in special situations in which prolonged dosing of up to 12 weeks should be considered (such as the mother having had limited ART and not being likely to be virally suppressed; the infant is identified as HIV exposed after birth and is breastfeeding (Table 7.9). This is based on the dosing required to sustain exposure among infants of >100 ng/ml with the least dose changes.

7. Clinical guidance across the continuum of care: antiretroviral therapy

119

Simplified infant prophylaxis dosing recommendations: AZT (only recommended in settings with replacement feeding) Infant age Birth a to 6 weeks • Birthweight 2000−2499 g a • Birthweight ≥2500 g a

7.2 What ART regimen to start with (first-line ART)

Daily dosing 10 mg twice daily 15 mg twice daily

Infants weighing <2000 g should receive mg/kg dosing; the suggested starting dose is 2 mg/kg once daily.

No new data inform any change in the recommendations on infant prophylaxis. For breastfeeding infants, six weeks of infant NVP is recommended; for infants receiving replacement feeding, four to six weeks of infant NVP or AZT continues to be recommended. If toxicity from infant NVP requires discontinuing the drug or if infant NVP is not available, infant 3TC can be substituted. Several studies (146,147) have safely used infant prophylaxis during breastfeeding with 3TC. Although the Guidelines Development Group did not formally review this, it considered several scenarios in which longer infant prophylaxis might be appropriate. Because several weeks or months are required for maternal ART to achieve viral suppression and a breastfeeding infant may not be protected against postnatal transmission during that period, or when a breastfeeding mother initiates ART very late in pregnancy (such as less than four weeks prior to delivery) during labour or postpartum, increasing the duration of infant NVP prophylaxis to 12 weeks can be considered. Infant prophylaxis is also important when a breastfeeding mother interrupts ART during breastfeeding, as this places her infant at increased risk of postnatal transmission. In such situations, providing daily infant NVP during the period of maternal ART interruption should be considered, and this could be stopped six weeks after maternal ART is restarted (or one week after breastfeeding ends, whichever comes first). Table 7.9 summarizes the range of scenarios for maternal and infant prophylaxis.

120

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 7.9 Summary of maternal and infant ARV prophylaxis for different clinical scenarios Scenario Mother diagnosed with HIV during pregnancyc,d Mother diagnosed with HIV during labour or immediately postpartum and plans to breastfeed Mother diagnosed with HIV during labour or immediately postpartum and plans replacement feeding Infant identified as HIV exposed after birth (through infant or maternal HIV antibody testing) and is breastfeeding Maternal ARV prophylaxis a Initiate maternal ART Initiate maternal ART Infant ARV prophylaxisb NVPc Duration of infant ARV prophylaxis 6 weeksc 6 weeks; consider extending this to 12 weeks

NVP

Refer mother for HIV care and evaluation for treatment

NVPc

6 weeksc

Initiate maternal ART

NVP

Perform infant PCR early infant diagnosis test and then immediately initiate 6 weeks of NVP – strongly consider extending this to 12 weeks Do HIV PCR test in accordance with national recommendations on early infant diagnosis; no infant ARV prophylaxis; initiate treatment if the infant is infected Until 6 weeks after maternal ART is restarted or until 1 week after breastfeeding has ended

Infant identified as HIV exposed after birth (through infant or maternal HIV antibody testing) and is not breastfeeding

Refer mother for HIV care and evaluation for treatment

No drug

Mother receiving ART but interrupts ART regimen while breastfeeding (such as toxicity, stock-outs or refusal to continue) a

Determine an alternative ART regimen or solution; counsel regarding continuing ART without interruption

NVP

Ideally, obtain the mother’s CD4 cell count at the time of initiating or soon after initiating ART; country guidelines should be used to determine whether ART is lifelong or is stopped after the risk for transmission has ended. b If infant NVP causes toxicity or NVP is not available, 3TC can be substituted. c If the mother is using replacement feeding, infant AZT can be substituted for infant NVP; if there is documented maternal viral suppression near delivery for a mother receiving ART and using replacement feeding, four weeks of infant ARV prophylaxis may be considered. d If it is known that the mother has initiated ART less than 4 weeks before delivery, consider extending infant NVP for infants who are breastfeeding to 12 weeks.

7. Clinical guidance across the continuum of care: antiretroviral therapy

121

Alternative regimens: for toxicity, intolerance or lack of availability of recommended regimens AZT is recommended as the alternative NRTI for non-pregnant women who cannot tolerate or receive TDF. Given the extensive safety and efficacy data on AZT in pregnant and breastfeeding women, AZT is also the recommended alternative NRTI for pregnant and breastfeeding women. For non-pregnant women who cannot tolerate or receive EFV, the recommended alternative NNRTI is NVP. However, because ART (triple ARV drugs) is now recommended for pregnant and breastfeeding women regardless of CD4 cell count, concerns remain regarding the use of NVP in women with higher CD4 counts. Although the 2010 guidelines (2,82) stated that the benefit of NVP outweighed the risk for women with CD4 counts of 250 to 350 cells/ mm3, data on safety in women with CD4 counts ≥350 cells/mm3 are limited, and the finding of life-threatening hepatic toxicity when NVP was used for occupational post-exposure prophylaxis in individuals without HIV infection raises concerns regarding its use for individuals with higher CD4 count. However, a recent systematic review of the risk of NVP-associated toxicity in pregnant women (134) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/ annexes) suggests that the frequency of adverse events is no higher than that in the general adult population. Further, data on the association between NVP toxicity and elevated CD4 cell counts are conflicting, and the risk of significant hepatic toxicity in most studies is about 3% (121). Data suggest that switching to NVP for individuals who have been treated and had viral suppression is not associated with elevated toxicity even where the immune system has reconstituted. Finally, the alternative to substituting NVP for EFV toxicity would be a PI, which is the recommended second-line therapy and is more expensive than NNRTI drugs. On balance, the Guidelines Development Group held that the overall benefit of substituting NVP for pregnant or breastfeeding women in the rare circumstances that EFV is not tolerated outweighs the potential risks.

7.2 What ART regimen to start with (first-line ART)

Clinical considerations Maintaining the drug supply chain and ensuring uninterrupted delivery of maternal ART and infant ARV drugs during pregnancy and breastfeeding are critical for PMTCT. All antenatal care and maternal and child health sites providing PMTCT services should have the capacity to initiate, support and monitor ongoing maternal ART and infant ARV drugs.

Key research gaps Surveillance of ARV drug toxicity. Research is needed to continue to evaluate both the short- and long-term effects of EFV, TDF and other ARV drugs on pregnant and breastfeeding women, fetuses and children, including monitoring for birth defects and other adverse pregnancy outcomes and evaluating the renal and bone effects of TDF on both the woman and HIV-exposed infant. Acceptability of EFV as first-line ART. The level of intolerance to EFV and whether switching to an alternative first-line regimen is necessary needs to be studied further, as do ways to support alternative first-line regimens in programme settings for pregnant and breastfeeding women. Infant prophylaxis. Better data are needed on the optimal duration of infant prophylaxis when mothers receive ART, especially if the mother starts ART late in pregnancy or during the postpartum period and hence is not virally suppressed at the time of delivery or when breastfeeding begins. NVP formulations that are improved and easier to administer are needed to facilitate drug administration to neonates and infants. Optimal management of infants identified as HIV exposed during breastfeeding. It is important to determine the extent to which perinatal HIV exposure is missed antenatally

122

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

and the extent of maternal seroconversion, appropriate strategies for postpartum screening of infants for HIV exposure and optimal testing and prophylaxis strategies. Stopping NNRTI-based ART (use of a “tail”) . Because of the prolonged half-life of EFV (and NVP), suddenly stopping an NNRTI-based regimen risks developing NNRTI resistance. For women who choose to or must stop EFV-based ART because of toxicity or other conditions, more data are needed to determine whether an NRTI “tail” coverage is needed to reduce this risk. Pharmacokinetic modelling reviewed for the guidelines suggests that, if the NRTI backbone included TDF, such a tail may not be needed, but if the NRTI backbone included AZT, a two-week tail is advisable (EFV has a longer half-life than NVP).

7.2.3 First-line ART for children younger than three years of age New recommendations New

A LPV/r-based regimen should be used as first-line ART for all children infected with HIV younger than three years (36 months) of age, regardless of NNRTI exposure. If LPV/r is not feasible, treatment should be initiated with a NVP-based regimen (strong recommendation, moderate-quality evidence). Where viral load monitoring is available, consideration can be given to substituting LPV/r with an NNRTI after virological suppression is sustained (conditional recommendation, low-quality evidence). Special note: The randomized control trial supporting the use of this approach (148,161) defined virological suppression as a viral load ≤400 copies/mm 3, with the goal of identifying the children who are more likely to be able to safely substitute LPV/r with NVP. The use of a higher viral load cut-off for determining virological suppression has not been studied in the context of this strategy.

For infants and children infected with HIV younger than three years, ABC + 3TC + AZT is recommended as an option for children who develop TB while on an ART regimen containing NVP or LPV/r. Once TB therapy has been completed, this regimen should be stopped and the initial regimen should be restarted (strong recommendation, moderate-quality evidence). For infants and children infected with HIV younger than three years, the NRTI backbone for an ART regimen should be ABC or AZT + 3TC (strong recommendation, low-quality evidence).

Table 7.10 Summary of first-line ART regimens for children younger than three years Preferred regimens Alternative regimens Special circumstancese ABCa or AZT + 3TC + LPV/rb ABCa or AZT + 3TC + NVPc d4Td + 3TC + LPV/r d4Td + 3TC + NVP Based on the general principle of using non-thymidine analogues in first-line regimens and thymidine analogues in secondline regimens, ABC should be considered as the preferred NRTI whenever possible. The CHAIN working group developed this recommendation. Availability and cost should be carefully considered. b As recommended by the United States Food and Drug Administration, using LPV/r oral liquid should be avoided in premature babies (born one month or more before the expected date of delivery) until 14 days after their due date or in full-term babies younger than a

7. Clinical guidance across the continuum of care: antiretroviral therapy 14 days of age. Dosing for children younger than 6 weeks should be calculated based on body surface area (Annex 3). During the finalization of these guidelines, the United States Food and Drug Administration approved the use of EFV in children 3 months to 3 years old weighing more than 3.5 kg. Due to the limited data to inform the best use of this drug in the use of this drug in this age group, the Guidelines Development Group agreed to maintain NVP as the recommended NNRTI for children under 3 years. WHO will provide further guidance as soon as the additional data become available. d Because of the limited options available for children younger than three years, d4T is still included among the recommended NRTIs, but its use should be restricted to the situations in which toxicity to AZT is suspected or confirmed and ABC cannot be used. The duration of therapy with this drug should be limited to the shortest time possible. Box 10.7 provides guidance on phasing out d4T. e S pecial circumstances may include situations where preferred or alternative regimens may not be available or suitable because of significant toxicities, anticipated drug-drug interactions, drug procurement and supply management issues, or for other reasons. c

123

7.2 What ART regimen to start with (first-line ART)

Background Optimizing first-line ART in children younger than three years is critical to achieving effective and rapid control of viral replication in the context of high viral load and rapid infant growth. Considerations that may require alternative therapeutic approaches include the limited availability of drugs in appropriate formulations, the long-term toxicities of ARV drugs, difficulty with adherence and the possibility of pre-existing viral resistance because of ARV drug exposure for PMTCT. Young children with HIV who are exposed to NNRTIs used for PMTCT have demonstrable viral resistance (150) , which compromises the response to NVP-containing first-line ART (151,152). For this reason, the 2010 WHO guidelines (105) recommended the use of LPV/r-based treatment in children younger than 24 months of age previously exposed to NNRTIs. For young children not exposed to NNRTIs or whose status was unknown, an NVP-based regimen was recommended (105). New evidence has become available for this age group suggesting the superiority of a LPV/r-based regimen regardless of PMTCT exposure (153,154). Several strategies have also been tested to overcome the challenges of using LPV/r-based regimens or to provide potent alternatives in settings in which using LPV/r is not feasible or is problematic because of the high prevalence of TB. (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes).

Rationale and supporting evidence This recommendation is based on evidence of the superiority of a LPV/r-based regimen for young children balanced against feasibility considerations. Efficacy of a LPV/r-based regimen for infants and young children A systematic review of two randomized trials (153,154) shows that children younger than 36 months have a reduced risk of discontinuing treatment and virological failure or death if they are started on a LPV/r-based regimen instead of a NVP-based regimen. At 24 weeks, LPV/r was demonstrated to be superior to NVP regardless of NNRTI exposure for PMTCT (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). In addition, surveillance of drug resistance among children younger than 18 months (149,155) provides further evidence of detectable NNRTI resistance even among children without any history of exposure to ARV drugs for PMTCT or whose exposure status is unknown, suggesting that a history of exposure for PMTCT may not be an accurate marker for identifying children at higher risk of HIV resistance to NNRTI. LPV/r is known to have a better resistance profile that protects against the selection of NRTI resistance without compromising the use of other PIs in second-line regimens (156,157–159). In addition, a potential advantage is offered by the considerable reduction in the incidence of malaria among children receiving LPV/r-based, as recently demonstrated in a randomized trial comparing the use of LPV/r versus NVP or EFV among children in Uganda receiving an artemether + lumefantrine combination for treating malaria episodes (160). New

124

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Feasibility of LPV/r in resource-limited settings Providing an LPV/r-based regimen to infants and children younger than three years in some resource-limited settings may be challenging. The current LPV/r syrup formulation has coldchain requirements until the point of dispensing. The syrup is unpalatable, with the potential for suboptimal adherence, as highlighted in the values and preferences survey among health workers, and the risk of metabolic complications among children who initiate LPV/r early in life is unknown. Further, LPV/r is costly and administering this with TB treatment is complex. Alternative approaches are proposed to overcome these challenges. A recent randomized clinical trial (148,161) and an ongoing randomized clinical trial (162) have evaluated a strategy in which LPV/r is started and later substituted with an NNRTI (NVP or EFV). Such PI-sparing strategies aim to reduce exposure to LPV/r, offer an easier approach to maintaining treatment and preserve PI-based therapy for second-line ART. This approach has been shown to be safe and effective in the trial setting for children with sustained virological suppression achieved after receiving LPV/r-based first-line therapy, especially in the absence of HIV resistance to NNRTI before initiating ART (148,161). However, this approach may also add complexity to treatment programmes and may require access to virological monitoring. This strategy may therefore only be viable in settings in which viral load and/or genotype testing are available. In settings in which none of these approaches is feasible or affordable, an NVP-based regimen provides an effective alternative, especially given the availability of two- and three-drug fixed-dose combinations. As observed in a recent randomized controlled trial, good virological outcomes (83% had a viral load less than 400 copies per ml for 3.7 years irrespective of age) can be achieved by starting children on ABC, 3TC and an NNRTI (163). EFV has not been used in this age group, however during the finalization of these guidelines the United States Food and Drug Administration approved this drug for children 3 months to 3 years old weighing more than 3.5 kg. Dosing for this population is provided in Annex 7 and further guidance on how best to use this drug as an alternative to LPV/r or NVP will be provided when additional data are available. Choice of NRTIs The choice of NRTIs should aim to construct a robust and durable backbone that balances minimizing toxicity, minimizing cost and maximizing feasibility. Only limited evidence (164) from head-to-head comparisons informs the selection of NRTIs (AZT or ABC) combined with 3TC in a triple ART regimen. However, the choice of first-line NRTIs affects second-line ART, and failure of AZT is known to result in the accumulation of thymidine analogue mutations, reducing susceptibility to ABC or TDF in a subsequent regimen (if two or more thymidine analogue mutations are present). The risk of this occurring is greater with an NNRTI-based regimen; using it in the context of an LPV/r-based regimen may therefore not be as critical. By contrast, HIV resistance to ABC does not lead to resistance to thymidine analogues and preserves or even increases the susceptibility of HIV to AZT and d4T for second-line use (159). Although ABC may be preferable in the interest of ART sequencing (159,165) and harmonizing with the regimens for older children, availability is limited in resource-limited settings. In addition, the cost of ABC may be a significant barrier to adopting it in many countries, especially when combined with LPV/r. Definitive data on the comparative efficacy of ABC and AZT are expected from ongoing studies (166). Since 2010, WHO has recommended that d4T be phased out because of its known long-term toxicity. However, in settings in which using AZT may not be advisable because of the high risk of anaemia (such as malaria-endemic settings) and in which ABC is not available, d4T remains an option within the limited treatment options for this specific age group. d4T also remains important in the situation in which toxicity to AZT is suspected or confirmed and ABC cannot

7. Clinical guidance across the continuum of care: antiretroviral therapy

125

be used. However, the duration of therapy with this drug should be limited to the shortest time possible. Box 10.7 provides guidance on phasing out d4T. In developing these recommendations, the Guidelines Development Group emphasized: the importance of potent, first-line regimens for which there is evidence of better virological response as indicated by randomized controlled trials in this age group; the need to address the increasing evidence of HIV resistance to NNRTI among children younger than 18 months, especially in the context of the recommendation to treat pregnant women with EFV-based regimens for PMTCT; t he desirability of having one preferred regimen for children younger than three years while providing alternative strategies that remain less costly, preserve second-line options and address feasibility concerns; anticipating the availability of new formulations during the next few years (sprinkles or sachets containing LPV/r); using non-thymidine analogues in first-line regimens to preserve the response to AZT in second-line regimens and to harmonize the regimens for older children and adults, while also recognizing the additional expense; identifying a subset of children who can benefit from alternative strategies to preserve PIs for use in second-line ART as indicated by a randomized trial; and identifying a manageable regimen, such as ABC + 3TC + AZT, for use in the context of TB co-treatment that can maintain good clinical and immunological response after virological suppression on standard ART.

7.2 What ART regimen to start with (first-line ART)

Clinical considerations Section 10.6 (Implementations considerations for key recommendations, Box 10.6) discusses implementation considerations relevant to programme managers. An important consideration for clinicians and other health care providers relates to the challenges of providing LPV/r for young children. When clinicians anticipate significant difficulties in dealing with storing or administering LPV/r, using NVP (especially an NVP-based fixed-dose combination) can be considered. In addition, using LPV/r oral liquid should be avoided in premature babies or in fullterm babies younger than 14 days (167). Dosing for children younger than six weeks should be calculated based on body surface area (Annex 3).

Key research gaps The extent to which new approaches to PMTCT influence the resistance pattern of children becoming infected with HIV despite exposure to ARV drugs for PMTCT still needs to be fully explored outside trial settings. In addition, more evidence is needed to inform the optimal choice of NRTIs and to confirm the safety of EFV-containing regimens, as a first-line option or within PI-sparing strategies in the absence of viral load or genotyping. Studies to fully address the long-term metabolic implications of using LPV/r-based regimens for infants and young children are also needed.

126

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.2.4 First-line ART for children three years and older (including adolescents) New recommendations For children infected with HIV three years and older (including adolescents), EFV is the preferred NNRTI for first-line treatment and NVP is the alternative (strong recommendation, low-quality evidence). Special note: In determining the choice of NNRTI for first-line therapy, national programmes should consider the dosing characteristics of EFV (once-daily) and NVP (twice-daily) and how this aligns with the NRTI backbone. For example, NVP may be a better choice if the recommended regimen is a twice-daily option using a fixed-dose combination.

New

For children infected with HIV three years to less than 10 years old (or adolescents less than 35 kg), the NRTI backbone for an ART regimen should be one of the following, in preferential order: • ABC + 3TC • AZT or TDF + 3TC (or FTC) (Conditional recommendation, low-quality evidence).

Special note: Consideration should be given to the relative merits of ABC versus TDF versus AZT for this population. There is no definitive evidence to make a preferred recommendation, and each option has its respective risks and benefits. ABC can be used once daily, is available across age groups as a fixed-dose combination with 3TC and harmonizes with TDF from a resistance perspective (168) . AZT has been widely used and is available as dual and triple fixed-dose combinations with NVP but is dosed twice daily and can cause severe anaemia. TDF has recently been approved for use in children (169) , and the advantages include once-daily dosing. However, paediatric TDF formulations are not widely available, experience with TDF in children is limited and there are concerns about the long-term effects of bone toxicity (170,171) . Considerations that support the adoption of TDF as the national recommendation include: the national programme uses TDF for adults and pregnant women and a suitable TDF fixed-dose combination formulation for children is available.

For adolescents infected with HIV (10 to 19 years old) weighing 35 kg or more, the NRTI backbone for an ART regimen should align with that of adults and be one of the following, in preferential order: • TDF + 3TC (or FTC) • AZT + 3TC • ABC + 3TC (Strong recommendation, low-quality evidence). Special note: TDF-containing fixed-dose combinations are currently only available in adult, unscored tablets for once-daily use. At or above 35 kg, the dose of TDF in adult dual and triple fixed-dose combinations and the dose of EFV in adult triple fixed-dose combinations are acceptable for use in adolescents. ABC or boosted PIs can be used in special circumstances.

7. Clinical guidance across the continuum of care: antiretroviral therapy

127

Table 7.11 Summary of recommended first-line ART regimens for children and adolescents Children 3 years to less than 10 years and adolescents <35 kg Preferred ABCa + 3TC + EFV ABC + 3TC + NVP AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP d4Tb + 3TC + EFV d4Tb + 3TC + NVP Adolescents (10 to 19 years) ≥35 kg TDF + 3TC (or FTC) + EFVa AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + NVP ABC + 3TC + EFV ABC + 3TC + NVP

7.2 What ART regimen to start with (first-line ART)

Alternatives

Special circumstancesc a

These recommendations apply to children and adolescents who are initiating first-line ART. Children and adolescents who are already taking ABC-containing regimens can safely substitute TDF for ABC, if this is needed for programmatic reasons. Children and adolescents who are on d4T-containing regimens without evidence of treatment failure can safely substitute ABC or TDF for d4T. Despite a lack of direct evidence, consideration can also be given to substituting ABC or TDF for AZT with the goal of simplifying and harmonizing treatment regimens across age groups. Including TDF in initial ART regimens for children with HBV coinfection offers the potential advantage of reducing the selection of HIV resistance to 3TC that may compromise future options for HBV treatment. b d4T use should be restricted to situations in which toxicity to AZT is suspected or confirmed and access to ABC or TDF is lacking. The duration of therapy with this drug should be limited to the shortest time possible. See Box 10.7 for guidance on phasing out d4T. c S pecial circumstances may include situations where preferred or alternative regimens may not be available or suitable because of significant toxicities, anticipated drug-drug interactions, drug procurement and supply management issues, or for other reasons.

Background Despite increased access to early infant diagnosis and the widespread availability of several child-friendly fixed-dose combinations, ART coverage among children lags significantly behind that of adults. Treatment recommendations for children should be easy to implement at all levels of the health system, including the primary care level, and by all ART service providers, rather than paediatric specialists alone. The 2010 WHO ART guidelines for children three years and older (105) recommended starting with an NVP- or EFV-containing regimen combined with an NRTI backbone. The recommended NRTI backbones, in preferential order, were 3TC + AZT or 3TC + ABC or 3TC + d4T. For adolescents with HBV, the preferred backbone was TDF + FTC or 3TC. The new recommendations in the 2013 guidelines are based on new evidence on the preferred NRTIs and NNRTIs to use in this group of children. New

Rationale and supporting evidence The United States Food and Drug Administration (172) and European Medicines Agency (173) approved using TDF for children older than two years of age, providing an opportunity to offer the same regimen to both adults and children. Harmonizing treatment recommendations with adult regimens could improve children’s access to ART. Other benefits of TDF include the ability to combine it with 3TC and EFV to create a potent once-daily regimen for children (169) . In addition, the fact that HIV resistance to TDF – specifically K65R – can enhance the antiviral effect of AZT may make TDF a good choice for first-line therapy in terms of sequencing NRTIs from first- to second-line regimens (165,174–176) . However, experience with TDF in young children is limited, and although TDF is known to reduce bone mineral density, it is not clear whether this is permanent

128

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

and how it might affect future patterns of growth and fracture risk, as highlighted in the values and preferences survey among health workers. In addition, TDF formulations for younger children are not widely available and to date there are no TDF-containing paediatric fixed-dose combinations. ABC shares many of the benefits of TDF (once-daily dosage and a favourable resistance profile) but, in contrast to TDF, ABC has been more thoroughly studied in children and is generally well tolerated. ABC is also available in paediatric fixed-dose combination formulations but is significantly more costly. Further, among people with HLA-B*5701, it can cause potentially fatal hypersensitivity; although this is very rare among African children, it can affect up to 3–4% of Caucasian and Asian children (177) . A systematic review based on observational data indicates that EFV has a better shortterm toxicity profile and is associated with better virological response than NVP (121,178) . Most children currently receiving ART are treated with regimens that contain NVP, whereas in adults, EFV is increasingly being selected as the preferred NNRTI. The primary reason for this discrepancy relates to the relative availability of NVP or EFV in fixed-dose combinations for children or adults. Children who are well controlled and stable on NVPcontaining regimens do not need to substitute EFV for NVP, but EFV would be a better choice for those initiating ART with other once-daily drugs. In developing these recommendations, the Guidelines Development Group emphasized: using potent first-line regimens; t he convenience of once-daily dosing and the use of fixed-dose combinations whenever possible; u sing non-thymidine analogues – either ABC or TDF – in first-line regimens to maximize the response to AZT in second-line ART; and p roviding treatment recommendations for older children and adolescents that are aligned with those for adults.

Clinical considerations for scaling up ART for children Section 10.6 (Implementations considerations for key recommendations, Box 10.6) discusses implementation considerations relevant to programme managers. An important consideration for clinicians and other health care providers relates to whether and how regimen changes can be introduced among children who are clinically stable. As children get older, new fixed-dose combinations become available and programmes transition into different first-line regimens. Modifying the ART regimens of clinically stable people can be considered to simplify treatment management and harmonize the ART regimens in use. Table 7.12 summarizes considerations for simplifying and harmonizing ART for children with no history of treatment failure.

7. Clinical guidance across the continuum of care: antiretroviral therapy

129

Table 7.12 Considerations for simplifying and harmonizing ART for children with no history of treatment failurea on any regimen Regimen containing: Guidance Change d4T to age-appropriate NRTI in accordance with the regimen recommended by the national programme No need to change, but consider substituting NVP or EFV for LPV/r if there is sustained virological response on LPV/r Individual advantages • R educed risk of d4T-related toxicity • M ay improve adherence as a result of once-daily dosing (if ABC or TDF are chosen) • May improve adherence as a result of better palatability and use of fixed-dose combinations in more manageable formulations ( once-daily scored tablets ) • Reduced risk of metabolic alterations No need to change but may consider changing to ABC or TDF • M ay improve adherence as a result of once-daily dosing (if on EFV) • M ay reduce the risk of exacerbating anaemia • F ixed-dose combinations can be used (if also on EFV) • Aligned with adult regimens • A ligned with adult regimens • P reserve PI for second-line ART • N o cold-chain requirement • R educed drug cost • A ligned with adult regimens Programmatic advantages • A ligned with adult regimens

7.2 What ART regimen to start with (first-line ART)

d4T

LPV/r

AZT

ABC

No need to change, but can consider changing to TDF, especially for adolescents weighing more than 35 kg No need to change, but may consider changing to EFV particularly from age 3 years

NVP

• M ay improve adherence as a result of once-daily dosing (if combined with ABC or TDF)

• Aligned with adult regimens

Defined based on the criteria for treatment failure adopted nationally.

130

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Key research gaps The long-term efficacy and safety of TDF, ABC and EFV and the recommended combination need further investigation. More data are needed on the bone, growth and renal toxicity profiles of TDF in children and adolescents, especially in the context of malnutrition and stunting. Similarly, adverse events associated with EFV during adolescence, such as central nervous system effects, require investigation to ensure safe harmonization with adult treatment regimens. Toxicity surveillance systems implemented alongside ART at sentinel sites can provide data to better understand the frequency and clinical relevance of these toxicities.

7.2.5 TB co-treatment in children with HIV TB is one of the most common opportunistic infections affecting children with HIV. Selecting regimens that are compatible with TB therapy is therefore essential. Interactions between rifampicin and LPV/r or NVP mean that co-treatment in children under three years is challenging, but a recent large randomized controlled trial (163) of ART in children has generated preliminary evidence on the efficacy of triple nucleoside therapy which, despite limited data in the context of TB co-treatment, offers a suitable option for children who require TB treatment while already receiving ART (Table 7.13). The recommended regimens for children diagnosed with TB and starting ART are consistent with the 2010 recommendations and are summarized in Table 7.13, together with broader guidance on choosing regimens for co-treatment of HIV and TB.

Table 7.13 Summary of recommended ART regimens for children who need TB treatment Recommended regimens for children and adolescents initiating ART while on TB treatment a b Younger than 3 years Two NRTIs + NVP, ensuring that dose is 200 mg/m2 or Triple NRTI (AZT + 3TC + ABC) c Two NRTIs + EFV or Triple NRTI (AZT + 3TC + ABC) c

3 years and older

Recommended regimen for children and infants initiating TB treatment while receiving ARTa Younger than 3 years Continue NVP, ensuring that dose is 200 mg/m2 or Triple NRTI (AZT + 3TC + ABC) c If the child is receiving EFV, continue the same regimen 3 years and older If the child is receiving NVP, substitute with EFV or Triple NRTI (AZT + 3TC + ABC) c

Child on standard NNRTI-based regimen (two NRTIs + EFV or NVP)

7. Clinical guidance across the continuum of care: antiretroviral therapy

131

Table 7.13 (continued) Recommended regimen for children and infants initiating TB treatment while receiving ARTa Triple NRTI (AZT + 3TC + ABC) c or Substitute NVP for LPV/r, ensuring that dose is 200 mg/m2 or Continue LPV/r; consider adding RTV to achieve the full therapeutic dosed If the child has no history of failure of an NNRTI-based regimen: Substitute with EFVe or Triple NRTI (AZT + 3TC + ABC) c or Continue LPV/r; consider adding RTV to achieve the full therapeutic dosed If the child has a history of failure of an NNRTI-based regimen: Triple NRTI (AZT + 3TC + ABC) c or Continue LPV/r consider adding RTV to achieve the full therapeutic dosed Consider consultation with experts for constructing a secondline regimen Ensure optimal dosing of rifampicin based on new dosing guidelines (Web Annex www.who.int/hiv/pub/guidelines/arv2013/ annexes). b Substitute ARV drugs based on an age-appropriate ART regimen in line with nationally recommended first-line ART. c Triple NRTI is only recommended for the duration of TB treatment; an age-appropriate PI- or NNRTI-based regimen should be restarted when rifampicin-based therapy ends. Based on the findings from the ARROW trial (163) , this regimen should be considered as the preferred option for children younger than three years who are receiving a LPV/r-based regimen when starting TB treatment. The United States Food and Drug Administration approval for the use of EFV in children 3 months to 3 years old weighing more than 3.5 kg offers a potential alternative to the triple NRTI approach. An EFV-based regimen in children under 3 years is still not recommended as pharmacokinetics data are needed to ensure that the co-administration of rifampicin does not decrease drug levels below the therapeutic level. Triple NRTI should also be considered as the preferred regimen for children older than 3 years with a history of failure on a NNRTI-based regimen. d Increase RTV until it reaches the same dose as LPV in mg, in a ratio of 1:1. e S ubstitution with EFV should be considered as the preferred option (179) , and EFV could be maintained after TB treatment ends to enable simplification and harmonization with the ARV drug regimens used for older children. a

7.2 What ART regimen to start with (first-line ART)

Younger than 3 years

Child on standard PIbased regimen (two NRTIs + LPV/r)

3 years and older

132

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.3 M onitoring response to ART and the diagnosis of treatment failure 7.3.1 Laboratory monitoring before and after initiating ART Clinical assessment and laboratory tests play a key role in assessing individuals before ART is initiated and then monitoring their treatment response and possible toxicity of ARV drugs. Table 7.14 summarizes recommended laboratory tests for HIV screening and monitoring, as well as approaches to screen for coinfections and noncommunicable diseases. Phase of HIV management Recommended HIV serology, CD4 cell count Desirable (if feasible) HBV (HBsAg) serologya HCV serology HIV diagnosis TB screening

Cryptococcus antigen if CD4 count ≤100 cells/mm3 b Screening for sexually transmitted infections Assessment for major noncommunicable chronic diseases and comorbiditiesc

Follow-up before ART

CD4 cell count (every 6–12 months) CD4 cell count Haemoglobin test for AZTd Pregnancy test Blood pressure measurement

ART initiation

Urine dipsticks for glycosuria and estimated glomerular filtration rate (eGFR) and serum creatinine for TDFe Alanine aminotransferase for NVP f CD4 cell count (every 6 months) HIV viral load (at 6months after initiating ART and every 12 months thereafter) Urine dipstick for glycosuria and serum creatinine for TDFc

Receiving ART

Treatment failure

CD4 cell count HIV viral load

HBV (HBsAg) serologya (before switching ART regimen if this testing was not done or if the result was negative at baseline)

If feasible, HBsAg testing should be performed to identify people with HIV and HBV coinfection and who therefore should initiate TDF-containing ART. b Can be considered only in settings with a high prevalence of cryptococcal antigenaemia (>3%) (180). c Consider assessing the presence of chronic conditions that can influence ART management such as hypertension and other cardiovascular diseases, diabetes and TB. d Among children and adults with a high risk of adverse events associated with AZT (low CD4 or low BMI). e Among people with a high risk of adverse events associated with TDF: underlying renal disease, older age group, low BMI, diabetes, hypertension and concomitant use of a boosted PI or potential nephrotoxic drugs. f Among people with a high risk of adverse events associated with NVP, such as being ART-naive, women with HIV with a CD4 count >250 cells/mm3 and HCV coinfection. However, liver enzymes have low predictive value for monitoring NVP toxicity. a

7. Clinical guidance across the continuum of care: antiretroviral therapy

133

7.3.2 Monitoring the response to ART and the diagnosis of treatment failure New recommendations New

7.3 Monitoring response to ART and the d iagnosis of treatment failure

Viral load is recommended as the preferred monitoring approach to diagnose and confirm ARV treatment failure (strong recommendation, low-quality evidence). If viral load is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure (strong recommendation, moderate-quality evidence). Special notes: Treatment failure is defined by a persistently detectable viral load exceeding 1000 copies/ml (that is, two consecutive viral load measurements within a three-month interval, with adherence support between measurements) after at least six months of using ARV drugs. Viral load testing is usually performed in plasma; however, certain technologies that use whole blood as a sample type, such as laboratory-based tests using dried blood spots and point-of-care tests, are unreliable at this lower threshold, and where these are used a higher threshold should be adopted. Viral load should be tested early after initiating ART (at 6 months) and then at least every 12 months to detect treatment failure. If viral load testing is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure, with targeted viral load testing to confirm virological failure where possible.

Background Monitoring individuals receiving ART is important to ensure successful treatment, identify adherence problems and determine whether and which ART regimens should be switched in case of treatment failure. Before 2010, WHO guidelines on ART recommended using clinical outcomes and CD4 count for routinely monitoring the response to ARV drugs. However, the value of viral load testing as a more sensitive and early indicator of treatment failure is increasingly recognized and is the gold standard for monitoring the response to ARV drugs in high-income settings. The 2010 WHO guidelines recommended that countries consider phasing in viral load testing to monitor the response to ART and use a viral load threshold above 5000 copies/ml in an adherent person with no other reasons for an elevated viral load (such as drug interactions, poor absorption and intercurrent illness). However, most ART programmes in resource-limited settings still do not have access to viral load testing and continue to rely on clinical and immunological monitoring. This limited use of viral load monitoring has been identified as a key reason for the lower than expected rates for switching ART regimens in resource-limited settings. New

Rationale and supporting evidence Although evidence from clinical trials for a survival benefit of viral load testing is limited, it can provide an early indication of treatment failure, and the 2013 guidelines strongly recommend using it for detecting virological failure and/or confirming treatment failure among people with evidence of clinical and/or immunological failure (Table 7.15). Since several clinical and epidemiological studies show that the risk of HIV transmission is very low when the viral load is lower than 1000 copies/ml (181) , the Guidelines Development Group also recommended reducing the viral load threshold for treatment failure from 5000 copies/ml to 1000 copies/ml.

134

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 7.15 WHO definitions of clinical, immunological and virological failure for the decision to switch ART regimens Failure Definition Adults and adolescents New or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 condition) a after 6 months of effective treatment Clinical failure Children New or recurrent clinical event indicating advanced or severe immunodefiency (WHO clinical stage 3 and 4 clinical condition with exception of TB) after 6 months of effective treatment Adults and adolescents CD4 count falls to the baseline (or below) or Persistent CD4 levels below 100 cells/mm3 Children Younger than 5 years Persistent CD4 levels below 200 cells/mm3 or <10% Older than 5 years Persistent CD4 levels below 100 cells/mm3 The condition must be differentiated from immune reconstitution inflammatory syndrome b occurring after initiating ART For adults, certain WHO clinical stage 3 conditions (pulmonary TB and severe bacterial infections) may also indicate treatment failure a Without concomitant or recent infection to cause a transient decline in the CD4 cell count A systematic review found that current WHO clinical and immunological criteria have low sensitivity and positive predictive value for identifying individuals with virological failure (182) . The predicted value would be expected to be even lower with earlier ART initiation and treatment failure at higher CD4 cell counts. There is currently no proposed alternative definition of treatment failure and no validated alternative definition of immunological failure The optimal threshold for defining virological failure and the need for switching ART regimen has not been determined Virological failure Plasma viral load above 1000 copies/ ml based on two consecutive viral load measurements after 3 months, with adherence support An individual must be taking ART for at least 6 months before it can be determined that a regimen has failed Assessment of viral load using DBS and point-of-care technologies should use a higher threshold a b

Comments

Immunological failure

See the list of clinical conditions associated with advanced or severe HIV disease associated with immunodeficiency in Annex 1. Section 6.1 discusses immune reconstitution inflammatory syndrome.

7. Clinical guidance across the continuum of care: antiretroviral therapy

135

Virological monitoring (viral load) versus immunological (CD4) and clinical monitoring (WHO clinical staging) The main rationale for recommending viral load monitoring as the preferred approach compared with immunological and clinical monitoring is to provide an early and more accurate indication of treatment failure and the need to switch to second-line drugs, reducing the accumulation of drug-resistance mutations and improving clinical outcomes. Measuring viral load can also help to discriminate between treatment failure and non-adherence (183) and can serve as a proxy for the risk of transmission at the population level (76). There is still limited evidence to support any additional survival benefit of viral load monitoring over CD4 and/or clinical monitoring among individuals with HIV receiving ART. A systematic review identified three randomized clinical trials on virological versus immunological and clinical monitoring (184–186) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). Compared with immunological and/or clinical monitoring, adding viral load monitoring has not been associated with reduced mortality. In one of these trials (185) , no significant difference in the incidence of clinical failure, switching to second-line regimens and resistance mutations was found. One cohort modelling study among adults also found that adding virological monitoring to clinical and/or immunological criteria made no difference in mortality or new AIDS-defining illnesses (187). Although randomized controlled trials have not yet shown that viral load monitoring translates into survival gains, follow-up has been limited (less than five years) and longer follow-up is required to examine the longer-term impact on survival, resistance profile and HIV transmission. A systematic review provided moderate-quality evidence that current WHO guidelines on immunological and clinical monitoring for treatment failure have poor sensitivity and lower positive predictive value for identifying virological failure in adults (187–200) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). This means that many of the people who are identified with immunological failure in fact have adequate virological suppression and risk being misclassified as having treatment failure and switched unnecessarily to second-line therapy. A further systematic review using data in children also provided moderate-quality evidence that immunological criteria (201–204) have low sensitivity and positive predictive value for identifying children with virological failure. Immunological monitoring versus clinical monitoring Where viral load monitoring is unavailable, clinical monitoring and CD4 monitoring are recommended (205). Although a systematic review of two randomized controlled trials (184,206) provide moderate-quality evidence of mortality and morbidity benefits with CD4 and clinical monitoring compared with routine clinical monitoring in adults receiving ART, these trials largely focused on CD4 and clinical monitoring in people who initiated ART at CD4 counts below 200 cells/mm3 (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). Existing immunological and clinical criteria may have decreased sensitivity and specificity to detect treatment failure in people who initiate ART at higher CD4 counts, and more accurate immunological criteria for these people remain to be identified. Routine versus targeted viral load monitoring to detect treatment failure Viral load should be monitored routinely (every 6–12 months) to enable treatment failure to be detected earlier and more accurately. In settings with limited access to viral load testing, a targeted viral load strategy to confirm failure suspected based on immunological or clinical criteria (Table 7.15) should be used to avoid unnecessary switching to second-line ART. Targeted viral load monitoring is less costly than routine viral load testing, but as with clinical and immunological monitoring, has the potential to delay switching to second-line ART and may subsequently increase the risk of disease progression, selection of ARV drug resistance and HIV transmission.

7.3 Monitoring response to ART and the d iagnosis of treatment failure

136

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Threshold for defining virological failure The optimal threshold for defining virological failure and for switching ART regimens has not been established. The rationale for the threshold of 1000 copies/ml was based on two main sources of evidence. First, viral blips or intermittent low-level viraemia (50–1000 copies/ml) can occur during effective treatment but have not been associated with an increased risk of treatment failure unless low-level viraemia is sustained (207) . Second, clinical and epidemiological studies show that the risk of HIV transmission and disease progression is very low when the viral load is lower than 1000 copies/ml (181,208,209) . Most standard blood and plasma viral load platforms available and being developed have good diagnostic accuracy at this lower threshold. However, the sensitivity of dried blood spots for viral load determination at this threshold may be reduced (210,211) . Programmes relying on dried blood spot technology for viral load assessment may therefore consider retaining the higher threshold (3000–5000 copies/ml) until sensitivity at lower thresholds is established (212–214) .

Fig. 7.1 Viral load testing strategies to detect or confirm treatment failure and switch ART regimen in adults, adolescents and children Targeted viral load monitoring (suspected clinical or immunological failure) Routine viral load monitoring (early detection of virological failure)

Test viral load

Viral load >1000 copies/ml

Evaluate for adherence concerns

Repeat viral load testing after 3–6 months

Viral load ≤1000 copies/ml

Viral load >1000 copies/ml

Maintain first-line therapy

Switch to second-line therapy

7. Clinical guidance across the continuum of care: antiretroviral therapy

137

Special considerations for children These guidelines aim to harmonize monitoring approaches for children with those recommended for adults. As more children start ART earlier and at higher CD4 counts, viral load monitoring to detect treatment failure and lack of adherence will be increasingly beneficial. In addition, viral load may be instrumental for implementing treatment strategies to preserve second-line options as children age (such as switching from LPV/r to an NNRTI once virological suppression is sustained) (see section 7.3.3). Evidence from one randomized controlled trial conducted in several countries (including the United States of America, European countries, Brazil and Thailand, PENPACT1 (158) , suggests that switching treatment at lower viral load thresholds does not lead to better clinical and virological outcomes but does minimize the development of HIV drug resistance, especially for NRTIs when an NNRTI-based regimen is used. In this context, alignment with the viral load thresholds recommended for adults is advisable. However, viral load results in the first six months after initiating ART should be interpreted carefully, as infants and young children may require longer to achieve virological suppression because of high baseline viral load. The recommendation to initiate ART for all children younger than five years of age regardless of clinical and immunological criteria means that CD4 cell count testing at baseline is not required for initiating ART. However, where viral load monitoring capacity is limited or unavailable, CD4 monitoring – including baseline measurement and CD4 percentage for children younger than five years of age – will still be important for monitoring treatment response. As in the case of adults, lack of viral load or CD4 capacity should not prevent children from starting ART. The results from a recently completed trial show that mortality and disease progression are comparable between clinical monitoring and laboratory monitoring, especially in the first year of treatment (163).

7.4 Monitoring and substitutions for ARV drug toxicities

Clinical considerations for scaling up viral load testing Section 10.6 (see section on implementation considerations for key recommendations, Box 10.3) discusses clinical and implementation considerations relevant to programme managers. Additional implementation considerations for clinicians and health workers include the following. Access to ART should be the first priority. Lack of laboratory tests for monitoring treatment response should not be a barrier to initiating ART. Setting priorities. If viral load testing is limited, it should be phased in using a targeted approach to confirm treatment failure. This may be especially relevant in populations receiving ARVs to reduce HIV transmission, such as pregnant and breastfeeding women and among serodiscordant couples, for whom sustained viral load suppression is critical to the efficacy of the strategy.

138

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.4 M onitoring and substitutions for ARV drug toxicities 7.4.1 Guiding principles The availability of laboratory monitoring is not required for initiating ART. Symptom-directed laboratory monitoring for safety and toxicity can be used for those receiving ART.

7.4.2 Major types of ARV toxicities The 2010 WHO ART guidelines recommended a symptom-directed approach to laboratory monitoring of the safety and toxicity of ART regimens. At the same time, several laboratory tests for monitoring ARV toxicity were advised (but not required) for specific high-risk people using certain drugs. Table 7.16 lists key types of toxicity and associated risk factors for the major ARV drugs. Monitoring drug toxicity using a symptom-directed approach needs to be investigated further to optimize treatment. More data are needed on whether routine or periodic laboratory monitoring for specific types of toxicity (such as renal function monitoring among TDF users) is required for all individuals or only people at higher risk.

Table 7.16 Types of toxicities associated with first-, second- and thirdline ARV drugs ARV drug Major types of toxicity Hypersensitivity reaction Risk factors Presence of HLA-B*5701 gene Suggested management If ABC is being used in first-line ART, substitute with TDF or AZT or d4T If ABC is being used in secondline ART, substitute with TDF

ABC

Electrocardiographic abnormalities (PR interval prolongation)

Pre-existing conduction disease Concomitant use of other drugs that may prolong the PR interval

ATV/r

Indirect hyperbilirubinaemia Underlying hepatic disease (clinical jaundice) HBV and HCV coinfection Concomitant use of hepatotoxic drugs Nephrolithiasis and risk of prematurity Anaemia, neutropaenia, myopathy, lipoatrophy or lipodystrophy Risk factors unknown Baseline anaemia or neutropaenia CD4 count ≤200 cells/mm3 BMI >25 (or body weight >75 kg) Prolonged exposure to nucleoside analogues

LPV/r or DRV/r. If boosted PIs are contraindicated and NNRTIs have failed in first-line ART, consider integrase inhibitors

AZT

Lactic acidosis or severe hepatomegaly with steatosis

If AZT is being used in first-line ART, substitute with TDF or ABC If AZT is being used in second-line ART, substitute with d4T

7. Clinical guidance across the continuum of care: antiretroviral therapy

139

Table 7.16 (continued) ARV drug Major types of toxicity Risk factors Suggested management

7.4 Monitoring and substitutions for ARV drug toxicities

d4T

Peripheral neuropathy, Older age lipoatrophy or lipodystrophy CD4 count ≤200 cells/mm3 Concomitant use of isoniazid or ddI Lactic acidosis or severe BMI >25 (or body weight hepatomegaly with >75 kg) steatosis, acute pancreatitis Prolonged exposure to nucleoside analogues Hepatotoxicity Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drugs Severe skin and hypersensitivity reactions Persistent central nervous system toxicity (such as abnormal dreams, depression or mental confusion) Hepatotoxicity Sulfonamide allergy Depression or other mental disorder (previous or at baseline) Daytime dosing Underlying hepatic disease – HBV and HCV coinfection Concomitant use of hepatotoxic drug History of seizure Risk factors unknown

If d4T is being used in first-line ART, substitute with TDF or AZT or ABC If d4T is being used in second-line ART (after TDF or ABC are used in first-line ART), substitute with AZT

DRV/r

If DRV/r is being used in secondline ART, substituting with ATV/r or LPV/r can be considered. When it is used in third-line ART, limited options are available

EFV

Convulsions Hypersensitivity reaction, Stevens-Johnson syndrome Potential risk of neural tube birth defects (very low risk in humans) (122,140) Male gynaecomastia Severe skin and hypersensitivity reactions

NVP. If the person cannot tolerate either NNRTI, use boosted PIs

ETV

Unknown

Limited options are available

140

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 7.16 (continued) ARV drug Major types of toxicity Electrocardiographic abnormalities (PR and QT interval prolongation, torsades de pointes) QT interval prolongation Risk factors People with pre-existing conduction system disease Concomitant use of other drugs that may prolong the PR interval Suggested management

LPV/r Hepatotoxicity

If LPV/r is used in first-line ART for children, use an age-appropriate Congenital long QT syndrome NNRTI (NVP for children younger Hypokalaemia than 3 years and EFV for children 3 years and older). ATV Concomitant use of drugs can be used for children older that may prolong the QT than 6 years interval Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drugs Advanced HIV disease If LPV/r is used in second-line ART for adults, use ATV/r or DRV/r. If boosted PIs are contraindicated and the person has failed on treatment with NNRTI in first-line ART, consider integrase inhibitors

Pancreatitis

Risk of prematurity, lipoatrophy or metabolic Risk factors unknown syndrome, dyslipidaemia or severe diarrhoea Hepatotoxicity Underlying hepatic disease HBV and HCV coinfection Concomitant use of hepatotoxic drugs CD4 >250 cells/mm3 in women EFV. If the person cannot tolerate CD4 >400 cells/mm3 for men either NNRTI, use boosted PIs First month of therapy (if lead-in dose is not used)

NVP

Severe skin rash and Risk factors unknown hypersensitivity reaction (Stevens-Johnson syndrome Rhabdomyolysis, myopathy, Concomitant use of other myalgia drugs that increase the risk of myopathy and rhabdomyolysis

RAL

Limited options are available

7. Clinical guidance across the continuum of care: antiretroviral therapy

141

Table 7.16 (continued) ARV drug Major types of toxicity Tubular renal dysfunction, Fanconi syndrome Risk factors Underlying renal disease Older age BMI <18.5 (or body weight <50 kg) Untreated diabetes mellitus Untreated hypertension Concomitant use of nephrotoxic drugs or a boosted PI History of osteomalacia and pathological fracture Risk factors for osteoporosis or bone loss Lactic acidosis or severe hepatomegaly with steatosis Exacerbation of hepatitis B (hepatic flares) Prolonged exposure to nucleoside analogues Obesity Discontinuation of TDF due to toxicity Use alternative drug for hepatitis B treatment (such as entecavir) Suggested management

7.4 Monitoring and substitutions for ARV drug toxicities

If TDF is being used in first-line ART, substitute with AZT or d4T or ABC If TDF is being used in second-line ART (after d4T + AZT use in firstline ART), substitute with ABC or ddI

TDF (169)

Decreases in bone mineral density

7.4.3 Monitoring TDF toxicity TDF nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease (130). According to a systematic review (Web Annex www.who.int/hiv/pub/guidelines/arv2013/ annexes), no studies have properly compared monitoring strategies for people receiving TDF, such as routine toxicity monitoring versus care with no monitoring or incidental monitoring in case of perceived clinical need. One clinical trial (the DART trial) comparing laboratory with clinical monitoring showed that individuals receiving TDF have an increased risk of reduced estimated glomerular filtration rate but no increased risk of renal failure over a median five years of follow-up (low-quality evidence). A few observational cohort studies reported that using TDF was associated with an increased risk of chronic kidney disease. However, the exposure time to TDF in all these studies was considered too short to indicate a long-term increased risk for renal failure, the occurrence of bone fractures or changes in fat distribution. The best parameter for TDF-related renal toxicity monitoring needs to be evaluated; meanwhile, laboratory monitoring using a creatinine test is not mandatory to initiate treatment with TDF. However, it is advisable for high-risk people (those who are older or have underlying renal disease, long-term diabetes or uncontrolled hypertension concomitant with boosted PIs or nephrotoxic drugs) to detect and limit further progression of renal impairment. High frequency of glycosuria has also been found in people without diabetes biopsied for TDF nephrotoxicity with increased serum creatinine compared with TDF-treated people with a normal glomerular filtration rate, suggesting that dipstick glycosuria may be a cost-effective screening test for serious TDF-induced kidney injury (215).

142

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

TDF-related decreases in bone mineral density have been observed in children, although it is unclear how reducing bone mineral density might impact future growth patterns or the risk of bone fracture. In addition, an accurate and feasible method to measure bone mineral density still needs to be identified, and significant uncertainty remains around how best to monitor TDF-related bone toxicity among children. Dual-energy X-ray absorptiometry testing is not possible in most settings, but careful growth monitoring is recommended while children are receiving treatment with TDF (169).

Clinical considerations Laboratory monitoring is not mandatory to initiate treatment with TDF. Routine blood pressure monitoring may be used to assess for hypertension. Urine dipsticks may be used to detect glycosuria or severe TDF nephrotoxicity in individuals without diabetes using TDF-containing regimens. If the creatinine test is routinely available, use the estimated glomerular filtration ratea at baseline before initiating TDF regimens. Do not initiate TDF when the estimated glomerular filtration rate is <50 ml/min, or in longterm diabetes, uncontrolled hypertension and renal failure. Monitor growth in children using TDF. a

Using the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) formulas for estimation. An online calculator is available at http://nephron.com/cgi-bin/CGSI.cgi. CG formula: eGFR = (140 – age) X (Wt in kg) X 0.85 (if female)/(72 X Cr in mg%). MDRD formula: eGFR = 175 X SerumCr–1.154 X age–0.203 X 1.212 (if patient is black) X 0.742 (if female).

Key research gaps More data are needed on how to best monitor renal function in people using TDF-containing regimens (whether toxicity monitoring should be routine or targeted in high-risk groups, with alternative drugs for high-risk people). In addition, more data are needed to understand the frequency and clinical relevance of reduced bone mineral density in children. More accurate and affordable methods to monitor bone toxicity should be identified for this specific population.

7.4.4 Toxicity monitoring for other ARV drugs AZT AZT is associated with a risk of haematological toxicity, and measuring haemoglobin is recommended before initiating ART, mainly among adults and children with low body weight, low CD4 counts and advanced HIV disease. People with HIV with severe anaemia at baseline (haemoglobin <7.0 g/dl) should avoid AZT as first-line therapy.

NVP The laboratory measurement of liver enzymes has very low predictive value for NVP-containing regimens. However, monitoring hepatic enzymes is recommended if feasible, especially for women with HIV who have CD4 cell counts >250 cells/mm3 and individuals with HIV who are coinfected with HBV or HCV. Section 7.2.1 provides more information on the safety of NVP among individuals with high CD4 cell counts.

7. Clinical guidance across the continuum of care: antiretroviral therapy

143

EFV The main type of toxicity of EFV is central nervous system side effects, which typically resolve after a few weeks. However, in some cases, they can persist for months or not resolve at all. Despite concerns about the potential risk of teratogenicity associated with using EFV during pregnancy, a recent meta-analysis found no overall increase in the incidence of birth defects for first-trimester EFV exposure compared with other ARV drugs (122). Section 7.3.2 provides more information on the safety of EFV among pregnant women.

7.4 Monitoring and substitutions for ARV drug toxicities

7.4.5 Drug substitutions for ARV drug toxicity Drug regimen or single agent substitutions may be required for drug toxicity and to avoid drug interactions. Section 7.4.3 provides guidance on managing specific types of ARV drug toxicity.

Clinical considerations Delaying substitutions or switches when there are severe adverse drug effects may cause harm and may affect adherence, leading to drug resistance and treatment failure. When drug interruptions are required, such as for severe and life-threatening adverse events related to toxicity, it is important to consider the various half-lives of ARV drugs. For example, when a NNRTI needs to be discontinued, a staggered approach should be used by prolonging the use of the NRTI backbone for two to three weeks. Alternatively, the NNRTI could be temporarily substituted with a boosted PI.

7.4.6 Drug substitutions for ARV drug toxicity Providers should be aware of all drugs that people with HIV are taking when ART is initiated and new drugs that are added during treatment maintenance. There are several key drug interactions (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). WHO TB treatment guidelines review key considerations for managing coinfection with TB and HIV (216). A key contraindicated drug combination includes rifampicin and PIs. When people coinfected with TB and HIV are receiving a boosted PI, rifampicin may need to be substituted with rifabutin. If rifabutin is not available, LPV/r and SQV/r can be used for the duration of TB treatment, if the boosting dose of RTV is increased or double the standard dose of LPV/r is used (see section 7.6.1). For children, using a triple NRTI regimen (such as AZT + 3TC + ABC) should also be considered. Ribavirin and peginterferon alpha-2a are often used for treating HCV. Administration of these agents with AZT has been associated with an increased risk of anaemia and hepatic decompensation. People coinfected with HCV and HIV and receiving AZT may need to be switched to TDF. Itraconazole and ketoconazole are often used to treat fungal infections. Studies have shown that NVP may decrease the concentrations of these antifungal agents to subtherapeutic levels. Alternative antifungal agents (such as fluconazole) could be used to ensure adequate treatment of fungal infections among people with HIV. WHO recommends artemisinin-based combination therapies for treating uncomplicated Plasmodium falciparum malaria (217). One recommended artemisinin-based combination therapy is artesunate and amodiaquine. EFV increases the concentrations of amodiaquine and has been associated with significant elevations of liver transaminases. Alternative artemisininbased combination therapies (such as artemether plus lumefantrine, artestunate plus mefloquine or artesunate plus sulfadoxine-pyrimethamine) could be used to prevent severe toxicity in people with HIV.

144

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

WHO recommends methadone and buprenorphine for treating opioid dependence (218). Co-administering EFV decreases methadone concentrations. This could subsequently cause withdrawal symptoms and increase the risk of relapse to opioid use. People receiving methadone and EFV should be monitored closely, and those experiencing opioid withdrawal may need to adjust their methadone dose. ARV drugs have the potential to either decrease or increase the bioavailability of steroid hormones in hormonal contraceptives (219). Limited data suggest potential drug interactions between many ARV drugs (especially some NNRTIs and RTV-boosted PIs) and estrogen-based hormonal contraceptives. These interactions may alter the safety and effectiveness of both the hormonal contraceptive and the ARV drug. If women receiving ART decide to initiate or continue using hormonal contraceptives, consistently using condoms and other contraceptive methods is recommended both to prevent HIV transmission and to compensate for any possible reduction in the effectiveness of the hormonal contraception. Concomitant use of boosted PIs and NNRTI with some antihistamine agents (such as astemizole and terfenadine) has been associated with severe and life-threatening reactions, such as cardiac arrhythmia. Alternative antihistamine agents include loratidine and cetirizine. WHO recommends using statins for people with a 10-year cardiovascular risk exceeding 30% (220). Boosted PIs may lead to increased concentrations of lovastatin and simvastatin. Increased concentrations may increase the risk of developing serious adverse events such as myopathy (including rhabdomyolysis). Alternative dyslipidaemia agents should be used to prevent severe toxicity among people with HIV.

Table 7.14 Key ARV drug interactions and suggested management a ARV drug AZT Key interactions Ribavirin and peg-interferon alfa-2a Rifampicin Suggested management First-line: substitute AZT with TDF Second-line: substitute AZT with d4T Substitute rifampicin with rifabutin Adjust the PI dose or substitute with three NRTIs (for children)

Lovastatin and simvastatin Boosted PI (ATV/r, LPV/r)

Use an alternative dyslipidaemia agent (for example pravastatin) Estrogen-based hormonal Use alternative or additional contraceptive methods contraception Methadone and Adjust methadone and buprenorphine doses as buprenorphine appropriate Astemizole and terfenadine Use alternative antihistamine agent TDF Monitor renal function Amodiaquine Use an alternative antimalarial agent Methadone Adjust the methadone dose as appropriate Estrogen-based hormonal contraception Astemizole and terfenadine Rifampicin Itraconazole and ketoconazole Use alternative or additional contraceptive methods Use an alternative anti-histamine agent Substitute NVP with EFV Use an alternative antifungal agent (for example fluconazole)

EFV

NVP a

This table was developed using the University of Liverpool’s drug interaction charts, a resource which can be found online at www.hiv-druginteractions.org. A more comprehensive table of ARV drug interactions is available on the Web Annex (www.who. int/hiv/pub/guidelines/arv2013/annexes).

7. Clinical guidance across the continuum of care: antiretroviral therapy

145

7.4 Monitoring and substitutions for ARV drug toxicities

Box 7.2 Surveillance of ARV drug toxicity WHO commissioned systematic reviews on specific types of toxicities associated with key ARV drugs and laboratory monitoring strategies to consolidate and update technical guidance (140,169) . The reviews highlighted remaining evidence gaps in the potential increased risk of toxicity associated with the long-term use of ARV drugs, the use of ARV drugs during pregnancy and in breastfeeding mothers, children and adolescents and populations with associated risk factors and in laboratory monitoring for toxicity. The available evidence is limited to studies with limited sample size or short duration. It is essential to monitor the use of ARV drugs in resource-limited countries where toxicities may present a different pattern in association with environmental or behavioural factors, the prevalence of other conditions and where ARV drugs are used in association with other medicines. Implementing toxicity surveillance will provide the opportunity to produce evidence on specific types of toxicity, increase confidence in the use of the drugs, identify populations with risk factors and plan preventive strategies. The Guidelines Development Group encouraged WHO to strengthen toxicity surveillance activities to increase evidence on toxicity in key areas. These areas cover a potential increased risk of toxicity associated with the long-term use of ARV drugs, renal and bone toxicity associated with using TDF among adults and children, the safety of using EFV- and TDF-containing regimens during pregnancy and in breastfeeding mothers and using TDF among children, adolescents and populations with associated risk factors. Developing laboratory markers to monitor renal function among people using TDF is another important area for research. Several toxicity surveillance activities have already started with WHO support, using standardized approaches at sentinel sites in resource-limited settings. Targeted and systematic surveillance is being conducted in Côte d’Ivoire to monitor renal toxicity associated with TDF in first- and second-line regimens, with an assessment of laboratory monitoring needs in three sentinel sites. A similar approach is being implemented in Viet Nam to assess renal toxicity associated with TDF and central nervous system toxicity associated with EFV in people who use ARV drugs to prevent HIV infection, such as in serodiscordant couples. In the Lao People’s Democratic Republic, anaemia associated with AZT and hypersensitivity associated with NVP are monitored using a targeted and systematic surveillance approach. In Malawi, a surveillance programme will monitor infant growth, following mothers who are breastfeeding and receiving TDF. The implementation of a pregnancy registry, including a surveillance programme for birth defects, is recommended where feasible to assess the safety of ARV drugs and any other medicines during pregnancy and risk factors for adverse pregnancy outcomes, including maternal health outcomes, premature births, stillbirths, low birth weight and congenital abnormalities. WHO, the United States President’s Emergency Plan for AIDS Relief, the United States Centers for Disease Control and Prevention and the United States National Institutes of Health support the establishment of ARV pregnancy registries and birth defect surveillance in sentinel sites in Malawi, South Africa and Uganda to assess the use of EFV-containing regimens at large scale among pregnant women. Surveillance of ARV drug toxicity will help to better understand the long-term risk of ART toxicity and optimize the management of ARV drugs for HIV treatment and prevention in all populations.

146

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.5 What ART regimen to switch to (second-line ART) Using a boosted PI + two NRTI combination is recommended as the preferred strategy for second-line ART for adults, adolescents and also for children when NNRTI-containing regimens were used in first-line ART. In children using a PI-based regimen for first-line ART, switching to NNRTI or maintaining the PI regimen is recommended according with age (Table 7.18).

Table 7.18 Summary of preferred second-line ART regimens for adults, adolescents, pregnant women and children Second-line ART Adults and adolescents ( ≥10 years), including pregnant and breastfeeding women If a NNRTI-based first-line regimen was used Children If a PI-based first-line regimen was used <3 years 3 years to less than 10 years Preferred regimens AZT + 3TC + LPV/r a AZT + 3TC + ATV/r a Alternative regimens TDF + 3TC (or FTC) + ATV/r TDF + 3TC (or FTC) + LPV/r ABC + 3TC + LPV/rb TDF + 3TC (or FTC) + LPV/rb AZT (or ABC) + 3TC + NVP ABC (or TDF) + 3TC + NVP

ABC + 3TC + LPV/rb No change from firstline regimen in usec AZT (or ABC) + 3TC + EFV

DRV/r can be used as an alternative PI and SQV/r in special situations; neither is currently available as a heatstable fixed-dose combination, but a DRV + RTV heat-stable fixed-dose combination is currently in development. b ATV/r can be used as an alternative to LPV/r for children older than six years. c Unless failure is caused by lack of adherence resulting from poor palatability of LPV/r. a

7.5.1 Second-line ART for adults and adolescents New recommendations New

Second-line ART for adults should consist of two nucleoside reverse-transcriptase inhibitors (NRTIs) + a ritonavir-boosted protease inhibitor (PI). • The following sequence of second-line NRTI options is recommended: • After failure on a TDF + 3TC (or FTC)–based first-line regimen, use AZT + 3TC as the NRTI backbone in second-line regimens. • After failure on an AZT or d4T + 3TC–based first-line regimen, use TDF + 3TC (or FTC) as the NRTI backbone in second-line regimens.

• Use of NRTI backbones as a fixed-dose combination is recommended as the preferred approach (strong recommendation, moderate-quality evidence). Heat-stable fixed-dose combinations of ATV/r and LPV/r are the preferred boosted PI options for second-line ART (strong recommendation, moderate-quality evidence).

7. Clinical guidance across the continuum of care: antiretroviral therapy

147

Table 7.19 Summary of preferred second-line ART regimens for adults and adolescents Target population Adults and adolescents ( ≥10 years) Pregnant women Preferred second-line regimena If d4T or AZT was used in first-line ART If TDF was used in firstline ART TDF + 3TC (or FTC) + ATV/r or LPV/r AZT + 3TC + ATV/r or LPV/r

7.5 What ART regimen to switch to (second-line ART)

Same regimens recommended for adults and adolescents If rifabutin is available Standard PI-containing regimens as recommended for adults and adolescents Same NRTI backbones as recommended for adults and adolescents plus double-dose LPV/r (that is, LPV/r 800 mg/200 mg twice daily) or standard LPV dose with an adjusted dose of RTV (that is, LPV/r 400 mg/400 mg twice daily)

HIV and TB coinfection

If rifabutin is not available

HIV and HBV coinfection a

AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)

BC and ddI can be used as NRTI backup options but add complexity and cost without clinical advantages. DRV/r A can be used as an alternative PI and SQV/r in special situations, but neither is currently available as a heat-stable fixed-dose combination, but a DRV + RTV heat-stable fixed-dose combination is in development.

Background The 2010 WHO ART guidelines recommended that second-line adult regimens include a boosted-PI plus two NRTIs (determined by the drug used in first-line therapy). Those guidelines placed a high value on using simpler second-line regimens, ideally heat-stable formulations and fixed-dose combinations (once-daily formulations when possible). Except for the recommendation for people with HIV and TB, the recommendations in 2013 remain unchanged from the 2010 recommendations.

Rationale and supporting evidence Protease Inhibitor (PI) options for second-line ART Since first-line ART should preferably be based on an NNRTI, PI-based regimens are recommended for second-line therapy. Of the PI options, ATV/r and LPV/r are preferred. DRV/r is an alternative but is currently not available as a fixed-dose combination, although one is in development. The other PIs (FPV/r, IDV/r and SQV/r) are not available as heat-stable fixed-dose combinations and/or are associated with high pill burden and higher frequency of side effects. The Guidelines Development Group emphasized the importance of simplifying second-line ART by reducing the pill burden and limiting the number of preferred second-line regimens that could be used across populations (adults, adolescents, children, pregnant women and people coinfected with TB, HBV and HCV). The use of less toxic, more convenient and more efficacious heat-stable fixed-dose combinations was also considered critical. A systematic review (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes) of data from six clinical trials comparing drugs used for second-line ART (ATV/r, LPV/r and DRV/r) concluded that there was no evidence to support changing the recommendation in the 2010

New

148

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

guidelines (221–226). These studies showed low- to very-low-quality evidence (downgraded in the GRADE evaluation primarily for indirectness and imprecision) for using ATV/r or DRV/r (once-daily) over LPV/r (twice-daily) or vice versa as preferred boosted PI options. ATV/r was considered to be comparable to LPV/r in one trial among ART-experienced individuals (221). In a trial among ART-naive individuals, ATV/r showed a better virological response and better retention in care when compared with LPV/r (224). In two studies, people receiving DRV/rcontaining regimens also showed better virological response and retention in care than people receiving LPV/r, both in treatment-naive and experienced people (222,226). This evidence was downgraded to low or very low quality, primarily for indirectness and imprecision. DRV/r has been used for second-line therapy in high-income settings. However, two key factors currently preclude DRV/r as a preferred option in these guidelines. These include the high cost and it not being available as a heat-stable fixed-dose combination. Additional research is required to better understand sequencing strategies for PIs in second- and third-line therapy. The different drug toxicity profiles of ATV/r and LPV/r, the contraindication of ATV/r and rifampicin and the lack of WHO approval for its use in children younger than six years provide additional grounds for maintaining both PIs as equal options (Table 7.20). The Guidelines Development Group recommended that DRV/r should be maintained as a preferred third-line drug. However, using it as an alternative option to LPV/r or ATV/r for second-line therapy can be considered, especially when competitively priced fixed-dose combinations are available.

NRTI backbone The Guidelines Development Group maintained the rationale adopted in 2010, recommending drug sequencing consistent with ART-optimizing principles (in particular, availability as fixeddose combinations and tolerability) and resistance mutation risk, based on the NRTIs used in the first-line regimen. If a thymidine analogue NRTI (AZT or d4T) was used in the failing firstline regimen, TDF should be used in the second-line regimen. If a non-thymidine analogue NRTI was used in first-line ART (that is, TDF), AZT should be used in second-line ART. Other NRTI drugs such as ABC and ddI are acceptable as potential back-up options in special situations but are not recommended as preferred alternatives, since they have no specific advantage and add complexity and cost. For individuals coinfected with HIV and HBV whose first-line regimen contained TDF + 3TC (or FTC), these NRTIs should be continued in the second-line regimen for the anti-HBV activity and to reduce the risk of hepatic flares, regardless of the selected second-line regimen, which should be AZT + TDF + 3TC (or FTC) + a boosted PI. For people with active TB disease receiving rifampicin, all boosted PIs in standard doses are contraindicated because of drug interactions and significant reductions in PI plasma concentrations (227–230). In this situation, LPV/r and SQV/r may be used with an adjusted, superboosted dose of RTV (LPV/r 400 mg/400 mg twice daily or SQV/r 400 mg/400 mg twice daily) or doubling the LPV/r daily dose (LPV/r 800 mg/200 mg twice daily), but this is associated with high levels of toxicity and requires close clinical and laboratory monitoring. The recommendation to use LPV/r 800 mg/200 mg twice daily is based on evidence graded as low-quality, and it is associated with a similar level of toxicity as LPV/r 400 mg/400 mg twice daily (230,231). However, this option may be less complex and more feasible, since LPV/r is widely available as a single formulation, whereas RTV is not. However, when rifabutin is used in place of rifampicin, all boosted PIs can be concomitantly administered in their standard doses (Table 7.20).

Clinical considerations Clinical and programmatic simplification can be promoted in the sequencing from first- to second-line ART. If AZT- or d4T-based regimens are failing, a second-line regimen with oncedaily dosing for boosted PI and NRTI components (such as TDF + 3TC (or FTC) + ATV/r) should

7. Clinical guidance across the continuum of care: antiretroviral therapy

149

be adopted. If a TDF-based regimen is failing, twice-daily dosing for boosted PI and NRTI components (such as AZT + 3TC + LPV/r) should be adopted.

7.5 What ART regimen to switch to (second-line ART)

Key research gaps Several ongoing studies comparing various drugs and ARV classes (232–236) will provide more data on appropriate second-line regimens, including NRTI-sparing and NRTI-limiting approaches (the results are expected after 2014). Further investigation is needed of the role of DRV in second- and third-line regimens (optimal dosing in adults and children, once versus twice daily, fixed-dose combinations with other boosting agents and integrase inhibitors and sequencing strategies). Several trials are underway that are examining induction and maintenance using PI/r monotherapy in maintenance. The potential of including rifabutin as part of fixed-dose combinations for TB treatment also needs to be explored.

Table 7.20 Comparative analysis: ATV/r versus LPV/r versus DRV/r Major parameters Consistency with paediatric regimens Number of pills per day (standard dose as a fixed-dose combination) Convenience (once- versus twice-daily regimen) Safety in pregnancy Gastrointestinal intolerance (diarrhoea) Availability of co-formulations (as heat-stable fixed-dose combinations) Use with a TB treatment regimen that contains rifampicin Hyperbilirubinaemia Dyslipidaemia Potential for future reduction in cost Accessibility in countries (registration status) Availability of generic formulations Approved only for children >6 years old. Approved only for children >3 years old. c Only if used in higher doses. d A heat stable FDC is currently under development. a b

ATV/r Noa 1 Once daily Yes Not frequent Yes No + ± Low Low Yes

LPV/r Yes 4 Twice daily Yes Common Yes Yesc – + Low High Yes

DRV/r Nob 2 to 4 Once or twice daily Yes Not frequent Nod No – ± High Low No

150

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

7.5.2 Second-line ART for children (including adolescents) New recommendations New

After failure of a first-line NNRTI-based regimen, a boosted PI plus two NRTIs are recommended for second-line ART; LPV/r is the preferred boosted PI. (Strong recommendation, moderate-quality evidence) After failure of a first-line LPV/r-based regimen, children younger than 3 years should remain on their first-line regimen, and measures to improve adherence should be undertaken. (Conditional recommendation, very-low-quality evidence) After failure of a first-line LPV/r-based regimen, children 3 years or older should switch to a second-line regimen containing an NNRTI plus two NRTIs; EFV is the preferred NNRTI. (Conditional recommendation, low-quality evidence) After failure of a first-line regimen of ABC or TDF + 3TC (or FTC), the preferred NRTI backbone option for second-line ART is AZT + 3TC. (Strong recommendation, low-quality evidence) After failure of a first-line regimen containing AZT or d4T + 3TC (or FTC), the preferred NRTI backbone option for second-line ART is ABC or TDF + 3TC (or FTC). (Strong recommendation, low-quality evidence)

Table 7.21 Summary of recommended first- and second-line ART regimens for children (including adolescents) Children Younger than 3 years 3 years and older First-line ART regimen ABC + 3TC + LPV/r AZT + 3TC + LPV/r ABC + 3TC + LPV/r AZT + 3TC + LPV/r ABC + 3TC + EFV (or NVP) Second-line ART regimen

LPV/r-based first-line regimen

No changea AZT + 3TC + EFV ABC or TDFb + 3TC + EFV AZT + 3TC + LPV/rc ABC or TDF + 3TCc (or FTC) + LPV/rc

NNRTI-based first-line regimen

All ages

TDFb + 3TC (or FTC) + EFV (or NVP) AZT + 3TC + EFV (or NVP)

o change is recommended unless in the presence of advanced clinical disease progression or lack of adherence N specifically because of poor palatability of LPV/r. In this case, switching to a second-line NVP-based regimen should be considered. Based on the recent approval of the use of EFV in children less than 3 years, an EFV-based regimen could be considered as an alternative. However, more data are needed to inform how best to use EFV in this population. b TDF may only be given to children >2 years. c ATV/r can be used as an alternative to LPV/r in children older than 6 years. a

7. Clinical guidance across the continuum of care: antiretroviral therapy

151

Background Recommending potent and effective second-line regimens for infants and children is especially difficult because of the current lack of experience in resource-limited settings and the limited formulations available. This highlights the importance of choosing potent and effective first-line regimens and ensuring their durability and effectiveness by optimizing adherence. The 2010 WHO guidelines recommended a regimen based on a PI boosted with RTV and combined with two NRTIs as the second-line treatment for children who fail a regimen of two NRTIs plus an NNRTI (105) . For infants and young children exposed to an NNRTI as part of PMTCT interventions and starting a PI-based regimen in first-line ART, the recommendation for second-line was to use two new NRTIs and an NNRTI, as this was the only new drug class available. The recommendations are now better informed by paediatric clinical trial data (156,158, 237) and observational data (157) . The Guidelines Development Group also considered operational and programmatic issues including the availability of heat-stable formulations and fixed-dose combinations for children.

7.5 What ART regimen to switch to (Second-line ART)

Rationale and supporting evidence After reviewing data for adults and children and considering factors such as the availability of a heat-stable fixed-dose combination, optimal daily dose, regimen harmonization with adults, high cost and availability of alternatives, the main recommendations established in the 2010 guidelines were maintained. For children for whom a LPV/r-based first-line regimen has failed, NNRTIs remain the only new drug class that can be introduced. Randomized data among older children (158) provide indirect evidence supporting the safe use of an NNRTI-based second-line regimen, but concerns remain about this approach for infants and young children. Based on the suboptimal performance of NVP-based regimens (and the limited data available to inform the use of EFV) in children younger than three years (153,154) and the potential rapid re-emergence of archived NNRTI-resistant HIV, second-line NNRTI-based regimens are expected to have limited durability in this age group (238) . Increasing evidence suggests that, in young children for whom LPV/r-based regimens have failed, selection of major PI mutations is rare and accumulation of thymidine analogue mutations is very limited (156,237,239,240) . In this context and in the absence of robust second-line alternatives such as DRV/r-containing regimens, the Guidelines Development Group recommended that children younger than three years of age should be maintained on LPV/r until the age of three years, despite treatment failure. However, a more rapid switch should be considered in situations in which failure results from poor adherence because of the poor palatability of LPV/r or in cases of advanced HIV disease. In such cases, children younger than three years should be switched to a NVP-based regimen, and close monitoring should be provided to ensure adequate adherence. For children starting first-line ART with an NNRTI-based regimen, PI-based regimens remain the recommended choice for second-line therapy. LPV/r is the preferred option, but ATV/r and DRV/r may be considered if more appropriate formulations become available. Despite its toxicity profile and limited role in TB and HIV coinfection, ATV/r is a promising alternative to LPV/r for children older than six years of age. ATV/r has some advantages over LPV/r, including lower cost and the potential for once-daily dosing. DRV/r is the PI of choice following LPV/r or ATV/r treatment failure and would be valuable as a third-line drug or as second-line therapy in young children for whom first-line ART with LPV/r has New

152

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

failed. However, ATV/r is currently only licensed for use among children older than six years and DRV/r in children older than three years. Neither ATV/r nor DRV/r is currently available as a co-formulated fixed-dose combination for children. The Paediatric ARVs Working Group identified appropriate doses of both drugs using current WHO weight bands and simply scaling down from the current adult fixed-dose combination tablets. Validation studies are urgently needed to develop adequate paediatric formulations. Unboosted PIs (such as fosamprenavir (FPV), DRV and ATV) and other PIs (such as IDV/r, SQV/r, FPV/r and TPV/r) are associated with reduced virological suppression, high pill burden and/or a higher frequency of side effects and are therefore discouraged (241) . Notably, liquid RTV requires cold storage, is unpalatable, has significant gastrointestinal intolerance and is poorly tolerated by infants and children. The heat-stable 100-mg fixeddose combination tablet formulation of LPV/r for children is better tolerated but cannot be cut or crushed; many children have difficulty in swallowing this tablet whole. Data on whether LPV/r can be given once daily are expected soon from an ongoing randomized trial (242) . New heat-stable paediatric sprinkle formulations appear to be a suitable alternative and will be available in the near future (243) . The sequencing of NRTI was determined based on optimizing principles for ARV drugs and the need to maximize antiviral activity despite the selection of resistance mutations. If a thymidine analogue NRTI drug (AZT or d4T) was used in the failing first-line regimen, ABC or TDF should be used in the second-line regimen. If a non-thymidine analogue drug (ABC or TDF) was used in the first-line regimen, AZT should be used in the second-line regimen. The added value of ddI in second-line regimens is unclear; continuing 3TC despite the likely presence of 3TC resistance is the preferred option. HIV harbouring 3TC resistance with the M184V mutation may have reduced viral replication and may also induce some degree of resensitization to AZT or TDF, although this is based on in vitro data (165,244) .

Key research gaps More evidence is needed to inform the choice of second-line regimens for young children for whom an LPV/r-based first-line regimen has failed. Validation studies to assess simplified dosing for ATV/r and DRV/r fixed-dose combinations are critical to ensure future effective alternatives. Innovative second-line strategies such as PI + integrase inhibitors or induction and maintenance using PI/r monotherapy among children should also be investigated.

7. Clinical guidance across the continuum of care: antiretroviral therapy

153

7.6 Third-line ART

7.6 Third-line ART New recommendations National programmes should develop policies for third-line ART (conditional recommendation, low-quality evidence). Third-line regimens should include new drugs with minimal risk of cross-resistance to previously used regimens, such as integrase inhibitors and second-generation NNRTIs and PIs (conditional recommendation, low-quality evidence). Patients on a failing second-line regimen with no new ARV options should continue with a tolerated regimen (conditional recommendation, very low-quality evidence). New

Background In 2010, WHO made recommendations on third-line ART in the context of limited evidence to guide third-line strategies. Although there were few studies of newer agents, cohort data showed high mortality among people for whom second-line ART had failed (245) .

Rationale and supporting evidence The Guidelines Development Group maintained the recommendations established in the 2010 WHO guidelines. In so doing, the Guidelines Development Group emphasized balancing the need to develop policies for third-line ART with the need to expand access to first-line and second-line ART. It also recognized that many counties have financial constraints that limit the adoption of third-line regimens. Data from randomized controlled trials are available for DRV/r, etravirine (ETV) and raltegravir (RAL), but most studies have been conducted in well-resourced or middle- to high-income countries. Taken together, these data support the efficacy of these agents in highly ART-experienced patients. In a published pooled subgroup analysis, DRV/r plus an optimized background regimen (OBR) chosen by genotyping and phenotyping was shown to be superior to the control group (boosted PI + OBR plus the optimized background regimen, where the investigator selected the boosted PI) among highly treatmentexperienced individuals (222) . DRV/r was also shown to be non-inferior to LPV/r among treatment-experienced people after 96 weeks (223) . Among individuals with limited treatment options, RAL + OBR provided better viral suppression than the OBR alone for at least 96 weeks (246,247) . Similarly, ETV + OBR provided better viral suppression and improved immunological response than the optimized background regimen alone after 96 weeks (248) . In people with multidrug-resistant HIV who have few remaining treatment options, the combination of RAL, ETV and DRV/r was well tolerated and was associated with a rate of virological suppression similar to that expected among treatment-naive people (249,250) . Evidence from post-marketing reports indicates higher rates of hypersensitivity to ETV than previously reported (251) . ETV + RAL is not approved for use in individuals younger than 16 years of age. There are limited data on the use of these newer drugs in infants, children and pregnancy, including very limited pharmacokinetic and safety data.

New

154

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Special considerations for children Strategies that balance the benefits and risks for children need to be explored when second-line treatment fails. For older children and adolescents who have more therapeutic options available to them, constructing third-line ARV regimens with novel drugs used in treating adults such as ETV, DRV and RAL may be possible (for details on using these drugs in children, see Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). Children on a second-line regimen that is failing with no new ARV drug options should continue with a tolerated regimen. If ART is stopped, opportunistic infections still need to be prevented, symptoms relieved and pain managed.

Clinical considerations The criteria for diagnosing the failure of second-line ART are the same as those used for diagnosing the failure of first-line ART. The demand for second- and third-line regimens will increase as access to viral load monitoring improves and first-line ART continues to be scaled up. Although developing a policy on access to third-line ART is desirable, it should not compromise access to initiation of first-line ART. The costs of potential third-line drugs, such as DRV, ETV and RAL, are not well established in resource-limited settings but are expected to be higher than those of first- and second-line regimens.

Key research gaps Many areas require more information to guide second- and third-line ART for resourcelimited settings, including monitoring critical outcomes for people receiving secondline ART, studying once-daily dosing for DRV/r and RAL as an alternative to NRTIbased regimens in second-line ART, and developing heat-stable formulations of DRV/r. Pharmacovigilance research is needed, including studies on the long-term safety and potential drug–drug interactions with TB, malaria, hepatitis and opioid substitution therapy drugs. As the epidemic matures in low- and middle-income countries, pilot studies are urgently needed on implementing third-line ART in settings with limited capacity and resources in the health system.

clinical guidance across the continuum of care:

MANAGING COMMON COINFECTIONS AND COMORBIDITIES

8.1 Prevention, screening and management of common coinfections 154 8.1.1 Co-trimoxazole preventive therapy 154 8.1.2 Tuberculosis 156 8.1.3 Cryptococcal infection 163 8.1.4 Hepatitis B and C 164 8.1.5 Malaria 165 8.1.6 Sexually transmitted infections and cervical cancer 166 8.1.7 Vaccines for people living with HIV 167 8.2 Preventing and managing other comorbidities and chronic care for people living with HIV 168 8.2.1 Screening for and care of noncommunicable diseases 168 8.2.2 Mental health 169 8.2.3 Drug use and drug use disorders 169 8.2.4 Nutritional care and support 170 8.2.5 Palliative care: symptom management and end-of-life care 171 8.2.6 Other relevant general guidance on care 171

Goal of this chapter To provide a summary of selected existing clinical recommendations and relevant resource documents on preventing and managing common coinfections and comorbidities in the context of the broad continuum of HIV care, with a focus on resource and capacity limited settings.

156

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

8 Clinical guidance across the continuum of care: managing common coinfections and comorbidities Introduction Various coinfections, comorbidities and other health conditions are common among people living with HIV and have implications for their treatment and care, including the timing and choice of ARV drugs. This section provides a brief overview of the most common and important conditions. It summarizes selected key recommendations from already existing WHO guidelines and related materials, focusing on the screening, prophylaxis and timing of ART for these conditions; it does not cover their broader management. Sources and links are provided for relevant guidelines, including the evidence base and rationale supporting different recommendations. The strength of recommendations and quality of evidence is rated using either the GRADE system (strong or conditional recommendations and high, moderate, low and very low quality of evidence) or an alternative grading used prior to 2008 (A (strongly recommended) to C (optional)) and I–IV (level of evidence). In some cases, the sources and web links only are provided. These recommendations were not reviewed or discussed during the 2013 guideline development process, but are included as part of the consolidation of guidance related to HIV care and ARV drugs.

8.1 P revention, screening and management of common coinfections 8.1.1 Co-trimoxazole preventive therapy Background Co-trimoxazole preventive therapy (CPT) should be implemented as an integral component of a package of HIV-related services. Existing recommendations cover initiation of co-trimoxazole preventive therapy among adults, adolescents, pregnant women and children for prevention of Pneumocystis pneumonia, toxoplasmosis and bacterial infections, as well as benefits for malaria prophylaxis and discontinuation of cotrimoxazole preventive therapy.

Source for recommendations Guidelines on co-trimoxazole prophylaxis for HIV-related infection among children, adolescents and adults: recommendations for a public health approach. Geneva, World Health Organization, 2006 (www.who.int/hiv/pub/plhiv/ctx/en) (1) . These recommendations will be updated in 2014.

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

157

Key selected existing recommendations Table 8.1 shows the recommendations. Refer to the Web Annex (www.who.int/hiv/pub/ guidelines/arv2013/annexes) for methodology used in rating the quality of evidence.

8.1 Prevention, screening and management of common coinfections

Table 8.1 Criteria for initiating, discontinuing and monitoring cotrimoxazole preventive therapy according to the 2006 WHO guidelines Age HIVexposed infants <1 year Criteria for initiation In all, starting at 4–6 weeks after birth (A-III) In all b (A-II) Criteria for discontinuationa Until the risk of HIV transmission ends or HIV infection is excluded (A-I) Until 5 years of age regardless of CD4% or clinical symptoms c (A-IV) or Never (A-IV) Never (A-IV) See Annex 7 Clinical at 3-monthly intervals (A-III) Dose of cotrimoxazole See Annex 7 Monitoring approach Clinical at 3-monthly intervals (A-III)

1–5 years

WHO clinical stages 2, 3 and 4 regardless of CD4 % or Any WHO stage and CD4 <25% (A-I) or In all b (C-IV) Any WHO stage and CD4 count <350 cells/mm 3 (A-III) d or WHO 3 or 4 irrespective of CD4 level (A-I) or In all b (C-III)

≥5 years, including adults

Never (A-IV) or when CD4 ≥350 cells/mm 3 after 6 months of ARTe (C-IV) or CD4 ≥200 cells/mm3 after 6 months of ARTc (B-I)

See Annex 7: for <30 kg, 960 mg daily

Clinical at 3-monthly intervals (A-III)

Discontinue also if the person has Stevens-Johnson syndrome, severe liver disease, severe anaemia, severe pancytopaenia or negative HIV status. Contraindications to co-trimoxazole preventive therapy: severe allergy to sulfa drugs; severe liver disease, severe renal disease and glucose-6-phosphate dehydrogenase (G6PD) deficiency. b In all regardless of CD4 percentage or clinical stage in settings with high HIV prevalence, high infant mortality due to infectious diseases and limited health infrastructure. c If initiated primarily for Pneumocystis pneumonia or toxoplasmosis prophylaxis. d Some countries may choose to adopt a CD4 threshold of <200 cells/mm 3. e In settings with high prevalence of bacterial infections or malaria. a

158

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

8.1.2 Tuberculosis Background Among people living with HIV, TB is the most frequent life-threatening opportunistic infection and a leading cause of death. ART should be provided to all people with HIV with active TB disease. HIV care settings should implement the WHO Three I’s strategy: intensified TB case-finding, isoniazid preventive therapy (IPT) and infection control at all clinical encounters.

Source for recommendations W HO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders. Geneva, World Health Organization, 2012 (www.who.int/tb/ publications/2012/tb_hiv_policy_9789241503006/en) (2) .

Additional guidance G uidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. Geneva, World Health Organization, 2011 (www.who.int/tb/challenges/hiv/ICF_IPTguidelines/en/index. html). W HO policy on TB infection control in health-care facilities, congregate settings and households. Geneva, World Health Organization, 2009 (www.who.int/tb/ publications/2009/9789241598323/en). Treatment of tuberculosis: guidelines for national programmes. 4th ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547833_eng.pdf). I mproving the diagnosis of and treatment of smear-negative pulmonary and extrapulmonary TB among adults and adolescents: recommendations for HIV prevalent and resource-constrained settings. Geneva, World Health Organization, 2007 (http://wholibdoc.who.int/2007/HTM). Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational “how-to”. Practical considerations. Geneva, World Health Organization, 2011 (whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf). Recommendations for investigating contact of persons with infectious tuberculosis in low- and middle-income countries. Geneva World Health Organization, 2012 (http:// apps.who.int/iris/bitstream/10665/77741/1/9789241504492_eng.pdf). G uidelines for the programmatic management of drug-resistant tuberculosis. Geneva World Health Organization, 2011 (http://whqlibdoc.who.int/ publications/2011/9789241501583_eng.pdf). Childhood tuberculosis guidelines. Geneva, World Health Organization, forthcoming (expected 2013).

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

159

8.1 Prevention, screening and management of common coinfections

Key selected existing recommendations TB case-finding and antituberculosis treatment (2) Adults and adolescents living with HIV should be screened for TB with a clinical algorithm; those who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases (Fig. 8.1) (strong recommendation, moderate-quality evidence). Children living with HIV who have any of the following symptoms of poor weight gain, fever or current cough or contact history with a TB case may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, children should be offered isoniazid preventive therapy regardless of their age (Fig. 8.2) (strong recommendation, lowquality evidence) . TB patients with known positive HIV status and TB patients living in HIV-prevalent settings should receive at least six months of rifampicin treatment regimen (strong recommendation, high-quality evidence). T he optimal dosing frequency is daily during the intensive and continuation phases (strong recommendation, high-quality evidence). Xpert MTB/RIF should be used as the initial diagnostic test in individuals suspected of having HIV-associated TB or multidrug-resistant TB (strong recommendation).

160

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Key selected existing recommendations Isoniazid preventive therapy (IPT) (2) Adults and adolescents living with HIV should be screened with a clinical algorithm; those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT (strong recommendation, moderate-quality evidence). D uration of IPT • Adults and adolescents who are living with HIV, have unknown or positive tuberculin skin test (TST) status and are unlikely to have active TB should receive at least six months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women (strong recommendation, high-quality evidence). • Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 36 months of IPT. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also those on ART, those who have previously been treated for TB and pregnant women (conditional recommendation, moderate-quality evidence). A TST is not a requirement for initiating IPT in people living with HIV (strong recommendation, moderate-quality evidence). People living with HIV who have a positive TST benefit more from IPT; TST can be used where feasible to identify such individuals (strong recommendation, high-quality evidence). Providing IPT to people living with HIV does not increase the risk of developing isoniazid-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT (strong recommendation, moderate-quality evidence). Children living with HIV who do not have poor weight gain, fever or current cough are unlikely to have active TB (strong recommendation, low-quality evidence). Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening and have no contact with a TB case should receive six months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care services (strong recommendation, moderate-quality evidence). In children living with HIV who are less than 12 months of age, only those who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease (strong recommendation, low-quality evidence). All children living with HIV, after successful completion of treatment for TB disease, should receive isoniazid for an additional six months (conditional recommendation, low-quality evidence).

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

161

Fig. 8.1 Algorithm for TB screening among adults and adolescents living with HIV in HIV-prevalent and resource-constrained settings Adults and adolescents with HIVa

8.1 Prevention, screening and management of common coinfections

Screen for TB with any one of the following symptoms: b Current cough Fever Weight loss Night sweats No Assess for contraindications to IPTc No Give IPT Yes Defer IPT Yes

Investigate for TB and other diseasesd

Other diagnosis

Not TB

Give appropriate treatment and consider IPT

Follow up and consider IPT

Treat for TB

Screen for TB regularly at each encounter with a health worker or visit to a health facility IPT: isoniazid preventive therapy a Every adult and adolescent should be evaluated for eligibility to receive antiretroviral therapy. Infection control measures should be given priority to reduce Mycobacterium tuberculosis transmission in all settings that provide care. b Chest radiography can be done if available but is not required to classify people into TB and non-TB groups. In settings with high HIV prevalence and a high TB prevalence among people living with HIV (such as exceeding 10%), strong consideration must be given to adding other sensitive investigations. c Contraindications include: active hepatitis (acute or chronic), regular and heavy alcohol consumption and symptoms of peripheral neuropathy. Past history of TB and current pregnancy should not be contraindications for starting isoniazid preventive therapy. Although not a requirement for initiating isoniazid preventive therapy, tuberculin skin testing may be performed as a part of eligibility screening in some settings. d Investigations for TB should be performed in accordance with existing national guidelines.

162

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Fig. 8.2 Algorithm for TB screening among children older than one year of age and living with HIV Child more than 12 months of age and living with HIVa

Screen for TB with any one of the following symptoms: Poor weight gainb Fever Current cough Contact history with a TB case No Assess for contraindications to IPTc No Give IPT Yes Defer IPT Yes

Investigate for TB and other diseasesd

Other diagnosis

Not TB

Give appropriate treatment and consider IPT

Follow up and consider IPT

Treat for TB

Screen for TB regularly at each encounter with a health worker or visit to a health facility IPT: isoniazid preventive therapy a A ll infants younger than one year should be provided with isoniazid preventive therapy if they have a history of household contact with a person with TB. b Poor weight gain is defined as (1) reported weight loss or very low weight (weight for age less than –3 z-score), (2) underweight (weight for age less than –2 z-score), (3) confirmed weight loss (>5%) since the last visit or (4) growth curve flattening. c Contraindications include: active hepatitis (acute or chronic) and symptoms of peripheral neuropathy. A past history of TB should not be a contraindication to starting isoniazid preventive therapy. Although not a requirement for initiating isoniazid preventive therapy, tuberculin skin testing may be performed as part of eligibility screening in some settings. d Investigations for TB must be performed in accordance with existing national guidelines.

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

163

Infection control Background People living with HIV are at high risk of acquiring TB in health care facilities and congregate settings. National TB programmes and national HIV programmes should provide managerial direction for implementing TB infection control programmes. Each health care facility should have a TB infection control plan for the facility that includes administrative, environmental and personal protection measures to reduce the transmission of TB in health care and congregate settings and surveillance of TB disease among workers (Box 8.1). Health care workers with HIV should be provided with ART and isoniazid preventive therapy if they are eligible.

8.1 Prevention, screening and management of common coinfections

Sources for recommendations WHO policy on TB infection control in health-care facilities, congregate settings and households. Geneva, World Health Organization, 2009 (www.who.int/tb/ publications/2009/9789241598323/en) (3). Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501583_ eng.pdf) (4). WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders. Geneva, World Health Organization, 2012 (www.who.int/tb/ publications/2012/tb_hiv_policy_9789241503006/en) (2). Childhood tuberculosis guidelines. Geneva, World Health Organization, forthcoming (expected 2013) (5).

Box 8.1. Summary of recommendations for key actions for infection control (3) Administrative (facility-level infection control committee and protocols) A triage system to identify people suspected of having TB Separate people with suspected or confirmed TB Cough etiquette and respiratory hygiene Rapid diagnosis with Xpert MTB/RIF (with prompt treatment of active TB) (strong recommendation, low-quality evidence). Health workers and carers Surveillance and information Package of care for HIV-positive workers (ART and isoniazid preventive therapy) Protective equipment (particulate respirator masks that meet or exceed N95 standards) Relocation for health care workers living with HIV to a lower-risk area (strong recommendation, high-quality evidence). Environmental Ventilation (mechanical) Ventilation (natural) Upper-room ultraviolet germicidal irradiation (strong recommendation, low-quality evidence). Personal Spend as much time as possible outside Cough etiquette Sleep alone while smear-positive Avoid congregate settings and public transport while smear-positive (strong recommendation, low-quality evidence).

164

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Key selected existing recommendations Timing of ART for adults and children with TB ART should be started in all TB patients, including those with drug-resistant TB, irrespective of the CD4 count (strong recommendation, low-quality evidence) (4). Antituberculosis treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment (strong recommendation, moderatequality evidence). The HIV-positive TB patients with profound immunosuppression (such as CD4 counts less than 50 cells/mm3) should receive ART immediately within the first two weeks of initiating TB treatment (2). ART should be started in any child with active TB disease as soon as possible and within eight weeks following the initiation of antituberculosis treatment irrespective of the CD4 count and clinical stage (strong recommendation, low-quality evidence) (5). Efavirenz should be used as the preferred NNRTI in patients starting ART while on antituberculosis treatment (strong recommendation, high-quality evidence) (2).

Section 7.2 provides more detailed information and recommendations on the co-treatment of TB and HIV. More detailed information and recommendations on drug interactions between ARV drugs and TB drugs are available in the Web Annex (www.who.int/hiv/pub/ guidelines/arv2013/annexes).

Multidrug-resistant TB and HIV Background Multidrug-resistant TB (MDR-TB) is defined as TB that is resistant to at least isoniazid and rifampicin. Patients with both HIV and MDR-TB face complicated clinical management, fewer treatment options and poorer treatment outcomes. Limited information is available about the association between HIV and MDR-TB at the population level, especially because only 40% of the people with active TB are tested for HIV (6). Outbreaks of MDR-TB among people with HIV have been documented in hospital and other settings, especially in eastern Europe and in southern African countries with a high HIV prevalence (7). People with HIV with suspected drug-resistant TB should be tested using Xpert MTB/RIF where possible, since this test is more sensitive for detecting TB among people with HIV and rapidly detects rifampicin resistance, thus greatly shortening the time to diagnosing and treating MDR-TB. The burden of MDR-TB should be reduced by strengthening HIV prevention, improving infection control and improving collaboration between HIV and TB control activities, with special attention to the groups at the highest risk of MDR-TB and HIV infection, such as people who inject drugs and those exposed in congregate settings.

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

165

Source for recommendation Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501583_ eng.pdf) (4)

8.1 Prevention, screening and management of common coinfections

Additional guidance Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational “howto”. Practical considerations. Geneva, World Health Organization, 2011 (http://whqlibdoc. who.int/publications/2011/9789241501569_eng.pdf).

Key selected existing recommendation (4) WHO recommends ART for all patients with HIV and drug-resistant TB, requiring second-line anti-tuberculosis drugs irrespective of CD4 cell count, as early as possible (within the first eight weeks) following initiation of anti-tuberculosis treatment (strong recommendation, very-low-quality evidence).

8.1.3 Cryptococcal infection Background Cryptococcal meningitis is one of the most important opportunistic infections and a major contributor to high mortality before and after ART is initiated. WHO 2011 Rapid Advice covers diagnosis, screening and prevention of cryptococcal infection, induction, consolidation and maintenance regimens, monitoring and managing toxicities, timing of ART and discontinuing maintenance regimens. Full guidelines will be published at the end of 2013.

Source for recommendations Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIVinfected adults, adolescents and children. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/cryptococcal_disease2011) (8).

Key selected existing recommendations Screening and prophylaxis (8) Use of routine serum or plasma Cryptococcus neoformans antigen (CrAg) screening in ART-naive adults, followed by pre-emptive antifungal therapy if CrAg-positive and asymptomatic, to reduce the development of cryptococcal disease, may be considered prior to ART initiation in patients with a CD4 count of less than 100 cells/mm3 and where this population also has a high prevalence of cryptococcal antigenaemia (conditional recommendation, low-quality evidence). Routine use of antifungal primary prophylaxis for cryptococcal disease in people living with HIV with a CD4 count of less than 100 cells/mm3 and who are CrAg-negative or where CrAg status is unknown is not recommended prior to ART initiation (strong recommendation, high-quality evidence). The use of routine CrAg screening and pre-emptive antifungal therapy in ART-naive adolescents and children with a CD4 count of less than 100 cells/mm3 prior to ART initiation is not recommended (conditional recommendation, low-quality evidence).

166

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Timing of ART (8) Immediate ART initiation is not recommended in patients with cryptococcal meningitis due to the high risk of immune reconstitution inflammatory syndrome with central nervous system disease, which may be life-threatening (conditional recommendation, low-quality evidence). Among people living with HIV with a recent diagnosis of cryptococcal meningitis, ART initiation should be deferred until there is evidence of a sustained clinical response to antifungal therapy and • after two to four weeks of induction and consolidation treatment with amphotericin containing regimens combined with flucytosine or fluconazole; or • after four to six weeks of induction and consolidation treatment with a high-dose oral fluconazole regimen (conditional recommendation, low-quality evidence). See the source above for recommendations on discontinuing secondary prophylaxis.

8.1.4 Hepatitis B and C Background Chronic hepatitis B virus infection affects 5–20% of the 33 million people living with HIV worldwide, and hepatitis C affects 5–15%, although this may be up to 90% among people who inject drugs (9,10). The burden of coinfection is greatest in low- and middle-income countries, particularly in South-East Asia and sub-Saharan Africa for hepatitis B. Viral hepatitis is an increasing cause of morbidity and mortality among people living with HIV, including those on ART. A comprehensive approach includes prevention, hepatitis B and hepatitis C screening, hepatitis B vaccination and treatment and care for people with HIV coinfected with hepatitis B and/or hepatitis C.

Additional guidance Guidance on prevention of viral hepatitis B and C among people who inject drugs. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/guidelines/hepatitis/en/index. html).

Guidance on timing of ART in hepatitis B and C Hepatitis B: when to start and what to start. See sections 7.1.1, 7.1.4 and 7.2.7.

Hepatitis C: when to start and what to start. Initiating ART among people with HIV and hepatitis C should follow the same general principles as for the general population of people living with HIV (section 7.1). The WHO guidelines for the management of hepatitis C are scheduled to be published in 2014. They will provide detailed guidance on hepatitis C screening, hepatitis C–specific treatment and general hepatitis C care.

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

167

8.1 Prevention, screening and management of common coinfections

8.1.5 Malaria Background People with HIV with immunosuppression living in malaria-endemic areas are at high risk of complications of malaria, and all infants and children under five years of age and pregnant women are at particular risk of severe malaria and its complications. Key interventions to control malaria include prompt and effective treatment with artemisinin-based combination therapies and using insecticide-treated nets and indoor residual spraying with insecticide to control the vector mosquitoes. An additional intervention recommended in areas of high transmission for specific high-risk groups is intermittent preventive treatment during pregnancy and seasonal malaria chemoprophylaxis. People living with HIV who develop malaria should receive prompt, effective antimalarial treatment regimens. Parasitological confirmation should be undertaken for all suspected malaria cases using either microscopy or a rapid diagnostic test. The drugs used to treat malaria and ARV drugs may share toxicities (particularly sulfabased drugs) and may have clinically important pharmacokinetic interactions (especially artemesinins, lumefantrine, NNRTIs and protease inhibitors). For this reason, people receiving treatment for both HIV and malaria should be monitored closely for adverse drug reactions, and people with HIV receiving zidovudine, or efavirenz should, if possible, avoid amodiaquine-containing artemisinin-based combination regimens because of increased risk of neutropaenia in combination with zidovudine, and hepatotoxicity in combination with efavirenz.

Source for recommendations Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, World Health Organization, 2008 (www.who.int/hiv/ pub/prev_care/OMS_EPP_AFF_en.pdf) (11) .

Additional guidance Guidelines for the treatment of malaria. 2nd ed. Geneva, World Health Organization, 2010 (www.who.int/malaria/publications/atoz/9789241547925/en/index.html). WHO policy recommendation: seasonal malaria chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa. Geneva, World Health Organization, 2012 (www.who.int/malaria/publications/atoz/who_smc_policy_recommendation/en/index.html). Technical Expert Group meeting on intermittent preventive treatment in pregnancy (IPTp). Geneva, World Health Organization, 2007 (www.who.int/malaria/ publications/9789241596640/en). Intermittent preventive treatment for infants using sulfadoxine-pyrimethamine (SP-IPTi) for malaria control in Africa: implementation field guide. Geneva, World Health Organization, 2011 (www.who.int/malaria/publications/atoz/whoivb11_07/en/index.html). Test, treat and track. Scaling up diagnostic testing, treatment and surveillance for malaria. Geneva, World Health Organization, 2012 (www.who.int/malaria/publications/atoz/test_ treat_track_brochure.pdf). Additional information: malaria [web site]. Geneva, World Health Organization, 2013 (www.who.int/topics/malaria/en).

168

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Key selected existing recommendations (11) a In areas of stable malaria transmission, people living with HIV (as for the general population) should routinely use insecticide-treated bed-nets or have access to indoor residual spraying to reduce their exposure to malaria infection. (A-I) Treatment or intermittent preventive treatment with sulfadoxine-pyrimethamine should not be given to patients with HIV receiving co-trimoxazole prophylaxis. (A-III) a

See the Web Annex (www.who.int/hiv/pub/guidelines/arv2013/annexes) for methodology used in rating quality of evidence.

8.1.6 Sexually transmitted infections and cervical cancer Background HIV, other sexually transmitted infections and non-sexually transmitted infections of the reproductive tract frequently coexist. Most of these infections are asymptomatic, especially among women. However, even asymptomatic sexually transmitted infections can cause complications, be transmitted to sexual partners and enhance HIV transmission. Further, HIV infection alters the natural history of sexually transmitted infections. The objectives of diagnosing and managing sexually transmitted infections include identifying the infection and providing appropriate treatment and preventing transmission. Screening, diagnosis and treatment of sexually transmitted infections should be offered routinely as part of comprehensive HIV care among adults and adolescents. WHO guidelines on treating and managing sexually transmitted infections are scheduled to be updated in 2014. Other recent guidelines cover recommendations on periodic screening and periodic presumptive treatment for asymptomatic sexually transmitted infections in sex workers, and periodic testing for asymptomatic urethral and rectal Neisseria gonorrhoeae and Chlamydia trachomatis infections and asymptomatic syphilis infection among female sex workers, men who have sex with men and transgender people. Cervical cancer is a preventable disease and is curable if diagnosed and treated early. Women living with HIV have a higher risk of pre-cancer and invasive cervical cancer. The risk and persistence of human papillomavirus infection increases with decreasing CD4 count and increasing HIV viral load. Invasive cervical cancer is a WHO HIV clinical stage 4 condition. Women living with HIV should be followed closely for evidence of pre-cancerous changes in the cervix, regardless of ART status or CD4 count and viral load. Cervical cancer screening leads to early detection of precancerous and cancerous cervical lesions that will prevent serious morbidity and mortality. Thus, all women with HIV should be screened for cervical cancer regardless of age. Immediate management for pre-cancerous and cancerous lesions should be provided. WHO guidance covers human papillomavirus vaccination and prevention, screening and treatment and palliative care of cervical cancer. To date, concerns about safety or reduced efficacy among females who may be infected with HIV should not defer the initiation of large-scale HPV immunization. HIV testing should not be a prerequisite before routine HPV immunization.

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

169

Additional guidance Sexually transmitted infections Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, World Health Organization, 2008 (www.who.int/hiv/ pub/prev_care/OMS_EPP_AFF_en.pdf). Guidelines for the management of sexually transmitted infections. Geneva, World Health Organization, 2004 (www.who.int/hiv/pub/sti/pub6/en). Global strategy for the prevention and control of sexually transmitted infections: 2006– 2015. Breaking the chain of transmission. Geneva, World Health Organization, 2007. (www.who.int/reproductivehealth/publications/rtis/9789241563475/en/index.html). WHO meeting report. Report of the Expert Consultation and review of the latest evidence to update guidelines for the management of sexually transmitted infections. Geneva, World Health Organization, 2011 (www.who.int/reproductivehealth/publications/rtis/ rhr_11_37/en). WHO guidelines on the syndromic approach to managing people with symptoms of sexually transmitted infections and treating specific sexually transmitted infections are scheduled to be updated in 2014. Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries. Geneva, World Health Organization, 2012 (www.who. int/hiv/pub/guidelines/sex_worker/en). Prevention and treatment of HIV and other sexually transmitted infections among men who have sex with men and transgender people. Recommendations for a public health approach. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/guidelines/ msm_guidelines2011/en).

8.1 Prevention, screening and management of common coinfections

Cervical cancer Human papillomavirus vaccines: WHO position paper. Weekly Epidemiological Record, 2009, 84:118–131 (www.who.int/wer/2009/wer8415.pdf). Comprehensive cervical cancer prevention and control: a healthier future for girls and women. Geneva, World Health Organization, 2013 (www.who.int/reproductivehealth/ topics/cancers/en/index.html). WHO guidelines on use of cryotherapy for cervical intraepithelial neoplasia. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502856_ eng.pdf).

8.1.7 Vaccines for people living with HIV Background People living with HIV should be assessed for eligibility for vaccination at all stages of care. HIV-exposed infants and children and young adults with HIV should receive all vaccines under routine vaccination according to recommended national immunization schedules. Those with more severe immunosuppression may be at higher risk of complications from live vaccines. Inactivated vaccines are more effective among people receiving ART and those without immunosuppression, but they are safe and can be used with some efficacy in all groups.

170

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Additional guidance F or complete vaccination schedules and detailed guidance: WHO recommendations for routine immunization – summary tables [web site]. Geneva, World Health Organization, 2012 (www.who.int/immunization/policy/immunization_tables/en/index.html). F or position papers on each vaccine, and statement about use in people living with HIV: (www.who.int/immunization/documents/positionpapers/en/index.html).

8.2 P reventing and managing other comorbidities and chronic care for people living with HIV 8.2.1 Screening for and care of noncommunicable diseases Background People living with HIV are at increased risk of developing a range of noncommunicable diseases (NCDs), including cardiovascular disease, diabetes, chronic lung disease and some types of cancer (12,13) . With effective ART, people living with HIV are also living longer and experiencing NCDs associated with ageing. Both HIV and NCDs require health systems that can deliver effective acute and chronic care and support adherence to treatment. Chronic HIV care provides the opportunity for screening, monitoring and managing NCDs, especially through primary care. Integrating interventions such as nutrition assessment, dietary counselling and support, smoking cessation, promoting exercise, monitoring blood pressure and where available cholesterol as part of HIV care provide opportunities for reducing the risks of NCDs among people living with HIV. WHO has defined a package of essential NCDs (WHO PEN) interventions along with recommendations on screening for and treating NCDs. Additional guidance on diagnosis and management of NCDs in people living with HIV is planned for 2014.

Additional guidance Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva, World Health Organization, 2010 (www.who.int/ cardiovascular_diseases/publications/pen2010/en). Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/76173/1/9789241548397_eng.pdf).

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

171

8.2 Preventing and managing other comorbidities and chronic care for people living with HIV

8.2.2 Mental health Background People living with HIV and their carers may have a wide range of mental health needs. The most common mental health comorbidities among people living with HIV include depression, anxiety, dementia and other cognitive disorders and substance use disorders. HIV care settings provide an opportunity to ensure the detection and management of mental disorders among people living with HIV. Treatment or lack of treatment for these conditions can affect adherence to ARV drugs, retention in care and may involve potential side effects and drug interactions. WHO has no specific recommendations on screening and treatment for mental disorders among people living with HIV. The Mental Health Gap Action Programme (mhGAP) intervention guide for mental, neurological and substance use disorders in non-specialized health settings makes recommendations related to general mental health that can be relevant to people living with HIV. Additional guidance on management of mental health conditions in people living with HIV is planned for 2014.

Additional guidance mhGAP Intervention Guide for mental, neurological and substance use disorders in nonspecialized health settings. Geneva, World Health Organization, 2010 (http://whqlibdoc. who.int/publications/2010/9789241548069_eng.pdf).

8.2.3 Drug use and drug use disorders Background People living with HIV who use drugs may experience a range of disorders related to their drug use, including drug dependence, intoxication, withdrawal and overdose. Injecting drug use is associated with a range of bloodborne and local infections, including viral hepatitis, septicaemia and bacterial endocarditis, in addition to HIV. WHO has developed guidance for the treatment of opioid dependence and prevention of hepatitis B and C among people who inject drugs. WHO, UNODC and UNAIDS recommend a comprehensive package of nine interventions for HIV prevention, treatment and care for people who inject drugs, including needle and syringe programmes, opioid substitution therapy, HIV testing and counselling, ART, preventing and treating sexually transmitted infections, condom programmes, targeted behaviour change communication, preventing and treating viral hepatitis and preventing and treating TB.

Additional guidance WHO, UNODC and UNAIDS. Technical guide for countries to set targets for universal access to HIV prevention, treatment and care for injecting drug users. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/idu/targets_universal_access/en/index.html). Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/ publications/2009/9789241547543_eng.pdf). Guidance on prevention of viral hepatitis B and C among people who inject drugs. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/guidelines/hepatitis/en/ index.html).

172

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

8.2.4 Nutritional care and support 8.2.4.1 Among adolescents and adults living with HIV Background Low energy intake combined with increased energy demands because of HIV infection (14–17) and related infections may lead to HIV-related weight loss and wasting. In addition, an altered metabolism, reduced appetite and higher incidence of diarrhoea may lower nutrient intake and absorption and also lead to nutrient losses. These effects may all be compounded in low income, food insecure contexts. Low body mass in adults (body mass index vi less than 18.5kg/m 2 ), weight loss and wasting in children are all independent risk factors for HIV disease progression and mortality (18,19) . Nutritional assessment (anthropometry, clinical and dietary assessment), counselling and support should be an integral component of HIV care and conducted at enrolment in care and monitored during all HIV care and treatment. Malnourished HIV patients, especially in food insecure contexts, may require food supplements, in addition to ART, to ensure appropriate foods are consumed to support nutritional recovery. Weight loss or failure to regain or maintain a healthy weight at any stage of HIV infection or ART should trigger further assessment and appropriate interventions. WHO is currently revising recommendations for nutritional care and support of adolescents and adults living with HIV, including pregnant and lactating women.

8.2.4.2 Among children living with HIV Background Nutritional assessment is essential to identify malnutrition and growth faltering early. Infants and children should undergo initial nutritional assessment (evaluation of nutritional status, diet and symptoms) and then be weighed and have height measured at each visit and monitored with reference to WHO or national growth curves. Growth monitoring should also be integrated into the assessment of ART response (20) . If poor growth is identified, then further assessment should be performed to determine the cause, and plan appropriate response. The 2009 guidelines for an integrated approach to the nutritional care of children living with HIV provide details of nutritional interventions.

Additional guidance Guidance on Nutrition assessment, education, counselling and support for adolescents and adults living with HIV. Geneva, World Food Programme and World Health Organization, 2013. Guidelines on HIV and infant feeding. Geneva, World Health Organization, 2010 (http:// whqlibdoc.who.int/publications/2010/9789241599535_eng.pdf). Guidelines for an integrated approach to the nutritional care of HIV-infected children (6 months – 14 years): handbook. Preliminary version for country introduction. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241597524_ eng_Handbook.pdf). WHO and FAO. Nutritional care and support for people living with HIV/AIDS: a training course. Geneva, World Health Organization, 2009 (www.who.int/nutrition/publications/ hivaids/9789241591898/en/index.html). vi

Body mass index: indicates adequacy of weight in relation to height for older children, adolescents and adults. It is calculated as the weight in kg divided by the height in metres squared. The acceptable range for adults is 18.5 to 24.9, and for children this varies with age.

8. Clinical guidance across the continuum of care: managing common coinfections and comorbidities

173

8.2.5 Palliative care: symptom management and end-of-life care Background Throughout all stages of HIV disease, and when receiving treatment, people living with HIV may experience various forms of pain and other discomfort. Care providers should identify and treat the underlying cause when possible, while controlling the pain. Further, effectively managing the side effects of ART is important to support adherence.

8.2 Preventing and managing other comorbidities and chronic care for people living with HIV

Additional guidance IMAI district clinician manual: hospital care for adolescents and adults. Guidelines for the management of common illnesses with limited resources. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/imai/imai2011/en).

8.2.6 Other relevant general guidance on care 8.2.6.1 Family planning, counselling and contraception Additional guidance M edical eligibility criteria for contraceptive use. 4th ed. Geneva, World Health Organization, 2009 (www.who.int/reproductivehealth/publications/family_ planning/9789241563888/en/index.html). H ormonal contraception and HIV. Technical statement 16 February 2012. Geneva, World Health Organization, 2012 (www.who.int/reproductivehealth/publications/ family_planning/9789241563888/en/index.html).

174

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

8.2.6.2 Providing safe water, sanitation and hygiene Additional guidance E ssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, World Health Organization, 2008 (www.who.int/ hiv/pubprev_care/OMS_EPP_AFF_en.pdf). Evaluating household water treatment options: health-based targets and microbiological performance specifications. Geneva, World Health Organization, 2011 (www.who.int/water_sanitation_health/publications/2011/evaluating_water_ treatment.pdf). G uidelines for drinking-water quality. 4th ed. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241548151_eng.pdf).

OPERAtions and service delivery

guidance on

09 174 174 176 179 183 183 183 188

9.1 Introduction 174 9.2 Adherence to ART 9.2.1 Barriers to adherence 9.2.2 Interventions to optimize adherence to ART 9.2.3 Monitoring adherence to ART in routine programme and care settings

9.3 Retention across the continuum of care 180 9.3.1 Background 180 9.3.2 Good practices for retention across the continuum of care 180 9.4 Service delivery 9.4.1 Good practices in providing chronic care 9.4.2 Integrating and linking services 9.4.3 Decentralizing HIV treatment and care

9.5 Human resources 190 9.5.1 Building human resource capacity 190 9.5.2 Task shifting for HIV treatment and care 190 9.6 Laboratory and diagnostic services 192 9.6.1 Overview 192 9.6.2 Implementation considerations and good practices 192 9.6.3 Strengthening and expanding laboratory and diagnostic services 192 9.6.4 Supporting a dedicated specimen referral system 193 9.6.5 Increasing access to HIV viral load testing 193 9.6.6 Expanding diagnostic services to point-of-care settings 193 9.6.7 Providing guidance for developing health workers’ capacity including staff training and certification 195 9.6.8 Implementing comprehensive quality management systems 195 9.7 Procurement and supply management systems 195 9.7.1 Overview 195 9.7.2 Rationale and supporting evidence 195 9.7.3 Implementation considerations and good practices 196

Goal of this chapter To provide guidance on key issues related to operations and service delivery that need to be addressed to strengthen the continuum of HIV care and further integrate the provision of ARV drugs into health systems.

176

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9 Guidance on operations and service delivery 9.1 Introduction ARV drugs and related services need to be delivered as effectively, equitably and efficiently as possible by optimizing available human and financial resources, ensuring appropriate links between care settings and services, supporting adherence to lifelong treatment and maximizing retention of patients across the continuum of care. This chapter provides broad guidance in six operational and service delivery areas in which action is essential to ensure the long-term effectiveness and sustainability of ARV programmes. These areas are: adherence to ART; retention across the continuum of care; service delivery, comprising service integration and linkage and decentralization of HIV care and treatment; human resources, including task shifting; laboratory and diagnostic services; and procurement and supply management systems. New recommendations, developed through the GRADE process, are found in the sections on adherence and service delivery and human resources and include: text messages to promote adherence; ART integration into and linkage with maternal and child health, TB and opioid substitution therapy services; decentralization of ART; and task shifting.

9.2 Adherence to ART 9.2.1 Barriers to adherence WHO defines treatment adherence as “the extent to which a person’s behaviour – taking medications, following a diet and/or executing lifestyle changes – corresponds with agreed recommendations from a health care provider” (1). For ART, a high level of sustained adherence is necessary to (1) suppress viral replication and improve immunological and clinical outcomes; (2) decrease the risk of developing ARV drug resistance; and (3) reduce the risk of transmitting HIV. Multiple factors related to health care delivery systems, the medication and the person taking ARV drugs may affect adherence to ART. The individual factors may include forgetting doses; being away from home; changes in daily routines; depression or other illness; a lack of interest or desire to take the medicines; and substance or alcohol use. Medication-related factors may include adverse events; the complexity of dosing regimens; the pill burden; and dietary restrictions. Health system factors may include requiring people with HIV to visit health services frequently to receive care and obtain refills; travelling long distances to reach health services; and bearing the direct and indirect costs of care. Lack of clear information or instruction on medication, limited knowledge on the course of HIV infection and treatment

9. Guidance on operations and service delivery

177

and adverse effects can all be barriers to adherence to ART. Moreover, uninterrupted ARV drug supply and continuity of care are essential for people to adhere to their medication. Lack of continuity of care is a strong predictor of non-adherence in the longer term. Adherence to ART may also be challenging in the absence of supportive environments for people living with HIV and due to HIV-related stigma and discrimination (2,3).

9.2 Adherence to ART

Pregnant and postpartum women The pregnancy and postpartum period presents significant biological, social and economic challenges that may affect treatment adherence. Pregnancy-related conditions such as nausea and vomiting may negatively affect treatment adherence. Other challenges during this period may include dealing with the diagnosis of HIV infection (many women learn about their HIV infection during routine screening during pregnancy); concerns about how ART affects the health of the fetus; pill burden; the number of clinic visits during pregnancy; fear of disclosure of HIV status to partners; long waiting times at clinics; and lack of follow-up and transfer to other clinics after delivery (4,5).

Adolescents Adherence challenges faced by adolescents include a potentially large pill burden if they are treatment-experienced; stigma and fear of disclosure; concerns about safety of medications; adverse effects; peer pressure and perceived need to conform; not remembering to take medications; and inconsistent daily routine. The transition from paediatric to adolescent care presents several challenges that may affect treatment adherence in adolescents. These include assuming increased responsibility for their own care (which may lead to treatment interruptions because of forgetfulness); an inability to navigate the health care system; lack of links between adult and paediatric services; lack of health insurance; and inadequately skilled health care providers (6,7). Depression and substance use have also been shown to present challenges in adolescents.

Infants and children Adherence among children is a special challenge. The limited choice of paediatric formulations, poor palatability of liquid formulations, high pill or liquid volume burden, large pill size, frequent dosing requirements, dietary restrictions, loss of primary caregiver, difficulties in swallowing tablets and adverse effects may all affect adherence (3,8,9). Successfully treating a child requires the commitment and involvement of a responsible caregiver. Parents and other family members of children living with HIV may themselves be living with HIV; suboptimal HIV care and treatment for family members could result in suboptimal care for the child.

Mental health disorders Adherence to ART is known to be complicated by mental health comorbidity that results in forgetfulness, poor organization and poor comprehension of treatment plans. Studies have linked uncontrolled depressive symptoms with low levels of adherence to ART and poor treatment outcomes. As a result, several treatment strategies target depression and psychosocial stress to improve adherence to ART, ranging from co-counselling for HIV and depression to appropriate medical therapies for individuals with mental disorders (10–13).

Substance use disorders Individuals with substance use disorders may have poor adherence to ART. Alcohol and other drug use could be associated with forgetfulness, poor organization and diversion of monetary and time priorities (10,14–16).

178

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Most-at-risk populations (including sex workers, men who have sex with men, transgender people and people who inject drugs) In several settings, most-at-risk populations face multiple challenges to accessing health services. Service delivery approaches to improve longitudinal care and maintain adherence for most-at-risk populations remains a critical gap in many settings. Experience indicates encouraging results with peer-based interventions that include strong social support such as outreach teams, peer educators and health workers providing multidisciplinary, nonjudgemental and respectful care.

Incarceration Incarceration may negatively affect continuity of care, diminish trust and predispose individuals to poor financial and social support both during and after incarceration. Substance use disorders may also be an additional challenge for this population. People who are incarcerated have the additional risk of acquiring TB, resulting in high morbidity and mortality rates in the absence of efficacious HIV and TB treatment (17). However, excellent outcomes can be achieved with adequate support and structured treatment programmes within the prison setting.

9.2.2 Interventions to optimize adherence to ART No single adherence intervention or package of interventions is effective for all populations and all settings. People’s needs and circumstances may also change over time, and programmes and care providers therefore need to tailor a combination of feasible interventions to maximize adherence to ART based on individual barriers and opportunities. Programme-level interventions for improving adherence to ART include: (1) avoiding imposing out-of-pocket payments at the point of care, (2) using fixed-dose combination regimens for ART and (3) strengthening drug supply management systems to reliably forecast, procure, and deliver ARV drugs and prevent stock-outs. The individual-level adherence intervention recommendation in this section relates to the use of mobile phone text messages. There have been simple and robust trials to demonstrate its importance as one of many adherence tools. Adherence interventions, such as text messaging, should clearly be provided as part of a total package of several interventions. Many individuallevel adherence interventions are indicated for reasons in addition to improving adherence to ART. For example, nutritional support, peer support, management of depression and substance use disorders and patient education are vital components of routine health and HIV care. Efforts to support and maximize adherence should begin before ART is initiated. Developing an adherence plan and education are important first steps. Initial patient education should cover basic information about HIV, the ARV drugs themselves, expected adverse effects, preparing for treatment and adherence to ART. Adherence preparation should not delay treatment initiation, when prompt action is necessary.

Patient education and counselling and peer support Patient education and counselling are essential both when ART is initiated and throughout the course of treatment. Informing and encouraging people receiving ART and their families and peers are essential components of chronic HIV care. Studies show that counselling improves adherence to ART, and in some settings there is an association between peer support and high rates of adherence and retention (18–23).

9. Guidance on operations and service delivery

179

Substance use and mental health interventions Studies indicate that improving well-being by treating depression and managing substance use disorders improves HIV treatment outcomes. The systematic review identified verylow-quality evidence from one observational study evaluating opioid substitution therapy for improving adherence. After 12 months, the rates of unsuppressed viral loads were comparable among people who inject drugs using opioid substitution therapy and people who inject drugs without opioid substitution therapy (24). The systematic review also identified very-low-quality evidence from one randomized trial evaluating the treatment of depression for improving adherence. After 12 months, the risk of non-adherence was similar among those who received depression treatment and those who did not (25). WHO recommends co-treatment of depression and substance use disorders irrespective of HIV status, and concurrent treatment should be evaluated in relation to adherence to ART. Other services for people living with HIV who use drugs, such as needle and syringe programmes, drug dependence treatment and peer outreach, provide opportunities for supporting treatment adherence.

9.2 Adherence to ART

Nutritional support Nutrition assessment, care and support are essential components of HIV care. HIV programmes should ensure that existing national policies on nutritional support are observed when it is necessary and feasible to maximize adherence to ART and achieve optimal health outcomes in food-insecure settings. Nutritional support could include nutritional counselling, cash transfers and subsidizing food costs and/or food vouchers. ART in conjunction with nutritional support could accelerate recovery. The systematic review identified one study from low- and middle-income countries with low-quality evidence showing that nutritional support provided by community health workers to people receiving ART reduces the risk of non-adherence after one year among food-insecure individuals relative to the standard of care (26).

Financial support Financial support may include reimbursement for the costs of receiving HIV care (including drugs, diagnostics, clinical services and transport vouchers) and may potentially mitigate the burden of HIV in disadvantaged settings. The systematic review identified very-low-quality evidence that financial support reduces the risk of non-adherence one year post-intervention relative to the standard of care (27). Programmes and care providers should consider a broader programmatic approach for reducing the costs of care for people living with HIV that would include avoiding out-of-pocket payments at the point of care, decentralizing and coordinating care and exploring opportunities to minimize health facility visits. Programmes need to consider ethical implications and equity in providing food and financial support or other similar interventions for people living with HIV and not others. Standardized criteria for supporting people receiving ART may need to be developed based on national poverty levels.

New

Reminder and engagement tools New recommendation New

Mobile phone text messages could be considered as a reminder tool for promoting adherence to ART as part of a package of adherence interventions (strong recommendation, moderate-quality evidence).

180

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Background Forgetfulness and changes in daily routines are often cited as the main reason for poor adherence to ART in most settings, although the specific reasons for forgetting to take medication could vary. Reminders and communication that engage people in taking ARV drugs could be an important intervention to improve adherence through behavioural change. The use of mobile text messages for supporting adherence and in health care delivery in general has increased as access to phone technology expands (28). Using this, however, requires adequate national regulations to protect the privacy of the people receiving text messages (29,30). Programmes may explore public-private partnerships to accelerate the scaling up of mobile phone–based interventions.

Rationale and supporting evidence Mobile phone technology may be a convenient reminder mechanism to engage people living with HIV in care. Moreover, since mobile phones are widely used globally, using them may not require major changes to people’s daily routines. Mobile phone text messaging is also relatively inexpensive or without marginal cost, is a succinct way of sending a message without the need to talk and offers a record of messages. The systematic review identified five randomized trials and two observational studies on mobile phone text messaging for improving adherence to ART. High-quality evidence from two randomized trials found that text messages contributed to reduced unsuppressed viral loads after one year (31,32). This finding was consistent with high-quality evidence from three randomized trials that found reduced non-adherence levels after one year (31,33,34). Four observational studies evaluated the use of text messaging for less than one year. Verylow-quality evidence from one observational study found reduced unsuppressed viral loads after nine months (35). Although moderate-quality evidence from two randomized trials showed similar non-adherence levels after 4–6 months (36,37) , very-low-quality evidence from two observational studies suggests reduced non-adherence levels after 6–9 months (35,38). Overall, the systematic review supports the use of text message reminders, although the quality of the data was variable and duration of follow-up short (up to one year).

Other patient reminders Other patient reminder tools include alarms, phone calls, diaries and calendars and are used to send brief reminders about the timing of ARV drugs, drug dosage and appointments. The evidence does not demonstrate that these interventions support treatment adherence better than the standard of care. The systematic review identified four randomized trials. Moderate-quality evidence from one randomized trial found that the risk of unsuppressed viral loads was similar after 18 months of follow-up using alarms versus the standard of care (19). Low-quality evidence from one randomized trial also found that rates of non-adherence and unsuppressed viral loads were similar after three months using phone calls compared with the standard of care (39). Very-low-quality evidence from one randomized trial further found that the risk of unsuppressed viral load and non-adherence was similar after 15 months using diaries relative to the standard of care (40). Finally, low-quality evidence from one randomized trial found that non-adherence was similar using calendars relative to the standard of care after one year of follow-up (41). Using these interventions requires further exploration among different populations and settings.

9. Guidance on operations and service delivery

181

9.2.3 Monitoring adherence to ART in routine programme and care settings Objective monitoring of adherence to ARV drugs is necessary for effective and efficient treatment planning and ongoing support. Each facility visit brings opportunity for assessing and supporting treatment adherence. Effectively monitoring adherence requires a combination of approaches based on human and financial resource capacity, acceptability to people living with HIV and to health workers and the local context.

9.2 Adherence to ART

Viral load monitoring These guidelines recommend viral load monitoring to diagnose and confirm treatment response and failure. Although treatment failure is often caused by lapses in adherence to ART, it may also result from other factors (such as drug stock-outs, drug interactions or malabsorption). However, viral load monitoring does not provide an opportunity for care providers to monitor non-adherence in real time and prevent progression to treatment failure. Viral load monitoring must therefore be combined with other approaches to monitoring adherence.

Pharmacy refill records Pharmacy refill records provide information on when people living with HIV pick up their ARV drugs (42,43). When people obtain pharmacy refills at irregular intervals, this may indicate non-adherence to ART; however, in many routine care settings, people may pick up their medications when receiving care irrespective of their adherence level. This behaviour could lead health care providers to overestimate adherence by solely using pharmacy refill records. A recent validation study to assess the usefulness of various adherence monitoring approaches found pharmacy records to be more reliable than self-report (44). In many settings, pharmacy refill records are already a part of national monitoring and evaluation frameworks and can also provide additional information on adherence to ART when used in combination with other tools.

Self-report Asking people living with HIV or their caregivers how many doses of medication they have missed since the last visit (or within a specified number of days in the past) can help to estimate non-adherence. However, although this method is commonly used, people may not remember missed doses accurately or may not report missed doses because they want to be perceived as being adherent and to avoid criticism. Counselling on the importance of remembering and/or documenting ARV drug doses and an environment that promotes and enables honest reporting of non-adherence are critical components of monitoring adherence to ART in routine care settings (45).

Pill counts Counting the remaining pills in bottles may help to assess adherence. Pill counts usually take place at routine health care visits. However, some people may throw away tablets prior to health care visits, leading to overestimated adherence (45,46). Although unannounced visits at people’s homes could lead to more accurate estimates, this approach poses financial, logistical and ethical challenges. Counting pills also requires health care personnel to invest significant time and may not be feasible in routine care settings.

182

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.3 Retention across the continuum of care 9.3.1 Background Retaining people living with HIV across the continuum of care is essential for optimal health outcomes. Among those who do not have immediate indications for ART, care visits provide opportunities for screening, prevention and treatment of other conditions and comorbid illnesses, including providing co-trimoxazole prophylaxis, PMTCT, isoniazid preventive therapy and regular screening for TB and clinical and laboratory monitoring to allow timely initiation of ART once the indications arise. For people who are eligible for ART at the time they test HIV-positive, rapid linkage to care is critical; delays of days or weeks with people already being ill with TB or other opportunistic infections increases the risk of mortality (47,48) . For people living with HIV who are receiving treatment, uninterrupted ART and continual monitoring are essential for sustained viral suppression and optimal treatment outcomes. Retaining people living with HIV in care, especially people who are not yet eligible for ART and those who are eligible but have not yet initiated treatment, poses a great challenge. Synthesis of available literature from sub-Saharan Africa showed that 54% of those who are not yet eligible for ART were lost to follow-up before becoming eligible, while 32% of the people living with HIV who were eligible for ART were lost before initiating treatment (49,50) . Outcomes among those lost to follow-up may vary, as loss to follow-up reported at the health facility level can include people who have self-transferred to another facility, unascertained deaths and true losses to follow-up. People who discontinue care – especially those who are not eligible for ART at initial assessment – frequently return to care only after they become ill with advanced HIV disease, when early mortality after initiating ART is significant (51,52) . Data on the proportion of people who remain on ART over time in low- and middle-income countries show that most discontinued care occurs within the first year of starting therapy. In some settings, many people living with HIV who are lost to follow-up in the first months after initiating ART have died (53) . In 2011, the average retention rate at 12 months after initiating ART was 81% (92 reporting countries), 75% at 24 months (73 reporting countries) and 67% at 60 months (46 reporting countries) (53) . Multiple factors relating to the health care delivery systems and patients could facilitate or hinder retention in HIV care. Interventions to improve linkage to and retention in HIV care, from diagnosis and across the continuum of care, need to address issues reported by the people receiving care and related to the health system and require a more targeted evaluation in different settings and populations (54–57) .

9.3.2 Good practices for retention across the continuum of care

New

Optimizing retention in HIV care requires interventions at multiple levels of the health care system as well as implementation research. Given the broad array of challenges and heterogeneity of barriers across settings, no single approach is likely to work for everyone in all settings. Improving the understanding of barriers and innovative strategies to address them are important priorities in implementation research and public health. Studies show that the direct and indirect costs of care affect the ability of people living with HIV to remain in care. They consistently report that the distance from health care facilities is a barrier to retention in diverse settings and along the continuum of HIV care. Related transport costs and loss of income while seeking care serve as disincentives when health facilities are located far from the person’s home. Bringing services closer to

9. Guidance on operations and service delivery

183

communities, where feasible, reduces the indirect costs of care for the people living with HIV and their families and improves retention. Waiting times at the facility during consultation are frequently high, especially in settings with a high burden of HIV infection (58,59) . Reorganizing services, such as systems for appointment, triage, separating clinical consultation visits from visits to pick up medicine, integrating and linking services and family-focused care may reduce waiting times at the health facility (59,60) . Many people living with HIV who are not yet eligible for ART may not attend clinic appointments and may not return to care until they are symptomatic. Regularly following up these individuals is important to ensure continual monitoring and timely initiation of ART. Countries have used approaches and achieved positive outcomes, including providing co-trimoxazole prophylaxis free of user charges, on-site or immediate CD4 testing with same-day results and peer support to improve retention in care (22,61,62) . Key populations generally experience more barriers to accessing health services. Interventions harnessing social support have emerged as a promising approach to counteract the structural, economic, service delivery and psychosocial constraints that affect retention in care. Table 9.1 summarizes the factors related to the health system and people receiving ART influencing retention and adherence and potential interventions.

9.3 Retention across the continuum of care

Table 9.1 Factors related to the health system and people receiving ART affecting retention and adherence with possible interventions Factors related to the health system High direct and indirect costs of receiving care Possible interventions

ART and related diagnostics and services free of charge at the point of care

Decentralize ART where feasible Scheduled facility visits Reduce waiting time at the facility level: • • • • A ppointment system eparate clinical consultation visits from appointments for S picking up medicines Link, integrate and coordinate care amily-focused care (organizing services around the needs of F the family) when appropriate

New

Stock-outs of ARV drugs

Optimize pharmaceutical supply management systems to forecast, procure and deliver ARV drugs. Use fixed-dose combinations to simplify forecasting and supply management systems Implement systems for patient monitoring across the continuum of care, including cohort analysis and patient tracking systems

Lack of a system for monitoring retention in care

184

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 9.1 (continued) Factors related to the health system Lack of a system for transferring people across different points of care Possible interventions

Interlinked patient monitoring system across services for HIV, TB, maternal and child health and PMTCT; system for transitioning from paediatric to adolescent and adult services and from maternal and child health and TB services to chronic HIV care Use fixed-dose combinations to reduce the pill burden and simplify the regimens Engage and integrate community health workers, volunteers and people living with HIV in peer support, patient education and counselling, and community-level support Task shifting for involving community health workers Linking with community-level interventions and resources such as peer adherence support Using known effect reminder methods (such as text messaging) Peer support also provides opportunities for in-person reminders

Pill burden and complex ARV drug regimens Lack of accurate information for patients and their families and peer support Adherence support

Poor relationship between patient and care provider

Train health workers on how to: reduce stigma; improve treatment preparedness, adherence and retention; provide adherence support and care for key populations; and provide simplified approaches for educating patients and their families Task shifting and sharing among clinic team members People living with HIV as patient experts and peer supporters A team approach to care

Lack of time for educating people in HIV care

Adverse drug effects

Preparedness and knowledge of how and when to self-manage adverse effects and when to return to the clinic Possible interventions

Factors related to the people receiving HIV care Forgetfulness, life stress, stigma and discrimination

Using text messaging to keep patients engaged Peer and family support Link to community support group

Comorbidity, substance and alcohol use disorders and mental health disorders Patient knowledge and beliefs related to HIV infection, its course and treatment

Manage HIV with mental health disorders, alcohol and other substance use disorders and link with community and social support

Integrate the education of patients and their families and counselling, broader community literacy and education and community engagement

9. Guidance on operations and service delivery

185

9.4 Service delivery 9.4.1 Good practices in providing chronic care (63) In many countries, health services are organized primarily to provide episodic acute care. As HIV begins to become a manageable, chronic condition, programme managers and care providers need to consider how current health delivery systems can be reorganized to provide chronic care. Once people are diagnosed and enrolled in chronic care, follow-up visits should be scheduled and planned. Waiting until people present with symptoms or preventable complications is costly and inefficient. People living with HIV require care that anticipates their needs at different stages of the care continuum. Compared with the acute care model, planned chronic care models provide opportunities for prevention, early identification of issues and timely intervention. Chronic care requires broad support for people living with HIV from their communities and health care teams to stay in care, adhere to treatment and cope with stigma. People living with HIV and their families need to be informed about HIV infection and the anticipated side effects of medicines and supported to adhere to treatment. Health care teams play an important role in linking people living with HIV with community-level interventions, resources and support. A system to keep information on the people receiving care at health facilities is critical for ensuring the continuity of chronic care. A patient registry serves a reminder function for follow-up services. Health care teams can use it to identify people’s needs, to follow-up and plan care, to monitor responses to treatment and to assess outcomes for both individuals and for the overall treatment cohort. Information systems can be paper-based or based on an electronic registry, depending on local context. Programmes should develop a systematic strategy for collecting and aggregating key information that supports better management of the patient and ensures high-quality care. A robust patient information system is also critical for high-quality monitoring and evaluation of programmes and for supply management systems. When effective operational solutions such as successful service delivery models and processes of care are identified in existing systems, programmes need to consider scaling up such models of care.

9.4 Service delivery

9.4.2 Integrating and linking services Chronic care requires integrating and linking related services to ensure comprehensive and consistent patient management over time, including providing related services in single settings, systems to share information and effective referrals across settings and providers. Integrating and linking services are likely to reduce missed opportunities for initiating ART, enhance long-term adherence support and optimize patient retention in care. Programmes for HIV, sexual and reproductive health, maternal and child health, TB and drug dependence need to collaborate to successfully implement ART and related services at different levels of the health system. Issues to be considered include mobilizing and allocating resources; training, mentoring and supervising health workers; procuring and managing drugs and other medical supplies; and monitoring and evaluation.

186

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.4.2.1 Delivering ART in antenatal care and maternal and child health settings New recommendation New

In generalized epidemic settings, ART should be initiated and maintained in eligible pregnant and postpartum women and in infants at maternal and child health care settings, with linkage and referral to ongoing HIV care and ART, where appropriate (strong recommendation, very-low-quality evidence).

Background In 2011, coverage of effective ARV drug regimens for PMTCT reached 57% in low- and middle-income countries. However, in the same year, only 30% of pregnant women who needed ART for their own health received it, compared with 54% ART coverage for all eligible adults in low- and middle-income countries (53) . Ensuring access to ART for pregnant women with HIV who are eligible for treatment continues to be a challenge, as does provision of ARVs for PMTCT among pregnant adolescent girls living with HIV, female sex workers and women who inject drugs. Because many women living with HIV only access health services at the time of pregnancy, maternal and child health settings provide a key opportunity to expand access to ART for those who need treatment (56,57) . In most generalized epidemic settings, maternal and child health services are provided at the primary care level, where pregnant women and children predominantly access health services. Existing WHO guidance recommends that provider-initiated HIV testing and counselling be implemented in all antenatal and maternal and child health care settings in generalized epidemics and that it should be considered in antenatal and maternal and child health settings for key populations in concentrated and low-level epidemics (64) . These 2013 guidelines recommend that triple-drug ART or ARV prophylaxis be initiated among all pregnant and breastfeeding women living with HIV, regardless of CD4 count, and that countries decide whether to continue this for all pregnant and breastfeeding women or just those who are eligible for treatment for their own health. Therefore, ART should be available in maternal and child health clinics or easily accessible in a linked clinic approach. Countries with generalized epidemics may consider a phased approach to providing ART in maternal and child health settings and effectively transforming such settings into ART sites, giving priority to facilities with the largest burden of HIV and building health systems to ensure uninterrupted ART, adherence and retention. A challenge is to continue ART beyond the mother-to-child transmission risk period. Not all maternal and child health settings will have capacity to provide long-term HIV care and treatment for women, their partners and infants. These settings will need to assess the best time for referring and linking mothers and their infants to chronic HIV care. This assessment may include the women’s progress in treatment and the capacity and quality of HIV care in the maternal and child health setting as well as the acceptability and proximity of alternative HIV care settings.

9. Guidance on operations and service delivery

187

Rationale and supporting evidence The systematic review evaluated the effect of delivering HIV care and treatment in antenatal care and maternal and child health settings on access to ART, mortality, morbidity and retention on ART in generalized epidemic settings. One clusterrandomized trial and three observational studies assessed the impact of delivering ART in antenatal care and maternal and child health settings compared with referring people to HIV care clinics for ART. This positively influenced adherence to ART during pregnancy, enrolment in care and the uptake of ART among women living with HIV. Comparable outcomes were observed for maternal mortality, morbidity, immune response, infant HIV testing uptake, mother-to-child transmission and satisfaction with care. The quality of some of these studies was downgraded because of relatively few events (65–70) . The alternative to providing ART in antenatal care and maternal and child health settings is to refer eligible women and infants to HIV facilities to receive HIV treatment. Referral systems may contribute to the low ART coverage among pregnant and breastfeeding women and infants (57) . Referral-based models may further require women and infants to receive care at separate service delivery points that may require pregnant women to travel and wait in queues to receive HIV care and treatment. Studies from Malawi (55) , Uganda (56) and Zimbabwe (57) have found that long queues at HIV clinics and the cost of transport from homes to clinics were among the main reasons for loss to follow-up for pregnant and breastfeeding women. Although HIV programmes may invest to expand access and reduce health facility waiting times, delivering ART in settings where pregnant and breastfeeding women are already receiving care could improve access and provide opportunities for a continuum of care from providing HIV testing to ART at a single site that is also providing antenatal and postnatal care. In a recent study, women had positive experiences in antenatal care clinics providing ART. They reported that the personnel had “treated them” well and “given them helpful counselling” and that their babies had received “good care” and were free from HIV infection because of this. Other research has explored the operational feasibility of providing ART in maternal and child health care settings and its acceptability to health care personnel in antenatal care clinics. Providers felt that integration increased efficiency, decreased the time people spent in clinics, improved relationships with providers and adherence to ART because of decreased stigma and increased confidentiality. All these factors increased the satisfaction of the people receiving care and may have contributed to improving the quality of care (66,71) .

New

9.4 Service delivery

188

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.4.2.2 Delivering ART in TB treatment settings and TB treatment in HIV care settings New recommendations In settings with a high burden of HIV and TB, ART should be initiated for an individual living with HIV in TB treatment settings, with linkage to ongoing HIV care and ART (strong recommendation, very-low-quality evidence). In settings with a high burden of HIV and TB, TB treatment may be provided for an individual living with HIV in HIV care settings where TB diagnosis has also been made (strong recommendation, very-low-quality evidence).

Background In 2011, 79% and 48% of the people with TB who were known to be living with HIV received co-trimoxazole prophylaxis and ART, respectively (72). The percentage of people with TB with a documented HIV-positive test result who received ART exceeded 75% in only 6 of the 41 countries with the highest burden of HIV and TB, globally. Since 2010, WHO has recommended ART for everyone with TB who is living with HIV, regardless of their CD4 count. TB treatment should be initiated first, followed by ART as soon as possible within the first eight weeks of starting TB treatment. Co-trimoxazole prophylaxis is also recommended for all TB patients with HIV. These service delivery recommendations are intended to facilitate expanded ART coverage for people with HIV and TB and to support the early diagnosis and treatment of TB among people living with HIV. Although the treatment of TB has been decentralized to the community level in most settings, HIV treatment remains difficult to access in many places. Data from a WHO survey indicate that the ratios of the number of health facilities providing TB treatment to the number of health facilities providing ART ranged from 1.3 to 30.2 (72). Moreover, despite a high burden of HIV and TB coinfection, services for HIV and TB treatment may be offered at geographically different sites. Although HIV and TB programmes may invest financial and human resources to improve access and reduce the time associated with receiving care, offering ART and TB treatment at a single point could improve access and adherence to HIV and TB treatment by providing a continuum from HIV testing to HIV and TB co-treatment at a single site. Implementing TB infection control measures is crucial in HIV care settings to minimize the risk of nosocomial (occurring in a health care setting) transmission of TB. See section 8.1.2 for WHO recommendations on TB infection control in health care settings.

Rationale and supporting evidence Since people with HIV and TB who do not initiate ART and co-trimoxazole prophylaxis have high mortality and since the combination of ART and co-trimoxazole improves survival (73–75) , increasing ART and co-trimoxazole coverage is probably paramount in reducing the large number of people who die from having HIV and TB globally. The systematic review evaluating the effectiveness of delivering ART in TB treatment settings identified 19 observational studies, many of which showed increased ART uptake and timeliness of ART initiation. However, data on mortality and TB treatment success were inconsistent. The systematic review evaluating the effect of delivering TB treatment in HIV care settings identified five observational studies: two studies reported decreased mortality

9. Guidance on operations and service delivery

189

and another showed comparable mortality rates. TB treatment success rates and ART uptake were comparable across studies. The quality of evidence was weighed along with programmatic risks and benefits; acceptability; values; preferences; cost implications; feasibility; critical contextual constraints; and contextual relevance. There was consensus that, although the quality of evidence was not high using the GRADE method, there was sufficient rationale to proceed with strong recommendations (76–96) .

9.4 Service delivery

9.4.2.3 ART in settings providing opioid substitution therapy New recommendation New

ART should be initiated and maintained in eligible people living with HIV at care settings where opioid substitution therapy (OST) is provided (strong recommendation, very-low-quality evidence).

Background Data from 49 countries indicate that injecting drug use increases the risk of acquiring HIV infection 22-fold relative to the general population, and in countries in eastern Europe up to 40% of the people acquiring HIV infection are people who inject drugs and their sexual partners (97) . Existing WHO guidance states that consideration should be given to recommending HIV testing and counselling to all people attending drug dependence treatment services in generalized, concentrated and low-level epidemics when this is socially acceptable and epidemiologically appropriate. Plans for provider-initiated testing and counselling in such settings should emphasize supportive social, policy and legal frameworks (64) . These guidelines recommend the same criteria for eligibility for ART for all adults regardless of drug use behaviour. Limited global data are available on ART coverage among key populations; however, where data are available, there are often gaps between the coverage among people who inject drugs relative to that of the general population. In 2010, a report including 19 low- and middle-income countries in Europe and central Asia indicated that only 22% of people living with HIV who inject drugs and are eligible for ART received it (53) . For treating opioid dependence, WHO recommends opioid substitution therapy (with methadone or buprenorphine) combined with psychosocial assistance (98) . Where there are many opioid-dependent people living with HIV, treatment of opioid dependence should be integrated with and administered in conjunction with HIV treatment. Although ART outcomes improve among people living with HIV who inject drugs and are also accessing opioid substitution therapy, enrolment in settings providing opioid substitution therapy should not be a prerequisite for initiating or maintaining ART for people who use opioids. Nevertheless, providing ART in settings providing opioid substitution therapy may expand access to ART for people who inject drugs. Common comorbidities such as alcohol use disorders, mental health disorders, TB and viral hepatitis also need to be addressed as part of a comprehensive package of harm reduction interventions, requiring a multi-skilled workforce and close collaboration within the health sector.

New

190

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Given the high incarceration rates of people who inject drugs, efforts should be made to ensure that ART is available as part of prison health services and continuity of HIV care and ART when people transition from incarceration to the community.

Rationale and supporting evidence In many countries, people who inject drugs are a marginalized population with limited access to and utilization of health care services. Drug overdose and AIDS are leading causes of death in this population (99) . Randomized trials found that opioid substitution therapy decreases illicit drug use and increases retention in care relative to placebo (98) . Observational studies found that opioid substitution therapy decreases mortality relative to not being in care (100) . ART outcomes also improved among people with HIV who inject drugs and are accessing opioid substitution therapy (16) . The systematic review found one randomized trial and three observational studies evaluating the effect of delivering ART in settings providing opioid substitution therapy. Most of these studies had small sample sizes that limited the statistical power. Some studies observed trends for improved viral suppression and reduced mortality, whereas others found comparable rates of viral suppression and mortality (101–103) . This recommendation focuses on expanding access to ART by delivering the service in settings providing opioid substitution therapy. Coverage of opioid substitution therapy also remains low in many settings, and policy-makers should evaluate whether providing opioid substitution therapy in settings providing HIV care and treatment is feasible. Where health authorities or the health sector do not manage drug-dependence services, HIV programmes need to collaborate closely with social welfare departments and community and nongovernmental organizations that provide these services.

9.4.3 Decentralizing HIV treatment and care New recommendations New

The following options should be considered for decentralization of ART initiation and maintenance. Initiation of ART in hospitals with maintenance of ART in peripheral health facilities (strong recommendation, low-quality evidence). Initiation and maintenance of ART in peripheral health facilities (strong recommendation, low-quality evidence). Initiation of ART at peripheral health facilities with maintenance at the community level (that is outside health facilities in settings such as outreach sites, health posts, home-based services or community-based organizations) between regular clinical visits (strong recommendation, moderate-quality evidence).

9. Guidance on operations and service delivery

191

Background Although rapidly scaling up HIV programmes has significantly improved access to ART and increased the health and survival of people living with HIV, it also poses significant challenges to health systems. Decentralizing ART to primary care settings may ease the burden of routine management on other parts of the health system and may improve equity by promoting access to ART in rural areas. In several settings, transport cost is a significant barrier to access and retention in care. In many settings with a high burden of HIV infection, hospitals have long waiting times because of a large flow of patients needing care. Decentralizing HIV care and treatment could reduce the workload for health care personnel, thereby reducing waiting times for people with HIV and people receiving care at hospitals for other conditions and bring HIV services closer to people’s homes. HIV-related services such as TB care and maternal and child health services are decentralized to primary care in several settings. People living with HIV, affected communities and community-based interventions play a pivotal role in providing HIV testing, care and treatment and social support. Decentralizing HIV care and treatment can further strengthen community engagement, linking community-based interventions with health facilities, and may optimize access to services, care-seeking behaviour and retention in care.

9.4 Service delivery

Rationale and supporting evidence The systematic review identified two observational studies evaluating how decentralization of initiating and maintaining ART in peripheral health facilities affects patient attrition (patient death and losses to follow-up). Attrition declined after 12 months, resulting largely from significantly reduced losses to follow-up. The systematic review identified four observational studies evaluating how maintaining ART at peripheral health facilities affected patient attrition. Attrition declined after 12 months, due to losses to follow-up and death. The systematic review also identified two cluster-randomized trials evaluating how community-based maintenance of ART affects attrition. Comparable rates of attrition were observed after 12 months (104–115) . When deciding which decentralization option to implement, programme managers may consider (1) the number of people living with HIV likely to attend decentralized settings; (2) whether decentralization brings services closer to people who would otherwise travel long distances to receive ART; and (3) whether decentralizing ART reduces the workload at centralized facilities. This recommendation calls for links to the supply of diagnostics and medicines, services, training and supervision of health workers to maintain the quality of care. In addition, in several settings, decentralizing ART will involve task shifting to ensure an appropriate mix of health care personnel at peripheral facilities. A WHO operations manual for delivering HIV care and treatment at primary health centres in high-prevalence, resource-limited settings (116) provides additional guidance.

New

Implementation considerations for decentralizing ART Box 10.5 discusses implementation considerations relevant to programme managers.

192

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.5 Human resources 9.5.1 Building human resource capacity Within the past decade, in the context of the rapid scaling up of HIV care and treatment, in-service training has assumed a key role in rapidly upgrading the competencies of health practitioners. All health workers, including community health workers, need to be regularly trained, mentored and supervised to ensure high-quality care and the implementation of updated national recommendations. Given the rapidly evolving knowledge on HIV care and treatment, countries need to consider a system for supporting health workers’ continuing education, including clinical mentoring and regular supportive supervision. The use of new technologies such as computer-based self-learning, distance education, online courses and phone-based consultation may supplement classroom in-service training and support the efficient use of health workers’ time and other resources (116,117). It is, however, equally important to fully embrace and strengthen HIV care and treatment in existing pre-service courses leading to health workers graduating and being certified in various disciplines. Health workers also need to be equipped to manage HIV as a chronic condition, and to work in a team and need to be familiar with the national guidelines and care protocol. In several countries, people living with HIV, other community workers and volunteers are already involved in delivering HIV testing, counselling, care, treatment and social support services. In addition, people living with HIV are involved in training health workers as expert trainers. Involving people living with HIV in both training health workers and delivering HIV services may have the additional benefit of overcoming HIV-related stigma. Countries should consider long-term reform that could support human resource strategies related to task shifting and introducing new types of health workers (such as for HIV testing or peer counsellors) on a sustainable basis within a comprehensive and nationally endorsed regulatory framework (laws and proclamations, rules and regulations, policies and guidelines). Although volunteers can make a valuable contribution on a short-term or parttime basis, all trained health workers who are providing essential health services, including community health workers, should receive adequate wages and/or other appropriate and commensurate incentives (116).

9.5.2 Task shifting for HIV treatment and care New recommendations New

Trained non-physician clinicians, midwives and nurses can initiate first-line ART (strong recommendation, moderate-quality evidence). Trained non-physician clinicians, midwives and nurses can maintain ART (strong recommendation, moderate-quality evidence). Trained and supervised community health workers can dispense ART between regular clinical visits (strong recommendation, moderate-quality evidence).

9. Guidance on operations and service delivery

193

Background Reorganizing, integrating and decentralizing HIV treatment and care will require reexamining the roles and tasks of teams of health care providers involved in delivering chronic HIV care. Task shifting involves the rational redistribution of tasks among health workforce teams. With this approach, specific tasks are reassigned, where appropriate, from highly qualified health workers to health workers with shorter training and fewer complementary qualifications to more efficiently and effectively use the available human resources. Task shifting should be implemented alongside other strategies designed to increase the total numbers and capacity of all types of health workers. Health care personnel remain insufficient in many settings with a high burden of HIV. Although increasing the capacity of countries to train more health care personnel is crucial, clinical tasks need to be shared and shifted to ensure that enough health workers are available to care for people with HIV. Task shifting improves access to ART at sites without physicians (such as rural health facilities, TB services and maternal and child health services). Task shifting also allows physicians to spend more time managing more complex clinical conditions such as coinfection and other comorbidities, toxicity of ART or treatment failure. WHO guidance in 2008 (118) recommended that nurses and non-physician clinicians may initiate and maintain first-line ART and that community health workers may monitor people receiving ART during long-term follow-up. Since these recommendations were largely based on programme review and good practices, the evidence related to task shifting for ART was reviewed when developing these consolidated guidelines. In this guideline, initiation of ART includes assessment for ART eligibility (based on clinical and/or immunological criteria); assessment for opportunistic infections; adherence counselling; and the prescribing of first-line ART. Maintenance of ART includes ongoing clinical assessment; monitoring for toxicity, treatment failure (clinical, immunological and virological) and opportunistic and other coinfections; adherence counselling; and the further prescribing of ART. Dispensing ART includes assessment for any new signs and symptoms, adherence monitoring and support and dispensing medication to patients who are already on ART between regular clinic visits.

9.5 Human resources

Rationale and supporting evidence The systematic review identified three randomized trials and six observational studies addressing task shifting. Overall, the data showed no difference in mortality and losses to care when nurses or non-physician clinicians initiate or maintain people on ART or when community health workers maintain people on ART, relative to physicians providing this care. The quality of care in these studies was ensured by (1) providing training, mentoring, supervision and support for nurses, non-physician clinicians and community health workers; (2) ensuring clear indications for patient referral; (3) implementing referral systems and (4) implementing monitoring and evaluation systems. Patient education could help people and their families understand that care provided by nurses and community health workers is not of lower quality than that provided by physicians (106–108,111,113,114,119–121). Shifting the initiation and maintenance of ART to adequately trained and supervised nurses and community health workers may enable substantial cost savings through (1) the ability to decentralize care to primary care facilities; (2) lower overhead costs for delivering quality care (with comparable or better outcomes) by nurses, non-physician clinicians and community health workers compared with physicians; and (3) decreased facility and utility costs (if care is being delivered in health facilities complemented with community-level services). New

194

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.6 Laboratory and diagnostic services 9.6.1 Overview These guideline recommendations support increased access to HIV care and treatment, which will also require increased access to laboratory and diagnostic services. To ensure that testing services are accurate and reliable, relevant quality assurance systems need to be developed and strengthened. Within a country, a multiplicity of testing settings may exist, such as laboratories, maternal and child health clinics, HIV testing and counselling sites, community-based testing and thus a multipronged and networked approach to selecting diagnostics and laboratory systems should be planned and adopted. Since an increasing number of new diagnostic tests and point-of-care systems is entering the market, the use of only high-quality diagnostics and equipment needs to be ensured. Strategic planning for properly placing and harmonizing testing platforms should be carried out to ensure appropriate use and cost–effectiveness.

9.6.2 Implementation considerations and good practices This guidance to strengthen laboratory and diagnostic services emphasizes the importance of leadership and governance, high-quality laboratory services, expanding testing services and developing the health workforce: to strengthen and expand laboratory and diagnostic services; to support a dedicated specimen referral system; to increase access to HIV viral load testing; to support the expansion of diagnostic services to include testing at the point of care; to train and certify health workers who perform the testing; and to ensure high-quality diagnostics and plans for implementation, including quality assurance.

9.6.3 Strengthening and expanding laboratory and diagnostic services The following areas are important to strengthen the network of laboratory and diagnostic services for implementing the guideline recommendations: standardizing testing methods to streamline procurement, quality assurance and training; incorporating new testing approaches and systems into national laboratory strategic plans and policies; evaluating diagnostics for their performance and operational characteristics to validate testing algorithms (with back-up options) before introduction; carrying out strategic planning for properly placing and harmonizing testing platforms to ensure appropriate use and cost–effectiveness; expanding current laboratory networks to support and monitor the decentralization and integration of testing services or to provide access to testing when diagnostic services are unavailable at service delivery sites; and allocating appropriate resources to ensure the availability of testing services, including human and financial resources.

9. Guidance on operations and service delivery

195

9.6.4 Supporting a dedicated specimen referral system Laboratory referral systems and procedures for collecting and processing specimens need to be strengthened to increase access to viral load testing and other testing (for example, CD4 and early infant diagnosis). Providing for and strengthening a dedicated, efficient, safe and cost-effective specimen referral system requires reliable specimen transport with adequate conditions for whole blood, plasma and dried blood spot specimens and rapidly and dependably reporting test results back to the referring site with linkage to care. Rapidly reporting results is essential for timely care.

9.6 Laboratory and diagnostic services

9.6.5 Increasing access to HIV viral load testing The guidelines call for monitoring the response to treatment and diagnosing and confirming treatment failure with viral load testing. This will require strengthening the existing laboratory services and phased expansion of monitoring services into peripheral facilities and can include: strengthening and leveraging existing CD4 and early infant diagnosis networks; ensuring that laboratories have adequate infrastructure, technical testing expertise and quality assurance and quality improvement programmes; ensuring an appropriate mix of high-volume centralized laboratory testing and testing at the point of care for facilities in remote locations; and the use of dried blood spots as a tool to increase access to viral load testing.

9.6.6 Expanding diagnostic services to point-of-care settings Decentralizing laboratory and diagnostic services requires that all aspects of testing be in place before implementing services, including: using only high-quality, evaluated and reliable diagnostic tests; supervising and monitoring point-of-care testing for quality and reliability; implementing a strategy for managing supply chain and equipment service; and establishing data management systems for timely identification of quality issues and regional and national data reporting.

196

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 9.2 provides guidance on organizing testing services at various levels of the health care delivery system.

Table 9.2 Tiered laboratory network at various levels of the health care delivery system Health care delivery level National Laboratory service Human resources

Enzyme immunoassays for diagnosis Higher throughput CD4 HIV molecular technologies including HIV viral load testing and quantitative and qualitative early infant diagnosis HIV resistance testing

Senior laboratory specialists

Regional or provincial

Enzyme immunoassays for diagnosis Higher throughput CD4 HIV molecular technologies including HIV viral load testing and quantitative and qualitative early infant diagnosis

Laboratory specialists and senior technicians

District

Enzyme immunoassays for diagnosis Low-throughput CD4 Chemistry, haematology and microbiology

Laboratory technicians and assistants

Primary care

HIV rapid diagnostic tests and other point-of-care tests Collecting DBS

First-level trained health workers such as nurses and clinical officers Community health workers

Community-based

HIV rapid diagnostic tests

Source: adapted from: WHO expert meeting report on short, medium, longer term product development priorities for HIV-related diagnostics, 6–7 June 2012, Geneva, Switzerland (122).

9. Guidance on operations and service delivery

197

9.6.7 Providing guidance for developing health workers’ capacity, including staff training and certification Countries require guidelines for the qualification of personnel who will perform the laboratory tests. The guidelines should include training requirements for specific tests and the process for certification and recertification. All health workers assigned to perform pointof-care testing must be trained and proficient on the testing procedure, specimen collection and quality assurance before implementing these services.

9.7 Procurement and supply management systems

9.6.8 Implementing comprehensive quality management systems Developing a comprehensive quality management system including external quality assessment and quality control is essential. The quality management system should: be implemented within the laboratory network and all remote testing sites; be incorporated into the routine testing procedures and monitored; ensure that testing sites undertake quality control, as appropriate; ensure that testing sites are enrolled in an external quality assessment scheme (proficiency testing programme); ensure the use of standard operating procedures for all processes, including specimen collection and processing, test methods, interpreting results and reporting; ensure the use of standardized logbooks or electronic data management and reporting, including identifying errors and potential misclassification; and ensure that equipment and facilities are maintained, both preventive and corrective.

9.7 Procurement and supply management systems 9.7.1 Overview Ensuring adequate and continuous availability of quality and affordable essential medicines, diagnostics and other consumables at service delivery sites is a critical role of procurement and supply management systems. The increasing number of people who need chronic HIV care, especially in settings with a high burden of HIV infection, necessitates an uninterrupted supply of HIV-related health products. This can be achieved only if the procurement and supply management system is strengthened at all levels of the health system. Moreover, ARV drug regimens and formulations and HIV treatment recommendations need to be regularly updated in response to new developments and emerging evidence. This requires a more efficient and dynamic supply management system to prevent waste and shortages.

9.7.2 Rationale and supporting evidence Successful HIV programmes are only possible if all services providing ART are equipped with an uninterrupted and sustained supply of high-quality ARV drugs, preferably WHOprequalified products. Other pharmaceuticals that are needed to support ART services include medicines to prevent or treat opportunistic infections, and laboratory reagents, supplies and equipment to diagnose HIV and opportunistic infections, monitor the progression of HIV infection and treatment response and detect adverse drug reactions. Since a single health facility may not carry out the dispensing of all needed pharmaceuticals, in some settings clients would need to be able to access services through a referral system.

198

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

9.7.3 Implementation considerations and good practices Management support is integral to each component of the procurement and supply management cycle: selection, procurement, storage and distribution, use and monitoring. It includes a variety of activities at all levels of the health care delivery system: from the national programme level down to where medicines are dispensed and diagnostics are used. The main activities include managing the information system, ensuring timely information flow between stakeholders at different levels and securing financial and other resources, including the medicines and diagnostics needed for the programme. The following provides broad guidance on key activities at each stages of the supply management cycle.

9.7.3.1 Selecting pharmaceuticals and diagnostics Countries adapting these guidelines may need to update national medicine lists to include newly recommended ARV drug regimens and formulations and diagnostics. The advantage of using the essential list concept is to enable a health system to limit other more expensive or WHO-delisted medicines and diagnostics from being purchased and accelerating the registration of WHO-prequalified products to facilitate quality-assured procurement (123) . If a selected fixed-dose combination or other ARV drug regimen is not on the national list or not registered in the country, HIV programme managers need to coordinate with the national drug regulatory authority and request that these drugs be put on the list and registered. Detailed national ART guidelines, for example, that provide recommendations for managing toxicity or treatment failure and recommended formulations for weight and age can help to standardize prescribing and dispensing practices and facilitate forecasting for ARV drugs. Synchronized introduction of new guidelines with forecasting, procurement and distribution planning during the phasing in and phasing out of new and old ARV drug products will minimize the waste of products that are being phased out and shortages of newly recommended products. In several settings, paediatric formulations are not widely available. The national medicine list should be optimized for paediatric ARV drug formulations, to include fixeddose combinations, scored or dispersible products that facilitate adherence and supply management. Countries may consider removing less preferred products and aligning paediatric formulations with those of adults, where possible. Health workers need to be trained at different levels in managing pharmaceuticals and diagnostics, including forecasting, procurement and distribution and ensuring adequate supervision throughout the supply system.

9.7.3.2 Procurement A uniform and harmonized national procurement system is required for efficiently procuring quality-assured affordable ARV drugs and diagnostics (124,125) . Procurement should be based on appropriate selection of products and need-based forecasting, considering consumption, expanding services, phasing in and phasing out formulations and implementing new recommendations. Transparent procedures should be adopted to achieve best-value procurement and a quality assurance system implemented to procure, store and distribute high-quality pharmaceuticals, diagnostics and other health products (124,126) .

9. Guidance on operations and service delivery

199

Procurement systems should: p rocure the most effective, heat-stable, fixed-dose quality-assured ARV drug formulations in the right quantities, at the lowest possible cost and in a timely manner; r equest that the partners supporting the national HIV programme consolidate and harmonize ARV drugs and diagnostics procurement and supply management systems and pool demands for ARV drugs and diagnostics, exploring options for pooling under a common tender system; u se a publicly accessible database to facilitate access to information about prices and support competition (127–130) ; and f ollow the principles described in the United Nations interagency guidelines for donated drugs (131) .

9.7 Procurement and supply management systems

9.7.3.3 Storage and distribution Appropriate storage and distribution of HIV medicines, diagnostics and other commodities are important components of the supply management system (Table 8.3). Product integrity and quality need to be maintained during storage and distribution (125,132) , and waste from spoilage and expired products should be minimized. Integrated supply systems should be promoted when planning for decentralization, building on what exists and strengthening capacity where required. For example, existing immunization programme infrastructure, including cold chains, could be used to expand the supply of paediatric formulations, such as LPV/r liquid formulations. Facilities should have adequate storage space, trained personnel and the tools to manage supplies effectively. The number of storage levels should be rationalized to reduce the supply pipeline. Accurate inventory records should be maintained and a system created to track products that enter and leave the supply system. A routine consumption-based reordering cycle at service delivery sites should be established. Flexibility should be introduced in the supply system such as procedures for reporting and redistribution of excess ARV drug supplies, more frequent ordering and filling of non-routine orders to minimize expiry and stockouts. Pharmaceutical and diagnostic products need to be adequately stored, especially if ART delivery is further decentralized and is dispensed from an increasing number of peripheral health facilities. Measures are required during transport and storage to prevent theft and fraud such as vehicle tracking systems, secured storage areas, audits and labelling of ARV drug products procured by HIV programmes.

9.7.3.4 Use and monitoring Robust information systems ensure the availability of accurate and timely consumption data on ARV drugs and other information required for effectively monitoring the performance of the entire supply system and for forecasting the ARV drugs and diagnostics needed. Monitoring procurement and supply management through the effective use of early warning indicators prevents stock-outs and overstocks leading to expiry (126) .

200

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 9.3 Summary checklist of pharmaceutical supply management issues Phase Planning Activity Selecting products Determination Updated national HIV guidelines Updated national lists to include newly recommended ARV drug regimens and formulations and diagnostics Estimating and quantifying ARV drug requirements Procurement Selecting and locating suppliers Open and transparent communication with industry Prequalified suppliers Implementing review mechanisms Assuring the quality of products and sources Criteria for manufacturer prequalification Implementing a prequalification system Using the WHO certification scheme, inspecting and testing the quality of samples Pre-shipment physical inspection with random sampling for laboratory testing Systems for records and supply monitoring Arranging for purchasing Ongoing assessment of purchasing options Need for special labelling and packing Need for reserve or buffer stocks Managing purchasing arrangements Distribution, rational use and monitoring Receiving supplies in the country Port clearance, including availability of funds for paying duties and taxes Securing appropriate warehousing at all levels needed Physical inspection on arrival of each consignment with random sampling for laboratory testing Distributing in the country Rationally using and monitoring pharmaceuticals A logistics system for timely distribution to end-users

Providers adequately trained Systems for monitoring and reporting, including monitoring adverse effects feeding into the selection; rational prescription; and forecasting in place At the central level, any problem such as theft, recall by the supplier, poor quality and adverse drug reactions should be recorded and reported at different levels to all relevant bodies. This would involve developing problemreporting forms, indicating to whom they should be sent, and what action should be taken

guidance for

programme managers

10.1 Introduction 200 10.2 Decision-making process 201 10.3 Data to support decision-making 201 10.3.1 Overview 201 10.3.2 National and local HIV epidemiology 202 10.3.3 Programme performance and response analysis 202 10.3.4 Socioeconomic, policy and legal context 202 10.4 Key parameters for decision-making 205 10.4.1 Ethics, equity and human rights 205 10.4.2 Impact and cost–effectiveness 205 10.4.3 Opportunities and risks 206 10.5 Implementation considerations across the health system 207 10.6 Implementation considerations for key recommendations 209 10.7 Implementing recommendations in different contexts 215 10.7.1 Overview 215 10.7.2 Implementing recommendations in different epidemic settings 215 10.8 Useful tools for costing and planning 216

Goal of this chapter To provide programmatic guidance for decision-makers and planners at the national level as they work to adopt and implement the clinical and operational recommendations in these guidelines.

202

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

10. Guidance for programme managers 10.1 Introduction The recommendations in these guidelines increase the number of people eligible for ART, promote new first- and second-line regimens and propose changes in approaches and strategies to laboratory monitoring to maximize treatment effectiveness. National stakeholders face several important choices on how to optimally translate these recommendations into national practice. For example, although evidence of clinical efficacy supports the uptake of interventions, issues such as cost and cost– effectiveness, ethical and human rights considerations, the perceptions of various stakeholders and the legal and regulatory environment must also be taken into account (1) . National HIV programme managers play a unique role in managing the process for adapting and implementing the HIV guideline recommendations in their respective countries. First, convening a broad, inclusive and transparent consultative process can help to define what programme changes are relevant and necessary, such as revising national protocols, guidelines and regulations. Second, in parallel, it is necessary to secure the financial resources and political support required to implement the proposed changes. Third, systems are required to ensure broad accountability for implementation from all partners at all levels and adequately document performance to inform programming decisions and maintain political support. Lastly, implementation and operations research should be supported so that innovative approaches can be assessed and taken to scale. Human rights and ethical principles should guide the revision of national treatment policies to ensure that they are equitable and meet the specific needs of all beneficiaries. New recommendations should inform the HIV programme’s overarching vision, goals and objectives, and existing strategic plans should be adapted accordingly to assure consistency, avoid duplication and leverage potential economies of scale (2) . As HIV programmes mature and increasingly focus on the challenges of long-term prevention, treatment, care and support, national responses need to be considered within the broader health and development contexts. The sustainability and effectiveness of HIV programmes can be greatly enhanced by creating and strengthening linkages with other health and non-health programmes (3) .

10. Guidance for programme managers

203

10.2 Decision-making process Decisions regarding the implementation of global recommendations should be made through a transparent, open and informed process that recognizes the multisectoral nature of the HIV response. National HIV programmes should consider convening a multidisciplinary working group, if one is not already in place, to advise on the choices and decisions necessary for updating and implementing national guidelines. The role of the guideline group may include (1) reviewing the current context of national HIV and TB epidemics, including the health sector response and the broader policy environment; (2) assessing global and local evidence related to the new recommendations and advising on how to adequately interpret them within the local context; and (3) identifying implementation issues such as estimated costs, human resource and infrastructure requirements and how these should be addressed (4) . Sections 10.3 and 10.5 address these topics in greater detail. Although national programme managers should oversee the decision-making process, it should also be broadly representative. Broad stakeholder engagement in policy design, implementation, monitoring and evaluation will help to ensure that the national adaptation of global guidelines results in HIV programmes that are legitimate, acceptable, effective and equitable and address community needs (1,5) . The composition of the working group may vary over time and depend on the specific recommendations under discussion. For example, when considering how to improve programmes for preventing the mother-to-child transmission of HIV (PMTCT), joint planning with those responsible for maternal and child health should be undertaken. Checklist 10.1 provides a checklist of key elements to consider in implementing a transparent and inclusive decision-making process.

10.2 Decision-making process

10.3 Data to support decision-making (5) 10.3.1 Overview Decisions on how to adapt and implement these guidelines should be based on a careful assessment of epidemiological dynamics and programme performance to identify programme strengths and weaknesses and necessary policy changes, consistent with the principles of “know your epidemic, know your response” (Checklist 10.1) (6,7) . In some countries, these data may be available from regular monitoring and evaluation activities or from recent programme assessments. Elsewhere, new analyses may be warranted, such as studies of the modes of HIV transmission, to shed light on key epidemiological or response elements. Quantitative and qualitative data should, whenever possible, be disaggregated by gender, age, subnational administrative categories (such as regions and districts) and other relevant stratifications, including key populations, to ensure that new policies address inequities in access and increase the coverage of interventions. The consolidation of health information systems, including patient record registries, into electronic databases is critical to facilitate the management of increasing amounts of data and improve their robustness and availability for programme decision-making (see section 11.5).

204

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

10.3.2 National and local HIV epidemiology An epidemiological analysis should describe the prevalence levels among the general population and in specific key populations, the rate at which HIV infection is acquired and among whom, including infants, young children, pregnant women and serodiscordant couples. Both prevalence and incidence measurements should aim to identify populations at higher risk for HIV infection, including in generalized epidemic settings,9 and adequate population size estimates for these populations should be available so that results can be interpreted appropriately (9) . Data on the prevalence and incidence of key coinfections (such as TB and hepatitis B and C) and other comorbidities should also be gathered to inform decision-making.

10.3.3 Programme performance and response analysis Determining whether current ARV programmes are adequate to address the needs that have been identified requires understanding who is currently accessing these services. Programmes should assess present ARV coverage levels among the general population as well as key populations, the disease stage at which they access care, how well these groups are retained in care and treatment, the ARV regimens used and the impact of ART on viral load suppression, morbidity and mortality. Programmes that are considering raising the CD4 cell count threshold for ART eligibility should ideally have data on the median CD4 cell counts and the stage of HIV disease of people at the time of their HIV diagnosis and at the time of initiating treatment. Disaggregated data for various groups enable assessment of ARV needs and establishment of priorities for delivering services. Data on adherence, retention and viral load suppression are key to assess the quality of the services provided. Surveillance of transmitted and acquired HIV drug resistance can also be instrumental in informing decisions on optimal regimen choices (Box 11.1). Whenever possible, indicators of impact, such as changes in HIV-related incidence, prevalence, morbidity and mortality, should also be reviewed.

10.3.4 Socioeconomic, policy and legal context A review of epidemiological and programmatic data is incomplete without a deeper understanding of what drives HIV vulnerability and how various political, social, economic and legal factors affect the ability and willingness of various groups – such as men, women, adolescents, sex workers, men who have sex with men, transgender people and people who inject drugs – to seek and access health services. Stigma, discrimination, poverty, gender inequality, education and migration status are key elements that should be taken into account to inform effective HIV programming. The legal context can also affect access to interventions, such as laws related to intellectual property rights and those that criminalize homosexuality, HIV exposure and/ or transmission, drug use and sex work. Such laws should be reviewed and reformed to eliminate discriminatory practices, decrease HIV vulnerability, improve access to health services and protect human rights.

ncidence estimates by modes of transmission have already been developed for some countries and are available I from UNAIDS (8) .

10. Guidance for programme managers

205

10.3 Data to support decision-making

Checklist 10.1 Process and evidence for decision-making Process for decision-making (10,11) 1. D oes the process follow principles for sound and appropriate decision-making? ublicity: Is the process transparent and open? Are the evidence and rationale for P decisions publicly available? Relevance: Do stakeholders affected by these decisions agree that the rationale rests on relevant reasons, principles and evidence? Revisability and appeals: Can decisions be revised and/or appealed in light of new evidence and arguments? Enforcement: Are all stakeholders aware of the means to ensure that these conditions (publicity, relevance and revisability) are met? 2. Have representatives from all relevant stakeholders been included? rogramme experts and managers, including experts and representatives of sexual and P reproductive health, maternal and child health, TB, HIV programmes (ART, HIV testing and counselling and PMTCT), drug dependence and harm reduction Health care providers, including physicians, nurses and counsellors from adult and child HIV clinics, prison health programmes, maternal and child health, TB clinics and harm reduction and drug dependence services in the public and private sectors Civil society, including people living with HIV, women and youth groups, religious leaders, people with disabilities and representatives of key populations, including men who have sex with men, transgender people, sex workers and people who inject drugs Technical specialists, including experts in specific technical areas, such as laboratory services, pharmacy, drug resistance, toxicity management, supply chain and community health Government partners, including representatives of other relevant ministries (such as finance and planning) and decentralized (such as provincial) authorities, international agencies, faith-based groups, other local nongovernmental and community-based organizations and private-sector service providers Finance and budget experts, such as programme budget officers and health economists Academic institutions, including experts in operational research, implementation science, training and supervision Professional associations of different cadres of health workers (such as physicians, nurses and community health workers) 3. C an all stakeholders participate effectively, be heard and influence decisionmaking? s information accessible to all key stakeholders in written and understandable language? I Is the process organized to ensure the meaningful participation of all relevant stakeholders? Have the potential social, cultural, and legal barriers that deter the meaningful participation of historically marginalized stakeholders been identified and addressed? 4. Transparency regarding the grounds for decisions Are the decision-making criteria transparent and is the rationale stated explicitly with reference to: Scientific evidence, including effectiveness and risk? Opportunity costs of interventions, including cost–effectiveness? Equity impact (distribution of health benefits and burdens for different groups)?

206

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Evidence for decision-making 1. HIV incidence and prevalence I n what population groups are HIV incidence and prevalence highest? Relevant criteria include gender, location (urban versus rural), age, income, general population and pregnant women, and key populations (such as men who have sex with men, people who inject drugs, sex workers and prisoners) W hat is the HIV seroprevalence among the partners of index cases? What is the incidence of HIV infection in serodiscordant couples? 2. Programme and response analysis Has the decision-making process taken into account: t he current coverage of HIV testing and counselling disaggregated by relevant stratifiers? the current coverage of ART disaggregated by relevant stratifiers? t he current coverage of ARV drugs for PMTCT and ART among pregnant women living with HIV? the median CD4 cell count and HIV disease stage of people initiating ART? t he proportion of people starting ART who are alive and still receiving ART after 12, 24 and 60 months? t he prevalence of viral suppression (and % treatment failure) among people receiving ART after 12 months? t he prevalence of HIV drug resistance among people starting first-line ART and among those already receiving treatment? 3. Equity in access B ased on a review of epidemiological and programme response data, do the recommendations promote greater access to ARV drugs and other services for people with least access or those most in need, including key populations? 4. Alignment between evidence and recommendations A re the recommendations appropriate for the epidemiological setting in which they will be implemented? A re the recommendations aligned with and do they support the implementation of the programme’s overarching vision, goals and objectives? Have the recommendations been informed by local and national evidence? 5. Contextual issues H as the decision-making process taken into account how poverty, gender inequality, education, stigma, discrimination and migration status affect HIV vulnerability and access to services? A re there any punitive laws and practices, at any levels, related to HIV transmission, sex work, drug use or homosexuality? H as it been determined how such barriers will be dealt with and how the responses will affect programme planning? A re there legal or regulatory barriers to adolescents being able to have independent access to HIV testing, counselling, treatment and care?

10. Guidance for programme managers

207

10.4 Key parameters for decision-making 10.4.1 Ethics, equity and human rights Multiple legal, social and normative obstacles have resulted in inequitable access to HIV treatment and care. For example, data from 19 countries in Europe and central Asia showed that, although people who inject drugs accounted for 62% of cumulative reported HIV cases with a known transmission route in 2010, they represented only 22% of the people receiving ART in countries surveyed (12,13). Global and national commitments require providing HIV treatment and prevention to everyone in need, following the human rights principles of non-discrimination, accountability and participation (14–16). National HIV strategies should be planned and implemented from the outset with the ultimate goal of delivering the full package of services and interventions recommended in these guidelines as soon as possible. Key ethical principles of fairness, equity and urgency should also be observed in the process of reviewing and adapting guidelines. The design of effective and equitable policies implies that strategies should focus comprehensively on addressing barriers to access testing, prevention and treatment services, particularly those faced by key populations. Facility- and community-level reviews may be useful to understand the extent to which services are acceptable and adapted to the specific needs of key populations.

10.4 Key parameters for decision-making

10.4.2 Impact and cost–effectiveness Realizing positive impact for a population is an important goal of public health programmes and policies. Examples of the impact of HIV programmes include reduced HIV incidence, prevalence, morbidity and mortality and improved quality of life (17). Impact is often a result of a complex set of factors and a combination of diverse inputs and activities or processes, and it is often not attributable to a single intervention or programme (5). Cost–effectiveness analysis is one of several economic evaluation tools used to measure the value of delivering particular services. Economic evaluation measures the costs and consequences of alternative programmes, which are then compared to assess how the greatest health benefits can be generated. In cost–effectiveness analysis, impact is often measured using indicators related to a change in health status, such as disability-adjusted life-years (DALYs) gained, which includes the estimated number of deaths and infections averted. As the experience of scaling up ART in low- and middle-income countries demonstrates, the cost–effectiveness of health interventions also changes over time, as costs fall because of gains in scale, improvements in technology or the design of more efficient delivery systems. During the development of these guidelines, a consortium of research groups independently developed and then compared mathematical models to assess the epidemiological and clinical impact as well as cost–effectiveness ratios of various interventions, notably those related to earlier initiation of ART (Box 10.1). Although evaluating cost–effectiveness and health impact may be useful in systematically comparing various programme interventions, they should be considered in the light of the ethical, equity and human rights implications associated with different courses of action, especially in settings in which not all eligible individuals currently have access to ART. Investments in critical enabler programmes (such as integrated treatment and rights literacy programmes, legal services, stigma and discrimination reduction programmes, training for health care workers and law enforcement) can play a role in overcoming barriers to accessing treatment and other HIV-related services and keeping people connected to care. As such, these programmes can contribute to overall cost–effectiveness, in addition to achieving other important objectives, such as reducing discrimination (18).

208

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Box 10.1 Estimating the impact and cost–effectiveness of selected recommendations using mathematical models: results from the independent HIV Modelling Consortium As HIV programme managers work to implement these guidelines, they may face complex choices on how to optimally allocate resources for HIV treatment: for example, determining the relative allocation of resources for scaling up HIV testing and linkage to care and for increasing access to ART based on expanded eligibility criteria. The HIV Modelling Consortium, an independent group of research institutions (www. hivmodelling.org), used multiple independent mathematical models based on data sets from four countries with different types of epidemics and current ART coverage – India, South Africa, Viet Nam and Zambia – to examine the health benefits, costs and cost–effectiveness of various strategies for expanding eligibility for ART as well as testing and access to HIV care (19) (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes). In each case, a range of potential options was investigated, including various thresholds for ART eligibility (CD4 cell count less than 500 cells/mm 3, all people with HIV and specific key populations), assuming current as well as expanded patterns of HIV testing and linkage to care. The costs and both individual and preventive health benefits associated with each intervention were estimated, including changes in HIV incidence, reductions in the loss of healthy life-years and costs over time. These models also considered the relative cost–effectiveness of strategies, highlighting which of them, for a given budget, would be expected to maximize health gains. Expanding the criterion for ART eligibility to CD4 cell count ≤500 cells/mm 3 was found to be highly cost-effective in low- and middle-income settings. However, combining expanded eligibility with a large increase in HIV testing and linkage to care produced the greatest benefits, especially in settings with low ART coverage. Expanding ART eligibility to all adults with HIV (irrespective of CD4 count) was less cost-effective than expanding the criterion to ≤500 cells/mm 3 because of less immediate improvements in health as the CD4 threshold for initiating ART is increased. The modelling results should be interpreted in light of some important limitations. Many of these conclusions could change substantially depending on cost assumptions, especially those related to testing and counselling and to retaining people in pre-ART care. Moreover, the models did not consider how the estimated impact and cost–effectiveness of the various interventions would change if they were combined or only partly implemented. Models also did not address potential trade-offs with non-antiretroviral interventions, and several important issues were not covered, such as treatment of children (section 6.2.4 discusses the relative cost-effectiveness of various treatment options for children).

10.4.3 Opportunities and risks The recommendations in these guidelines have the potential to further reduce HIV-related mortality, improve the quality of life, reduce the number of people acquiring HIV infection and enhance treatment effectiveness. The benefits accrued from implementing them are likely to considerably outweigh the upfront investment needed and have the potential to fundamentally change the course of the epidemic. Nevertheless, domestic factors (such as budget cuts, theft of ARV drugs, attrition of trained health workers and emergence of drug resistance) and external contingencies (such as withdrawal of external financial support, political instability and natural disasters) could negatively affect their implementation. It is essential to design strategies to mitigate such events so that continued service delivery can be assured, especially for those most in need (20).

10. Guidance for programme managers

209

10.5 Implementation considerations across the health system As countries consider how to optimally implement these guidelines, the budgetary, human resource requirements and other health system implications should be analysed to identify which inputs and systems are currently available and which areas require additional investment. The six building blocks for health systems identified by WHO provide a useful analytical framework (21). Checklist 10.2 provides a checklist of key critical issues in these areas. Such considerations should not determine whether a particular recommendation is included or excluded from national guidelines but can be used as a tool to understand the impact of a recommendation and how best to adapt it and mobilize resources for its implementation. When the relative budget implications of specific recommendations are considered, it is also important to take into account the costs of inaction in terms of increased mortality, morbidity and HIV transmission. An implementation plan should clearly define the set of activities required in a specified period of time to achieve targeted outcomes, with a clear division of labour among all stakeholders involved in implementing programmes. Robust procurement and supply management systems are needed to ensure the continued availability of all necessary drugs, diagnostics and other commodities across the various levels of the health system. Pooled or joint procurement can be used to secure lower costs through economies of scale, and careful demand forecasting is key to minimizing waste. Fixed-dose combinations and once-daily therapy should be used whenever possible to support adherence and make treatment as convenient as possible for the people receiving therapy and their caregivers. Laboratory capacity must also be reviewed and services should be strengthened to cope with higher demand, and nationally standardized health information systems and patient monitoring tools should be used in all settings. Stronger interventions are also needed to maximize treatment adherence and retention across the continuum of care. Specific interventions may be needed in particular settings, such as postpartum followup of mother–infant pairs. The quality of health care is a critical dimension to consider in the planning and adaptation process. The rapid scale-up observed during the past decade has left gaps in the quality of service delivery at times that have negatively affected, for example, adherence rates, timely enrolment in care or retention on ART. The implementation of new guidelines provides an opportunity to comprehensively review and address such gaps. Critically, this requires effective monitoring and evaluation systems (see Chapter 11). A key component of sound quality assurance mechanisms is a clear delineation of roles and responsibilities for the delivery of the various functions and inputs (such as leadership, financing, supply chain management, human resources, monitoring and evaluation needed for effectively providing services at the national, regional, district, facility and individual clinician levels). A quality assurance and improvement framework developed for HIV testing and counselling may inform broader quality assurance and quality improvement interventions across the continuum of care (22). Effective HIV programming is multisectoral in nature and goes beyond biomedical interventions. It is essential to assess how HIV interventions can be optimally linked with other health programmes and non-health services to increase coverage and optimize resources. Planning should also take into account the variety of providers involved in health service delivery, including public, private and not-for-profit organizations. Community involvement and peer outreach strategies are key to improve programme design, promote its sustainability and maximize coverage.

10.5 Implementation considerations across the health system

210

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Checklist 10.2 Implementation checklist of key health system issues The successful implementation of new recommendations depends on several critical decisions in key programme areas. 1. Communication, leadership and advocacy H as it been determined who will be responsible for updating currently existing materials, including service delivery guidelines, protocols, clinical and laboratory standard operating procedures, monitoring and evaluation tools, patient monitoring mechanisms or systems, reference manuals, health worker training materials, job aids, supervisory checklists and materials for public information, education and communication? H as it been decided how new recommendations will be communicated to (1) local programme managers, including public, not-for-profit and private institutions; (2) health workers; and (3) other relevant stakeholders, such as people living with HIV? H as it been agreed who will take overall responsibility for advocacy with stakeholders such as political leaders, health personnel and the mass media? 2. Staffing and human resources H as it been determined how many additional workers are required to implement new recommendations? Which cadres of health workers (physicians, health officers, nurses, midwifes, community health workers and laboratory assistants) are needed and how they can be recruited? C an task shifting and sharing be employed to optimize available human resources and expand service delivery? (see section 9.5.2) 3. Drugs and supplies A re any new medicines (such as ARV drugs) needed to implement the new recommendations? In what quantities? H as it been determined what systems are required for forecasting needs and procuring medicines and other commodities at the best possible prices? H as a transition plan been developed to phase out old medicines (such as d4T) and introduce new ones? D o supply management systems – especially at the peripheral level – need to be strengthened to manage increased demand? I s a regulatory process in place to approve and register new medicines and diagnostics in a timely manner? A re laboratory quality control and external quality assurance systems in place and fully functional? D o national laws allow for the purchase and importation of all necessary commodities? Do patent issues exist and can TRIPS flexibilities be leveraged to promote access? 4. System organization Are linkages and referrals systems adequate? D o services need to be decentralized and/or integrated to support policy implementation? H as the policy been developed in consultation with managers of other relevant programmes (such as TB, maternal and child health and drug dependence services)? 5. Infrastructure H as the necessary physical infrastructure (such as warehouses, meeting rooms, consultation space, laboratories, pharmacies, administration areas and equipment) and transport infrastructure (such as vehicles) needed to support implementation been identified? Is it available somewhere in the health system or does it require additional investments from the ARV programme? I s additional communication infrastructure needed, including between health facilities, health workers, laboratories and clients?

10. Guidance for programme managers

211

10.5 Implementation considerations across the health system

Checklist 10.2 (continued) 6. Costs H as the total annual investment of implementing new recommendations, including ancillary and other services, been estimated? Have the unit costs for the following programme components been determined? ART; PMTCT (for women during pregnancy and breastfeeding only, or lifelong ART?); testing and counselling; general HIV care; clinical monitoring; mentoring, quality assurance and monitoring; and community-level services. 7. Funding H ave the sources of funds, such as government budget, social security or health insurance, Global Fund, United States Presidents’ Emergency Plan for AIDS Relief, UNITAID and private foundations, been identified? (It is important to consider that outof-pocket expenditure may limit access to and uptake of interventions) Are new strategies needed to raise funds to meet estimated investment needs? C an potential cost-savings be achieved through economies of scale or synergies with other interventions and programmes? 8. Monitoring and evaluation D oes the monitoring and evaluation plan clearly identify the facility- and programme level indicators needed to adequately monitor the coverage of interventions and impact of new recommendations? Have the human resources, equipment and infrastructure requirements been identified? A re monitoring and evaluation systems interoperable (between the local and central levels and among various donors) to avoid duplication and ensure consistency? H ave the necessary quality control, quality assurance and quality improvement systems been identified and put in place to optimize service delivery? 9. Implementation plan Does the plan have time-bound targets or objectives? Does the plan contain specific outcomes? D oes the plan clearly identify the roles and responsibilities of the various stakeholders (such as government at the central, provincial and local levels, nongovernmental organizations, technical partners, communities and people living with or affected by HIV) involved in the roll-out process?

10.6 Implementation considerations for key recommendations Boxes 10.2 to 10.7 discuss implementation considerations for programme managers for six key recommendation areas in these guidelines: (1) changing the CD4 cell count threshold for initiating ART for adults and adolescents from 350 to 500 cells/mm3 ; (2) scaling up viral load testing; (3) moving to lifelong ART for all pregnant and breastfeeding women; (4) decentralizing ARV services; (5) expanding treatment for children; and (6) phasing out d4T.

212

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Box 10.2 Key implementation considerations for programme managers: raising the CD4 threshold for initiating ART in adults and adolescents from 350 to 500 cells/mm3 (section 7.1.1) 1. Treat the sickest people first. Individuals with CD4 cell counts of less than 350 cells/mm3 have a different mortality profile than those with higher CD4 cell counts. What systems will be in place to ensure that the sickest people are adequately given priority, especially in settings with low ART coverage? 2. P hase out d4T. Given the long-term toxicity and side effects of d4T, programmes raising the ART initiation threshold to 500 CD4 cells/mm3 should have significantly progressed in phasing out d4T in adult and adolescent regimens to optimize treatment outcomes. 3. C onsider task shifting and decentralization. Human resource plans should be developed or adjusted to support the policy decision to increase the CD4 eligibility threshold, including through task shifting and training new cadres of health workers (see section 9.5.2). 4. Reinforce adherence support. A higher threshold for initiating ART means that more people who feel healthy will become eligible for treatment. What interventions to promote and reinforce adherence will be implemented for these people? 5. Provide treatment monitoring. As more people initiate ART earlier and stay on it for longer, monitoring viral suppression becomes increasingly important, as keeping people on failing regimens may lead to higher levels of drug resistance, which might compromise the efficacy of treatment, especially of NNRTIs. How will access to viral load monitoring be scaled up?

Box 10.3 Key implementation considerations for programme managers: scaling up viral load testing (section 7.3.2) 1. C onsider the various diagnostic options. Several strategies exist to increase access to viral load testing, including the use of dried blood spots (DBS) and, in the near future, point-of-care technologies. Programme managers need to consider the optimal choice in light of multiple factors, such as the availability of existing infrastructure and the number of people receiving services at different levels of care (such as centralized versus peripheral sites). 2. R eview the use of viral load monitoring in the context of alternative patient monitoring strategies. The relative benefit of CD4 monitoring in a context of greater viral load availability may need to be reassessed considering the different specificity profiles of these technologies as markers of treatment failure, their cost and technical requirements for implementation. For example, programmes may consider reducing the number of CD4 tests done for people whose viral load is being routinely measured. CD4 testing is still required to determine ART eligibility. 3. P rovide adherence support. An important proportion of people receiving ARV drugs develop detectable viral load because of inadequate adherence to treatment and can return to undetectable levels if adequate counselling is in place, avoiding unnecessary switching to second-line regimens. 4. D evelop treatment literacy on the use of viral load. As most programmes in low- and middle-income countries have historically relied on CD4 monitoring, people receiving ARV drugs and health care providers may not be familiar with the concept and importance of viral load. Counselling should be provided so that people receiving ARV drugs and health care providers understand the meaning and implications of having a detectable or undetectable viral load and its relation to adherence.

10. Guidance for programme managers

213

10.6 Implementation considerations for key recommendations

Box 10.3 (continued) 5. Ensure an adequate supply of second-line ARV drugs. People whose viral load remains detectable following adherence support have probably developed drug resistance and may need to switch regimens. Programme managers should be prepared to offer alternative regimens, including second-line ARV combinations, to address these situations. 6. I mplement quality assurance strategies. As viral load testing is scaled up, its quality must be assured. Centralized systems should be enrolled in external quality assurance programmes, while new quality assurance approaches are needed for decentralized and point-of-care systems.

Box 10.4 Key implementation considerations: moving to lifelong ART for all pregnant and breastfeeding women (option B+) (section 7.1.2 and Annex 6) 1. Consider the appropriate approach to scaling up. The infrastructure and operational implications of providing lifelong ART to all pregnant and breastfeeding women living with HIV must be carefully reviewed. Countries may consider a phased approach with an early learning phase before full scale-up. 2. Assure linkages to care and patient transfer. The location in which ARV drugs are provided to pregnant and breastfeeding women and the provision of long-term ART should be considered and decided before the programme is implemented. Will women continue to receive ART at the site providing ARV drugs for PMTCT or will they be transferred to an existing ART site? What strategies will be put in place to minimize the risk of women being lost to care as they are transferred to various ART service locations? 3. Review human resource requirements. Many staff at PMTCT sites have had limited training in and experience with providing ART, especially in settings in which Option A has been implemented for PMTCT. Capacity-building, task shifting and potential expansion of health personnel may be needed to allow PMTCT sites to successfully take on the additional responsibility of providing lifelong ART. 4. Promote adherence and retention. Adherence to therapy and retention in care of mother–baby pairs may be especially difficult in the postpartum breastfeeding period. What strategies will be put in place to monitor and support adherence and retention and re-engage in care those lost to follow-up, including both the mother and the HIV-exposed children? 5. Consider ethical issues. Initiating lifelong ART for all pregnant and breastfeeding women regardless of CD4 count may result in temporary disparities in access to treatment. For example, a pregnant woman with a high CD4 count may continue to receive ART after delivery, whereas her husband, other family members, neighbours or other women intending to get pregnant with a lower CD4 count may not yet be eligible for treatment. What process and strategies will be put in place at the policy and service delivery levels to address such possible disparities? How can the enrolment of all pregnant and breastfeeding women into lifelong treatment be leveraged to enhance a family approach, including getting partners and other household members tested for HIV and treatment? 6. Assure the quality of HIV testing. Developing quality-assurance programmes, including for HIV rapid testing (which in some settings may be the only test used to determine the initiation of lifelong ART) and appropriate use of testing algorithms, will be important to ensure optimal implementation in all areas of the country.

214

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Box 10.4 (continued) 7. Assess laboratory monitoring needs. Although CD4 testing may not be required to initiate ART among pregnant women, toxicity and ART response monitoring, including viral load (which is key for assessing viral suppression), should be available, similar to all people receiving ART. Infant diagnosis is also essential to identify infants infected with HIV and to link them to the necessary treatment and care. Surveillance systems (which can be sentinel sites) should be established to evaluate the impact of ART on birth defects, pregnancy outcomes, safety among infants and young children exposed to breastfeeding as well as transmission outcomes and tolerance of first-line ART. 8. Implement adequate monitoring and evaluation frameworks. New strategies are needed to ensure high quality and longitudinal cohort data on the mothers and their HIVexposed infants across a range of service delivery entry points and across the continuum of care. For breastfeeding mothers and infants, the true effectiveness of a PMTCT programme depends on infant infection status and HIV-free survival at the end of the breastfeeding period and not on early infection status at age six weeks. 9. Provide infant prophylaxis. Infant prophylaxis is particularly critical for PMTCT in situations of late HIV diagnosis in the mother, limited or no antepartum maternal ART or if maternal ART is interrupted due to toxicity, intolerance or lack of adherence. 10. A ssure continuous drug supply. An uninterrupted supply of maternal ART during pregnancy and breastfeeding is critical for PMTCT as well as maternal health. Adequate drug forecasting and drug supply chain is essential. Contextual issues to consider for PMTCT options Although country programmes will define the choice between (1) providing ART to pregnant or breastfeeding women living with HIV for the duration of the risk of mother-to-child transmission or (2) lifelong ART regardless of CD4 cell count based on local circumstances, preferences and values, several contextual features are especially relevant for decision-making. 1. Providing lifelong ART (“Option B+”) to all pregnant and breastfeeding women is particularly relevant in settings with the following characteristics: • generalized epidemics; • high repeat pregnancy rates11 and low family planning coverage; • low partner testing rates; • limited access to CD4 testing; • low existing coverage of ART for pregnant women who meet the treatment eligibility • criteria for non-pregnant individuals; and • long duration of breastfeeding by women living with HIV. 2. P roviding ART only during the period of risk of mother-to-child transmission (Option B) with continuing lifelong ART only for those women meeting standard eligibility criteria for the treatment of non-pregnant adults is especially relevant in settings with the following characteristics: • concentrated epidemics; • lower repeat pregnancy rates and higher family planning coverage; • high access to CD4 testing; • h igh existing coverage of ART for pregnant women who meet the treatment eligibility criteria for non-pregnant individuals; and • formula feeding is recommended, available and safe.

10. Guidance for programme managers

215

10.6 Implementation considerations for key recommendations

Box 10.5 Key implementation considerations for programme managers: decentralizing ART services (section 9.4.3) 1. E xamine the models and options. Programmes should determine which clinical and laboratory services will be available at what level of the health care delivery system. The optimal model for ART decentralization (partial or full) depends on the local context. 2. Consider human resources policies and task shifting. All health workers, including community health workers, need to be trained regularly, mentored and supervised to ensure high-quality care and implementation of updated national recommendations. In many settings, decentralizing ART requires task shifting to ensure an appropriate mix of health workers at peripheral facilities. An appropriate regulatory framework (laws, regulations, policies and guidelines) is needed to allow tasks to be performed by different cadres of health workers, in addition to nationally standardized training, mentoring and supervision for all health workers involved in HIV care. 3. I mplement strategies for retaining staff. Programme managers should support the development and implementation of policies to create a suitable environment for recruiting, retaining and motivating personnel in rural or remote areas, where health worker turnover and attrition may be considerably higher than in urban settings. 4. Strengthen linkages and referral systems. Although community-based treatment programmes provide an important option for decentralizing ART, they should always be linked with regular care at health facilities and with adequate laboratory, diagnostics, monitoring and evaluation and drug and supply management systems. 5. Agree on a division of labour. An efficient division of responsibilities among levels of the health system (national, provincial or regional and district) is crucial to minimize duplication and to optimize the use of resources. The role of each level should match its capacity, and the lines of authority and accountability should be clear and well understood by all. 6. B uild partnerships. National regulatory bodies, professional associations and other stakeholders need to be involved when addressing the scope of practice, roles and responsibilities of health workers. Box 10.6 Key implementation considerations for programme managers: scaling up treatment for children – treating all children under 5 years and raising the CD4 threshold in older children from 350 to 500 cells/mm³ (sections 7.1.4 and 7.2.3) 1. E xpanding ART coverage should be the first priority. Since all treatment regimen options have been shown to reduce morbidity and mortality, the use of less preferred options is better than leaving children untreated. 2. Younger children are at greater risk of poor outcomes. Children younger than two years living with HIV have higher mortality rates and more rapid disease progression than older children. Early diagnosis and prompt initiation of ART are especially critical for infants and young children. 3. S trengthen links between diagnosis and treatment. Diagnosis and treatment for children are often performed at different facilities, increasing the risk of their being lost to follow-up. Improving links between early infant diagnosis and ART sites is essential to minimize such losses and improve uptake of ART among children. Family-based approaches to HIV testing and provider-initiated testing and counselling are important approaches to increase HIV diagnosis and treatment among children. 4. Optimize and improve the choice of ARV formulations available. It is critical to accelerate regulatory approval of preferred formulations. Scored dispersible fixed-dose combinations for children with dosage based on weight bands can support the scaling up of ART for children in remote areas.

216

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Box 10.6 (continued) 5. Leverage existing infrastructure and channels. Making ART available for children wherever adult ART and PMTCT interventions are provided is key to improving access and uptake, especially as service delivery is decentralized to lower-level health facilities. 6. P romote retention and adherence. Children depend on adults for their treatment. It is important to design and implement family-based care strategies that can support and facilitate retention and adherence among children. Interventions must also take into account the special adherence challenges of children who move between households.

Box 10.7 Key implementation considerations for programme managers: phasing out d4T (section 7.2) 1. C hoose a suitable alternative. WHO recommends TDF as the preferred alternative to d4T in firstline regimens. TDF is also more likely to be effective than AZT among people who have developed resistance while on d4T. 2. Design a costed phase-out plan. The overall operational plan for phasing out d4T should be fully costed and should consider any additional investment in laboratory strengthening and capacitybuilding that may be required to support implementation. 3. I dentify priorities for implementation. Because of programme constraints, not all countries may be able to promptly switch everyone receiving d4T to new regimens. Priorities should be clearly defined and agreed with all relevant stakeholders. 4. Avoid treatment disruption. Although new d4T orders should be discontinued, adequate and timely forecasting and procurement of the preferred alternative drug are critical to avoid stock-outs and treatment interruption. 5. Review and compare prices. Substantial reductions in the price of both TDF and its preferred companion drug EFV have been observed in recent years. Countries are encouraged to ensure they are procuring these drugs at the best possible price. WHO’s Global Price Reporting Mechanism may be a useful source of price information (23). 6. M anage stockpiles. Options include reserving stocks for back-up situations for individuals who may require d4T in the absence of alternative choices. 7. T rain and educate both clinic staff and people receiving ART. Clinic staff should be trained and prepared to carry out the transition and to educate ART patients about their new regimens. 8. P hase out d4T among children when alternatives are available. WHO’s recommendation to phase out the use of d4T applies equally to both adults and children. However, considering the limited availability of age-appropriate NRTI formulations, d4T may be used in special circumstances, especially in settings where formulations of abacavir for children are not available (see sections 7.2.3. and 7.2.4).

10. Guidance for programme managers

217

10.7 Implementing recommendations in different contexts 10.7.1 Overview Although all countries have agreed to provide universal access to HIV prevention, treatment, care and support by 2015, the local context – including epidemiology and current coverage of interventions – will determine their trajectory towards this goal. This section provides a broad outline of possible sequencing approaches to phasing in key recommendations, considering the available scientific evidence, results from mathematical models (Box 10.2) and ethical and human rights issues. It draws on views expressed in the Guidelines Development Group on Programmatic Issues and therefore does not constitute formal recommendations. National stakeholders are responsible for the process of revising and adapting the guidelines, and different approaches may be necessary and equally valid.

10.6 Implementation recommendations in different contexts

10.7.2 Implementing recommendations in different epidemic settings The guidelines recommend that, in all settings, everyone (adults, adolescents and children) presenting with CD4 cell counts less than 500 cells/mm3 should be offered ART. People with CD4 cell counts of 350 cells/mm3 or less should receive ART as a priority. This is a highly cost-effective intervention that can dramatically reduce HIV-related mortality and morbidity, in addition to HIV incidence. ART should also be initiated in all pregnant and breastfeeding women with HIV, regardless of CD4 count, and be provided to all individuals with active TB and HBV coinfection with severe chronic liver disease and for HIV-positive partners in a serodiscordant couple, irrespective of CD4 count. Coverage of ART among children is also often low, and targeted investment is needed to ensure that all eligible children, including all children younger than five years, have timely access. In addition, the guidelines recommend phasing out d4T and increasing the use of fixed-dose combinations of ARV drugs. In concentrated epidemic settings with low ART coverage, it is critical to identify opportunities to expand access to HIV treatment and care, including testing and counselling, to most-at-risk populations, such as men who have sex with men, transgender people, sex workers, people who inject drugs and prisoners. This requires addressing any structural barriers that may prevent these populations from seeking and accessing care. Integrating HIV services into drug dependence treatment and harm reduction services and TB clinics can be a highly effective approach to reaching these populations (see section 9.4.2). In these settings, given the relatively limited number of pregnant women living with HIV, phasing out option A for PMTCT and providing ART during pregnancy and breastfeeding to reduce the risk of mother-to-child transmission of HIV (option B) are highly effective and relatively low-cost strategies. In generalized epidemic settings with low ART coverage, ensuring that all individuals with CD4 counts of less than 350 cells/mm3 are identified and enrolled in care and treatment is a priority and requires greatly increasing HIV testing and counselling rates among the general population. This can be accomplished by scaling up an appropriate mix of approaches to HIV testing and counselling, including provider-initiated HIV testing and counselling for everyone seeking care as well as all pregnant or breastfeeding women, with effective referral systems and links to care and treatment (section 5.1). Identifying individuals with CD4 counts between 350 and 500 cells/mm3 provides an important opportunity to link them into care and initiate ART early. Other strategies to improve the overall levels of access to and uptake of ART include decentralizing HIV services to the primary health care level and integrating HIV services with TB and antenatal care and maternal and child health services (see section 9.4.2), and offering pregnant and breastfeeding women living with HIV the option of receiving lifelong ART, based on national programme decisions. In addition, as in concentrated epidemics, it important to identify and reach key populations and those with poor access to clinical and community-based services. These may include sex workers, people who inject drugs, men who have sex with

218

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

men, transgender people or other groups such as adolescent girls, migrants and other mobile populations, older women and certain high-risk occupational groups. As coverage of ART increases and programmes mature, expanding access to second-line regimens increasingly becomes a programmatic priority. Scaling up viral load monitoring will be important to adequately identify treatment failure and to avoid switching unnecessarily to second-line regimens. Viral load monitoring is also likely to play a central monitoring role in places in which ART is being broadly expanded to reduce HIV incidence. As people initiate treatment earlier and stay on it for longer, monitoring the quality of service delivery and strengthening service linkages to improve retention throughout the cascade of care are essential to optimize treatment outcomes and long-term programme performance.

10.8 Useful tools for costing and planning Estimating the costs associated with implementing new recommendations is a key step in the roll-out process. Several costing tools and resources are available to assist countries in estimating the costing and budgeting of HIV and related interventions and services. Spectrum is a suite of models and analytical tools to support decision-making. It comprises several software applications including AIM (AIDS Impact Model) and Goals (Cost and Impact of HIV Interventions). The AIM and Resource Needs modules can be used to estimate the impact of key new recommendations on number of deaths averted by ART, the number of infant infections averted by PMTCT and adult, PMTCT and paediatric treatment needs and costs. The key data needed to generate these estimates are demographic projections, HIV incidence trends, historical data on the numbers of people receiving ART, the numbers of pregnant women receiving PMTCT interventions and the unit costs for ART for adults and for PMTCT. All countries already have AIM files prepared as part of their national epidemiological estimates, so both modules can be rapidly applied. The Goals module can be used to estimate the number of adult HIV infections averted by ART under different eligibility criteria and rates of scale-up. The key inputs required are the distribution of the adult population by risk group (such as stable couples, those with casual partners, female sex workers, male clients of sex workers, men who have sex with men, transgender people and people who inject drugs); sexual behaviour by risk group (numbers of partners per year, acts per partner and condom use) and needle sharing among people who inject drugs. Goals models already exist for about 25 countries, and other countries have compiled these data in the context of modes of transmission studies. OneHealth is a software tool designed to strengthen health system analysis and costing and to develop financing scenarios at the country level. It is specifically designed to assess health investment needs in low- and middle-income countries and provides planners with a single framework for planning, costing, impact analysis, budgeting and financing of strategies for all major diseases and health system components. OneHealth can also be downloaded free of charge (24). WHO and collaborating organizations have recently developed a variety of tools to assist with drug quantification and supply management. Several are available for download, with a description of their main purposes and programmatic focus (25). Guidance on the costing of different PMTCT options has also been developed (26). A flexible tool for costing investments in critical enablers (such as integrated treatment and rights literacy programmes, legal services, stigma and discrimination reduction programmes, training for health care workers and law enforcement) has also been developed and can be downloaded for free, along with a user guide (27,28).

MONITORING AND EVALUATION

11.1 Introduction 218 11.2 Monitoring implications of new recommendations 219 11.3 Monitoring the outputs and outcomes of scaling up access to ARV drugs 220 11.4 Other monitoring considerations 223 11.4.1 HIV drug resistance 223 11.4.2 Sentinel surveillance for ARV toxicity monitoring 223 11.4.3 E valuation, including impact and programme performance, and implementation research 223 11.5 Reviewing and strengthening monitoring and evaluation systems 225

Goal of this chapter To provide programmatic guidance for decision-makers and planners at the national level in tracking the implementation of these guidelines and monitoring their impact on HIV programmes and people receiving ART.

220

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

11. Monitoring and evaluation 11.1 Introduction As countries adapt and implement these guidelines, monitoring and evaluation frameworks and systems need to be adapted to collect and analyse information to track the implementation and impact of new recommendations. Monitoring and evaluation will help programme managers to assess the effectiveness of interventions and linkages between services along the cascade of treatment and care for HIV and associated conditions (Fig. 11.1). Such information is essential to detect and respond to bottlenecks or gaps in programme performance and to adequately characterize and respond to patient attrition. As programmes mature, monitoring individual- and population-level outcomes, including toxicity and adverse events, drug resistance, viral suppression, mortality, survival and incidence, is also essential to assess the impact of programmes.

Fig. 11.1 The HIV treatment and care cascade People living with HIV HIV diagnosis Linkage and enrolment in care Antiretroviral therapy Viral suppression Populationlevel Impact

Data can be collected in many ways, including routinely reported data from all facilities or sentinel sites; population-based surveys; surveillance data; observations on cohorts of people living with HIV; and periodic evaluation. Programme input and processes can also be monitored through facility surveys or updated lists of service availability; documenting the availability and training of human resources; and monitoring the availability of HIV medicines and diagnostics at various geographical and facility levels. Special studies can be considered where routine monitoring is inappropriate. In considering how best to collect critical data, efforts should also be made to review monitoring systems, such as better linking the monitoring of services for PMTCT, TB and ART and integrating HIV drug resistance monitoring into routine health information systems. Involving civil society in monitoring and evaluation activities is also critical to better understand successes and failures, especially in assessing the perceptions, values and experiences of people living with HIV, key populations and the broader community in accessing and using services. The community can also play a key role in designing and implementing data collection tools and analysing and interpreting findings. WHO is developing a consolidated guide on monitoring and evaluation of HIV in the health sector that brings together the various elements of monitoring and evaluation systems for HIV programmes. The guide will consolidate and align existing monitoring and evaluation approaches in relevant programmatic areas (such as HIV testing and counselling, ART, PMTCT and HIV drug resistance) with the recommendations in these guidelines and will also include new guidance in emerging areas for HIV monitoring and evaluation. The publication on three interlinked patient monitoring systems (1) will also be updated to reflect this new monitoring and evaluation guidance.

11. Monitoring and evaluation

221

11.2 Monitoring implications of new recommendations The monitoring and evaluation strategy should monitor service delivery, including inputs and processes as well as outputs and outcomes, such as the number of people receiving interventions and the impact at the individual and population levels (see section 11.3). The monitoring and evaluation plan should include a framework to track progress in implementing the guidelines to verify whether new policies on ART eligibility and recommendations on and plans for treatment or service delivery are actually implemented. This will enable national programmes to document the effect of the shift in guidelines and can contribute to evaluating the impact of the guidelines. Table 11.1 lists key areas to review when implementing major new recommendations in these guidelines. For each key area, potential topics to monitor and possible implications for revising monitoring systems are provided. Not all information needs to be captured routinely; data needs and the timing of data collection depend on the local context.

11. Monitoring and evaluation

Table 11.1 Implications for monitoring of the key recommendations in these guidelines Summary of new recommendation areas HIV testing and counselling When to start ART Implications for monitoring

Monitor the uptake of community-based HIV testing strategies and testing services for adolescents, including systems for linkages to care Monitor the number and percentage of different populations (such as adults, adolescents, children and pregnant and breastfeeding women) who have initiated ART based on the new eligibility criteria Review the monitoring system to assess what disaggregation is needed for what purpose (such as CD4 counts ≤200 cells/mm3 to routinely monitor late diagnosis or CD4 counts ≤350 cells/mm3 and 350–500 cells/mm3 to periodically assess the distribution of CD4 when ART is initiated) and how to best collect the relevant data, and age disaggregation of children (such as <2 years and <5 years).

Which ART regimen to start

Monitor the first- and second-line ART regimens people are receiving Monitor the phasing out and/or introduction of specific drugs (such as d4T and TDF) Monitoring tools may need to be adjusted to reflect new regimen options

Response to ART and diagnosing treatment failure

Monitor the percentage of people receiving ART who had a viral load test and received the results Monitor the reasons for switching ART regimen

222

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 11.1 (continued) Summary of new recommendation areas Service delivery Implications for monitoring

Monitor retention and adherence among various populations Monitor the integration of ART into facilities providing maternal and child health services, TB services and drug dependence services if planned by documenting the facilities providing ART Monitor whether the initiation and maintenance of ART has been decentralized as planned at various facilities by documenting the expansion of ART facilities Monitor the functionality of linkages from maternal and child health services, TB services and drug dependence services to HIV care and ART and linkages between communities, peripheral facilities and hospitals by documenting transfers

Task shifting

Monitor the number of non-physician clinicians, midwives and nurses who are trained in ART Monitor the number of non-physician clinicians, midwives and nurses who are initiating first-line ART and maintaining ART and the number of people they have initiated or maintained on ART Monitor the number of community health workers who are trained and are dispensing ART between regular clinical visits, and capture the number of people to whom they dispense ART

11.3 M onitoring the outputs and outcomes of scaling up access to ARV drugs In addition to monitoring the implementation of new recommendations, health information systems need to be reviewed and adapted to appropriately monitor the outputs and outcomes associated with the new recommendations. Table 11.2 lists areas for gathering data for assessing whether scaling up programmes leads to the anticipated outputs and outcomes at various points along the cascade of HIV treatment and care. Most of the areas have associated indicators in existing WHO guidance (Web Annex www.who.int/hiv/pub/guidelines/arv2013/annexes provides additional details on indicators and references) and/or form part of internationally agreed core indicators that all countries should track within the framework of the Global AIDS Response Progress Reporting process (2) . In some evolving areas (such as links between HIV diagnosis and ART, retention of pregnant women in using ARV drugs and viral load monitoring), indicators are still being reviewed and evaluated. The forthcoming consolidated monitoring and evaluation guide for HIV in the health sector will provide more detailed guidance.

11. Monitoring and evaluation

223

Table 11.2 Overview of data areas for monitoring and evaluating the HIV treatment cascade Step in the cascade People living with HIV Indicator areas Estimated number of people living with HIV in various categories Relevance Estimates the distribution of people living with HIV among the population Estimates the size of relevant populations and need for HIV interventions, to help focus planning The level of testing coverage of relevant populations indicates efforts to scale-up HIV testing and counselling, including provider-initiated testing and counselling Measuring the proportion of population groups aware of their HIV status identifies where more effort may be needed Number of people living with HIV newly diagnosed with HIV infection in a given period Indicates the pool of people who should be linked to care Measures strength of link between diagnosis and enrolment in care Indicates access to and uptake of HIV care following a positive HIV test Identifies who is enrolled in care and whether key populations and priority groups are linked to care Acts as a proxy measure for maintained linkage to the care of adults and children who may start ART in the future Coverage of ART among eligible people living with HIV, by population groups of interest and regimen Indicates trends in the number of people receiving ART, to be used to review programme expansion and plan drug supply Helps estimate unmet need for ART and equity in access to ART Coverage of ARV drugs for PMTCT among pregnant women with HIV Estimates unmet need for ARV drugs for PMTCT Input to model the impact of services for PMTCT

11.3 Monitoring the outputs and outcomes of scaling up access to ARV drugs

HIV diagnosis

Percentage of the general population with known HIV test status and witwhin specific populations as well

Number of people newly diagnosed with HIV infection

Linkage and enrolment in HIV care

Percentage of people newly diagnosed with HIV infection enrolled in HIV care Profile of people living with HIV initiating HIV care Retention in care of people living with HIV not yet initiating ART, including HIV-exposed infants Number of people receiving ART (and coverage)

Antiretroviral drugs: coverage Number of people receiving ARV drugs for PMTCT (and coverage)

224

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 11.2 (continued) Step in the cascade Antiretroviral drugs: drug supply Indicator areas Relevance

Percentage of ART facilities with ARV drug stock-outs in a given period

Indicates stock-outs, which could directly affect treatment adherence and clinical outcomes, and may contribute to HIV drug resistance Indicates the quality of care and the likelihood of viral suppression Adherence acts as an early warning indicator of drug resistance

Adherence

Antiretroviral drugs: adherence and retention

Percentage retained on ART and PMTCT

Indicates retention over time and the success of ART programmes Helps to monitor losses and identify where to strengthen engagement in care Low retention acts as an early warning indicator for HIV drug resistance

Viral suppression

Percentage of viral suppression

Effectiveness of ART programmes in achieving viral suppression Decline in HIV-related deaths and even overall mortality in countries with a high burden of HIV indicates successful HIV programmes Decline in incidence indicates how successful HIV prevention and treatment programmes are in limiting the number of people acquiring HIV infection Identifying who is acquiring HIV infection and where the infection was acquired helps to focus planning

Mortality

Incidence and the number of adults and children acquiring HIV infection

Impact

Elimination of new HIV infections among children is a measure of the success of PMTCT programmes Mother-to-child transmission rate The mother-to-child transmission rate indicates how much vertical transmission occurs Increased survival and extended life-years of people living with HIV receiving ART is a measure of the impact of ART Survival, including HIV-exposed children and children living with HIV, indicates the levels of access to and the quality of health care

Survival

11. Monitoring and evaluation

225

11.4 Other monitoring considerations Programmes are increasingly moving beyond coverage indicators to focus on critical outcomes, such as viral load suppression and immune reconstitution, and on the broader impact of HIV treatment, including HIV-related mortality and HIV incidence. However, programmes also need to measure potential unintended outcomes, such as HIV drug resistance and ARV-related toxicities. Periodic evaluations and implementation research are also central to reviewing programmes.

11.4 Other monitoring considerations

11.4.1 HIV drug resistance WHO recommends the use of early warning indicators to help identify deficits in programme performance that favour the emergence of HIV drug resistance (Box 11.1). WHO also recommends that countries undertake surveillance of HIV drug resistance and provides specific guidance on how to do the surveys required.

11.4.2 Sentinel surveillance for ARV toxicity monitoring Surveillance of the toxicity of ARV drugs is essential to identify and address preventable adverse events. Various approaches have been developed to monitor the toxicity of ARV drugs, including targeted and systematic surveillance reporting on specific types of toxicity and serious adverse events caused by a specific drug in targeted populations, and the pregnancy exposure registry following a cohort of pregnant women exposed to ART, including birth defect surveillance. WHO technical guidance on implementing toxicity monitoring at sentinel sites will become available in 2013.

11.4.3 Evaluation, including impact and programme performance, and implementation research Routine monitoring should be complemented by systematic evaluations and programme reviews to assess the performance and effects of HIV programmes, either comprehensively or with respect to specific priority areas. Social science and implementation research are important to assess perceptions and values of service recipients and communities along with barriers, facilitators and experiences in delivering and receiving services. Impact indicators, such as incidence, morbidity and mortality, are often difficult to measure. Guidance on the use of assays for recent infection to estimate HIV incidence at the population level has been recently developed (3) , and guidance on monitoring mortality, including the cause of death, will be available in 2013. A short guide summarizing five methods to measure the impact of programmes for PMTCT (4) is already available, and detailed guidance that can be adapted to implement each method will become available in 2013. Mathematical modelling is often undertaken to project various scenarios for programme planning and evaluating impact. Ensuring the availability of robust data is especially important when estimating the prevention impact of ARV drugs at the population level, as multiple sources of information and uncertainty come into play. Specific data collection efforts and models for particular contexts may provide more accurate estimates.

226

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Box 11.1 Monitoring HIV drug resistance HIV drug resistance poses a significant threat to the success of national HIV programmes. Drug resistance results in more rapid virological failure among people receiving first-line regimens and increases the need for second-line regimens, which may be associated with greater toxicity, adverse events, poorer adherence and higher costs. Drug resistance may also affect the ability to prevent HIV transmission using ARV-based pre- or post-exposure prophylaxis or topical microbicides. Surveillance of drug resistance should be an integral component of national HIV programmes. Surveillance data should inform the selection of first- and second-line regimens for ART, as well as ARV drugs for PMTCT, to optimize treatment outcomes within a public health approach. WHO and its partners have developed a standardized and complementary assessment strategy to be implemented by countries, for both adult and paediatric populations, with the following components. Monitoring early warning indicators for HIV drug resistance. Early warning indicators use existing clinic and pharmacy records to assess the factors associated with the emergence of HIV drug resistance at the level of ART programmes and clinics. These factors include ART prescribing practices; drug supply continuity; adherence to ARV drug regimens measured by on-time pick-up of ARV drugs; retention in care; and viral load suppression, when available. The monitoring of early warning indicators should be integrated into a country’s monitoring and evaluation system and provides the information needed to address practices that may lead to poor outcomes and HIV drug resistance. Surveys to monitor acquired HIV drug resistance and associated factors in populations receiving ART. The WHO generic protocol for monitoring acquired HIV drug resistance uses a standardized survey methodology to assess population-level virological suppression at the national level and the emergence of HIV drug resistance among populations receiving treatment. Performed regularly at representative sites, these surveys provide evidence for action at the programme and clinic level to minimize HIV drug resistance. They also provide evidence to optimize the selection of first- and second-line ART regimens. Surveys to monitor pre-treatment HIV drug resistance. The WHO generic protocol for surveillance of pre-treatment HIV drug resistance provides a nationally representative estimate of HIV drug resistance in populations initiating therapy. Performed regularly at representative ART clinics, these surveys support national, regional and global decision-making regarding the choice of first-line regimens. Surveillance of transmitted HIV drug resistance among individuals recently infected with HIV. The WHO generic protocol for surveillance of transmitted HIV drug resistance provides estimates of transmitted HIV drug resistance in recently infected populations, and the results should contribute to ART policy decisions, including guidelines on ART regimens and HIV prophylaxis. Surveillance of HIV drug resistance among infants under 18 months of age. The WHO generic protocol for surveillance of HIV drug resistance among children under 18 months of age can provide estimates of national prevalence of HIV drug resistance among infants diagnosed with HIV infection through early infant diagnosis testing. The results assess differences in HIV drug resistance prevalence between populations exposed to ARV drugs for PMTCT and those with unknown exposure to support the selection of optimal first-line ART for this population. National strategies for assessing HIV drug resistance should be developed and routinely implemented as part of comprehensive HIV treatment programmes.

11. Monitoring and evaluation

227

11.5 Reviewing and strengthening monitoring and evaluation systems The recommendations in these guidelines may require certain adaptations to the monitoring and evaluation system. Guidance is available on the 12 components of a monitoring and evaluation system and tools to review and strengthen national HIV monitoring and evaluation systems (5). Table 11.3 highlights some specific areas to review to ensure that monitoring and evaluation systems are aligned to the new ARV guidelines.

11.5 Reviewing and strengthening monitoring and evaluation systems

Table 11.3 Critical aspects of monitoring and evaluation systems and implications of the new recommendations Selected elements of monitoring and evaluation systems Patient monitoring system Key considerations to review with new guidelines

Improving the monitoring of enrolment and retention in HIV care Accurate accounting for transfers and losses Updating data elements required for patient monitoring in line with new guidelines, such as changes in regimen and including viral load (where available) Revisit disaggregation categories and links and synergy for systems for monitoring ARV drugs for PMTCT, TB and ART Move to electronic systems where feasible One standardized monitoring and evaluation system, agreed on by all partners and stakeholders, including necessary updates based on evolving ARV drug policies and practices Common country standards and data flow, based on any changes in service delivery Clarify integration of programmes for PMTCT, TB programmes and ART programmes and transfer to ART programmes Consider a unique patient identifier Use of mobile phones where proven opportunities exist Functional links between HIV and health management information systems Clear protocols for data generation, standard operating procedures for aggregation, where they do not exist, for any new indicators and for new service delivery scenarios Review available laboratory data as a source of key information Regular assessment of the data quality in facilities and at the subnational level Supportive supervision, including new elements of ARV drug policy and implementation plans Update national reporting forms to capture any new national-level data, including identifying the frequency of data collection necessary for various indicators Regular review of standardized data at the facility, regional and national levels to identify issues and improve programmes, including a review of early warning indicators for HIV drug resistance Review and update the strategy for using data based on new ARV drug policies and a corresponding monitoring and evaluation framework and plan

Data flow and integration

Data generation and quality assurance approach

Data use at various levels and programme reviews

228

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Table 11.3 (continued) Selected elements of monitoring and evaluation systems Periodic reporting and data accessibility Key considerations to review with new guidelines

Maintaining national and subnational databases, to include new data elements Regular data dissemination and public accessibility of data related to the evolving HIV programme Periodic (sub-) national and international reports to reflect and document the roll-out of new ARV drug policies and their impact

Monitoring and evaluation system capacity

Human and institutional capacity for data generation and analysis at the facility, subnational and national levels, for monitoring and evaluation that is relevant to updated ARV drug guidance and policies Appropriate investment in monitoring and evaluation and reflection in grants (including those from the Global Fund to Fight AIDS, Tuberculosis and Malaria) of the monitoring and evaluation adjustments required to strengthen existing capacity and capture new guidance on ARV drugs

Monitoring and evaluation plan

A costed national plan with a list of core indicators and planned evaluations, with focus on results and accountability, revisited in light of new guidelines on ARV drugs Regular assessment of the implementation of the monitoring and evaluation plan, based on the updated plan

Evaluation and operational and implementation research

Plan and strategy for evaluating impact, considering the rollout of the new guidelines on ARV drugs Agenda and plan for implementation research, considering the rollout of the new guidelines on ARV drugs Review of research results for improving programmes

Monitoring and evaluation partnerships and coordination

Coordinating programme monitoring and reporting activities among key stakeholders and partners Alignment with national health strategy, link with other programme strategies (maternal and child health services, TB and key populations) and international initiatives (Commission for Information and Accountability for Women’s and Children’s Health, ending mother-to-child transmission of HIV (eMTCT) and Global AIDS Response Progress Reporting (2) )

12. Annexes

ANNexes

Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children 228 Annex 2. Annex 3. lgorithm for the 2013 recommendations for adults A and adolescents 230 lgorithms for the 2013 recommendations for pregnant A and breastfeeding women 232

Annex 4. Algorithm for the 2013 recommendations for children 234 Annex 5. Algorithm for early infant diagnosis 235 Annex 6. Annex 7. eadiness assessment checklist: moving towards R ART for pregnant and breastfeeding women 236 Dosages of recommended antiretroviral drugs 240

230

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

12. Annexes Annex 1. WHO clinical staging of HIV disease in adults, adolescents and children Source: Adapted from WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. Geneva, World Health Organization, 2007 (www.who.int/hiv/pub/guidelines/ HIVstaging150307.pdf). Adults and adolescents a Clinical stage 1 Asymptomatic Persistent generalized lymphadenopathy Clinical stage 2 Moderate unexplained weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis) Herpes zoster Angular cheilitis Recurrent oral ulceration Papular pruritic eruption Fungal nail infections Seborrhoeic dermatitis Clinical stage 3 Unexplained severe weight loss (>10% of presumed or measured body weight) Unexplained chronic diarrhoea for longer than 1 month Unexplained moderate malnutrition b not adequately responding to standard therapy Unexplained persistent diarrhoea (14 days or more) Unexplained persistent hepatosplenomegaly Recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis, tonsillitis) Herpes zoster Lineal gingival erythema Recurrent oral ulceration Papular pruritic eruption Fungal nail infections Extensive wart virus infection Extensive molluscum contagiosum Unexplained persistent parotid enlargement Children Asymptomatic Persistent generalized lymphadenopathy

Unexplained persistent fever (above 37.5°C, intermittent Unexplained persistent fever (intermittent or or constant, for longer than one 1 month) constant for longer than 1 month) Persistent oral candidiasis (after first 6 weeks of life) Persistent oral candidiasis Oral hairy leukoplakia Oral hairy leukoplakia Lymph node tuberculosis Pulmonary tuberculosis Pulmonary tuberculosis Severe bacterial infections (such as Severe recurrent bacterial pneumonia pneumonia, empyema, pyomyositis, bone or Acute necrotizing ulcerative gingivitis or joint infection, meningitis, bacteraemia) periodontitis Acute necrotizing ulcerative stomatitis, Unexplained anaemia (<8 g/dl), neutropaenia gingivitis or periodontitis (<0.5 x 10 9 /l) or chronic thrombocytopaenia Unexplained anaemia (<8 g/dl), (<50 x 10 9 /l) neutropaenia (<0.5 x 10 9 /l) and/or chronic thrombocytopaenia (<50 x 10 9 /l)

12. Annexes

231

Annex 1 WHO clinical staging of HIV disease in adults, adolescents and children

Adults and adolescents a Clinical stage 3

Children Symptomatic lymphoid interstitial pneumonitis Chronic HIV-associated lung disease, including bronchiectasis

Clinical stage 4 c HIV wasting syndrome

Pneumocystis ( jirovecii ) pneumonia Recurrent severe bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal of more than 1 month’s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extrapulmonary tuberculosis Kaposi sarcoma Cytomegalovirus infection (retinitis or infection of other organs) Central nervous system toxoplasmosis HIV encephalopathy Extrapulmonary cryptococcosis, including meningitis

Unexplained severe wasting, stunting or severe malnutrition d not responding to standard therapy

Pneumocystis ( jirovecii ) pneumonia Recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia) Chronic herpes simplex infection (orolabial or cutaneous of more than 1 month’s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extrapulmonary tuberculosis Kaposi sarcoma Cytomegalovirus infection (retinitis or infection of other organs with onset at age more than 1 month) Central nervous system toxoplasmosis (after the neonatal period)

Disseminated nontuberculous mycobacterial HIV encephalopathy infection Extrapulmonary cryptococcosis, including meningitis Progressive multifocal leukoencephalopathy Disseminated nontuberculous mycobacterial infection Chronic cryptosporidiosis Chronic isosporiasis Disseminated mycosis (extrapulmonary histoplasmosis, coccidioidomycosis) Lymphoma (cerebral or B-cell non-Hodgkin) Progressive multifocal leukoencephalopathy Chronic cryptosporidiosis (with diarrhoea) Chronic isosporiasis

Disseminated endemic mycosis (extrapulmonary Symptomatic HIV-associated nephropathy or histoplasmosis, coccidioidomycosis, penicilliosis) cardiomyopathy Cerebral or B-cell non-Hodgkin lymphoma Recurrent septicaemia (including HIV-associated nephropathy or cardiomyopathy nontyphoidal Salmonella ) Invasive cervical carcinoma Atypical disseminated leishmaniasis

In the development of this table, adolescents were defined as 15 years or older. For those aged less than 15 years, the clinical staging for children should be used. b For children younger than 5 years, moderate malnutrition is defined as weight-for-height <–2 z-score or mid-upper arm a

circumference ≥115 mm to <125 mm. Some additional specific conditions can be included in regional classifications, such as penicilliosis in Asia, HIV-associated rectovaginal fistula in southern Africa and reactivation of trypanosomiasis in Latin America. d For children younger than 5 years of age, severe wasting is defined as weight-for-height <–3 z-score; stunting is defined as length-for-age/height-for-age <–2 z-score; and severe acute malnutrition is either weight for height <–3 z-score or mid-upper arm circumference <115 mm or the presence of oedema. c

232

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Annex 2. A lgorithm for the 2013 recommendations for adults and adolescents ART-naive adults and adolescents with HIV Clinical assessment

WHEN TO START ART

Symptomatic HIV disease or presence of CD4-independent conditions?

Asymptomatic HIV infection? a

WHO clinical stage 3 or 4?a b Active TB disease? c

WHO clinical stage 1 or 2? a CD4 cell count CD4 ≤ 500 cells/mm³? b

Severe chronic HBV liver disease?d Pregnancy or breastfeeding?e HIV+ in a serodiscordant relationship?f

Yes

No Do not initiate Art

Yes

No Do not initiate Art

Initiate ART

WHAT FIRST-LINE ART TO START

Initiate one of the following ART regimensg : Preferred option: • TDF + 3TC (or FTC) + EFV Alternative options: • TDF + 3TC (or FTC) + NVP • AZT + 3TC + EFV • A ZT + 3TC + NVP

Annex 1 lists the WHO clinical staging for HIV disease. ART initiation in individuals with severe or advanced symptomatic disease (WHO clinical stage 3 or 4), regardless of CD4 cell count, or with CD4 count ≤ 350 cells/mm 3, regardless of clinical symptoms, should be prioritized. c Active TB disease refers to the time when TB breaks out of latency and causes disease. Latent TB infection refers to the period of time when the immune system has been successful in containing the Mycobacterium tuberculosis and preventing disease. d Severe chronic liver disease includes cirrhosis and end-stage liver disease and is categorized into compensated and decompensated stages. Decompensated cirrhosis is defined by the development of clinically evident complications of portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy) or liver insufficiency (jaundice). e F or details on ARVs for pregnant and breastfeeding women with HIV (Option B and Option B+), see Annex 3 and sections 7.1.2, 7.1.3 and 7.2.2. f A HIV-serodiscordant couple is a couple in which one of the sexual partners is HIV-positive and one is HIV-negative. Although one partner is currently HIV-negative, this does not mean that this partner is immunized or protected against getting HIV in the future. g For adolescents weighing less than 35 kg, refer to the algorithm for children in annex 4 which indicates the appropriate first-line ART regimen options. a b

12. Annexes

233

Annex 2 Alogirthm for the 2013 recommendations for adults and adolescents

234

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Annex 3. A lgorithms for the 2013 recommendations for pregnant and breastfeeding women Lifelong ART for all pregnant and breastfeeding women with HIV (Option B+)

PREGNANT AND BREASTFEEDING WOMEN WITH HIV

HIV-EXPOSED INFANTS

Breastfeeding MTCT RISK PERIOD Daily NVP for 6 weeks

Replacement feeding 4-6 weeks of NVP or twice-daily AZT

Initiate lifelong ART: TDF + 3TC (or FTC) + EFV (Preferred regimen) (assess CD4 baseline where possible) CESSATION OF MTCT RISK

Early infant diagnosisa

Final infant diagnosis

LINKAGE TO TREATMENT AND CARE FOR BOTH WOMAN AND INFANT

See Annex 5. Algorithm for early infant diagnosis

12. Annexes

235

Annex 3 Algorithms for the 2013 recommendations for pregnant and breastfeeding women

ART for women with HIV during pregnancy and breastfeeding (Option B)

PREGNANT AND BREASTFEEDING WOMEN WITH HIV

HIV-EXPOSED INFANTS

recommended ART: TDF + 3TC (or FTC) + EFV MTCT RISK PERIOD (assess eligibility (WHO clinical stage 3 or 4 or CD4 ≤500 cells/mm3) for treatment for her own health)

Initiate the following

Breastfeeding Daily NVP for 6 weeks

Replacement feeding 4-6 weeks of NVP or twice-daily AZT

Eligible for treatment for her own health at baseline assessment

Early infant diagnosisa Yes CESSATION OF MTCT RISK

Continue ART

Stop ART after 1 week of complete cessation of breastfeeding and refer to care for reassessment

Final infant diagnosis

LINKAGE TO TREATMENT AND CARE FOR BOTH WOMAN AND INFANT

See Annex 5. Algorithm for early infant diagnosis

236

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Annex 4. A lgorithm for the 2013 recommendations for children Infants and children infected with HIV

<5 years of age

≥5 years of age

WHEN TO START ART IN CHILDREN

WHO clinical stage 3 or 4 or CD4 ≤500 cells/mm³?

Yes

No Monitor clinical stage and CD4

Initiate ARTa

Initiate ARTb

<3 years of age?

< 10 years of age or weighing <35kg

WHAT FIRST-LINE ART TO START IN CHILDREN

Yes Initiate one of the following regimens: c Preferred option: ABC or AZT + 3TC + LPV/r Alternative option ABC or AZT + 3TC + NVP

Yes

No Initiate one of the following regimens: Preferred option: TDF + 3TC (or FTC) + EFV Alternative options: AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + NVP

Initiate one of the following regimens: c Preferred option: ABC + 3TC + EFV Alternative options: ABC + 3TC + NVP AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP

f this recommendation to treat all children between one and under five years of age is not adopted: initiate ART with WHO I clinical stage 3 and 4 or with CD4 count ≤750 cells/mm 3 or <25%, whichever is lower, regardless of WHO clinical stage (105) . b I f this recommendation is not adopted ART should be initiated at WHO HIV clinical stage 3 and 4 or with CD4 count ≤ 350 cells/mm 3 regardless of WHO clinical stage (105, Chapter 7). c S pecial note: d4T use should be restricted to those situations where there is suspected or confirmed toxicity to AZT and lack of access to ABC or TDF. The duration of therapy with this drug should be limited to the shortest time possible. a

12. Annexes

237

Annex 5. Algorithm for early infant diagnosis Establishing the presence of HIV infection in HIV-exposed infants and children less than 18 months of age in resource-limited settings. Source: Adapted from Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. 2010 revision. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599801_eng.pdf). HIV-exposed infant or child <18 months Conduct diagnostic viral testa Viral test available Viral test not available

Annex 5 Algorithm for early infant diagnosis

Positive Infant or child is likely infected <24 months: immediately start ARTb And repeat viral test to confirm infection

Negative Ever breastfed or currently breastfeeding Infant or child remains at risk of acquiring HIV infection until complete cessation of breastfeedingc Regular and periodic clinical monitoring

Never breastfed

Infant or child is uninfected

Infant or child develops signs or symptoms suggesting HIV

Infant remains well and reaches 9 months of age Conduct HIV antibody test at approximately 9 months of age

Viral test not available

Viral test available

Positive

Negative

Positive Infant or child is HIV infected Start ARTb and repeat viral test to confirm infection

Viral test not available: assume infected if sick; assume uninfected if well sick well

HIV unlikely unless still breastfeedingc

Repeat antibody test at 18 months of age and/or 6 weeks after cessation of breastfeeding For newborns, test first at or around birth or at the first postnatal visit (usually 4–6 weeks). See also Table 5.1 on infant diagnosis. Start ART, if indicated, without delay. At the same time, retest to confirm infection. c The risk of HIV transmission remains as long as breastfeeding continues. a b

238

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Annex 6. R eadiness assessment checklist: moving towards ART for pregnant and breastfeeding women The 2013 consolidated guidelines recommend that all pregnant and breastfeeding women with HIV should initiate ART and, based on national programme decisions, that either all women continue ART as lifelong treatment or women not eligible for ART for their own health stop after the mother-to-child transmission risk period. Countries planning for this transition, and those working to expand and strengthen their programme, may find it useful to refer to this readiness assessment checklist, which addresses a range of issues from national policy to facility readiness. The checklist (adapted below), as well as a discussion guide, were developed by the United States President’s Emergency Plan for AIDS Relief, and are included as part of the larger Elimination of Mother-to-Child Transmission Inter-Agency Task Team’s Toolkit: Expanding and Simplifying Treatment for Pregnant Women Living with HIV: Managing the Transition to Option B/B+: • Checklist Link: www.emtct-iatt.org/wp-content/uploads/2013/03/Toolkit-Section-2.pdf; • Full Toolkit Link: www.emtct-iatt.org/toolkit Recommended timing key: Before implementation Early in implementation During implementation

POLITICAL COMMITMENT & POLICY ENDORSEMENT Commitment to Global Plan goals (national and subnational) Full-time MoH staff responsible for PMTCT (national & possibly subnational) Functional technical working group inclusive of stakeholders from MNCH, PMTCT, and HIV treatment, including health care workers and people living with HIV National and subnational endorsement of ART for all pregnant and breastfeeding women (Option B or B+) Guidelines incorporate offering ART to all pregnant and breastfeeding women FINANCIAL CONSIDERATIONS Costing of current PMTCT strategy Costing of ART for all pregnant and breastfeeding women, both short and long term Conduct resource gap analysis Increased programme funding needs reflected in budget Demonstration of national financial commitment SERVICE DELIVERY MODEL Defining minimum package of services to provide ART to all pregnant and breastfeeding women Assessment of system capacity (infrastructure, human resources, and commodities) to decentralize ART to MNCH settings, including absorbing women with HIV and their families

Completed

In Process

Not yet started

Completed

In Process

Not yet started

Completed

In Process

Not yet started

12. Annexes

239

Annex 6 Readiness assessment checklist: moving towards ART for pregnant and breastfeeding women

SERVICE DELIVERY MODEL Timing and location of transition between PMTCT and long-term treatment services has been determined (including consideration of lifelong ART provision within MNCH) Systematic identification of ART clients who become pregnant and linkage to MNCH Testing and treating partners and family members within MNCH Referral of stable ART clients at current ART facilities to new decentralized ART sites HUMAN RESOURCE CAPACITY National endorsement of task shifting/sharing for ART initiation and maintenance Assessment of human resource capacity (nurse, midwife, pharmacy, lab) to support ART scale-up Core competencies in HIV management for each health worker cadre Training strategy for ART provision to support rapid scale-up Updating of national in-service and pre-service curricula Strategy for retention, retraining, and continuing professional development of health workers, especially those providing in PMTCT/ART ART REGIMEN CHOICE Simplification and harmonization of PMTCT and adult treatment regimens Plan for alternate regimen for pregnant women not tolerant of 1st-line ART Optimization of 1st-line regimen for infants Establishment of pharmacovigilance system, where appropriate (see discussion guide) SUPPLY CHAIN MANAGEMENT Supply chain gap assessment including quantification, distribution and stock management 18 month forecast, quantification, and supply plan developed Stock management of ART in MNCH settings (training, capacity, and security) SUPPLY CHAIN MANAGEMENT If modifying 1st line regimen, plan to for using ARVs already ordered Revised supply chain management system (consumption, forecasting, and distribution)

Completed

In Process

Not yet started

Completed

In Process

Not yet started

Completed

In Process

Not yet started

Completed

In Process

Not yet started

Completed

In Not yet Process started

240

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

MONITORING, EVALUATION, AND DATA USE Antenatal care (ANC) and PMTCT register allows for documentation of initiation versus those already on ART ART register allows for documentation of pregnancy and breastfeeding status Tools and registers in MNCH allow for cohort monitoring of maternal ART retention and exposed infant retention in care Pregnant and breastfeeding women initiated on ART in MNCH settings are included in site and national level ART M&E systems System to track and measure linkages and transition between MNCH and long-term HIV care & treatment for mother and infant (for example, a mother-baby longitudinal registry, unique identifier) Program evaluation designed to detect early successes and challenges, and to assess longer term maternal and infant outcomes, including mother-to-child transmission Routine data quality assurance Harmonization of PMTCT and ART M&E systems and data review processes Standardized file or card for pregnant and breastfeeding women with HIV and exposed infants SITE SUPERVISION AND QUALITY MANAGEMENT Routine site supervision and clinical mentoring for quality of care Continuous quality improvement process for the PMTCT program HIV TESTING AND COUNSELLING IN PMTCT SETTINGS Quality assurance measures for rapid HIV testing in all PMTCT sites Policy decision on treatment of discordant couples Couples HTC and follow-up of discordant couples incorporated into PMTCT Strategy to link or register male partners with HIV in ART program COUNSELLING ON ART INITIATION AND ADHERENCE Specialized messaging and support services for pregnant and Breastfeeding women initiating ART Structures to expedite preparation for ART initiation Alternative protocols developed for women not in need ART for their own health who decline treatment for life LABORATORY AND CLINICAL MONITORING Treatment monitoring capability for toxicity Availability of baseline CD4 (point of care or reliable sample transport) Algorithm for CD4 and/or viral load monitoring

Completed

In Not yet Process started

Completed

In Not yet Process started

Completed

In Not yet Process started

Completed

In Not yet Process started

Completed

In Not yet Process started

12. Annexes

241

Annex 6 Readiness assessment checklist: moving towards ART for pregnant and breastfeeding women

INFANT DIAGNOSIS AND PEDIATRIC TREATMENT EID capacity paralleling PMTCT programme scale-up Strengthening of “EID cascade” – early diagnosis, rapid results return, active case finding of infants infected with HIV and initiation of treatment Retention of HIV exposed infants through end of breastfeeding including assuring final diagnosis Expand access to pediatric treatment RETENTION IN CARE AND TREATMENT System to ensure that ALL pregnant and postpartum women with HIV are enrolled in ongoing HIV care and/or treatment Models of service delivery that consider harmonized mother-infant pair follow-up Facility- and community-based services to support adherence and trace defaulters Innovative solutions to improving the accessibility of ART FAMILY PLANNING Assessment of family planning service availability and commodities Access to and uptake of voluntary family planning services in settings providing ART COMMUNITY INVOLVEMENT Women living with HIV are engaged in the planning, implementation and monitoring at national, subnational and community levels Community-based activities and services to support PMTCT scaleup and retention Community structures to support orphans and vulnerable children ROLL-OUT STRATEGY Roll-out strategy has been planned Real-time evaluation of implementation in order to inform further scale-up

Completed

In Not yet Process started

Completed

In Not yet Process started

Completed

In Not yet Process started

Completed

In Not yet Process started

Completed

In Not yet Process started

Acronyms used: MoH (Ministry of Health); MNCH (maternal, newborn, and child health); M&E (monitoring and evaluation); HTC (HIV testing and counselling); and EID (early infant diagnosis).

242

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Annex 7. Dosages of recommended antiretroviral drugs a Dosages of antiretroviral drugs for adults and adolescents Generic name Dose

Nucleoside reverse-transcriptase inhibitors (NRTIs) Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Zidovudine (AZT) 300 mg twice daily or 600 mg once daily 400 mg once daily (>60 kg) 250 mg once daily (≤60 kg) 200 mg once daily 150 mg twice daily or 300 mg once daily 30 mg twice daily 250−300 mg twice daily

Nucleotide reverse-transcriptase inhibitors (NtRTIs) Tenofovir (TDF) 300 mg once daily

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) Efavirenz (EFV) Etravirine (ETV) Nevirapine (NVP) Proteases inhibitors (PIs) Atazanavir + ritonavir (ATV/r) Darunavir + ritonavir (DRV/r) Lopinavir/ritonavir (LPV/r) 300 mg + 100 mg once daily 800 mg + 100 mg once daily or 600mg + 100 mg twice daily 400 mg/100 mg twice daily Considerations for individuals receiving TB therapy In the presence of rifabutin, no dose adjustment required. In the presence of rifampicin, adjusted dose of LPV/r (LPV 800 mg + RTV 200 mg twice daily or LPV 400 mg + RTV 400 mg twice daily) or SQV/r (SQV 400 mg + RTV 400 mg twice daily), with close monitoring. Integrase strand transfer inhibitors (INSTIs) Raltegravir (RAL) a

600 mg once daily 200 mg twice daily 200 mg once daily for 14 days, followed by 200 mg twice daily

400 mg twice daily

For adolescents weighing less than 35 kg, see the next page for weight-based dosing for ARV formulations for children.

12. Annexes

243

Weight-based dosing for antiretroviral formulations for children Prescribing information and weight-based dosing of available ARV formulations for infants and children This annex contains information on antiretroviral drugs for which there are paediatric indications, formulations or sufficient information and evidence to provide guidance on prescribing and dosing. The work to develop and update simplified guidance on antiretroviral drugs for use in children has been undertaken by WHO through the Paediatric Antiretroviral Working Group.1 For simplification and ease of implementation, doses are expressed per weight-band rather than per kilogram or per square metre of body surface area. When this simplified weight-band dosing was developed, careful consideration was given to the usual body surface area of children from low- and middle-income countries in that weight band. The primary source of information for the guidance provided is the manufacturer’s package insert. This was supplemented with data from other clinical studies as well as expert paediatric pharmacology consultations. For fixeddose combinations, a dose-modelling tool (www.who.int/hiv/paediatric/generictool/en/index. html) was used to predict the dose delivered for each component drug against the recommended dosing schedule. In some cases the dose for a component in a particular weight band may be somewhat above or below the target dose recommended by the manufacturer. This is inevitable given the limitations imposed by a fixed-dose combination, but care was taken to ensure that in no case would a child receive more than 25% above the maximum target dose or more than 5% below the minimum target dose. For simplification, Antiretroviral drugs that are no longer considered preferred or alternative options for children such as didanosine and saquinavir are no longer included in the dosing guidance. In addition, dosing for postnatal prophylaxis for HIVexposed infants is not provided here but can be found in Chapter 7, Table 7.8. During the finalisation of these Guidelines FDA approval was granted for the use of EFV in children 3 months to 3 years old weighing at least 3.5 kg. While recognizing the opportunity to provide an additional option to children and allow further harmonisation across age groups, the GDG highlighted the need for further data prior to recommending EFV as a treatment option in children less than 3 years. This dosing annex and the simplified dosing schedule will be regularly reviewed and updated as further data or newer formulations become available, but national programmes are advised to consider the most recent product labelling for up-to-date information. Additional information can also be found in specific drug information sheets in the Web Annex at www.who.int/hiv/pub/ guidelines/antiretroviral2013/annexes. Antiretroviral drugs and formulations are available from several companies, and the dose strengths of tablets, capsules and liquid formulations may vary from the information given here. In addition, the listing of a formulation in this annex does not equate to quality assurance of that formulation. National programme managers should ensure that any product procured for use is approved and of appropriate quality and stability. For guidance on the quality assurance of medicines, see the WHO medicines web site (www.who.int/medicines/areas/quality_safety/ quality_assurance/about/en/index.html) and the Access to HIV/AIDS drugs and diagnostics of acceptable quality, which is available and updated at www.who.int/hiv/amds/selection/ en/index.html. The current list of WHO prequalified drugs is available at http://apps.who. int/prequal. For the current list of antiretroviral drugs approved and tentatively approved by the United States Food and Drug Administration, see www.fda.gov/internationalprograms/ FDAbeyondourbordersforeignoffices/AsiaandAfrica/ucm119231.htm. For the policy of the Global Fund to Fight AIDS, Tuberculosis and Malaria on procurement and quality assurance, see www.theglobalfund.org/en/procurement/quality/pharmaceutical. 1

Annex 7 Dosages of recommended antiretroviral drugs

The current members are listed in the annex to the most recent Paediatric Antiretroviral Working Group meeting report: Paediatric Antiretroviral Working Group. Developing dosing guidance for new and upcoming formulations of paediatric antiretrovirals in line with Treatment 2.0 priorities. Meeting report, Paediatric Antiretroviral Working Group, Geneva, Switzerland, 25–26 October 2011. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75159/1/ WHO_HIV_2012.8_eng.pdf, accessed 15 May 2013).

244

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

General principles The principles followed in developing the WHO simplified tables include the following; I t is preferable to use an age-appropriate fixed dose combination for any regimen if such a formulation is available. O ral liquid or syrup formulations should be avoided where possible, especially if volumes are large – such as above 10 ml. D ispersible tablets (or tablets for oral solution) are the preferred solid oral dosage forms, since each dispersible tablet can be made into liquid at the point of use. I n general, young children should be switched to available solid oral dosage forms as soon as they are tolerated. W here children have to use adult formulations, care must be taken to avoid underdosing. Adult tablets that are scored are more easily split. For tablets that are not easily split, WHO recommends that this be done in the dispensing pharmacy using appropriate tablet cutters. S ome tablets such as LPV/r heat-stable tablets are made in a special embedded matrix formulation (a proprietary melt extrusion technology that stabilizes drug molecules that are normally heat labile) and should not be cut, split or crushed, since they lose bioavailability. D ifferent dosing between morning and evening doses should be avoided where possible. Children have to be weighed at each clinic visit, and dose changes are required as children grow and/or gain weight.

Table 1. Simplified dosing of child-friendly fixed-dose solid formulations for twice-daily dosing among children Number of tablets by weight band morning and evening Strength of adult tablet (mg) Number of tablets by weight band 25–34.9 kg AM 300/150 300/150/200 3 3 3 2.5 2.5 2.5 3 3 3 3 3 300/300/150 3 600/300 2.5 30/150 2.5 – 2 1 1 1 0.5 1 4 PM 1 1 1 0.5 1 4

Drug

Strength of tablets (mg)

3–5.9 kg PM 1 1 1 1 1 1 1.5 1.5 2 1.5 1.5 2 2 1.5 1.5 2 2 2.5 1.5 1.5 2 2 2.5 2.5 1.5 1.5 2 2 2.5 2.5 3 1.5 1.5 2 2 2.5 2.5 3 3 AM PM AM PM AM PM AM PM

6–9.9 kg

10–13.9 kg

14–19.9 kg

20–24.9 kg

AZT/3TC

Tablet (dispersible) 60 mg/30 mg

AZT/3TC/ NVP

Tablet (dispersible) 60 mg/30 mg/50 mg

ABC/ AZT/3TC

Tablet (dispersible) 60 mg/60 mg/30 mg

ABC/3TC

Tablet (dispersible) 60 mg/30 mg

d4T/3TC

Tablet (dispersible) 6 mg/30 mg

d4T/3TC/ NVP

Tablet (dispersible) 6 mg/30 mg/50 mg

12. Annexes

245

Annex 7 Dosages of recommended antiretroviral drugs

246

Table 2. Simplified dosing of child-friendly solid formulations for once-daily dosing in children Strength of tablet (mg) Number of tablets or capsules by weight band once daily 25–34.9 kg 200 600 600 + 300 2 2/3 1

Drug

Strength of tablets (mg) 6–9.9 kg – – 3 4 5 6 one third one half two thirds 1 1.5 1.5 10–13.9 kg 14–19.9 kg 20–24.9 kg

Number of tablets or capsules by weight band once daily

3–5.9 kg

Tablet (scored) 200 mg

–

EFVa

Tablet (double scored) 600 mg

–

ABC/3TC

Tablet (dispersible) 60/30 mg

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

EFV is not recommended for children younger than 3 years and weighing less than 10 kg. FDA approval for use in children less than 3 years weighing more than 3.5 kg was granted during the finalisation of these guidelines (3.5-5 kg two 50 mg capsules; 5-7.5 kg three 50 mg capsules; 7.5-15 kg one 200 mg capsule), however more data are urgently needed to inform recommendations for use of EFV in this age group. b The double-scored tablet has two score lines on one side of the tablet and one score line on the other side, enabling the tablet to be divided into thirds and halves as needed.

Table 3. Simplified dosing of child-friendly solid and oral liquid formulations for twice-daily dosing Number of tablets by weight band morning and evening Strength of adult tablet (mg) 20–24.9 kg AM PM Number of tablets by weight band 25–34.9 kg AM PM

Drug

Strength of tablets (mg) or oral liquid (mg/ml) 6–9.9 kg AM Solid formulations 1.5 1.5 1.5 1.5 – Liquid formulations 9 ml 4 ml 4 ml 8 ml 1.5 ml 1.5 ml 2 ml 8 ml 10 ml 10 ml 2 ml 4 ml 6 ml 6 ml 4 ml 6 ml 6 ml – – – 2.5 ml 9 ml 12 ml 12 ml – – – – – 2.5 ml – – – – 3 ml – – – – 3 ml – – – – – – – – – – 2 1 2 2 2 1.5 2 2 2.5 2.5 3 1.5 2 2 2.5 2.5 3 3 3 2 1.5 2 2 2.5 2.5 3 3 1.5 2 2 2.5 2.5 3 3 150 300 300 200 100/25 1 1 1 1 3 PM AM PM AM PM 10–13.9 kg 14–19.9 kg

3–5.9 kg

3TC

Tablet (dispersible) 30 mg

1 1 1 1 3

AZT

Tablet (dispersible) 60 mg

ABC

Tablet (dispersible) 60 mg

NVPa

Tablet (dispersible) 50 mg

LPV/rb

Tablet (heat stable) 100 mg/25 mg

–

AZT

10 mg/ml

6 ml

– –

ABC

20 mg/ml

3 ml

3TC

10 mg/ml

3 ml

NVP

10 mg/ml

5 ml

– –

LPV/r

80/20 mg/ml

1 ml

NVP dose escalation with half dose for 2 weeks when initiating ART is still recommended to avoid toxicity from high initial NVP levels. However, secondary analysis from the (CHAPAS)-1 trial recently suggested that younger children have a lower risk of toxicity, and consideration can be given to starting with a full dose (Fillekes Q et al. Is nevirapine dose escalation appropriate in young African HIV+ children? 20th Annual Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, USA, 3–6 March 2013 (http://retroconference.org/2013b/Abstracts/46904.htm, accessed 15 May 2013). More definitive evidence is expected from an ongoing trial. b LPV/r liquid requires a cold chain during transport and storage. The LPV/r heat-stable tablet formulation must be swallowed whole and should not be split or crushed.

12. Annexes

247

Annex 7 Dosages of recommended antiretroviral drugs

248

Table 4. Simplified harmonized dosing for currently available TDF formulations for children Number of scoops or tablets by weight band once daily 6–9.9 kg – – – 1 (150 mg) 1 (200 mg) 3 – – 300 mg 10–13.9 kg 14–19.9 kg 20–24.9 kg 25–34.9 kg 1 (200 mg) b or 1 (300 mg) Strength of adult tablet (mg) Number of tablets by weight band

Drug

Size of powder scoop (mg) or strength of tablet (mg)

3–5.9 kg – –

TDFa

Oral powder scoops 40 mg/scoop

Tablets 150 mg or 200 mg

Target dose: 8 mg/kg or 200 mg/m 2 (maximum 300 mg). The Paediatric Antiretroviral Working Group developed this guidance to harmonize TDF dosing with WHO weight bands and to reduce the numbers of strengths to be made available. The WHO generic tool was used based on the target dose provided by the manufacturer’s package insert. In accordance with the standard Paediatric Antiretroviral Working Group approach, dosing was developed ensuring that a child would not receive more than 25% above the maximum target dose or more than 5% below the minimum target dose. b 200-mg tablets should be used for weight 25–29.9 kg and 300 mg tablets for 30–34.9 kg.

Table 5. Simplified dosing of isoniazid (INH) and co-trimoxazole (CTX) prophylaxis Number of scoops or tablets by weight band once daily 6–9.9 kg 1 5 ml 2 one half – – – – one half 2 5 ml 1.5 2 10 ml 4 1 one half one half 10–13.9 kg 14–19.9 kg 20–24.9 kg 2.5 10 ml 4 1 one half one half 300 mg – – 400/80 mg 800/160 mg 960 mg/300 mg/ 25 mg Strength of adult tablet (mg) Number of tablets by weight band 25–34.9 kg 1 – – 2 1 1

Drug

Strength of tablet or oral liquid (mg or mg/5 ml)

3–5.9 kg 0.5 2.5 ml 1 – – –

INH

100 mg

CTX

Suspension 200/40 per 5ml

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

Tablets (dispersible) 100/20 mg

Tablets (scored) 400/80 mg

Tablets (scored) 800/160 mg

INH/CTX/ B6a

Tablets (scored) 960 mg/ 300 mg/25 mg

This formulation is currently awaiting regulatory approval, and a scored junior tablet (480 mg/150 mg/12.5 mg) is also under development.

12. Annexes

249

The need for new formulations The work of the Paediatric Antiretroviral Working Group has highlighted the urgent need for formulations, especially fixed-dose combination formulations containing LPV/r in solid forms, suitable for treating younger children, scored tablets of TDF and TDF-based fixed-dose formulations for children. In addition, the availability of ATV/r and DRV/r in heat-stable fixeddose combination formulations is becoming more critical to facilitate treatment sequencing. Access to a heat-stable formulation containing 30 mg of RTV is also important for “superboosting” LPV in the setting of rifampicin-based TB treatment. The table below contains some duplication of formulations. for example, a scored adult fixed-dose combination of TDF + 3TC + EFV is not needed if a formulation for children is available. However, the Paediatric Antiretroviral Working Group recognized that, although a child-specific formulation may be ideal, a scored adult formulation may be easier to develop as a first step. The recent approval of EFV for use in children 3 months to 3 years old has provided an additional option for young children and offers further opportunity for harmonisation. As more data are obtained to inform the best use of this drug in young children, sprinkles formulation should be made available in resource limited settings. In moving towards the joint UNAIDS/WHO Treatment 2.0 initiative, WHO will continue to work to simplify prescribing, dispensing and dosing guidance and work with the pharmaceutical industry (originator and generic) and other partners to develop more practical recommendations on the range of formulations required to safely accelerate the scaling up of ART for children.

Annex 7 Dosages of recommended antiretroviral drugs

Table 6. Simplified dosing for urgently needed ARV drugs for children recommended by the Paediatric Antiretroviral Working Group Drug Strength of tablet or sprinkle sachet or capsule (mg) 60mg/30mg/50mg 40mg/10 mg 30mg/15mg/ 40mg/10mg 30mg/15mg/ 40mg/10mg 240/40mg 100/33mg 120/60mg 75mg/75mg 75mg/75mg/ 150mg 300mg/ 300mg 300mg/300mg/ 600mg No. of tablets or sprinkle capsules/sachets by weight band 3– 5.9kg 1 2 2 2 – – 1 – – – – 1 2 2 2 – 6– 9.9kg 1.5 3 3 3 – – 1.5 – – – – 1.5 3 3 3 – 10– 13.9 kg 2 4 4 4 1 1 2 1.5 1.5 one third one third 2 4 4 4 1 14– 19.9kg 2.5 5 5 5 1 1 2.5 2 2 one half one half 2.5 5 5 5 1 20– 24.9kg 3 6 6 6 2 2 3 2.5 2.5 two thirds two thirds 3 6 6 6 1 25– 34.9kg 4 – – – – – – 3–3.5a 3–3.5a 1 1 4

AM PM AM PM AM PM AM PM AM PM AM PM

ABC/3TC/NVP LPV/r sprinkles ABC/3TC/ LPV/r AZT/3 TC/ LPV/r DRV/r ATV/r ABC/3TC TDF/3TC TDF/3TC/ EFV TDF/3TC adult double scoredb TDF/3TC/EFV adult double scoredb a b

3 tablets for 25–29.9 kg and 3.5 tablets for 30–34.9 kg. A double-scored tablet has two score lines on one side of the tablet and one score line on the other side, enabling it to be divided into thirds or halves as needed

REFERENCES

252

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection

13. References Chapter 1 1. S caling up antiretroviral therapy in resource-limited settings. Guidelines for a public health approach . Geneva, World Health Organization, 2002 (www.who.int/hiv/pub/prev_care/ScalingUp_E.pdf, accessed 15 May 2013). 2. A ntiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines on care, treatment and support for women living with HIV/AIDS and their children in resource-constrained settings . Geneva, World Health Organization, 2004 (www.who.int/hiv/pub/mtct/en/arvdrugswomenguidelinesfinal.pdf, accessed 15 May 2013). 3. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2006 revision . Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf, accessed 15 May 2013). 4. A ntiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access: recommendations for a public health approach. 2006 revision . Geneva, World Health Organization, 2006 (http://www.who. int/hiv/pub/mtct/antiretroviral/en/index.html, accessed 15 May 2013). 5. A ntiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach. 2006 revision. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/ paediatric020907.pdf, accessed 15 May 2013). 6. Gilks C et al. WHO public health approach to ART against HIV in resource-limited settings. Lancet , 2006, 368:505–510. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2010 7. revision . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf, accessed 15 May 2013). 8. A ntiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access: recommendations for a public health approach. 2010 revision . Geneva, World Health Organization, 2010 http://whqlibdoc. who.int/publications/2010/9789241599818_eng.pdf, accessed 15 May 2013). 9. A ntiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. 2010 revision . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599801_eng.pdf, accessed 15 May 2013). 10. T he strategic use of antiretrovirals for treatment and prevention of HIV infection. Report of a WHO technical consultation, 14–16 November 2011, Geneva, Switzerland . Geneva, World Health Organization, 2011 (https://extranet.who.int/iris/ restricted/bitstream/10665/70912/5/9789241503808_eng.pdf, accessed 15 May 2013).

Chapter 2 1. United Nations General Assembly. 2006 Political Declaration on HIV/AIDS . New York, United Nations, 2006. 2. United Nations General Assembly. 2011 Political Declaration on HIV and AIDS: Intensifying Our Efforts to Eliminate HIV and AIDS . New York, United Nations, 2011. G lobal health sector strategy on HIV/AIDS 2011–2015. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/ 3. hiv_strategy/en, accessed 15 May 2013). 4. G lobal Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva, UNAIDS, 2011 (http://www.unaids.org/believeitdoit/the-global-plan.html, accessed 15 May 2013).

Chapter 3 1. W HO handbook for guideline development . Geneva, World Health Organization, 2012 (www.who.int/kms/guidelines_ review_committee/en, accessed 15 May 2013). 2. Guyatt GH et al. GRADE guidelines. 1. Introduction – GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology, 2011, 64:383–394. 3. Guyatt GH et al. GRADE guidelines. 2. Framing the question and deciding on the importance of outcomes. Journal of Clinical Epidemiology, 2011, 64:395–400. 4. Balshem H et al. GRADE guidelines. 3. Rating the quality of evidence introduction. Journal of Clinical Epidemiology, 2011, 64:401–406. 5. Guyatt GH et al. GRADE guidelines. 4. Rating the quality of evidence – study limitations (risk of bias). Journal of Clinical Epidemiology, 2011, 64:407–415. 6. Guyatt GH et al. GRADE guidelines. 5. Rating the quality of evidenced publication bias. Journal of Clinical Epidemiology, 2011, 64:1277–1282. 7. Guyatt GH et al. GRADE guidelines. 6. Rating the quality of evidenced imprecision (random error). Journal of Clinical Epidemiology, 2011, 64:1283–1293. 8. Guyatt GH et al. GRADE guidelines. 7. Rating the quality of evidenced inconsistency. Journal of Clinical Epidemiology, 2011, 64:1294–1302. 9. Guyatt GH et al. GRADE guidelines. 8. Rating the quality of evidenced indirectness. Journal of Clinical Epidemiology, 2011, 64:1303–1310. 10. Guyatt GH et al. GRADE guidelines. 9. Rating up the quality of evidence. Journal of Clinical Epidemiology, 2011, 64:1311– 1316.

13. References 11. Andrews J et al. GRADE guidelines. 15. Going from evidence to recommendations: the significance and presentation of recommendations. Journal of Clinical Epidemiology, in press. doi: 10.1016/j.jclinepi.2012.03.013.

253

13 References

Chapter 5 ervice delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework . Geneva, World S Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75206/1/9789241593877_eng.pdf, accessed 15 May 2013). 2. G uidance on provider-initiated HIV testing and counselling in health facilities . Geneva, World Health Organization, 2007 (http://whqlibdoc.who.int/publications/2007/9789241595568_eng.pdf, accessed 15 May 2013). 3. Sweat M et al. Community-based intervention to increase HIV testing and case detection in people aged 16-32 years in Tanzania, Zimbabwe, and Thailand (NIMH Project Accept, HPTN 043): a randomised study. Lancet Infectious Diseases , 2011, 11:525–532. 4. Corbett EL et al. Uptake of workplace HIV counselling and testing: a cluster-randomised trial in Zimbabwe. PLoS Medicine, 2006, 3:e238. 5. Grabbe KL et al. Increasing access to HIV counseling and testing through mobile services in Kenya: strategies, utilization, and cost-effectiveness. Journal of Acquired Immune Deficiency Syndromes , 2010, 54:317–323. 6. Granich R et al. Achieving universal access for human immunodeficiency virus and tuberculosis: potential prevention impact of an integrated multi-disease prevention campaign in Kenya. AIDS Research and Treatment , 2012, 412643. 7. Lugada E et al. Comparison of home and clinic-based HIV testing among household members of persons taking antiretroviral therapy in Uganda: results from a randomized trial. Journal of Acquired Immune Deficiency Syndromes, 2010, 55:245–252. 8. Menzies N et al. The costs and effectiveness of four HIV counseling and testing strategies in Uganda. AIDS, 2009, 23:395–401. 9. van Schaik N et al. Earlier HIV diagnosis – are mobile services the answer? South African Medical Journal, 2010, 100:671–674. 10. Wolff B et al. Evaluation of a home-based voluntary counselling and testing intervention in rural Uganda. Health Policy and Planning , 2005, 20:109–116. 11. Bingham TA et al. HIV risk factors reported by two samples of male bathhouse attendees in Los Angeles, California, 2001–2002. Sexually Transmitted Diseases , 2008, 35:631–636. 12. Lahuerta M et al. Comparison of users of an HIV/syphilis screening community-based mobile van and traditional voluntary counselling and testing sites in Guatemala. Sexually Transmitted Infections , 2011, 87:136–140. 13. Nhurod P et al. Access to HIV testing for sex workers in Bangkok, Thailand: a high prevalence of HIV among street-based sex workers. Southeast Asian Journal of Tropical Medicine and Public Health , 2010, 41:153–162. 14. Kranzer K et al. Individual, household and community factors associated with HIV test refusal in rural Malawi. Tropical Medicine and International Health , 2008, 13:1341–1350. 15. Negin J et al. Feasibility, acceptability and cost of home-based HIV testing in rural Kenya. Tropical Medicine and International Health , 2009, 14:849–855. 16. Chirawu P et al. Acceptability and challenges of implementing voluntary counselling and testing (VCT) in rural Zimbabwe: evidence from the Regai Dzive Shiri Project. AIDS Care, 2010, 22:81–88. 17. Ostermann J et al. Who tests, who doesn’t, and why? Uptake of mobile HIV counseling and testing in the Kilimanjaro Region of Tanzania. PLoS One, 2011, 6:e16488. 18. Choko AT et al. The uptake and accuracy of oral kits for HIV self-testing in high HIV prevalence setting: a cross-sectional feasibility study in Blantyre, Malawi. PLoS Medicine, 2011, 8:e1001102. 19. Frank AP et al. Anonymous HIV testing using home collection and telemedicine counseling. A multicenter evaluation. Archives of Internal Medicine, 1997, 157:309–314. 20. Spielberg F et al. Home collection for frequent HIV testing: acceptability of oral fluids, dried blood spots and telephone results. HIV Early Detection Study Group. AIDS , 2000, 14:1819–1828. 21. Feeley FG et al. A successful workplace program for voluntary counseling and testing and treatment of HIV/AIDS at Heineken, Rwanda. International Journal of Occupational and Environmental Health , 2007, 13:99–106. 22. Outlaw AY et al. Using motivational interviewing in HIV field outreach with young African American men who have sex with men: a randomized clinical trial. American Journal of Public Health , 2010, 100(Suppl. 1):S146–S151. 23. Bell DN et al. Case finding for HIV-positive youth: a special type of hidden population. Journal of Adolescent Health , 2003, 33:10–22. 24. Champenois K et al. ANRSCOM’TEST: description of a community-based HIV testing intervention in nonmedical settings for men who have sex with men. BMJ Open , 2012, 2:e000693. 25. Morin SF et al. Removing barriers to knowing HIV status: same-day mobile HIV testing in Zimbabwe. Journal of Acquired Immune Deficiency Syndromes , 2006, 41:218–224. C ouples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples. 26. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/publications/2012/9789241501972_eng.pdf, accessed 15 May 2013). 27. W HO recommendations on the diagnosis of HIV infection in infants and children . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599085_eng.pdf, accessed 15 May 2013). 28. G uideline on HIV disclosure counselling for children up to 12 years of age. Geneva, World Health Organization, 2011 (http:// whqlibdoc.who.int/publications/2011/9789241502863_eng.pdf, accessed 15 May 2013). 29. G uidance on provider-initiated HIV testing and counselling in health facilities . Geneva, World Health Organization, 2007 (http://www.who.int/hiv/pub/vct/pitc2007/en, accessed 15 May 2013). 30. G uidance on HIV testing and counselling for adolescents and care for adolescents living with HIV. Geneva, World Health Organization, 2013. 1.

254

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 31. D elivering HIV test results and messages for re-testing and counselling in adults . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599115_eng.pdf, accessed 15 May 2013). 32. P lanning, implementing and monitoring home-based HIV testing . Geneva, World Health Organization, 2012 (http://apps. who.int/iris/bitstream/10665/75366/1/9789241504317_eng.pdf, accessed 15 May 2013). 33. P revention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach . Geneva, World Health Organization, 2012 (http://apps.who.int/ iris/bitstream/10665/77745/1/9789241504744_eng.pdf, accessed 15 May 2013). 34. P revention and treatment of HIV and other sexually transmitted infections among men who have sex with men and transgender people: recommendations for a public health approach . Geneva, World Health Organization, 2011 (http:// whqlibdoc.who.int/publications/2011/9789241501750_eng.pdf, accessed 15 May 2013). 35. Baeten JM, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. New England Journal of Medicine, 2012, 367 (5):399-410 36. Grant R et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. New England Journal of Medicine, 2010, 363 (27):2587-2599. 37. Thigpen MC, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. New England Journal of Medicine, 2012, 367(5):423-434 38. Choopanya K, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet , 2013, 381 (9883): 2083-2090 G uidance on oral pre-exposure prophylaxis (PrEP) for serodiscordant couples, men and transgender women who have sex 39. with men at high risk of HIV: recommendations for use in the context of demonstration projects . Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75188/1/9789241503884_eng.pdf, accessed 15 May 2013). 40. R esponding to intimate partner violence and sexual violence against women: clinical and policy guidelines . Geneva, World Health Organization, in press. 41. Weller SC, Davis-Beaty K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database of Systematic Reviews , 2009, (1):CD003255. 42. French PP et al. Use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women. Sexually Transmitted Diseases , 2003, 30:433–439. Effectiveness of sterile needle and syringe programming in reducing HIV/AIDS among IDUs . Geneva, World Health 43. Organization, 2004 (www.who.int/hiv/pub/idu/e4a-needle/en/index.html, accessed 15 May 2013). 44. Effectiveness of drug dependence treatment in preventing HIV among injecting drug users . Geneva, World Health Organization, 2003 (www.who.int/entity/hiv/pub/idu/drugdependencefinaldraft.pdf, accessed 15 May 2013). 45. G uidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241547543_eng.pdf, accessed 15 May 2013). 46. Siegfried N et al. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database of Systematic Reviews , 2009, (2):CD003362.

Chapter 6 1. S ervice delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework . Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75206/1/9789241593877_eng.pdf, accessed 15 May 2013). 2. Kranzer K et al. Quantifying and addressing losses along the continuum of care for people living with HIV infection in subSaharan Africa: a systematic review. Journal of the International AIDS Society, 2012, 15:173–183. 3. Faal M et al. Providing immediate CD4 count results at HIV testing improves ART initation. Journal of Acquired Immune Deficiency Syndromes , 2011, 58:e54–e59. 4. Jani IV et al. Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study. Lancet , 2011, 378:1572–1579. E ssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings . Geneva, 5. World Health Organization, 2008 (www.who.int/hiv/pub/prev_care/OMS_EPP_AFF_en.pdf, accessed 15 May 2013). 6. P riority interventions. HIV/AIDS prevention, treatment and care in the health sector. Geneva, World Health Organization, 2010 (http://www.who.int/hiv/pub/guidelines/9789241500234_eng.pdf, accessed 15 May 2013). 7. I MAI district clinician manual: hospital care for adolescents and adults . Geneva, World Health Organization, 2011 (http:// www.who.int/hiv/pub/imai/imai2011/en, accessed 15 May 2013). 8. Gupta A et al. Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis. PLoS One, 2011, 6:e28691. 9. Brinkhof MW et al. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality. PLoS Medicine, 2009, 6:e1000066. 10. Mocroft A et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet , 2007, 370:407–413. 11. Haddow LJ et al. Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa. PLoS One, 2012, 7:e40623. 12. Huis in ‘t Veld D et al. The immune reconstitution inflammatory syndrome related to HIV co-infections: a review. European Journal of Clinical Microbiology and Infectious Diseases , 2012, 31:919–927.

13. References

255

Chapter 7 1. Vitoria M, Vella S, Ford N. Scaling up antiretroviral therapy in resource-limited settings: adapting guidance and meet the challenges. Current Opinion in HIV and AIDS , 2013, 8:12–18. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach . Geneva, 2. World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf, accessed 15 May 2013. 3. Emery S et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. Journal of Infectious Diseases , 2008, 197:1133–1144. 4. Severe P et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. New England Journal of Medicine, 2010, 363:257–265. 5. Badri M et al. Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines. AIDS , 2004, 18:1159–1168. 6. Moha R et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIVinfected adults in west Africa. AIDS , 2007, 21:2483–2491. 7. Wong KH et al. Establishing CD4 thresholds for highly active antiretroviral therapy initiation in a cohort of HIV-infected adult Chinese in Hong Kong. AIDS Patient Care and STDs , 2007, 21:106–115. 8. Sterne JA et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet , 2009, 373:1352–1363. 9. Granich RM et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet , 2009, 373:48–57. G lobal HIV/AIDS response: epidemic update and health sector progress towards universal access: progress report 2011. 10. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502986_eng.pdf, accessed 15 May 2013). 11. U NAIDS report on the global AIDS epidemic 2012. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/ documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_en.pdf, accessed 15 May 2013). 12. Mugglin C et al. Immunodeficiency at the start of ART: global view. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 27 February – 2 March 2012 (http://retroconference.org/2012b/Abstracts/43569.htm, accessed 15 May 2013). 13. Egger M et al. Immunodeficiency at start of combination antiretroviral therapy in low, middle and high income countries. Journal of Acquired Immune Deficiency Syndromes , in press. 14. Lessells RJ et al. Reduction in early mortality on antiretroviral therapy for adults in rural South Africa since change in CD4+ cell count eligibility criteria. Journal of Acquired Immune Deficiency Syndromes , in press. 15. Kowalska JD et al. A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or nonAIDS related: results from the EuroSIDA study. HIV Clinical Trials , 2011, 12:109–117. 16. Moore RD et al. Rate of comorbidities not related to HIV infection or AIDS among HIV-infected patients, by CD4 cell count and HAART use status. Clinical Infectious Diseases , 2008, 47:1102–1104. 17. Baker JV et al. CD4R count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS , 2008, 22:841–848. 18. Cohen MS et al. Prevention of HIV-1 infection with early antiretroviral therapy. New England Journal of Medicine, 2011, 365:493–505. 19. Ahdieh-Grant L et al. When to initiate highly active antiretroviral therapy: a cohort approach. American Journal of Epidemiolog y, 2003, 157:738–746. 20. Althoff K et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS , 2010, 24:2469–2479. 21. Antiretroviral Therapy (ART) Cohort Collaboration. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet , 2003, 362:679–686. 22. Antiretroviral Therapy (ART) Cohort Collaboration. Effect of baseline CD4 cell counts on the clinical significance of shortterm immunologic response to antiretroviral therapy in individuals with virologic suppression. Journal of Acquired Immune Deficiency Syndromes , 2009, 52:357–363. 23. CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Archives of Internal Medicine, 2011, 171:1560–1569. 24. CASCADE Collaboration. Short-term CD4 cell response after highly active antiretroviral therapy initiated at different times from seroconversion in 1500 seroconverters. Journal of Acquired Immune Deficiency Syndromes , 2003, 32:303–310. 25. Cozzi Lepri A et al. When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from ICONA study. AIDS , 2001, 15:983–990. 26. Egger M et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet , 2002, 360:119–129. 27. Garcia F et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. Journal of Acquired Immune Deficiency Syndromes , 2004, 36:702–713. 28. Gras L et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. Journal of Acquired Immune Deficiency Syndromes , 2007, 45:183–192. 29. HIV-CAUSAL Collaboration. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS , 2010, 24:123–137. 30. HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries. Annals of Internal Medicine, 2011, 154:509–515.

13 References

256

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 31. Kitahata M et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. New England Journal of Medicine, 2009, 360:1815–1826. 32. Krishnan S et al. Incidence of non-AIDS-defining cancer in antiretroviral treatment-naïve subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. Oncology, 2011, 80:42–49. 33. Merito M, Pezzotti P. Comparing costs and effectiveness of different starting points for highly active antiretroviral therapy in HIV-positive patients. European Journal of Health Economics , 2006, 7:30–36. 34. Opravil M et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count >350 106/l. AIDS , 2002, 16:1371–1381. 35. Palella F et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Annals of Internal Medicine, 2003, 138:620–626. 36. Phillips A et al. HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load. JAMA , 2001, 286:2560–2567. 37. Plettenberg A et al. Impact of earlier HAART initiation on the immune status and clinical course of treated patients on the basis of cohort data of the German Competence Network for HIV/AIDS. Infection , 2011, 39:3–12. 38. Gallant JE et al. Health outcomes associated with the timing of antiretroviral therapy initiation. 6th IAS Conference on HIV Pathogenesis and Treatment, 17–20 July 2011, Rome, Italy (Abstract CDB320; www.iasociety.org/Abstracts/A200742892. aspx, accessed 15 May 2013). 39. When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet , 2009, 373:1352–1362. 40. Grant P et al. Association of baseline viral load, CD4 count, and week 4 virologic response (VR) with virologic failure (VF) in ACTG Study A5202. 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 5–8 March 2011 (http://retroconference.org/2011/PDFs/535.pdf, accessed 15 May 2013). 41. Suthar AB et al. Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and metaanalysis. PLoS Medicine, 2012, 9:e1001270. 42. Golub JE et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007, 11;21:1441–1448. 43. Badri M et al. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet , 2002, 359:2059–2064. 44. G olub JE et al. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS , 2008, 22:2527–2533. 45. Williams BG et al. Antiretroviral therapy for tuberculosis control in nine African countries. Proceedings of the National Academy of Sciences of the United States of America , 2010, 107:19485–19489. 46. Donnell D et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet , 2011, 375:2092–2098. 47. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989 through 31 July 2012. Wilmington, NC, Registry Coordinating Center, 2012 (www.APRegistry.com, accessed 15 May 2013). 48. Akinbami A et al. CD4 count pattern and demographic distribution of treatment-naive HIV patients in Lagos, Nigeria. AIDS Research and Treatment , 2012, 2012:352753. G uidance on couples HIV testing and counseling including antiretroviral therapy for treatment and prevention in 49. serodiscordant couples: recommendations for a public health approach . Geneva, World Health Organization, 2012 (http:// whqlibdoc.who.int/publications/2012/9789241501972_eng.pdf, accessed 15 May 2013). 50. Abdool Karim SS et al. Integration of antiretroviral therapy with tuberculosis treatment. New England Journal of Medicine, 2011, 365:1492–1501. 51. Havlir DV et al. Timing of antiretroviral therapy for HIV 1 infection and tuberculosis. New England Journal of Medicine, 2011, 365:1482–1491. 52. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine, 2011, 365:1471–1481. 53. Hoffmann CJ et al. Hepatitis B and long-term HIV outcomes in coinfected HAART recipients. AIDS , 2009, 23:1881–1889. 54. Thio CL et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet , 2002, 360:1921–1926. 55. Konopnicki D et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS , 2005, 19:593–601. 56. Puoti M et al. Mortality for liver disease in patients with HIV infection: a cohort study. Journal of Acquired Immune Deficiency Syndromes , 2000, 2:211–217. 57. Weber R et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D: A:D study. Archives of Internal Medicine, 2006, 166:1632–1641. 58. Salmon-Ceron D et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. Journal of Hepatology, 2005, 42:799–805. 59. Nikolopoulos GK et al. Impact of hepatitis B virus infection on the progression of AIDS and mortality in HIV-infected individuals: a cohort study and meta-analysis. Clinical Infectious Diseases , 2009, 48:1763–1771. 60. Martin-Carbonero L et al. Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. AIDS , 2011, 25:73–79. 61. Matthews GV et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology, 2008, 48:1062–1069. 62. Matthews G et al. Combination HBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HIV/HBV coinfected individuals. AIDS , 2009, 23:1707–1715.

13. References 63. Benhamou Y et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology, 1999, 30:1054–1058. 64. Deng LP et al. Impact of human immunodeficiency virus infection on the course of hepatitis C virus infection: a metaanalysis. World Journal of Gastroenterology, 2009, 15:996–1003. 65. Pineda JA et al. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis. Hepatology, 2005, 41:779–789. 66. Thein HH et al. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS , 2008, 22:1979–1991. 67. Castel AD et al. Use of the community viral load as a population-based biomarker of HIV burden. AIDS , 2012, 26:345–353. 68. Cowan SA et al. Stable incidence of HIV diagnoses among Danish MSM despite increased engagement in unsafe sex. Journal of Acquired Immune Deficiency Syndromes . 2012, 61:106–111. 69. Das M et al. Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. PLoS ONE , 2010, 5:e11068. 70. Fang C-T et al. Decreased HIV transmission after a policy of providing free access to highly active antiretroviral therapy in Taiwan. Journal of Infectious Diseases , 2004, 190:879–885. 71. Hogg RS et al. HAART-related decrease in the rate of new HIV diagnoses – a unique trend. 19th Annual Conference on Retroviruses and Opportunistic Infections. Seattle, WA, USA, 5–8 March 2012 (http://retroconference.org/2012b/ Abstracts/42768.htm, accessed 15 May 2013). 72. Geng EH et al. The effect of a “universal antiretroviral therapy” recommendation on HIV RNA levels among HIV-infected patients entering care with a CD4 count greater than 500/μL in a public health setting. Clinical Infectious Diseases , 2012, 55:1690–1697. 73. Katz MH et al. Impact of highly active antiretroviral treatment on HIV seroincidence among men who have sex with men: San Francisco. American Journal of Public Health , 2002, 92:388–394. 74. Law MG et al. Trends in detectable viral load by calendar year in the Australian HIV observational database. Journal of the International AIDS Society, 2011, 14:10. 75. Manavi K et al. Community viral load counts and new HIV-positive patients in Birmingham, United Kingdom, between 2006 and 2011. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract TUPE213; www.iasociety. org/Abstracts/A200747416.aspx, accessed 15 May 2013). 76. Montaner JS et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet , 2010, 376:532–539. 77. Montaner J et al. Expanded HAART coverage is associated with decreased HIV/AIDS morbidity and new HIV diagnoses: an update on the ‘treatment as prevention’ experience in British Columbia, Canada. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract THPE103; www.iasociety.org/Abstracts/A200745196.aspx, accessed 15 May 2013). 78. Porco TC et al. Decline in HIV infectivity following the introduction of highly active antiretroviral therapy. AIDS, 2004, 18:81–88. 79. Wood E et al. Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 among injecting drug users: prospective cohort study. British Medical Journal, 2009, 338:b1649. Strategic timing of antiretroviral treatment (START) . Minneaolis, Clinical and Translational Science Institute, University of 80. Minnesota, 2012 (http://apps.who.int/trialsearch/Trial.aspx?TrialID =EUCTR2008-006439-12-FI, accessed 15 May 2013). 81. E arly antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in HIV-infected adults (ANRS 12136 TEMPRANO). Paris, French National Agency for Research on AIDS and Viral Hepatitis, 2012 (http://apps.who.int/trialsearch/ Trial.aspx?TrialID =NCT00495651, accessed 15 May 2013). 82. A ntiretroviral drugs for treating pregnant women and preventing HIV infections in infants: recommendations for a public health approach. 2010 version . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599818_eng.pdf, accessed 15 May 2013). 83. C ountdown to zero: global plan for the elimination of new HIV infections among children by 2015 and keeping their mothers alive, 2011–2015. Geneva, UNAIDS, 2011 (http://www.unaids.org/en/media/unaids/contentassets/documents/ unaidspublication/2011/20110609_JC2137_Global-Plan-Elimination-HIV-Children_en.pdf, accessed 15 May 2013). 84. Schouten EJ et al. Prevention of mother-to-child transmission of HIV and the health-related Millennnium Development Goals: time for a public health approach. Lancet , 2011, 378:282–284. I ntegrated HIV program report July–September 2012. Lilongwe, Ministry of Public Health, Government of Malawi (http:// 85. www.hivunitmohmw.org/uploads/Main/Quarterly_HIV_Programme_Report_2012_Q3.pdf, accessed 15 May 2013). 86. United States Centers for Disease Control and Prevention. Impact of an innovative approach to prevent mother-to-child transmission of HIV – Malawi, July 2011 –September 2012. MMWR Morbidity and Mortality Weekly Report , 2013, 62:148–151. U se of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: programmatic update. 87. Geneva, World Health Organization, 2012 (http://www.who.int/hiv/pub/mtct/programmatic_update2012/en/index.html, accessed 15 May 2013). 88. Taha TE et al. Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial. Journal of Acquired Immune Deficiency Syndromes , 2011, 57:319–325. 89. The Kesho Bora Study Group. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infectious Diseases , 2011, 11:171–180. 90. Coovadia HM et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomized, double-blind, placebo-controlled trial. Lancet , 2012, 379:221–228. 91. Jamieson DJ et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission (the BAN Study Group). New England Journal of Medicine, 2010, 362:2271–2281.

257

13 References

258

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 92. Jamieson DJ et al. Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial. Lancet , 2012, 379:2449–2458. 93. The Kesho Bora Study Group. Maternal HIV-1 disease progression 18–24 months post delivery according to antiretroviral prophylaxis regimen (triple-antiretroviral prophylaxis during pregnancy and breastfeeding vs zidovudine/single-dose nevirapine prophylaxis): the Kesho Bora randomized controlled trial. Clinical Infectious Diseases , 2012, 55:449–460. 94. Ciaranello AL et al. Cost-effectiveness of World Health Organization 2010 guidelines for prevention of mother-to-child HIV transmission in Zimbabwe. Clinical Infectious Diseases , 2013, 56:430–446. 95. Olufunke Fasawe O et al. Cost-effectiveness analysis of option B+ for HIV prevention and treatment of mothers and children in Malawi. PLoS ONE , 8:e57778. 96. Nachega JB et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and highincome countries: a systematic review and meta-analysis. AIDS , 2012, 26:2039–2052. 97. Ekouevi D et al. Maternal CD4+ cell count decline after interruption of antiretroviral prophylaxis for the prevention of mother-to-child transmission of HIV. PLoS ONE , 2012, 7:e43750. Toolkit – expanding and simplifying treatment for pregnant women living with HIV: managing the transition to option B/ 98. B+. New York, Interagency Task Team on the Prevention and treatment of HIV Infection in Pregnant Women, Mothers and Children, 2013 (www.emtct-iatt.org/toolkit, accessed 15 May 2013). 99. G uidelines on HIV and infant feeding: principles and recommendations for infant feeding in the context of HIV. 2010 version. Geneva, World Health Organization, 2010 (www.who.int/child_adolescent_health/documents/en, accessed 15 May 2013). 100. S chneider S et al. Efavirenz in human breast milk, mothers’, and newborns’ plasma. Journal of Acquired Immune Deficiency Syndromes , 2008, 48:450–454. 101. G ibb DM et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Med , 2012, 9):e1001217. 102. B enaboud S et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d’Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrobial Agents and Chemotherapy, 2011, 55:1315. 103. C outsoudis A et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. Journal of Infectious Diseases , 2004, 189:2154–2166. 104. Kuhn L et al. Potential impact of new WHO criteria for antiretroviral treatment for prevention of mother-to- child HIV transmission. AIDS , 2010, 24:1374–1377. 105. A ntiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach: 2010 revision . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599801_eng.pdf, accessed 15 May 2013). 106. N ewell ML et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet , 2004, 364:1236–1243. 107. D unn D et al. Current CD4 cell count and the short-term risk of AIDS and death before the availability of effective antiretroviral therapy in HIV-infected children and adults. Journal of Infectious Diseases , 2008, 197:398–404. 108. C ross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee. Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. AIDS , 2008, 22:97–105. 109. R aguenaud M et al. Excellent outcomes among HIV+ children on ART, but unacceptably high pre-ART mortality and losses to follow-up: a cohort study from Cambodia. BMC Pediatrics , 2009, 9:54. 110. T he South African antiretroviral treatment guidelines . Pretoria, Republic of South Africa National Department of Health 2013 (www.sahivsoc.org/upload/documents/2013%20ART%20Guidelines-Short%20Combined%20FINAL%20draft%20 guidelines%2014%20March%202013.pdf, accessed 15 May 2013). 111. National guidelines on management of HIV in Rwanda . 4th ed. Kigali, Ministry of Health, 2011. 112. S iegfried N et al. Optimal time for initiating antiretroviral therapy (ART) in HIV-positive, treatment-naive children aged 24 to 59 months (2 to 5 years old). Cochrane Database of Systematic Reviews , in press. 113. P uthanakit T et al. Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial. Lancet Infectious Diseases , 2012, 12:933–941. 114. D avies MA et al. When to start ART in children aged 2-5 years? Causal modeling analysis of IeDEA Southern Africa. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia . 115. P enazzato M et al. Programmatic impact of the evolution of WHO pediatric antiretroviral treatment guidelines for resourcelimited countries 2012. Tukula Fenna Project, Uganda). Journal of Acquired Immune Deficiency Syndromes, 2012, 61:522–525. 116. P enazzato M et al. Paediatric antiretroviral treatment (ART): health care worker perspectives contributing to the WHO 2013 consolidated guidelines development. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia . 117. B arker PM, Mate K. Eliminating mother-to-child HIV transmission will require major improvements in maternal and child health services. Health Affairs , 2012, 31:1489–1497. 118. H ealy SA, Gupta S, Melvin AJ. HIV/HBV coinfection in children and antiviral therapy. Expert Review of Anti-infective Therapy, 2013, 11:251–263. 119. T he Treatment 2.0 framework for action: catalysing the next phase of treatment, care and support . Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501934_eng.pdf, accessed 15 May 2013). 120. D uncombe C et al. Treatment 2.0: catalyzing the next phase of treatment, care and support Current Opinion in HIV and AIDS , 2013, 8:4–11. 121. S hubber Z et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS , 2013, 27:1403-1412. 122. F ord N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and metaanalysis. AIDS , 2011, 25:2301–2304.

13. References 123. Technical update on treatment optimization: pharmacological equivalence and clinical interchangeability between lamivudine and emtricitabine, a review of current literature. Geneva, World Health Organization, 2012 (http://apps.who.int/ iris/bitstream/10665/70936/1/9789241503815_eng.pdf, accessed 15 May 2013). 124. P hanuphak N et al. Nevirapine-associated toxicity in HIV-infected Thai men and women, including pregnant women. HIV Medicine, 2007, 8:357–366. 125. J amisse L et al. Antiretroviral-associated toxicity among HIV-1-seropositive pregnant women in Mozambique receiving nevirapine-based regimens. Journal of Acquired Immune Deficiency Syndromes , 2007, 44:371–376. 126. A aron E et al. Adverse events in a cohort of HIV infected pregnant and non-pregnant women treated with nevirapine versus non-nevirapine antiretroviral medication. PLoS One, 2010, 5:e12617. 127. F ord N et al. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS , 2010, 27:1135–1143. 128. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach . Geneva, World Health Organization, 2006 (www.who.int/hiv/pub/guidelines/artadultguidelines.pdf, accessed 15 May 2013). 129. Z erit – CHMP renewal assessment report, March 2011 (EMA/CHMP/103159/2011) . London, European Medicines Agency (www.ema.europa.eu/docs/en_GB/document_library/EPAR_-Assessment_Report_-_Variation/human/000110/ WC500106749.pdf, accessed 15 May 2013). 130. Fernandez-Fernandez B et al. Tenofovir nephrotoxicity: 2011 update. AIDS Research and Treatment , 2011, 2011:354908. 131. Young J et al. Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or atazanavir. AIDS , 2012, 26:567–575. 132. Sturt AS, Dokubo EK, Sint TT. Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women. Cochrane Database of Systematic Reviews , 2010, (3):CD008440. 133. B era E, Mia R. Safety of nevirapine in HIV-infected pregnant women initiating antiretroviral therapy at higher CD4 counts: a systematic review and meta-analysis. South African Medical Journal, 2012, 102:855–859. 134. F ord N et al. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS , 2013, [Epub ahead of print]. 135. L alllemant M et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. New England Journal of Medicine, 2000, 343:982–991. 136. S ix Week Extended-Dose Nevirapine Study Team et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet , 2008, 372:300–313. 137. Taha TE et al. Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial. Journal of Acquired Immune Deficiency Syndromes , 2011, 57:319–325. R ecommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions 138. to reduce perinatal HIV transmission in the United States . Washington, DC, United States Department of Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012 (http:// aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf, accessed 15 May 2013). 139. E kouevi DK et al. Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS Databases, Abidjan, Côte d’Ivoire. Journal of Acquired Immune Deficiency Syndromes , 2011, 56:183–187. 140. U se of efavirenz during pregnancy: a public health perspective. Technical update on treatment optimization . Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/treatment2/efavirenz/en, accessed 15 May 2013). 141. Nightingale SL. From the Food and Drug Administration. JAMA , 1998, 280:1472. 142. D e Santis M et al. Periconceptional exposure to efavirenz and neural tube defects. Archives of Internal Medicine, 2002, 162:355. 143. B ritish HIV Association. Guidelines for the management of HIV infection in pregnant women 2012. HIV Medicine, 2012, 13(Suppl. 2):87–157. 144. V igano A et al. In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antiviral Therapy, 2011, 16:1259–1266. 145. Siberry GK et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS , 2012, 26:1151–1159. 146. K ilewo C et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. Journal of Acquired Immune Deficiency Syndromes , 2008, 48:315·323. 147. N agot N et al. Lopinavir/ritonavir versus lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174. BMC Infectious Diseases , 2012, 6:246. 148. C oovadia A et al. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA , 2010, 304:1082–1090. 149. K uhn L et al. Pre-treatment drug resistance mutations among HIV+ children <2 years of age who failed or missed PMTCT: Johannesburg, South Africa. 20th Annual Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, USA, 3–6 March 2013 (http://retroconference.org/2013b/Abstracts/46091.htm, accessed 15 May 2013). 150. A rrivé E et al. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. International Journal of Epidemiology, 2007, 36:1009–1021. 151. M usiime V et al. Response to nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-infected children with perinatal exposure to single-dose nevirapine. AIDS Research and Human Retroviruses , 2009, 25:989–996. 152. L ockman S et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. New England Journal of Medicine, 2007, 356:135–147. 153. P alumbo P et al. Antiretroviral treatment for children with peripartum nevirapine exposure. New England Journal of Medicine, 2010, 363:1510–1520.

259

13 References

260

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 154. V iolari A et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. New England Journal of Medicine, 2012, 366:2380–2389. 155. A pollo T et al. World Health Organization HIV drug resistance surveillance in children less than 18 months newly diagnosed with HIV in Zimbabwe. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia. 156. V iolari A. CHER Trial: virological responses achieved in infants with early ART. Eleventh International Congress on Drug Therapy in HIV Infection, Glasgow, United Kingdom, 11–15 November 2012. 157. D onegan KL et al. The prevalence of darunavir-associated mutations in HIV-1-infected children in the UK. Antiviral Therapy, 2012, 17:599–603. 158. P ENPACT-1 (PENTA 9/PACTG 390) Study Team et al. First-line antiretroviral therapy with a protease inhibitor versus nonnucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infectious Diseases , 2011, 11:273–283. 159. F itzgerald F, Penazzato M, Gibb D. Development of antiretroviral resistance in children with HIV in low and middle-income countries. Journal of Infectious Diseases , in press. 160. A chan J et al. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children. New England Journal of Medicine, 2012, 367:2110–2118. 161. Kuhn L et al. Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial. Lancet Infectious Diseases , 2012, 12:521–530. 162. N EVEREST 3 trial. Treatment options for protease inhibitor-exposed children (NEVEREST-III) . Washington, DC, ClinicalTrials. gov, 2013 (Identifier: NCT01146873; www.clinicaltrials.gov/ct2/show/NCT01146873?term=NEVEREST&rank=1, accessed 15 May 2013). 163. A RROW trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet , 2013, doi:pii: S01406736(12)62198-9. 10.1016/S0140-6736(12)62198-9 [Epub ahead of print]. 164. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet , 2002, 359:733–740. 165. P illay D et al. Implications of HIV drug resistance on first and second line therapies in resource-limited settings: recommendations from the Collaborative HIV and Anti-HIV Drug Resistance Network. Antiviral Therapy, in press. 166. C hildren with HIV in Africa – pharmacokinetics and adherence/acceptability of simple antiretroviral regimens (CHAPAS-3) . Kampala, CHAPAS 3 trial, 2013 (www.chapas3trial.org, accessed 15 May 2013). 167. K aletra (lopinavir/ritonavir): label change – serious health problems in premature babies . Washington, DC, United States Food and Drug Administration, 2013 (www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm246167.htm). 168. Tolle M et al. Reverse transcriptase genotypes in pediatric patients failing initial antiretroviral therapy in Gaborone, Botswana. Journal of the International Association of Physicians AIDS Care, 2012, 11:260–268. 169. U se of tenofovir in HIV-infected children and adolescents: a public health perspective – technical update on treatment optimization . Geneva, World Health Organization, 2012 (http://www.who.int/hiv/pub/treatment2/tenofovir/en, accessed 15 May 2013). 170. H azra R et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics , 2005, 116:e846. 171. P urdy J et al. Decreased bone mineral density with off-label use of tenofovir in HIV-infected children and adolescents. Journal of Pediatrics , 2008, 152:582–584. 172. V iread . Washington, DC, United States Food and Drug Administration, 2013 (www.accessdata.fda.gov/scripts/cder/ drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=VIREAD, accessed 15 May 2013). 173. V iread . London, European Medicines Agency, 2013 (http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/ EMEA-000533-PIP01-08-M04/pip_000375.jsp&mid=WC0b01ac058001d129, accessed 15 May 2013). 174. Lyseng-Williamson KA, Reynolds NA, Plosker GL. Tenofovir disoproxil fumarate: a review of its use in the management of HIV infection. Drugs , 2005, 65:413–432. 175. M artin A et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clinical Infectious Diseases , 2009, 49:1591–1601. 176. F itzgerald F, Penazzato M, Gibb D. Development of antiretroviral resistance in children with HIV in low- and middle-income countries. Journal of Infectious Diseases , in press. 177. P uthanakit T et al. Prevalence of human leukocyte antigen-B*5701 among HIV-infected children in Thailand and Cambodia: implications for abacavir use. Pediatric Infectious Diseases , 2013, 32:252–253. 178. Tang MW, Kanki PJ, Shafer RW. A review of the virological efficacy of the 4 World Health Organization–recommended tenofovir-containing regimens for initial HIV therapy. Clinical Infectious Diseases , 2012, 54:862–875. 179. v an Dijk JH et al. Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings. PLoS One, 2013, 8:e55111. 180. M eya D et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cells count <100 cells/μl who start HIV therapy in resource-limited settings. Clinical Infectious Diseases , 2010, 51:448–455. 181. L outfy MR et al. Systematic review of HIV transmission between heterosexual serodiscordant couples where the HIV-positive partner is fully suppressed on antiretroviral therapy. PLoS One, 2013, 8:e55747. 182. R utherford GW et al. Predicting treatment failure (TF) in patients on antiretroviral therapy (ART): a systematic review of the performance characteristics of the 2010 World Health Organization (WHO) immunologic and clinical criteria for virologic failure. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia .

13. References 183. O rrell C et al. Conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. Antiviral Therapy, 2007, 12:83–88. 184. M ermin J et al. Utility of routine viral load, CD4 cell count, and clinical monitoring among adults with HIV receiving antiretroviral therapy in Uganda: randomised trial. BMJ , 2011, 343:d6792. 185. J ourdain G et al. PHPT-3: a randomized clinical trial comparing CD4 vs viral load ART monitoring/switching strategies in Thailand. 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 5–8 March 2011 (http:// retroconference.org/2011/Abstracts/41399.htm, accessed 15 May 2013). 186. S aag MS et al. A cluster randomized trial of routine vs discretionary viral load monitoring among adults starting ART: Zambia. 19th Annual Conference on Retroviruses and Opportunistic Infections. Seattle, WA, USA, 5–8 March 2012 (http:// retroconference.org/2012b/Abstracts/44483.htm, accessed 15 May 2013). 187. K eiser O et al. Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy. Tropical Medicine and International Health , 2009, 14:1220–1225. 188. A bouyannis M et al. Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa. AIDS , 2011, 25:1627–1635. 189. C haiwarith R et al. Sensitivity and specificity of using CD4+ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. International Journal of Infectious Diseases , 2007, 11:413–416. 190. H osseinipour M et al. Validating clinical and immunological definitions of antiretroviral treatment failure in Malawi. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22–25 July 2007 (Abstract WEAB101; www. iasociety.org/Abstracts/A200701701.aspx, accessed 15 May 2013 191. K antor R et al. Misclassification of first-line antiretroviral treatment failure based on immunological monitoring of HIV infection in resource-limited settings. Clinical Infectious Diseases , 2009, 49:454–462. 192. L abhardt ND et al. A clinical prediction score in addition to WHO criteria for anti-retroviral treatment failure in resourcelimited settings - expeirence from Lesotho. PLoS ONE , 2012, 7:e47937. 193. M ee P et al. Evaluation of World Health Organization criteria for antiretroviral treatment failure in resource-limited settings. XVI International AIDS Conference, Toronto, Canada, 13–18 August 2006 (Abstract WEPE065; www.iasociety.org/Abstracts/ A2191232.aspx, accessed 15 May 2013). 194. M ee P et al. Evaluation of WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS , 2008, 22:1971–1977. 195. M eya D et al. Development and evaluation of a clinical algorithm to monitor patients on antiretrovirals in resource-limited settings using adherence, clinical and CD4 cell count criteria. Journal of the International AIDS Society, 2009, 12:3. 196. M oore DM et al. CD4+ T-cell count monitoring does not accurately identify HIV-infected adults with virologic failure receiving antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes , 2008, 49:477–484. 197. R awizza H et al. Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings. Clinical Infectious Diseases , 2011, 53:1283–1290. 198. R ewari BB. Evaluating patients for second-line antiretroviral therapy in India: the role of targeted viral load testing. Journal of Acquired Immune Deficiency Syndromes , 2010, 55:610–614. 199. R eynolds SJ et al. Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda. AIDS , 2009, 23:697–700. 200. v an Oosterhout JJ et al. Diagnosis of antiretroviral therapy failure in Malawi: poor performance of clinical and immunological WHO criteria. Tropical Medicine and International Health , 2009, 14:856–861. 201. B arlow-Mosha L et al. Validation of WHO 2010 immunologic criteria in predicting pediatric first-line antiretroviral treatment (ART) failure in ART-experienced children in Uganda: CD4 is a poor surrogate for virologic monitoring of pediatric ART failure. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract THPE062; http://www.iasociety. org/Abstracts/A200744978.aspx, accessed 15 May 2013). 202. D avies M-A, Boulle A, Eley B, et al. Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy – the IeDEA Southern Africa Collaboration. Tropical Medicine and International Health , 2011, 16:1367–1371. 203. D avies M-A et al. The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure. Tropical Medicine and International Health , 2012, doi: 10.1111/j.1365-3156.2012.03073.x [Epub ahead of print]. 204. W estley BP et al. Prediction of treatment failures using 2010 World Health Organization guidelines is associated with high misclassification rate and drug resistance among HIV-infected Cambodian children. Clinical Infectious Diseases , 2012, 55:432–440. 205. L aurent C et al. Monitoring of HIV viral loads, CD4 cell counts, and clinical assessments versus clinical monitoring alone for antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER): a randomised non-inferiority trial. Lancet Infectious Diseases , 2011, 11:825–833. 206. M ugyenyi P et al. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet , 2010, 375:123–131. 207. H avlir DV et al. Prevalence and predictive value of intermittent viremia with combination HIV therapy. JAMA , 2001, 286:171–179. 208. M ocroft A et al. Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/µl? Clinical Infectious Diseases , 2010, 51:611–619. 209. G ale HB et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts ≥ 300 cells/μl and HIV-1 suppression? Clinical Infectious Diseases , in press. 210. J ohannessen A et al. Dried blood spots perform well in viral load monitoring of patients who receive antiretroviral treatment in rural Tanzania. Clinical Infectious Diseases , 2009, 49:976–981.

261

13 References

262

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 211. G arrido C et al. Correlation between human immunodeficiency virus type 1 (HIV-1) RNA measurements obtained with dried blood spots and those obtained with plasma by use of Nuclisens EasyQ HIV-1 and real time HIV load tests. Journal of Clinical Microbiology, 2009, 47:1031–1036. 212. M onleau M et al. Evaluation of different RNA extraction methods and storage conditions of dried plasma or blood spots for human immunodeficiency virus type 1 RNA quantification and PCR amplification for drug resistance testing. Journal of Clinical Microbiology, 2009, 47:1107–1118. 213. S teinmetzer K et al. HIV load testing with small samples of whole blood. Journal of Clinical Microbiology, 2010, 48(8): 2786–2792. 214. V iljoen J et al. Dried blood spot HIV-1 RNA quantification using open real-time systems in South Africa and Burkina Faso. Journal of Acquired Immune Deficiency Syndromes , 2010, 55:290–298. 215. B onjoch A et al. High rate of reversibility of renal damage in a cohort of HIV-infected patients receiving tenofovir-containing antiretroviral therapy. Antiviral Research , 2012, 96:65–69. Treatment of tuberculosis: guidelines for national programmes . 4th ed. Geneva, World Health Organization, 2010 (http:// 216. whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf, accessed 15 May 2013). 217. G uidelines for the treatment of malaria . 2nd ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547925_eng.pdf, accessed 15 May 2013). 218. G uidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241547543_eng.pdf, accessed 15 May 2013). 219. M edical eligibility criteria for contraceptive use. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241563888_eng.pdf, accessed 15 May 2013). 220. P ackage of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241598996_eng.pdf, accessed 15 May 2013). 221. J ohnson M et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS , 2006, 20:711–718. 222. A rasteh K et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antiviral Therapy, 2009, 14:859–864. 223. B anhegyi D et al. Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN. Current HIV Research , 2012, 10:171–181. 224. M olina JM et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. Journal of Acquired Immune Deficiency Syndromes , 2010, 53:323–332. 225. J osephson F et al. The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naive HIV-1 infected patients. European Journal of Clinical Pharmacology, 2010, 66:349–357. 226. O rkin C et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1infected treatment-naive patients in the ARTEMIS trial. HIV Medicine, 2012, doi: 10.1111/j.1468-1293.2012.01060.x. 227. A costa EP et al. Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily. Antimicrobial Agents and Chemotherapy, 2007, 51:3104–3110. 228. B urger DM et al. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrobial Agents and Chemotherapy, 2006, 50:3336–3342. 229. J ustesen US et al. Pharmacokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir in HIV-infected patients. Clinical Infectious Diseases , 2004, 38:426–429. 230. L aPorte C et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrobial Agents and Chemotherapy, 2004, 48:1553–1560. 231. D ecloedt EH et al. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavirritonavir tablets. Antimicrobial Agents and Chemotherapy, 2011, 55:3195–3200. A trial of 2 options for second line combination antiretroviral therapy following virological failure of a standard non232. nucleoside reverse transcriptase inhibitor (NNRTI)+2N(t)RTI first line regimen SECOND-LINE . Darlinghurst, Kirby Institute, 2012 (http://apps.who.int/trialsearch/Trial.aspx?TrialID =NCT00931463, accessed 15 May 2013). 233. S tudy of Options for Second-Line Effective Combination Therapy (SELECT) SELECT. AIDS Clinical Trials Group, 2013 (http:// apps.who.int/trialsearch/Trial.aspx?TrialID =NCT01352715, accessed 15 May 2013). 234. E valuation of three strategies of second-line antiretroviral treatment in Africa (Dakar – Bobo-Dioulasso – Yaoundé) 2LADY. Paris, French National Agency for Research on AIDS and Viral Hepatitis, 2012 (http://apps.who.int/trialsearch/Trial. aspx?TrialID =NCT00928187, accessed 15 May 2013). 235. A multicentre trial of second-line antiretroviral treatment strategies in African adults using atazanavir or lopinavir/ritonavir ALISA . Paris, French National Agency for Research on AIDS and Viral Hepatitis, 2013 (http://apps.who.int/trialsearch/Trial. aspx?TrialID =NCT01255371, accessed 15 May 2013). 236. E urope–Africa Research Network for Evaluation of Second-line Therapy EARNEST. London, United Kingdom Medical Research Council, 2013 (http://apps.who.int/trialsearch/Trial.aspx?TrialID =ISRCTN37737787, accessed 15 May 2013). 237. Taylor BS et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Research and Human Retroviruses , 2011, 27:945–956. 238. Z anoni B et al. Predictors of poor CD4 and weight recovery in HIV-infected children initiating ART in South Africa. PLOS ONE , 2012, 7:e33611. 239. O rrell C et al. Resistance in pediatric patients experiencing virologic failure with first- and second-line antiretroviral therapy. Pediatric Infectious Diseases Journal, in press [Epub ahead of print]. 240. van Zyl GU et al. Protease inhibitor resistance in South African children with virologic failure. Pediatric Infectious Diseases Journal, 2009, 28:1125–1127.

13. References 241. K ing JR et al. Antiretroviral pharmacokinetics in the paediatric population: a review. Clinical Pharmacokinetics , 2002, 41:1115–1133. 242. KONCERT A Kaletra ONCE Daily Randomised Trial of the Pharmacokinetics, Safety and Efficacy of Twice-daily Versus Oncedaily Lopinavir/Ritonavir Tablets Dosed by Weight as Part of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-1 (HIV-1) Infected Children (PENTA 18). Identifier: NCT01196195. Bethesda, MD, www.clinicaltrials.gov, 2012 (http:// clinicaltrials.gov/ct2/show/NCT01196195?term=penta+18&rank=1, accessed 15 May 2013). 243. B akeera-Kitaka S et al. Pharmacokinetics and acceptability of a new generic lopinavir/ritonavir sprinkle formulation in African, HIV+ children 1–4 years: CHAPAS-2. 20th Annual Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, USA, 3–6 March 2013 (http://retroconference.org/2013b/Abstracts/47964.htm, accessed 15 May 2013). 244. G otte M et al. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. Journal of Virology, 2000, 74:3579–3585. 245. A jose O et al. Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. AIDS , 2012, 26:929–938. 246. G atell JM et al. Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study. Journal of Acquired Immune Deficiency Syndromes , 2010, 53:456–463. 247. Steigbigel RT et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatmentexperienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clinical Infectious Diseases , 2010, 50:605–612. 248. K atlama C et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antiviral Therapy, 2010, 15:1045–1052. 249. I maz A et al. Efficacy and safety of nucleoside reverse transcriptase inhibitor-sparing salvage therapy for multidrug-resistant HIV-1 infection based on new-class and new-generation antiretrovirals. Journal of Antimicrobial Chemotherapy, 2011, 66:358–362. 250. Fagard C et al. Long-term efficacy and safety of raltegravir, etravirine, and darunavir/ritonavir in treatment-experienced patients: week 96 results from the ANRS 139 TRIO trial. Journal of Acquired Immune Deficiency Syndromes , 2012, 59:489–493. 251. E travirine full prescribing information . Titusville, NJ, Janssen Products, 2008 (www.intelence.com/shared/product/intelence/ prescribing-information.pdf, accessed 15 May 2013).

263

13 References

Chapter 8 1. G uidelines on co-trimoxazole prophylaxis for HIV-related infection among children, adolescents and adults: recommendations for a public health approach . Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/ plhiv/ctx/en, accessed 15 May 2013). 2. W HO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders . Geneva, World Health Organization, 2012 (http://www.who.int/tb/publications/2012/tb_hiv_policy_9789241503006/en) 3. W HO policy on TB infection control in health-care facilities, congregate settings and households . Geneva, World Health Organization, 2009 (http://www.who.int/tb/publications/2009/9789241598323/en, accessed 15 May 2013). 4. G uidelines for the programmatic management of drug-resistant tuberculosis . Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf, accessed 15 May 2013). 5. Childhood tuberculosis guidelines . Geneva, World Health Organization, forthcoming (expected 2013). G lobal tuberculosis report 2012. Geneva, World Health Organization, 2012 (www.who.int/iris/ 6. bitstream/10665/75938/1/9789241564502_eng.pdf, accessed 15 May 2013). 7. Zignol M, Falzon D, Getahun H. HIV infection and multidrug-resistant tb: 2 overlapping epidemics. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, Georgia, USA, 3–6 March 2013 (www.retroconference.org/2013b/ Abstracts/46973.htm, accessed 15 May 2013). 8. R apid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children . Geneva, World Health Organization, 2011 (http://www.who.int/hiv/pub/cryptococcal_disease2011, accessed 15 May 2013). 9. Mathers BM et al. Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. Lancet , 2008, 372:1733–1745. 10. Easterbrook P, Sands A, Harmanci H. Challenges and priorities in the management of HIV/HBV and HIV/HCV coinfection in resource-limited settings. Seminars in Liver Disease, 2012, 32:147–157. E ssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings . Geneva, 11. World Health Organization, 2008 (http://www.who.int/hiv/pub/prev_care/OMS_EPP_AFF_en.pdf) 12. Muronya W et al. Cardiovascular risk factors in adult Malawians on long-term antiretroviral therapy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2011, 105:644–649. N utrient requirements for people living with HIV/AIDS: report of a technical consultation, 13–15 May 2003, Geneva, 13. Switzerland. Geneva, World Health Organization, 2003 (http://www.who.int/nutrition/publications/hivaids/9241591196/en, accessed 15 May 2013). 14. E xecutive summary of a scientific review – Consultation on Nutrition and HIV/AIDS in Africa: evidence, lesson and recommendations for action, Durban, South Africa, 10–13 April 2005. Geneva, World Health Organization, 2005 (www.who. int/nutrition/topics/Executive_Summary_Durban.pdf, accessed 15 May 2013). 15. E xecutive summary of a scientific review – Consultation on Nutrition and HIV/AIDS in Africa: evidence, lesson and recommendations for action, Durban, South Africa, 10–13 April 2005. Geneva, World Health Organization, 2005 (http:// www.who.int/nutrition/topics/Executive_Summary_Durban.pdf, accessed 15 May 2013).

264

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 16. N utrition counselling, care and support for HIV-infected women. Geneva, World Health Organization, 2005 (www.who.int/ nutrition/topics/consultation_nutrition_and_hivaids.en, accessed 15 May 2013). 17. Participants’ Statement – Consultation on Nutrition and HIV/AIDS in Africa: evidence, lesson and recommendations for action, Durban, South Africa, 10–13 April 2005. Geneva, World Health Organization, 2005 (www.who.int/nutrition/topics/ consultation_nutrition_and_hivaids.en, accessed 15 May 2013). 18. Paton NI et al. The impact of malnutrition on survival and the CD4 count response in HIV-infected patients starting antiretroviral therapy. HIV Medicine, 2006, 7:323–330. 19. van der Sande MA et al. Body mass index at time of HIV diagnosis: a strong and independent predictor of survival. Journal of Acquired Immune Deficiency Syndromes, 2004, 37:1288–1294. 20. WHO Multicentre Growth Reference Study Group. WHO child growth standards: methods and development. Length/ height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Geneva, World Health Organization, 2006 (www.who.int/childgrowth/standards/technical_report/en, accessed 15 May 2013).

Chapter 9 A dherence to long-term therapies: evidence for action . Geneva, World Health Organization, 2003 (www.who.int/entity/chp/ knowledge/publications/adherence_full_report.pdf, accessed 15 May 2013). 2. Mills EJ et al. Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Medicine, 2006, 3:2039. 3. Martin S et al. Patient, caregiver and regimen characteristics associated with adherence to highly active antiretroviral therapy among HIV-infected children and adolescents. Paediatric Infectious Disease Journal, 2007, 26:61–67. 4. Reddington C et al. Adherence to medication regimens among children with human immunodeficiency virus infection. Paediatric Infectious Disease Journal, 2000, 19:1148–1153. 5. Murphy DA et al. Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA. AIDS Care, 2001, 13:27–40. 6. Dowshen N, D’Angelo L. Health care transition for youth living with HIV/AIDS. Paediatrics , 2011, 128:762–771. 7. Murphy DA et al. Barriers to HAART adherence among human immunodeficiency virus-infected adolescents. Archives of Paediatrics and Adolescent Medicine, 2003, 157:249–255. 8. Duff P et al. Barriers to accessing highly active antiretroviral therapy by HIV-positive women attending an antenatal clinic in a regional hospital in western Uganda. Journal of the International AIDS Society, 2010, 13:37. 9. Nachega JB et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and highincome countries: a systematic review and meta-analysis. AIDS , 2012, 26:2039–2052. 10. Nakimuli-Mpungu E et al. Depression, alcohol use and adherence to antiretroviral therapy in sub-saharan Africa: a systematic review. AIDS and Behavior, 2012, 16:2101–2118. 11. Gonzalez JS et al. Depression and HIV/AIDS treatment non-adherence: a review and meta-analysis. Journal of Acquired Immune Deficiency Syndromes , 2011, 58:181–187. 12. Bottonari KA et al. Correlates of antiretroviral and antidepressant adherence among depressed HIV-infected patients. AIDS Patient Care and STDs , 2012, 26:265–273. 13. Springer SA, Dushaj A, Azar MM. The impact of DSM-IV mental disorders on adherence to combination antiretroviral therapy among adult persons living with HIV/AIDS: a systematic review. AIDS and Behavior, 2012, 16:2119–2143. 14. Altice FL et al. HIV treatment outcomes among HIV-infected, opioid-dependent patients receiving buprenorphine/ naloxone treatment within HIV clinical care settings: results from a multisite study. Journal of Acquired Immune Deficiency Syndrome s, 2011, 56(Suppl. 1):S22–S32. 15. Roux P et al. The impact of methadone or buprenorphine treatment and ongoing injection on highly active antiretroviral therapy (HAART) adherence: evidence from the MANIF2000 cohort study. Addiction , 2008;103:1828–1836. 16. Malta M et al. Adherence to antiretroviral therapy among HIV-infected drug users: a meta-analysis. AIDS and Behavior, 2010, 14:731–747. 17. Rich JD et al. HIV-related research in correctional populations: now is the time. Current HIV/AIDS Reports , 2011, 8:288–296. 18. Bärnighausen T et al. Interventions to increase antiretroviral adherence in sub-Saharan Africa: a systematic review of evaluation studies. Lancet Infectious Diseases, 2011, 11:942–951. 19. Chung MH et al. A randomized controlled trial comparing the effects of counselling and alarm device on HAART adherence and virologic outcomes. PLoS Medicine, 2011, 8:e1000422. 20. Rueda S et al. Patient support and education for promoting adherence to highly active antiretroviral therapy for HIV/AIDS. Cochrane Database of Systematic Reviews , 2006, (3):CD001442. 21. Altice FL et al. Trust and the acceptance of and adherence to antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes , 2001, 28:47–58. 22. Decroo T et al. Distribution of antiretroviral treatment through self-forming groups of patients in Tete Province, Mozambique. Journal of Acquired Immune Deficiency Syndromes , 2011, 56:e39–e44. 23. Bupamba et al. (2010). Ambassadors for adherence: provision of highly effective defaulter tracing and re-engagement by peer educators in Tanzania. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract MOAE0303; www.iasociety.org/Abstracts/A200739059.aspx, accessed 15 May 2015). 24. Lucas GM et al. Directly administered antiretroviral therapy in methadone clinics is associated with improved HIV treatment outcomes, compared with outcomes among concurrent comparison groups. Clinical Infectious Diseases , 2006, 42:1628– 1635. 25. Pyne JM et al. Effectiveness of collaborative care for depression in human immunodeficiency virus clinics. Archives of Internal Medicine, 2011, 171:23–31. 1.

13. References 26. Cantrell RA et al. A pilot study of food supplementation to improve adherence to antiretroviral therapy among food-insecure adults in Lusaka, Zambia. Journal of Acquired Immune Deficiency Syndromes , 2008, 49:190–195. 27. Muñoz M et al. Community-based DOT-HAART accompaniment in an urban resource-poor setting. AIDS and Behavior, 2010, 14:721–730. 28. m Health: new horizons for health through mobile technologies, based on the findings of the second global survey on eHealth . Geneva, World Health Organization, 2011 (www.who.int/goe/publications/goe_mhealth_web.pdf, accessed 15 May 2013). 29. Haberer JE et al. Challenges in using mobile phones for collection of antiretroviral therapy adherence data in a resourcelimited setting. AIDS and Behavior, 2010, 14:1294–1301. 30. Sidney K et al. Supporting patient adherence to antiretrovirals using mobile phone reminders: patient responses from South India. AIDS Care, 2012, 24:612–617. 31. Lester RT et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet , 2010, 376:1838–1845. 32. Ikeda JM et al. SMS messaging improves treatment outcome among the HIV-positive Mayan population in rural Guatemala. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract TUPE673; www.iasociety.org/ Abstracts/A200745374.aspx, accessed 15 May 2013). 33. Pop-Eleches C et al. Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS , 2011, 25:825–834. 34. Curioso W et al. Evaluation of a computer-based system using cell phones for HIV-infected people in Peru . PhD dissertation. Seattle, University of Washington, 2012. 35. Ammassari A et al. Timed short messaging service improves adherence and virological outcomes in HIV-1-infected patients with suboptimal adherence to antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes , 2011, 58:e113–e115. 36. da Costa TM et al. Results of a randomized controlled trial to assess the effects of a mobile SMS-based intervention on treatment adherence in HIV/AIDS-infected Brazilian women and impressions and satisfaction with respect to incoming messages. International Journal of Medical Informatics , 2012, 81:257–269. 37. Mbuagbaw L et al. The Cameroon Mobile Phone SMS (CAMPS) trial: a randomized trial of text messaging versus usual care for adherence to antiretroviral therapy. PLoS One, 2012, 7:e46909. 38. Dowshen N et al. Improving adherence to antiretroviral therapy for youth living with HIV/AIDS: a pilot study using personalized, interactive, daily text message reminders. Journal of Medical Internet Research , 2012, 14:e51. 39. Uzma Q et al. Efficacy of interventions for improving antiretroviral therapy adherence in HIV/AIDS cases at PIMS, Islamabad. Journal of the International Association of Physicians in AIDS Care (Chicago), 2011, 10:373–383. 40. Wamalwa DC et al. Medication diaries do not improve outcomes with highly active antiretroviral therapy in Kenyan children: a randomized clinical trial. Journal of the International AIDS Society, 2009, 12:8. 41. Mugusi F et al. Enhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries; the Tanzanian experience. Tropical Medicine and International Health , 2009, 14:1226–1232. 42. Bisson GP et al. Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy. PLoS Medicine, 2008, 5:e109. 43. Ndubuka NO et al. Adult patients’ adherence to anti-retroviral treatment: a survey correlating pharmacy refill records and pill counts with immunological and virological indices. International Journal of Nursing Studies , 2011, 48:1323–1329. 44. McMahon J et al. Pharmacy adherence measures to assess adherence to antiretroviral therapy: review of the literature and implications for treatment monitoring. Clinical Infectious Diseases , 2011, 52:493–506. 45. Minzi OM, Naazneen AS. Validation of self-report and hospital pill count using unannounced home pill count as methods for determination of adherence to antiretroviral therapy. Tanzania Journal of Health Research , 2008, 10:84–88. 46. Kalichman SC et al. Adherence to antiretroviral therapy assessed by unannounced pill counts conducted by telephone. Journal of General Internal Medicine, 2007, 22:1003–1006. 47. Zolopa A et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One, 2009, 4:e5575. 48. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine, 2011, 365:1471–1481. 49. Fox MP, Rosen S Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007–2009: systematic review. Tropical Medicine and International Health, 2010, 15(Suppl. 1):1–16. 50. Mugglin C et al. Loss to programme between HIV diagnosis and initiation of antiretroviral therapy in sub-Saharan Africa: systematic review and meta-analysis. Tropical Medicine and International Health , 2012, doi: 10.1111/j.13653156.2012.03089.x. 51. Brinkhof MW et al. Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis. PLoS One, 2009, 4:e5790. 52. Kranzer K et al. Quantifying and addressing losses along the continuum of care for people living with HIV infection in subSaharan Africa: a systematic review. Journal of the International AIDS Society, 2012, 15:173–183. 53. WHO, UNAIDS and UNICEF. Progress report 2011: global HIV/AIDS response. Epidemic uptake and health sector progress towards universal access . Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/progress_report2011/en/index. html, accessed 15 May 2013). 54. Sprague C et al. Health system weaknesses constrains access to PMTCT and maternal HIV services in South Africa: a qualitative enquiry. AIDS Research and Therapy, 2011, 8:10. 55. Bwirire LD et al. Reasons for loss to follow-up among mothers registered in a prevention-of-mother-to-child transmission program in rural Malawi. Transactions of the Royal Soceity of Tropical Medicine and Hygiene, 2008, 102:1195–1200. 56. Duff P et al. Barriers to accessing highly active antiretroviral therapy by HIV-positive women attending an antenatal clinic in a regional hospital in western Uganda. Journal of the International AIDS Society, 2010, 13:37.

265

13 References

266

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 57. Muchedzi A et al. Factors associated with access to HIV care and treatment in a prevention of mother to child transmission programme in urban Zimbabwe. Journal of the International AIDS Society, 2010, 13: 38. 58. Wanyenze RK et al. Evaluation of the efficiency of patient flow at three HIV clinics in Uganda. AIDS Patient Care and STDs , 2010, 24:441–446. 59. Were MC et al. Patterns of care in two HIV continuity clinics in Uganda, Africa: a time-motion study. AIDS Care, 2008, 20:677–682. 60. Mahomed H, Bachmann MO. Block appointments in an overloaded South African health centre: quantitative and qualitative evaluation. International Journal of Health Care Quality Assurance, 1998, 11:123–126. 61. Kohler P et al. Free co-trimoxazole prophylaxis substantially improves clinic retention among ART-ineligible clients in Kenya. AIDS , 2011, 25:1657–1661. 62. Nwuba et al. A laboratory-based approach to reduce loss to follow-up of HIV-positive clients. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract WEAE0202; www.iasociety.org/Abstracts/A200745121.aspx, accessed 15 May 2015). 63. I nnovative care for chronic conditions: building blocks for action . Geneva, World Health Organization, 2002 (www.who.int/ chp/knowledge/publications/icccreport/en, accessed 15 May 2013). 64. G uidance on provider-initiated HIV testing and counselling in health facilities . Geneva, World Health Organization, 2007 (http://whqlibdoc.who.int/publications/2007/9789241595568_eng.pdf, accessed 15 May 2013). 65. Killam WP et al. Antiretroviral therapy in antenatal care to increase treatment initiation in HIV-infected pregnant women: a stepped-wedge evaluation. AIDS , 2010, 24:85–91. 66. Ong’ech JO et al. Provision of services and care for HIV-exposed infants: a comparison of maternal and child health (MCH) clinic and HIV comprehensive care clinic (CCC) models. Journal of Acquired Immune Deficiency Syndromes , 2012, 61:83–89. 67. Turan J et al. Effects of antenatal care–HIV service integration on the prevention of mother-to-child transmission cascade: results from a cluster-randomized controlled trial in Kenya. Integration for Impact: Reproductive Health & HIV Services in sub-Saharan Africa, Nairobi, Kenya, 12–14 September 2012 (http://integrationforimpact.org/abstract-presentationsseptember-1-2012, accessed 15 May 2013). 68. Washington S et al. The impact of integration of HIV care and treatment into antenatal care clinics on mother-to-child HIV transmission and maternal outcomes in Nyanza, Kenya: results from a cluster randomized trial. Integration for Impact: Reproductive Health & HIV Services in sub-Saharan Africa, Nairobi, Kenya, 12–14 September 2012 (http:// integrationforimpact.org/abstract-presentations-september-1-2012, accessed 15 May 2013). 69. Vo BN et al. Patient satisfaction with integrated HIV and antenatal care services in rural Kenya. AIDS Care, 2012, 24:1442– 1447. 70. Tsague L et al. Comparing two service delivery models for the prevention of mother-to-child transmission (PMTCT) of HIV during transition from single-dose nevirapine to multi-drug antiretroviral regimens. BMC Public Health , 2010, 10:753. 71. Winestone LE et al. Acceptability and feasibility of integration of HIV care services into antenatal clinics in rural Kenya: a qualitative provider interview study. Global Public Health , 2012, 7:149–163. G lobal tuberculosis report 2012. Geneva, World Health Organization, 2012 (www.who.int/iris/ 72. bitstream/10665/75938/1/9789241564502_eng.pdf, accessed 15 May 2013). 73. Havlir DV et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. New England Journal of Medicine, 2011, 365:1482–1491. 74. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine, 2011, 365:1471–1481. 75. Suthar AB et al. Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis. Bulletin of the World Health Organization, 2012, 90:128C–138C. 76. Bento C et al. Assessment of the effectiveness of a home-based care program for patients coinfected with tuberculosis and human immunodeficiency virus after discharge from a reference hospital in South-Eastern Brazil. Brazilian Journal of Infectious Diseases , 2010, 14:594–600. 77. Cerda R et al. Health care utilization and costs of a support program for patients living with the human immunodeficiency virus and tuberculosis in Peru. International Journal of Tuberculosis and Lung Diseases , 2011, 15:363–368. 78. Hermans SM et al. Integration of HIV and TB services results in improved TB treatment outcomes and earlier prioritized ART initiation in a large urban HIV clinic in Uganda. Journal of Acquired Immune Deficiency Syndromes , 2012, 60:e29–e35. 79. Howard A et al. PEPFAR support for the scaling up of collaborative TB/HIV activities. Journal of Acquired Immune Deficiency Syndromes , 2012, 60:S136–S144. 80. Huerga H et al. Impact of introducing human immunodeficiency virus testing, treatment and care in a tuberculosis clinic in rural Kenya. International Journal of Tuberculosis and Lung Diseases , 2010, 14:611–615. 81. Kerschberger B et al. The effect of complete integration of HIV and TB services on time to initiation of antiretroviral therapy: a before-after study. PLoS One, 2012, 7:e46988. 82. Lawn SD et al. Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical services in a South African township. BMC Infectious Diseases , 2011, 11:258. 83. Louwagie G et al. Missed opportunities for accessing HIV care among Tshwane tuberculosis patients under different models of care. International Journal of Tuberculosis and Lung Diseases , 2012, 16:1052–1058. 84. Pevzner E et al. Evaluation of the rapid scale-up of collaborative TB/HIV activities in TB facilities in Rwanda, 2005–2009. BMC Public Health , 2011, 11:550. 85. Phiri S et al. Integrated tuberculosis and HIV care in a resource-limited setting: experience from the Martin Preuss centre, Malawi. Tropical Medicine and International Health , 2011, 16:1397–1403. 86. Bygrave H et al. TB/HIV integration: lessons learned from implementation of a TB/HIV “one stop shop” at primary health care clinics in rural Lesotho. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract MOAB0301; www. iasociety.org/Abstracts/A200740348.aspx, accessed 15 May 2015). 87. Chifundo K et al. What is the best model of TB/HIV service delivery? Experience from Malawi. XVIII International AIDS

13. References

267

Conference, Vienna Austria, 18–23 July 2010 (Abstract MOPE0858; www.iasociety.org/Abstracts/A200740018.aspx, accessed 15 May 2015). 88. Dube C et al. Step forward to health system strengthening: the impact of scaling up of ART services on TB services in rural settings, Zambia. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract THAE0104; http://www. iasociety.org/Abstracts/A200737901.aspx, accessed 15 May 2015). 89. Howard AA et al. On-site location of TB services is associated with TB screening of HIV-infected patients at enrollment in HIV care programs in 6 sub-Saharan African countries. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 8–11 February 2009 (Abstract 590; http://retroconference.org/2009/Abstracts/36106.htm, accessed 15 May 2013). 90. Ikeda J et al. HIV and TB and integration reduces mortality among the indigenous population in rural Guatemala. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract MOPE643; www.iasociety.org/Abstracts/ A200744285.aspx, accessed 15 May 2015). 91. Kaplan R et al. Provision of ART in TB facilities in Cape Town South Africa: impact on TB treatment outcomes. 43rd Union World Conference on Lung Health, Kuala Lumpur, Malaysia, 13–17 November 2012 (Abstract OP-147-16). 92. Morse J et al. Integrated TB/ART clinics in Lusaka, Zambia: an evaluation of enrollment into HIV care and early initiation of antiretroviral therapy in TB/HIV co-infected patients. 43rd Union World Conference on Lung Health, Kuala Lumpur, Malaysia, 13–17 November 2012 (Abstract PC-545-17). 93. Mugo P et al. Integrating TB and HIV care services: experience from a rural district hospital in Kenya. 40th Union World Conference on Lung Health, Cancun, Mexico, 3–7 December 2009 (Abstract PS-94524-07). 94. Muvuma S et al. Poor linkages between TB and HIV services affects the quality of care; a retrospective cohort study of TB/ HIV patients from HIV testing to ART initiation in a rural setting in Zambia. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract MOPE644; www.iasociety.org/Abstracts/A200744841.aspx, accessed 15 May 2013). 95. Odhiambo J et al. Models of TB-HIV integration and accomplishments in Nyanza Province, Kenya. 43rd Union World Conference on Lung Health, Kuala Lumpur, Malaysia, 13–17 November 2012 (Abstract PC-542-17). 96. Schwartz A et al. Outcomes among HIV+ adults with active pulmonary TB treated in clinics with and without on-site HIV clinics – a retrospective cohort study: Botswana. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 5–8 March 2012 (Abstract 928; http://retroconference.org/2012b/Abstracts/43189.htm, accessed 15 May 2013). 2012 World AIDS Day report: results . Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/ 97. epidemiology/2012/gr2012/JC2434_WorldAIDSday_results_en.pdf, accessed 15 May 2013). 98. G uidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241547543_eng.pdf, accessed 15 May 2013). 99. Mathers MB et al. Mortality among people who inject drugs: a systematic review and meta-analysis. Bulletin of the World Health Organization , 2013, 91:102–123. 100. Y an Zhao et al. Methadone maintenance treatment and mortality in HIV-positive people who inject opioids in China. Bulletin of the World Health Organization, 2013, 91:93–101 101. A chmad Y et al. Integration of methadone maintenance treatment and HIV care for injecting drug users: a cohort study in Bandung, Indonesia. Acta Medica Indonesiana , 2009, 41(Suppl. 1):23–27. 102. L ucas G et al. Clinic-based treatment for opioid-dependent HIV-infected patients versus referral to an opioid treatment program: a randomized controlled trial. Annals of Internal Medicine, 2010, 152:704–711. 103. Z aller N et al. A model of integrated primary care for HIV-positive patients with underlying substance use and mental illness. AIDS Care, 2007, 19:1128–1133. 104. Fatti G et al. Better antiretroviral therapy outcomes at primary healthcare facilities: an evaluation of three tiers of ART services in four South African provinces. PLoS One, 2010, 5:e12888. 105. B ock P et al. Provision of antiretroviral therapy to children within the public sector of South Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2008, 102:905–911. 106. H umphreys CP et al. Nurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland. BMC Health Services Research , 2010, 10:229. 107. A ssefa Y et al. Effectiveness and acceptability of delivery of antiretroviral treatment in health centres by health officers and nurses in Ethiopia. Journal of Health Services Research and Policy, 2012, 1:24–29. 108. B rennan AT et al. Outcomes of stable HIV-positive patients down-referred from a doctor-managed antiretroviral therapy clinic to a nurse-managed primary health clinic for monitoring and treatment. AIDS , 2011, 25:2027–2036. 109. C han AK et al. Outcome assessment of decentralization of antiretroviral therapy provision in a rural district of Malawi using an integrated primary care model. Tropical Medicine and International Health , 2010, 15(Suppl. 1):90–97. 110. B alcha TT, Jeppsson A. Outcomes of antiretroviral treatment: a comparison between hospitals and health centers in Ethiopia. Journal of the International Association of Physicians in AIDS Care, 2010, 9:318–324. 111. B edelu M et al. Implementing antiretroviral therapy in rural communities: the Lusikisiki model of decentralized HIV/AIDS care. Journal of Infectious Diseases , 2007, 196(Suppl. 3):S464–S468. 112. M assaquoi M et al. Patient retention and attrition on antiretroviral treatment at district level in rural Malawi. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2009, 103:594–600. 113. J affar S et al. Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial. Lancet , 2009, 374:2080–2089. 114. K ipp W et al. Results of a community-based antiretroviral treatment program for HIV-1 infection in western Uganda. Current HIV Research , 2010, 8:179–185. 115. S elke HM et al. Task-shifting of antiretroviral delivery from health care workers to persons living with HIV/AIDS: clinical outcomes of a community-based program in Kenya. Journal of Acquired Immune Deficiency Syndromes , 2010, 55:483–490. O perations manual for delivery of HIV prevention, care and treatment at primary health centres in high-prevalence, resource116. constrained settings . Geneva, World Health Organization, 2008 (www.who.int/entity/hiv/pub/imai/om.pdf, accessed 15 May 2013).

13 References

268

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection 117. W HO recommendations for clinical mentoring to support scale-up of HIV care, antiretroviral therapy and prevention in resource-constrained settings . Geneva, World Health Organization, 2006 (www.who.int/hiv/pub/meetingreports/ clinicalmentoring/en/index.html, accessed 15 May 2013). 118. Task shifting: global recommendations and guidelines . Geneva, World Health Organization, 2008 (www.who.int/ healthsystems/TTR-TaskShifting.pdf, accessed 15 May 2013). 119. Fairall L et al. Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial. Lancet , 2012, 380:889–898. 120. S herr KH et al. Quality of HIV care provided by non-physician clinicians and physicians in Mozambique: a retrospective cohort study. AIDS , 2010, 24(Suppl. 1):S59–S66. 121. S anne I et al. Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet , 2010, 376:33–40. W HO expert meeting report on short, medium, longer term product development priorities for HIV-related 122. diagnostics, 6–7 June 2012, Geneva, Switzerland . Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/75971/1/9789241504522_eng.pdf, accessed 15 May 2013). 123. W HO model list of essential medicines . 17th ed. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/ hq/2011/a95053_eng.pdf, accessed 15 May 2013). 124. A model quality assurance system for procurement agencies . Geneva, World Health Organization, 2007 (http://apps.who.int/ medicinedocs/documents/s14866e/s14866e.pdf, accessed 15 May 2013). 125. O perational principles for good pharmaceutical procurement . Geneva, World Health Organization, 1999 (http://apps.who. int/medicinedocs/pdf/whozip49e/whozip49e.pdf, accessed 15 May 2013). 126. H armonized monitoring and evaluation indicators for procurement and supply management systems . Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241500814_eng.pdf, accessed 15 May 2013). 127. T he price and quality reporting (PQR) . Geneva, Global Fund to Fight AIDS, Tuberculosis and Malaria, 2012 (www. theglobalfund.org/en/procurement/pqr, accessed 15 May 2013). 128. I nternational drug price indicator guide. Cambridge, MA, Management Sciences for Health, 2012 (http://erc.msh.org/ dmpguide/index.cfm?search_cat=yes&display=yes&module=dmp&language=english&year=2011, accessed 15 May 2013). 129. U ntangling the web of antiretroviral price reductions . Geneva, Médecins Sans Frontières, 2012 (http://utw.msfaccess.org, accessed 15 May 2013). 130. G lobal Price Reporting Mechanism [online database]. Geneva, World Health Organization, 2012 (http://apps.who.int/hiv/ amds/price/hdd, accessed 15 May 2013). 131. G uidelines for medicine donations . Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2011/9789241501989_eng.pdf, accessed 15 May 2013). 132. G uide to good storage practices for pharmaceuticals . Geneva, World Health Organization, 2003 (http://apps.who.int/ medicinedocs/documents/s18675en/s18675en.pdf, accessed 15 May 2013).

Chapter 10 W HO Consultation: the Strategic Use of Antiretrovirals for Treatment and Prevention of HIV Infection: 2nd Expert Panel Meeting, 2–4 May 2012, Geneva, Switzerland. Meeting report . Geneva, World Health Organization, 2012 (http://apps.who. int/iris/bitstream/10665/77946/1/WHO_HIV_2013.1_eng.pdf, accessed 15 May 2013). 2. A framework for national health policies, strategies and plans . Geneva, World Health Organization, 2010 (www.who.int/hiv/ topics/ppm/framework_nhpsp.pdf, accessed 15 May 2013). 3. G lobal health sector strategy on HIV/AIDS 2011–2015. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/ hiv_strategy, accessed 15 May 2013). 4. A dapting WHO normative HIV guidelines for national programmes . Geneva, World Health Organization, 2010 (www.who.int/ hiv/pub/who_normative, accessed 15 May 2013). 5. P lanning guide for the health sector response to HIV/AIDS . Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/ guidelines/9789241502535/en/index.html, accessed 15 May 2013). 6. P ractical guidelines for intensifying HIV prevention: towards universal access . Geneva, UNAIDS, 2007 (www.unaids.org/en/ resources/presscentre/featurestories/2007/march/20070306preventionguidelines, accessed 15 May 2013). 7. Schwartländer B et al. Towards an improved investment approach for an effective response to HIV/AIDS. Lancet , 2011, 377:2031–2041. 8. Incidence by modes of transmission [web site]. Geneva, UNAIDS, 2013 (www.unaids.org/en/dataanalysis/datatools/ incidencebymodesoftransmission, accessed 15 May 2013). 9. WHO and UNAIDS. Guidelines on estimating the size of populations most at risk to HIV. Geneva, World Health Organization, 2010 (http://data.unaids.org/pub/Manual/2010/guidelines_popnestimationsize_en.pdf, accessed 15 May 2013). 10. Daniels N. Fair process in patient selection for antiretroviral treatment in WHO’s goal of 3 by 5. Lancet , 2005, 366:169–171. G uidance on ethics and equitable access to HIV treatment and care. Geneva, World Health Organization, 2004 (www.who. 11. int/ethics/Guidance%20on%20Ethics%20and%20HIV.pdf, accessed 15 May 2013). 12. WHO, UNAIDS and UNICEF. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2011. Geneva, World Health Organization, 2011 (www.who.int/hiv/topics/universalaccess/en, accessed 15 May 2013). 13. WHO, UNODC and UNAIDS. WHO/UNODC/UNAIDS technical guide for countries to set targets for universal access to HIV prevention, treatment and care for injecting drug users . Geneva, World Health Organization, 2009 (www.who.int/hiv/pub/ idu/targets_universal_access/en/index.html, accessed 15 May 2013). 14. United Nations General Assembly. Declaration of Commitment on HIV/AIDS . New York, United Nations, 2001 (www.unaids. 1.

13. References org/en/media/unaids/contentassets/dataimport/publications/irc-pub03/aidsdeclaration_en.pdf, accessed 15 May 2013). 15. United Nations General Assembly. Political Declaration on HIV/AIDS – United Nations General Assembly Resolution 60/262. New York, United Nations, 2006. 16. I nternational Covenant on Economic, Social and Cultural Rights . New York, United Nations, 1966 (www.ohchr.org/EN/ ProfessionalInterest/Pages/CESCR.aspx, accessed 15 May 2013). 17. M onitoring and evaluation toolkit: HIV, tuberculosis, malaria and health and community systems strengthening . 4th ed. Geneva, Global Fund to Fight AIDS, Tuberculosis and Malaria, 2011 (www.theglobalfund.org/en/me/documents/toolkit, accessed 15 May 2013). 18. Key programmes to reduce stigma and discrimination and increase access to justice in national HIV responses . Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/document/2012/Key_Human_Rights_ Programmes_en_May2012.pdf, accessed 15 May 2013). 19. Eaton JW et al. How should HIV programmes respond to evidence for the benefits of earlier treatment initiation? A combined analysis of 12 mathematical models (http://www.hivmodelling.org). 20. G uidelines for HIV/AIDS interventions in emergency settings . New York, United Nations, 2003 (http://data.unaids.org/ Publications/External-Documents/iasc_guidelines-emergency-settings_en.pdf, accessed 15 May 2013). 21. Everybody’s business: strengthening health systems to improve health outcomes – WHO’s framework for action . Geneva, World Health Organization, 2007 (www.who.int/entity/healthsystems/strategy/everybodys_business.pdf, accessed 15 May 2013). 22. H andbook for improving HIV testing and counselling services. Field-test version . Geneva, World Health Organization, 2010 (www.who.int/hiv/pub/vct/9789241500463/en/index.html, accessed 15 May 2013). 23. Global Price Reporting Mechanism [online database]. Geneva, World Health Organization, 2013 (http://apps.who.int/hiv/ amds/price/hdd, accessed 15 May 2013). 24. Futures Institute [web site]. Glastonbury, CT, Futures Institute, 2013 (www.futuresinstitute.org/onehealth.aspx). 25. PSM Toolbox [web site]. Geneva, PSM Toolbox, 2013 (www.psmtoolbox.org, accessed 15 May 2013). Toolkit – expanding and simplifying treatment for pregnant women living with HIV: managing the transition to option B/ 26. B+. New York, Interagency Task Team on the Prevention and treatment of HIV Infection in Pregnant Women, Mothers and Children, 2013 (www.emtct-iatt.org/toolkit, accessed 15 May 2013). 27. T he human rights costing tool (HRCT): a tool to cost programs to reduce stigma and discrimination and increase access to justice. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/data-and-analysis/tools/ The_Human_Rights_Costing_Tool_v_1_5_May-2012.xlsm, accessed 15 May 2013). 28. T he user guide for the human rights costing tool: costing programmes to reduce stigma and discrimination and increase access to justice in the context of HIV. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/ document/2012/The_HRCT_User_Guide_FINAL_2012-07-09.pdf, accessed 17 June 2013).

269

13 References

Chapter 11 1. WHO, UNAIDS, UNICEF and Global Fund to Fight AIDS, Tuberculosis and Malaria. Three interlinked patient monitoring systems for HIV care/ART, MCH/PMTCT (including malaria prevention and pregnancy), and TB/HIV: standardized minimum data set and illustrative tools . Geneva, World Health Organization, 2013 (www.who.int/hiv/pub/me/patient_monitoring_ systems/en/index.html, accessed 15 May 2013). 2. The process of the Global AIDS Response Progress Reporting process now includes indicators from the Universal Access reporting process: UNAIDS, UNICEF and WHO. Global AIDS Response Progress Reporting: construction of core indicators for monitoring the 2011 UN Political Declaration on HIV/AIDS. Includes additional WHO/UNICEF universal access health sector indicators . Geneva, UNAIDS, 2013 (www.unaids.org/en/media/unaids/contentassets/documents/document/2013/ GARPR_2013_guidelines_en.pdf, accessed 17 June 2013). 3. UNAIDS/WHO working group on global HIV/AIDS and STI surveillance. When and how to use assays for recent infection to estimate HIV incidence at a population level. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/surveillance/ sti_surveillance/en, accessed 15 May 2013). 4. M easuring the impact of national PMTCT programmes: towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/mtct/national_ pmtct_guide/en/index.html, accessed 15 May 2013). 5. 12 components monitoring and evaluation system strengthening tool. Geneva, UNAIDS, 2010 (www.unaids.org/en/media/ unaids/contentassets/documents/document/2010/2_MERG_Strengthening_Tool_12_Components_ME_System.pdf, accessed 17 June 2013).

For more information, contact: World Health Organization Department of HIV/AIDS 20, avenue Appia 1211 Geneva 27 Switzerland E-mail: hiv-aids@who.int www.who.int/hiv ISBN 978 92 4 150572 7

руководство использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции рекомендации с позиций общественного здоровья Июнь 2013 г.

Сводное руководство по

использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции рекомендации с позиций общественного здоровья Июнь 2013 г.

Сводное руководство по

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 1.HIV infections – drug therapy. 2.HIV infections – prevention and control. 3.Anti-Retroviral agents – therapeutic use. 4.Guideline. I.World Health Organization. ISBN 978 92 4 450572 4 (NLM classification: WC 503.2) © Всемирная организация здравоохранения, 2013 г. Обозначения, используемые в настоящей публикации, и приводимые в ней материалы не отражают какого-либо мнения Всемирной организации здравоохранения относительно юридического статуса какой-либо страны, территории, города или района или их органов власти, либо относительно делимитации их границ. Пунктирные линии на географических картах обозначают приблизительные границы, в отношении которых пока еще может быть не достигнуто полное согласие. Упоминание конкретных компаний или продукции некоторых изготовителей не означает, что Всемирная организация здравоохранения поддерживает или рекомендует их, отдавая им предпочтение по сравнению с другими компаниями или продуктами аналогичного характера, не упомянутыми в тексте. За исключением случаев, когда имеют место ошибки и пропуски, названия патентованных продуктов выделяются начальными прописными буквами. Всемирная организация здравоохранения приняла все разумные меры предосторожности для проверки информации, содержащейся в настоящей публикации. Тем не менее, опубликованные материалы распространяются без какой-либо четко выраженной или подразумеваемой гарантии. Ответственность за интерпретацию и использование материалов ложится на пользователей. Всемирная организация здравоохранения ни в коем случае не несет ответственности за ущерб, возникший в результате использования этих материалов. Дизайн и макет по ACW, Лондон, Великобритания Отпечатано в Турции.

Содержание

СОДЕРЖАНИЕ Сокращения и акронимы Определения основных терминов Выражение признательности Предисловие Исполнительное резюме Краткое содержание новых рекомендаций 11 13 17 23 25 28 37 38 39 40 40 40 40 41 41 42 42 43 44 44 44 45 46 46 47 48 48 50 50 50

1. Введение 1.1 1.2 История вопроса и текущая ситуация Обоснование необходимости составления сводного руководства

1.3 Цели 1.4 Целевая аудитория 1.5 Сфера охвата и компоненты 1.5.2 Клинические рекомендации 1.5.3 Рекомендации по осуществлению деятельности и предоставлению услуг 1.5.4 Рекомендации для руководителей программ 1.5.5 Мониторинг и оценка

1.5.1 Вводные главы 2. 3.

Руководящие принципы 2.1 2.2 2.3 2.4 Вклад в достижение глобальных целей в области здравоохранения Подход с позиции общественного здравоохранения Укрепление систем здравоохранения с помощью инноваций и обучения Повышение эффективности и действенности программ

2.5 Соблюдение прав человека и принципа справедливости в отношении здоровья 2.6 Выполнение рекомендаций с учетом условий на местах

Методы и процесс подготовки руководства 3.1 Обзор 3.2 Источники информации 3.3.1 Группы по разработке рекомендаций и процесс коллегиальной экспертной оценки 3.3.2 Конфликт интересов 3.3 Внешнее участие

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья

3.4

Процесс подготовки рекомендаций

51 54 54 55 56 58 58 59 61 63 64 59

3.5 Другие методы 3.6 Распространение

4. Структура руководства 4 4.1 Непрерывное оказание помощи Структура представления новых рекомендаций

4.2 Структура представления некоторых рекомендаций, взятых из существующих руководств 4.3 Как использовать рекомендации для конкретных групп населения 4.3.1 Беременные и кормящие грудью женщины

4.3.2 Подростки 4.3.3 Дети

4.3.4 Ключевые группы населения

5. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: диагностика вич и арв-препараты для профилактики вич 5.1 Консультирование и тестирование на ВИЧ 5.1.2 Консультирование и тестирование на ВИЧ в медицинских учреждениях 5.1.3 Консультирование и тестирование на ВИЧ по месту жительства 5.1.4 Консультирование и тестирование на ВИЧ конкретных групп населения Профилактика ВИЧ за счет приема АРВ-препаратов 5.2.1 Пероральная доконтактная профилактика 5.1.1 Введение 5.2

67 68 68 70 71 74 85 85 86

5.2.2 АРТ на службе профилактики среди серодискордантных пар 5.2.3 Постконтактная профилактика на случай ВИЧ-инфицирования в процессе профессиональной и непрофессиональной деятельности 5.2.4 Комбинированная профилактика ВИЧ

86 87

6. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: установление связей между лицами с диагнозом вич-инфекции и службами лечения и оказания помощи при вич 6.1 Введение 6.2 Надлежащая практика установления связей со службами предоставления ухода 6.3 Оказание общей помощи людям, живущим с ВИЧ

89 90 90 90

Содержание

6.4 6.5

Подготовка к прохождению АРТ людей, живущих с ВИЧ Что можно ожидать от первых месяцев прохождения АРТ

94 94

Содержание

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия 7.1 Когда следует начинать АРТ 7.1.1 Когда следует начинать АРТ у взрослых и подростков 7.1.2 Когда следует начинать АРТ у беременных и кормящих грудью женщин

97 98

99 108 114

7.1.3 АРВ-препараты и продолжительность грудного вскармливания 7.2 7.1.4 Когда следует начинать АРТ у детей 7.2.1 АРТ первого ряда для взрослых

119 125 129 137 142 1 46

С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда) 124 7.2.2 АРТ первого ряда для беременных и кормящих грудью женщин и АРВ-препараты для их детей 7.2.3 АРТ первого ряда для детей моложе трех лет 7.2.4 АРТ первого ряда для детей в возрасте трех лет и старше (включая подростков)

7.2.5 Комбинированное лечение ТБ и ВИЧ-инфекции у детей

7.3 Мониторинг эффективности АРТ и выявление причин неудачи лечения 7.3.2 Мониторинг эффективности АРТ и выявление причин неудачи лечения

148 148 149 156 156 156 161 161 162 156 166 170 173

7.3.1 Лабораторный мониторинг до и после начала АРТ

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ 7.4.1 Основополагающие принципы 7.4.2 Основные типы проявления токсичности АРВ-препаратов 7.4.4 Мониторинг токсичности других АРВ-препаратов 7.4.5 Замена одних препаратов другими при лекарственной токсичности АРТ 7.4.6 Основные взаимодействия АРВ-препаратов

7.4.3 Мониторинг токсичности TDF 159

7.5 На какую схему АРВ-терапии следует переходить (АРВ-терапии второго ряда) 7.5.1 АРТ второго ряда для взрослых и подростков 7.5.2 АРТ второго ряда для детей (включая подростков) АРТ третьего ряда

7.6

8. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: ведение наиболее распространенных 175 коинфекций и сопутствующих заболеваний 8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций 8.1.1 Профилактическое лечение котримоксазолом 8.1.3 Криптококковая инфекция 8.1.4 Вирусные гепатиты B и C 8.1.6 Инфекции, передающиеся половым путем, и рак шейки матки 8.1.7 Вакцины для людей, живущих с ВИЧ 176 176 178 185 187 187 189 191 191 191 192 192 193 195 195

8.1.2 Туберкулез

8.1.5 Малярия

8.2 Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ 8.2.1 Скрининг на неинфекционные заболевания и уход за больными 8.2.2 Охрана психического здоровья 8.2.3 Употребление наркотиков и расстройства, связанные с этим 8.2.4 Оказание нутритивной помощи и поддержки 8.2.5 Паллиативная помощь: симптоматическое лечение и уход за умирающими больными 8.2.6 Другие соответствующие общие принципы организации помощи

9. Рекомендации по осуществлению деятельности и предоставлению услуг 9.1 Введение 9.2 Соблюдение режима АРТ 9.2.1 Факторы, препятствующие соблюдению

197 198 198 198 201 205 206 206 207 210 210

9.3

9.2.2 Меры, направленные на оптимизацию соблюдения режима АРТ 9.2.3 Мониторинг соблюдения режима АРТ в рамках плановых программ и мест оказания помощи Удержание пациентов в рамках непрерывного оказания помощи 9.3.1 Общие сведения 9.3.2 Надлежащая практика удержания пациентов на всех этапах оказания помощи 9.4.1 Надлежащая практика предоставления долгосрочной медицинской помощи

9.4 Предоставление услуг

Содержание

9.6

9.4.2 Интеграция и взаимодействие служб 9.4.3 Децентрализация лечения и помощи при ВИЧ 9.5.1 Наращивание кадрового потенциала 9.5.2 Перераспределение обязанностей для лечения и оказания помощи при ВИЧ Лабораторные и диагностические службы 9.6.2 Вопросы осуществления и передовой опыт 9.6.3 Укрепление и расширение лабораторных и диагностических служб 9.6.4 Поддержка создания специальной системы направления образцов на исследования 9.6.5 Расширение доступа к тестированию на вирусную нагрузку ВИЧ 9.6.6 Расширение диагностических служб для проведения тестирования по месту оказания помощи 9.6.7 Предоставление рекомендаций по наращиванию кадрового потенциала здравоохранения, включая обучение и сертификацию персонала 9.6.8 Внедрение комплексных систем управления качеством Системы управления закупками и поставками 9.7.2 Обоснование и подтверждающие данные 9.7.3 Вопросы осуществления и передовой опыт

211 217 219 219 219 221 221 222 222 223 223 223

Содержание

9.5 Кадровые ресурсы

9.6.1 Обзор

225 225 225 225 226 226 231 232 233 233 233 234 234 234 238 238 238 240

9.7

9.7.1 Обзор 10.

Рекомендации для руководителей программ 10.1 Введение 10.2 Процесс принятия решений 10.3 Данные в поддержку принятия решений 10.3.2 Эпидемиология ВИЧ на национальном и местном уровнях 10.3.3 Анализ эффективности программ и ответных мер 10.3.4 Социально-экономическая, политическая и правовая ситуация 10.4.1 Вопросы этики, справедливости и прав человека 10.4.2 Воздействие и экономическая эффективность 10.4.3 Благоприятные возможности и риски

10.3.1 Обзор

10.4 Основные параметры для принятия решений

10.5 Вопросы реализации в рамках системы здравоохранения 10.6 Вопросы реализации в отношении основных рекомендаций 10.7 Выполнение рекомендаций в разных условиях 10.7.2 Выполнение рекомендаций в разных эпидемиологических ситуациях

240 244 250 250 250 252 253 254 255 256 259 259 260 260 262 256

10.7.1 Обзор 11.

10.8 Полезные инструменты для калькуляции затрат и планирования Мониторинг и оценка 11.1 Введение 11.2 Значение новых рекомендаций для мониторинга 11.3 Мониторинг промежуточных и конечных результатов расширения доступа к АРВ-препаратам 11.4 Другие аспекты мониторинга 11.4.1 Лекарственная устойчивость ВИЧ 11.4.2 Дозорный эпиднадзор для мониторинга токсичности АРВ-терапии 11.4.3 Оценка, включая воздействие и результаты деятельности программ, а также внедренческие исследования

11.5 Изучение и укрепление систем мониторинга и оценки

12. Приложения Приложение 1. Клинические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей Приложение 2. Алгоритм для рекомендаций 2013 года в отношении взрослых и подростков Приложение 3. Алгоритмы для рекомендаций 2013 года в отношении беременных и кормящих грудью женщин Приложение 4. Алгоритм для рекомендаций 2013 года в отношении детей Приложение 5. Алгоритм для ранней диагностики у грудных детей

266 268

270 272 273

Приложение 6. Контрольный перечень вопросов для оценки готовности: переход к АРТ для беременных и кормящих грудью женщин Приложение 7. Дозировки рекомендованных антиретровирусных препаратов

274 279 289

13. Библиография

Сокращения и акронимы

СОКРАЩЕНИЯ И АКРОНИМЫ 3TC ABC СПИД АРТ АРВ ATV ATV/r AZT ИМТ CD4 CDC ЦНС d4T DALYs СККК ddI ДНК DRV DRV/r EFV рСКФ ELISA ETV FPV FPV/r FTC GNP+ ламивудин абакавир синдром приобретенного иммунодефицита антиретровирусная терапия антиретровирусный (препарат) атазанавир атазанавир/ритонавир зидовудин (также известен как ZDV) индекс массы тела Т-лимфоциты, экспрессирующие рецептор CD4 Центры США по контролю и профилактике заболеваний центральная нервная система ставудин годы жизни, скорректированные на летальные исходы и нетрудоспособность сухая капля капиллярной крови диданозин дезоксирибонуклеиновая кислота дарунавир дарунавир/ритонавир эфавиренз расчетная скорость клубочковой фильтрации иммуноферментный твердофазный анализ этравирин фосампренавир фосампренавир/ритонавир эмтрицитабин Глобальная сеть людей, живущих с ВИЧ

GRADE система классификации оценки, разработки и определения весомости рекомендаций HBsAg ВГВ ВГС ВИЧ поверхностный антиген гепатита В вирус гепатита В вирус гепатита С вирус иммунодефицита человека

HPTN ВПГ INH ПТИ ВСВИ LPV LPV/r

Сеть клинических испытаний методов профилактики передачи ВИЧ, не связанных с вакцинацией вирус простого герпеса изониазид профилактическая терапия изониазидом воспалительный синдром восстановления иммунитета лопинавир лопинавир/ритонавир

МЛУ-ТБ ТБ с множественной лекарственной устойчивостью; устойчивость, как минимум, к изониазиду и рифампицину ПМР NFV НИОТ NVP ОЗТ ПЦР ИП PICO ПЦП ППМР ДКП RAL RBV RIF РНК RTV TAM ТБ TDF TPV передача (ВИЧ) от матери ребенку нелфинавир нуклеозидный ингибитор обратной транскриптазы невирапин опиоидная заместительная терапия полимеразная цепная реакция ингибитор протеазы методология «Популяция – вмешательство – сопоставление – исход» пневмоцистная пневмония (возбудитель Pneumocystis jirovecii) профилактика передачи ВИЧ от матери ребенку доконтактная (химио)профилактика ВИЧ ралтегравир рибавирин рифампицин рибонуклеиновая кислота ритонавир мутация резистентности к аналогам тимидина туберкулез тенофовир дизопроксил фумарат типранавир

ННИОТ ненуклеозидный ингибитор обратной транскриптазы

sd-NVP однодозовый невирапин

ЮНЭЙДС Объединенная программа Организации Объединенных Наций по ВИЧ/СПИДу ЮНИСЕФ Детский фонд Организации Объединенных Наций ЮНОДК Управление Организации Объединенных Наций по наркотикам и преступности ВОЗ Всемирная организация здравоохранения

Определения основных терминов

ОПРЕДЕНИЯ ОСНОВНЫХ ТЕРМИНОВ ОБЩИЕ ВИЧ – вирус иммунодефицита человека. Имеются два типа ВИЧ: ВИЧ-1 и ВИЧ-2. ВИЧ является причиной подавляющего большинства случаев ВИЧ-инфекции в мире. В настоящем руководстве ВИЧ означает как ВИЧ-1, так и ВИЧ-2, если не указано иначе.

ВОЗРАСТНЫЕ ГРУППЫ И ГРУППЫ НАСЕЛЕНИЯ В целях обеспечения последовательности в рамках настоящего руководства, а также согласованности с другими руководствами ВОЗ используются следующие определения в отношении взрослых, подростков, детей и грудных детей. При этом признается, что другие учреждения могут использовать иные определения. Взрослыми являются лица старше 19 лет, если согласно национальному законодательству человек не считается взрослым в более раннем возрасте. Подростками являются лица в возрасте от 10 до 19 лет включительно. Детьми являются лица в возрасте 19 лет или младше, если согласно национальному законодательству человек не считается взрослым в более раннем возрасте. Однако в настоящем руководстве человек в возрастной категории от 10 до 19 лет считается подростком (см. определение подростка). Грудными детьми являются дети в возрасте до одного года. К категории ключевых групп населения в настоящем руководстве относятся как уязвимые группы населения, так и группы населения повышенного риска. Они имеют важное значение для изучения динамики передачи ВИЧ в данном месте и являются основными партнерами для принятия эффективных мер в ответ на эпидемию. Люди, живущие с ВИЧ, считаются одной из ключевых групп во всех эпидемиологических ситуациях. Группы населения повышенного риска в настоящем руководстве определяются как мужчины, практикующие секс с мужчинами, трансгендерные лица, потребители инъекционных наркотиков и работники секс-индустрии. Группы населения повышенного риска подвержены воздействию ВИЧ в непропорционально большей степени, чем другие группы в большинстве, если не во всех, эпидемиологических ситуаций. Уязвимыми группами населения являются группы людей, которые особенно уязвимы к ВИЧ-инфицированию при определенных ситуациях или обстоятельствах, такие как подростки (особенно девочки-подростки), сироты, беспризорные дети, люди в местах лишения свободы (таких, как тюрьмы и места заключения), люди с ограниченными возможностями, а также мигранты и мобильные работники. В каждой стране следует определить конкретные группы населения, являющиеся наиболее уязвимыми и имеющие важнейшее значение для борьбы с эпидемией и принятия ответных мер, исходя из эпидемиологических и социальных условий. Серодискордантными парами являются пары, в которых один из партнеров живет с ВИЧ, а второй является ВИЧ-отрицательным. Парой считаются два человека, поддерживающих постоянные сексуальные отношения; в рамках этих отношений каждый из них называется партнером. Определение этих взаимоотношений отдельными людьми значительно варьируется в зависимости от культурных и социальных факторов.

СЛУЖБЫ ЗДРАВООХРАНЕНИЯ Непрерывное оказание помощи при ВИЧ означает предоставление всеобъемлющего пакета услуг профилактики, диагностики, лечения и поддержки при ВИЧ людям, живущим с ВИЧ, и их семьям, включая: первичный диагноз ВИЧ и установление связи со службами помощи; ведение оппортунистических инфекций и других сопутствующих заболеваний; инициирование, проведение и мониторинг АРТ; переход на АРТ второго и третьего ряда; и оказание паллиативной помощи. Подход общественного здравоохранения направлен на удовлетворение медикосанитарных потребностей группы населения или улучшение состояния здоровья всех людей, а не отдельных лиц. Подход общественного здравоохранения предусматривает осуществление совместных действий всеми участниками сектора здравоохранения, целью которых является обеспечение благополучия общества с помощью всесторонней профилактики, лечения, помощи и поддержки. Применительно к ВИЧ это включает: упрощенные ограниченные формуляры лекарственных средств; широкое использование комбинированных препаратов с фиксированными дозами в схемах лечения первого ряда для взрослых и детей; оказание помощи и выдача препаратов в местах предоставления услуг; децентрализацию; и интеграцию служб, включая перераспределение обязанностей и упрощенную систему клинического и токсикологического мониторинга.

ТЕСТИРОВАНИЕ НА ВИЧ И ПРОФИЛАКТИКА Добровольное консультирование и тестирование (также называемое тестированием и консультированием по инициативе клиента) является процессом, инициируемым человеком, который желает узнать свой ВИЧ-статус. Поскольку в настоящее время имеется множество различных подходов к проведению тестирования на ВИЧ и консультирования на местах и люди часто имеют разную мотивацию, обращаясь с просьбой о проведении тестирования (рекомендуемого провайдером или инициируемого клиентом), ВОЗ предпочитает использовать термин тестирование на ВИЧ и консультирование. Все формы тестирования на ВИЧ и консультирования должны быть добровольными и основываться на пяти принципах: согласие, конфиденциальность, консультирование, правильные результаты тестирования и связь со службами по оказанию помощи, проведению лечения и профилактики. При всех подходах к тестированию на ВИЧ и консультированию важное значение имеет обеспечение качества как тестирования, так и консультирования. Тестирование и консультирование по инициативе провайдера является тестированием на ВИЧ и консультированием, рекомендованными провайдером медицинских услуг в клинических условиях. Тестирование и консультирование по инициативе провайдера, так же как и все формы тестирования на ВИЧ и консультирования, должны проводиться на добровольной основе и с соблюдением указанных выше пяти принципов. Комбинированная профилактика представляет собой сочетание поведенческих, биомедицинских и структурных подходов к профилактике ВИЧ для оказания максимального воздействия на снижение числа случаев передачи ВИЧ и инфицирования.

АРТ (АНТИРЕТРОВИРУСНАЯ ТЕРАПИЯ) Термин АРВ (антиретровирусные) препараты относится к самим лекарственным препаратам, а не их использованию. АРТ означает использование комбинации трех или более АРВ-препаратов для достижения вирусной супрессии. Это обычно касается пожизненного лечения. Синонимами являются комбинированная АРТ и высокоактивная АРТ.

Определения основных терминов

АРТ для профилактики используется для описания положительных эффектов АРТ в профилактике ВИЧ. Отвечающий критериям для проведения АРТ используется в отношении людей, живущих с ВИЧ, которым назначается проведение АРТ в соответствии с определениями клинических и иммунологических критериев, указанных в руководстве ВОЗ по вопросам лечения. Этот термин часто используется наравне с «необходимостью лечения», хотя последнее означает непосредственный риск или обязанность начать лечение. Вирусная супрессия является целью АРТ, заключающейся в поддержании вирусной нагрузки ниже уровня, выявляемого имеющимися тестами, который обычно составляет является 1000 копий/мл или более. Всеобщий доступ к АРТ в широком смысле определяется как переход к высокому уровню доступа (≥80% всех лиц, отвечающих критериям) к наиболее эффективным мерам вмешательства, которые предоставляются на справедливой основе, являются доступными, приемлемыми по стоимости, всесторонними и обеспечивающими долгосрочную устойчивость результатов; это не обязательно означает, что уровень охвата составляет 100%.

Определения основных терминов

КАДРОВЫЕ РЕСУРСЫ ЗДРАВООХРАНЕНИЯ Участковые работники здравоохранения – работники здравоохранения, которые получили стандартизированную и подтвержденную на национальном уровне подготовку, кроме программы обучения медсестер, акушерок или врачей. Акушерки – лица, прошедшие подготовку для оказания помощи при родах; в их число входят дипломированные и зарегистрированные акушерки. Неврачебный клинический персонал – профессиональные работники здравоохранения, способные выполнять многие диагностические и клинические функции врачей, но не прошедшие обучение в качестве врачей. Работники здравоохранения этого типа часто известны как медицинские работники, клинические работники, помощники врача, фельдшеры или санитарки. Медицинские сестры – этот термин включает профессиональных медсестер, аттестованных медсестер, младших медсестер, а также медсестер других категорий, таких как медсестры стоматологического кабинета или медсестры в учреждениях первичной медико-санитарной помощи.

ЭПИДЕМИОЛОГИЯ Концентрированная эпидемия ВИЧ-инфекции: ВИЧ-инфекция быстро распространяется в одной или нескольких определенных группах населения, но еще не получила широкого распространения среди населения в целом. Количественный эквивалент: распространенность ВИЧ-инфекции устойчиво превышает 5%, как минимум, в одной определенной группе населения, однако ниже 1% среди беременных женщин в городских районах. Генерализованная эпидемия ВИЧ-инфекции: ВИЧ-инфекция получила широкое распространение среди населения в целом. Количественный эквивалент: распространенность ВИЧ-инфекции среди беременных женщин стойко превышает 1%. В большинстве случаев генерализованные эпидемии ВИЧ носят смешанный характер, при котором в непропорционально большей степени затрагиваются некоторые (ключевые) группы населения. Смешанная эпидемия: люди, инфицируемые ВИЧ, имеются в одной или нескольких группах населения, а также среди населения в целом. Таким образом, смешанные эпидемии представляют собой одну или несколько концентрированных эпидемий в рамках генерализованной эпидемии.

Эпидемия низкого уровня: эпидемия, при которой распространенность ВИЧ-инфекции устойчиво не превышает 1% среди населения страны в целом или 5% в какой-либо группе населения. Места с низким, средним и высоким уровнем охвата АРТ – места, где уровень охвата АРТ среди лиц, отвечающих критериям проведения АРТ, составляет, соответственно, менее 50%, 50%-80% и более 80%. Места с высоким бременем ТБ и ВИЧ – места, где распространенность ВИЧ среди взрослого населения составляет ≥1% или распространенность ВИЧ среди лиц с ТБ ≥5%. Частота случаев ВИЧ – число новых случаев ВИЧ-инфицирования в течение определенного периода времени в определенной группе населения. Распространенность ВИЧ – количество людей, живущих с ВИЧ, в определенный момент времени, выраженное в процентной доле всего населения.

ППМР (ПРОФИЛАКТИКА ПЕРЕДАЧИ ВИЧ ОТ МАТЕРИ РЕБЕНКУ) В настоящем руководстве ВОЗ отходит от прежних терминов “Варианты A, B и B+”. Вместо них в руководстве рекомендуются два варианта: (i) предоставление пожизненной АРТ всем беременным и кормящим грудью женщинам, живущим с ВИЧ, независимо от количества CD4 или клинической стадии или (ii) предоставление АРТ (АРВ-препаратов) беременным и кормящим грудью женщинам с ВИЧ в течение периода риска передачи вируса от матери ребенку и затем пожизненное продолжение АРТ женщинам, отвечающим критериям проведения лечения по состоянию здоровья. В местах, где пожизненная АРТ всем беременным и кормящим грудью женщинам, живущим с ВИЧ, не предоставляется, важно проводить различие между профилактикой (прием АРВ-препаратов в профилактических целях в течение определенного периода времени, когда существует риск передачи ВИЧ от матери ребенку) и лечением (проведение АРТ в связи с состоянием здоровья матери, на основе критериев проведения лечения для взрослых, и для профилактики вертикальной передачи). АРВ-препараты для женщин, живущих с ВИЧ, во время беременности и кормления грудью: трехкомпонентная схема приема АРВ-препаратов, применяемая у матерей, живущих с ВИЧ, в первую очередь в профилактических целях в период беременности и кормления грудью (если осуществляется грудное вскармливание) для предупреждения передачи ВИЧ от матери ребенку. При этом варианте схема лечения матери сохраняется на протяжении всей жизни после родов или после окончания кормления грудью только в том случае, если она отвечает критериям проведения АРТ по состоянию здоровья на основе количества CD4 или клинической стадии. В предыдущем руководстве ВОЗ это являлось Вариантом B. Пожизненная АРТ для всех беременных и кормящих грудью женщин, живущих с ВИЧ: подход, при котором все беременные женщины, живущие с ВИЧ, получают трехкомпонентную схему АРВ-терапии, независимо от количества CD4 или клинической стадии, как по состоянию здоровья, так и для профилактики вертикальной передачи ВИЧ, а также для получения дополнительных положительных эффектов в целях профилактики ВИЧ. В предыдущем руководстве ВОЗ это являлось Вариантом B+.

Выражение признательности

Выражение Признательности Anthony Harries (Международный союз борьбы с туберкулезом и болезнями легких, Соединенное Королевство) и Gottfried Hirnschall (Департамент ВИЧ, Всемирная организация здравоохранения) в качестве сопредседателей возглавляли процесс подготовки руководства.

Группа по разработке рекомендаций для взрослых Сопредседатели: Serge Eholie (ANEPA/Treichville Hospital, Абиджан, Кот-д’Ивуар) и Stefano Vella (Istituto Superiore di Sanità, Италия). Методист по системе GRADE: Elie Akl (American University of Beirut, Ливан). Pedro Cahn (Fundación Huesped, Аргентина), Alexandra Calmy (University of Geneva, Швейцария), Frank Chimbwandira (Ministry of Health, Малави), David Cooper (University of New South Wales and St Vincent’s Hospital, Австралия), Judith Currier (UCLA Clinical AIDS Research & Education Center, США), François Dabis (School of Public Health (ISPED), University Bordeaux Segalen, Франция), Charles Flexner (Johns Hopkins University, США), Beatriz Grinsztejn (Fundação Oswaldo Cruz (FIOCRUZ), Бразилия), Diane Havlir (University of California at San Francisco, США), Charles Holmes (Centre for Infectious Disease Research in Zambia, Замбия), John Idoko (National Agency for the Control of AIDS, Нигерия), Kebba Jobarteh (Centers for Disease Control and Prevention, Мозамбик), Nagalingeswaran Kumarasamy (Y.R. Gaitonde Centre for AIDS Research and Education, Индия), Владимир Курпита (Всеукраинская сеть людей, живущих с ВИЧ, Украина), Karine Lacombe (Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), Франция), Albert Mwango (Ministry of Health, Замбия), Leonardo Palombi (DREAM Program, Community of Sant’Egidio, Рис, Италия), Anton Pozniak (Chelsea and Westminster Hospital, Соединенное Королевство), Luis Adrián Quiroz (Derechohabientes Viviendo con VIH del IMSS (DVIMSS), Мексика), Kiat Ruxrungtham (Chulalongkorn University, King Chulalongkorn Memorial Hospital, Таиланд), Michael Saag (University of Alabama at Birmingham, США), Gisela Schneider (German Institute for Medical Mission, Германия), Yanri Subronto (Universitas Gadjah Mada, Индонезия) и Francois Venter (University of the Witwatersrand, Южная Африка).

Группа по разработке рекомендаций в области охраны здоровья матери и ребенка Сопредседатели: Elaine Abrams (International Center for AIDS Care and Treatment Programs (ICAP), Columbia University, США) и Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Уганда). Методист по системе GRADE: Joerg Meerpohl (German Cochrane Centre, University Medical Center, Freiburg, Германия). Renaud Becquet (Internationale Institut de Santé Publique d’Epidémiologie et de Développement, Université Bordeaux Segalen, Франция), Deborah Birx (United States Centers for Disease Control and Prevention, США), Benjamin Chi (Centre for Infectious Disease Research in Zambia, Замбия), Mark Cotton (Stellenbosch University, Южная Африка), Nonhlanhla Dlamini (National Department of Health, Южная Африка), René Ekpini (United Nations Children’s Fund, США), Carlo Giaquinto (Paedatric Infectious Disease Unit and Clinical Trials Unit of Azienda Ospedaliera di Padua, Италия), Diana Gibb (Medical Research Council Clinical Trials Unit, Соединенное Королевство), Sabrina Bakeera-Kitaka (Makerere University and Mulago National Referral Hospital, Уганда), Louise Kuhn (Columbia University, США), Евгения Марон (Благотворительный женский фонд «Астра», Российская Федерация), Babalwa Mbono (mothers2mothers, Южная Африка), James McIntyre (University of Cape Town, Южная Африка), Lynne Mofenson (National Institutes of Health, США),

Angela Mushavi (Ministry of Health and Child Welfare, Зимбабве), Ryan Phelps (United States Agency for International Development, США), Jorge Pinto (Federal University of Minas Gerais, Бразилия), Andrew Prendergast (Queen Mary University of London, Соединенное Королевство), Thanyawee Puthanakit (Chulalongkorn University, Таиланд), Atiene Sagay (Unversity of Jos, Нигерия), Roger Shapiro (Harvard School of Public Health, США), George Siberry (National Institutes of Health, США), Landry Tsague (United Nations Children’s Fund, Замбия), Thorkild Tylleskar (University of Bergen, Норвегия), Paula Vaz (Fundação Ariel Glaser contra o SIDA Pediátrico, Мозамбик), Евгений Воронин (Российский педиатрический центр борьбы со СПИДом, Российская Федерация) и Linhong Wang (Chinese Center for Disease Control and Prevention, Китай).

Группа по разработке рекомендаций в области осуществления деятельности и предоставления услуг Сопредседатели: Kevin De Cock (United States Centers for Disease Control and Prevention, США) и Yogan Pillay (National Department of Health, Южная Африка). Методист по системе GRADE: Holger Schünemann (Faculty of Health Sciences, McMaster University, Канада). Tsitsi Mutasa Apollo (Ministry of Health and Child Welfare, Зимбабве), Yibletal Assefa (Ministry of Health, Эфиопия), Paula Braitstein (Indiana University School of Medicine, США), Zengani Chirwa (Ministry of Health, Малави), Bui Duc Duong (Ministry of Health, Вьетнам), Ade Fakoya (Global Fund to Fight AIDS, Tuberculosis and Malaria, Швейцария), Robert Ferris (United States Agency for International Development, США), Ronaldo Hallal (Departamento de DST, Aids e Hepatites Virais, Бразилия), Eihab Ali Hassan (Federal Ministry of Health, Судан), David Hoos (International Centre for AIDS Care and Treatment Programs, Columbia University, США), Barbara Milani (Médecins Sans Frontières (MSF), Швейцария) Christine Nabiryo (The AIDS Support Organization (TASO), Уганда), Наталья Низова (Министерство здравоохранения, Украина), Anupam Pathni (International Planned Parenthood Federation South Asia, Индия), Elliot Raizes (United States Centers for Disease Control and Prevention, США), Kenly Sekwese (Treatment Advocacy Literacy Campaign, Замбия), Larissa Stabinski (Office of the United States Global AIDS Coordinator, США), Miriam Taegtmeyer (Liverpool School of Tropical Medicine, Соединенное Королевство), Wim Van Damme (Institute of Tropical Medicine, Бельгия), Eric van Praag (Family Health International (FHI), Объединенная Республика Танзания), Mean Chhi Vun (Ministry of Health, Камбоджа), Larry Westerman (United States Centers for Disease Control and Prevention, США), Steve Wignall (Clinton Health Access Initiative (CHAI), Индонезия) и Anna Zakowicz (Глобальная сеть людей, живущих с ВИЧ (GNP+), Европа).

Группа по разработке рекомендаций в области программной деятельности Сопредседатели: Tsitsi Apollo (Ministry of Health and Child Welfare, Зимбабве) и Adeeba Kamarulzaman (University of Malaya, Малайзия). Ihab Abdelrahman (Ministry of Health and Population, Египет), John Aberle-Grasse (United States Centers for Disease Control and Prevention, США), Yibeltal Assefa (Ministry of Health, Эфиопия), Rob Baltussen (Radboud University Nijmegen, Нидерланды), Anton Best (Ministry of Health, Барбадос), John Blandford (United States Centers for Disease Control and Prevention, США), Сергей Филиппович (Международный альянс по ВИЧ/СПИДу в Украине, Украина), Eric Goemaere (Médecins Sans Frontières (MSF), Южная Африка), Dirceu Greco (Ministry of Health, Бразилия), Timothy Hallett (Imperial College London, Соединенное Королевство), Priscilla Idele (United Nations Children’s Fund, США), Control Programme, Кения), Jean Paul Moatti (French National Institute of Health and Medical Research (INSERM), Université de la Méditerranée, Франция), Наталья Низова (Министерство здравоохранения, Украина), Ole Frithjof Norheim (Positive Health Outcomes, Замбия), Jerome Singh (Centre for the AIDS

Выражение признательности

Programme of Research in South Africa, Южная Африка), Petchsri Sirinirund (Ministry of Public Health, Таиланд), John Stover (Futures Institute, США), Aliou Sylla (Ministry of Health, Мали), Wim Van Damme (Institute of Tropical Medicine, Бельгия), Stefan Weinmann (Deutsche Gessellschaft für Internationale Zusammenarbeit (GIZ) GmbH, Германия) и Annemarie M. J. Wensing (University Medical Centre Utrecht, Нидерланды). Наблюдатель на совещании Группы по разработке рекомендаций в области программной деятельности: Bernhard Schwartländer (ЮНЭЙДС, Швейцария).

Выражение признательности

Члены внешней группы по проведению коллегиальной экспертной оценки Michelle Adler (United States Centers for Disease Control and Prevention, США), Isabelle Andrieux-Meyer (Médecins Sans Frontières, Швейцария), Xavier Anglaret (Programme PACCI du site ANRS de Côte d’Ivoire, Кот-д’Ивуар), Marcelo Araujo de Freitas (Ministry of Health, Бразилия), Pamela Bachanas (United States Centers for Disease Control and Prevention, США), Shaiful Bahari Ismail (Universiti Sains Malaysia, Малайзия), Pierre Barker (University of North Carolina at Chapel Hill, США), David Barr (HIV Collaborative Fund at Tides Center, США), Jose Gerard Belimac (National AIDS and STI Prevention and Control Program, Филиппины), Soumia Benchekroun (Centre Hospitalier Universaitaire Ibn Sina de Rabat, Марокко), Mitchell Besser (mothers2mothers, Южная Африка), Marc Bulterys (Chinese Centers for Disease Control and Prevention, Китай), Helen Bygrave (Médecins Sans Frontières, Южная Африка), Carlos F. Cáceres (Universidad Peruana Cayetano Heredia, Перу), Georgina Caswell (Global Network of People Living with HIV, Южная Африка), Александр Чуйков (Фонд медицинской помощи при СПИДе, Российская Федерация), Polly Clayden (HIV i-base, Соединенное Королевство), Suzanne Crowe (Burnet Institute, Австралия), Margarett Davis (United States Centers for Disease Control and Prevention, США), Chris Duncombe (Bill & Melinda Gates Foundation, США), Marhoum El Filali (Ibn Rochd University Hospital, Марок ко), Wafaa El-Sadr (International Center for AIDS Care and Treatment Programs, США), Carlos Falistocco (SIDA y ETS del Ministerio de Salud de la Nación, Аргентина), Donna Futterman (Children’s Hospital at Montefiore, США), Elvin Geng (University of California at San Francisco, США), Charles Gilks (University of Queensland, Австралия), Giovanni Guidotti (DREAM Program, Community of Sant’Egidio, Италия), Bertrand Kampoer (Health consultant, Камерун), Jonathan Kaplan (United States Centers for Disease Control and Prevention, США), Сайранкуль Касымбекова (Республиканский центр по профилактике и борьбе со СПИДом, Казахстан), Tamil Kendall (Trudeau Fondation, Мексика), Karusa Kiragu (ЮНЭЙДС, Швейцария), Emily Koumans (United States Centers for Disease Control and Prevention, США ), Richard Lester (University of British Columbia, Канада), Oyun Lkhagvasuren (Geneva Foundation for Medical Education and Research, Швейцария), Rangsima Lolekha (Ministry of Public Health, Таиланд), Yolisa Mashologu (Human Sciences Research Council, Южная Африка ), Edward Mills (University of Ottawa, Канада), Thomas Minior (United States Agency for International Development, США), Julio Montaner (University of British Columbia, Канада), Lydia Mungherera (The AIDS Support Organization, Уганда), Joseph Murungu (Ministry of Health, Зимбабве), Anthony Mutiti (Kitwe Central Hospital, Замбия), Jean Nachega (Johns Hopkins Bloomberg School of Public Health, США), Steave Nemande (Alternatives-Cameroun, Камерун), John Nkengasong (United States Centers for Disease Control and Prevention, США ), Siobhan O’Connor (United States Centers for Disease Control and Prevention, США ), Sylvia Ojoo (University of Maryland, США), Nittaya Phanuphak (AIDS Research Centre, Таиланд), Christian Pitter (Elizabeth Glaser Pediatri AIDS Foundation, США), Praphan Pranuphak (Thai Red Cross AIDS Research Centre, Таиланд), Helena Rabie (University of Cape Town and Stellenbosch University, Южная Африка), Gilles Raguin (GIP Esther, Франция), Peter Saranchuk (Médecins Sans Frontières, Южная Африка), Erik Schouten (Management Sciences for Health, Малави), Jason Sigurdson (ЮНЭЙДС, Швейцария), Mariângela Simao (ЮНЭЙДС, Швейцария), Annette Sohn (TREAT Asia / amfAR – Foundation for AIDS Research, Таиланд), Luis Soto-Ramirez (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Мексика), Wendy Stevens (National Health Laboratory Service, Южная Африка),

Omar Sued (Fundacion Huésped, Аргентина), Fatiha Terki (World Food Programme, Швейцария), Тенгиз Церцвадзе (Тбилисский государственный университет, Грузия), Emilia Valadas (Clínica Universitária de Doenças Infecciosas e Parasitárias, Португалия), Helena Walkowiak (Management Sciences for Health, США), Alice Welbourn (Salamander Trust, Соединенное Королевство), Robin Wood (University of Cape Town, Южная Африка), Zhao Yan (Chinese Center for Disease Control and Prevention, Китай), Yazdan Yazdanpanah (Université Paris Diderot, Франция), José M. Zuniga (The International Association of Providers of AIDS Care, США) и Sheryl Zwerski (National Institutes of Health, США).

Участники подготовки систематических обзоров по GRADE и изучения подтверждающих фактических данных Обзоры по GRADE и изучения фактических данных: Folasade Adeniyi (Stellenbosch University, Южная Африка), Isabelle Andrieux-Meyer (Médecins Sans Frontières, Швейцария), Andrew Anglemyer (University of California at San Francisco, США), Hana Azman (University of California at San Francisco, США), Till Barnighausen (Harvard School of Public Health, США), Deborah Bain-Brickley (University of California at San Francisco, США), Hilary Barte (University of California at San Francisco, США), Moses Bateganya (University of Washington, США), Heiner Bucher (University Hospital Basel, Швейцария), Krisda Chaiyachati (Yale School of Medicine, США), Larry Chang (Johns Hopkins University, США), Andrea De Luca (Azienda Ospedaliera Universitaria Senese, Италия), Jane Drake (University of California at San Francisco, США), Didier Koumavi Ekouevi (PACCI Programme, Франция), Paul Garner (Liverpool School of Tropical Medicine, Соединенное Королевство), Elvin Geng (University of California at San Francisco, США), Tara Horváth (University of California at San Francisco, США), Andreas Jahn (Ministry of Health, Малави), Alexander Kay (Stanford University, США), Gail Kennedy (University of California at San Francisco, США), Tamara Kredo (South African Cochrane Centre, Южная Африка), Erin McCarthy (University of California at San Francisco, США), Joy Oliver (South African Cochrane Centre, Южная Африка), Rosanna Peeling (London School of Hygiene and Tropical Medicine, Соединенное Королевство), Martina Penazzato (консультант ВОЗ, Швейцария), Rose Phillips (University of California at San Francisco, США), Elizabeth Pienaar (South African Cochrane Centre, Южная Африка), Heike Raatz (University Hospital Basel, Швейцария), Jennifer Read (University of California at San Francisco, США), Sarah Royce (University of California at San Francisco, США), George Rutherford (University of California at San Francisco, США), Nandi Siegfried (University of California at San Francisco, США), Alicen Spaulding (University of Minnesota, США), Amitabh Suthar (консультант ВОЗ, Швейцария), Joseph Tucker (University of North Carolina School of Medicine, США), Gavrilah Wells (University of California at San Francisco, США) и Zara Shubber (Imperial College London, Соединенное Королевство). Работа по моделированию: Andrea Ciaranello (Massachusetts General Hospital, США), Anne Cori (Imperial College London, Соединенное Королевство), Mary-Ann Davies (University of Cape Town, Южная Африка), Jeffrey Eaton (Imperial College London, Соединенное Королевство), Matthias Egger (University of Berne, Швейцария), Christophe Fraser (Imperial College London, Соединенное Королевство), Timothy Hallett (Imperial College London, Соединенное Королевство), Daniel Keebler (South African DST/ NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Южная Африка), Nicolas Menzies (Harvard School of Public Health, США), Paul Revill (University of York, Соединенное Королевство), Michael Schomaker (University of Cape Town, Южная Африка), John Stover (Futures Institute, США) и Peter Vickerman (London School of Hygiene and Tropical Medicine, Соединенное Королевство).

Выражение признательности

Общественные ценности и предпочтения: Alice Kate Armstrong (Children’s HIV Association, Южная Африка), Laura Ferguson (Institute for Global Health, University of Southern California, США), Adam Garner (Global Network of People Living with HIV, США), Carolyn Green (International HIV/AIDS Alliance Associated Consultant, Соединенное Королевство), Amy Hsieh (Global Network of People Living with HIV, США), Nick Keeble (International HIV/AIDS Alliance, Соединенное Королевство), Gitau Mburu (International HIV/ AIDS Alliance, Соединенное Королевство), Florence Ngobeni (Children’s HIV Association, Южная Африка), Mala Ram (International HIV/AIDS Alliance, Соединенное Королевство), Anja Teltschik (International HIV/AIDS Alliance, Соединенное Королевство), Robert Worthington (Kwantu, Соединенное Королевство), и Референтная группа ВОЗ по вопросам гражданского общества i. Christoforos Mallouris (консультант ВОЗ) обеспечивал координационную поддержку для проведения общественных консультаций с Международным альянсом по ВИЧ/СПИДу и Глобальной сетью людей, живущих с ВИЧ.

Выражение признательности

Сотрудники и консультанты ВОЗ Andrew Ball и Philippa Easterbrook (Департамент ВИЧ) координировали весь процесс подготовки руководства при поддержке со стороны Cadi Irvine (консультант, Департамент ВИЧ). Контроль за подготовкой компонентов по клиническим аспектам и предоставлению услуг осуществлялся Meg Doherty (Департамент ВИЧ), а работа четырех групп по разработке рекомендаций координировалась Eyerusalem Kebede Negussie (группа по разработке рекомендаций в области осуществления деятельности и предоставлению услуг, Департамент ВИЧ), Lulu Muhe и Nathan Shaffer (группа по разработке рекомендаций в области охраны здоровья матери и ребенка, Департамент по охране здоровья матерей, детей и подростков и Департамент ВИЧ), Marco Vitoria (группа по разработке рекомендаций в отношении взрослых, Департамент ВИЧ) и Joseph Perriëns (группа по разработке рекомендаций в области программной деятельности). Вышеуказанные лица входят в состав Руководящей группы ВОЗ по подготовке руководства. Особая благодарность выражается следующим консультантам ВОЗ, которые внесли большой вклад в составление рекомендаций и проведение научных исследований: Jhoney Barcarolo (рекомендации для руководителей программ), Shaffiq Essajee (охрана здоровья матери и ребенка), Martina Penazzato (охрана здоровья матери и ребенка) и Amitabh Suthar (взрослые люди, осуществление деятельности и предоставление услуг). Ian Grubb оказывал общую помощь при составлении текста и координации этой работы. David Breuer осуществлял техническую редакцию текста. В подготовке руководства принимали участие также следующие консультанты ВОЗ: April Baller, Sally Girvin, Kathleen Fox, Elizabeth Marum, Priya Shetty и Michelle Williams. i

Референтная группа ВОЗ по вопросам гражданского общества: Eddie Banda (Malawi Network of People Living with HIV/AIDS (MANET+), Малави), Mabel Bianco (Fundación para el Estudio e Investigación de la Mujer (FEIM), Аргентина), Tung Bui (Youth Voices Count, Таиланд), Michaela Clayton (AIDS and Rights for Southern Africa, Намибия), Lee Hertel (International Network of People Who Use Drugs, США), Ruth Mery Linares Hidalgo (Ciudad Quesada, Коста-Рика), Noreen Huni (Regional Psychosocial Support Initiative (REPSSI), Южная Африка), Matthew Kavanagh (Health Gap, США), JoAnne Keatley (University of California at San Francisco, США), Sharonann Lynch (Doctors without Borders, США), Babalwa Mbono (Mothers to Mothers (M2M), Южная Африка), Gitau Mburu (International HIV/ AIDS Alliance, Соединенное Королевство), Othoman Mellouk (orum on MSM and HIV, Марокко), Luís Mendão (European AIDS Treatment Group, Португалия), Noah Metheny (Global Forum on MSM and HIV, США), Carlo Oliveras (Caribbean Treatment Action Group, Пуэрто-Рико), Rachel Ong (Communities Delegation to the Board of the Global Fund to Fight AIDS, Tuberculosis and Malaria, Сингапур), Asia Russell (Health Gap, США), Leickness Simbayi (Human Sciences Research Council, Южная Африка), Felly Nkweto Simmonds (Population Council, Замбия), Lucy Stackpool-Moore (International Planned Parenthood Federation, Соединенное Королевство), Ruth Morgan Thomas (Global Network of Sex Workers Projects, Соединенное Королевство) и Mary Ann Torres (International Council of AIDS Service Organizations, Канада).

В подготовку этого руководства внесли вклад следующие сотрудники ВОЗ: Rachel Baggaley (Департамент ВИЧ), Silvia Bertagnolio (Департамент ВИЧ), Jesus García Calleja (Департамент ВИЧ), Agnes Chetty (Региональное бюро ВОЗ для стран Восточного Средиземноморья), Ирина Ерамова (Европейское региональное бюро ВОЗ), Nathan Ford (Департамент ВИЧ), Masami Fujita (Региональное бюро ВОЗ для стран Западной части Тихого океана), Haileyesus Getahun (Департамент «Остановить ТБ»), Vincent Habiyambere (Департамент ВИЧ), Chika Hayashi ( Департамент ВИЧ), Masaya Kato (Региональное бюро ВОЗ для стран Западной части Тихого океана), Лали Хотенашвили, (Европейское региональное бюро ВОЗ), Ying-Ru Lo (Региональное бюро ВОЗ для стран Западной части Тихого океана), Frank Lule (Региональное бюро ВОЗ для стран Африки), Viviana Mangiaterra (Департамент по репродуктивному здоровью и научным исследованиям), Hernan Julio Montenegro (Департамент по политике, развитию и службам здравоохранения), Lisa Nelson (Департамент ВИЧ), Morkor Newman (Региональное бюро ВОЗ для стран Африки), Boniface Dongmo Nguimfack (Департамент ВИЧ), Linh Nguyen (Департамент «Остановить ТБ»), Kevin O’Reilly (Департамент ВИЧ), Brian Pazvakavambwa (Региональное бюро ВОЗ для стран Африки), Razia Pendse (Региональное бюро ВОЗ для стран Юго-Восточной Азии), Françoise Renaud-Théry (Департамент ВИЧ), Bharat B. Rewari (Региональное бюро ВОЗ для стран Юго-Восточной Азии), Nigel Rollins (Департамент по охране здоровья матерей, детей и подростков), Anita Sands (Департамент основных лекарственных средств и изделий медицинского назначения), Yves Souteyrand (Региональное бюро ВОЗ для стран Восточного Средиземноморья), Isseu Diop Toure (Региональное бюро ВОЗ для стран Африки), Annette Verster (Департамент ВИЧ), Gundo Weiler (Департамент ВИЧ) и Stefan Wiktor (Департамент пандемических и эпидемических заболеваний). Помощь в работе оказывали интерны ВОЗ: Grace Akol, Hanna Yemane Berhane, Jayne Ellis и Valentin Petey. Административная поддержка ВОЗ осуществлялась под руководством Hayet Souissi и Jasmin Leuterio. Коммуникационная поддержка была оказана Oyuntungalag Namjilsuren, Sarah Russell и Glenn Thomas. Maryann-Nnenkai Akpama, Afrah Al-Doori, Adriana De Putter, Lydia Mirembe Kawanguzi, Jane Ndanareh, Laurent Poulain и Ophelia Riano также оказывали поддержку в административно-управленческой работе.

Финансирование Данная работа была проведена при финансовой поддержке, предоставленной Центрами США по контролю и профилактике заболеваний, Фондом Билла и Мелинды Гейтс, Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ), Единым бюджетом, планом работы и рамками отчетности ЮНЭЙДС, Агентством США по международному развитию и отдельными фондами путем оплаты рабочего времени сотрудников ВОЗ. Кроме того, ВОЗ выражает особую благодарность учреждениям, которые внесли вклад в процесс подготовки данного руководства путем предоставления рабочего времени своих сотрудников и других нематериальных ресурсов.

Предисловие

ПРЕДИСЛОВИЕ Данная публикация является первым сводным руководством ВОЗ по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции. Оно ставит смелые задачи в плане ожидаемого воздействия, однако отличается простотой подходов и основывается на надежных фактических данных. В нем использован ряд новейших тенденций, включая предпочтительную схему лечения, которая была упрощена до приема один раз в день одной таблетки комбинированного препарата с фиксированными дозами, что обеспечивает большую безопасность и доступность по цене. В руководстве также использованы фактические данные, убедительно демонстрирующие многочисленные преимущества антиретровирусной терапии. При правильном и своевременном лечении люди с ВИЧ теперь могут рассчитывать на долгую и здоровую жизнь. Они также способны защитить своих сексуальных партнеров и грудных детей, поскольку риск передачи вируса значительно снижается. Это руководство представляет собой новый важный шаг вперед на пути к достижению еще более грандиозных целей и успехов. В Африке, регионе, который несет наибольшее бремя эпидемии ВИЧ, к концу 2012 года лечение получали примерно 7,5 миллиона человек, в то время как десять лет назад их число составляло лишь 50 тысяч. Во всем мире лечение получали примерно 9,7 миллиона человек, что указывает на возможность достижения глобальной цели охвата антиретровирусной терапией 15 миллионов человек к 2015 году. Это достижение является результатом самых высоких темпов расширения масштабов мер общественного здравоохранения, сохраняющих жизни людей, за всю историю. Одним из важнейших условий ускорения прогресса является начало лечения в более ранние сроки в соответствии с рекомендациями, содержащимися в руководстве. Как показывают имеющиеся фактические данные, более раннее начало лечения обеспечивает двойное преимущество увеличения продолжительности здоровой жизни людей и резкого снижения риска передачи вируса другим людям. Проведение лечения в более ранние сроки способствует также упрощению операционных требований, предъявляемых к программам. В руководстве рекомендуется начинать лечение беременных женщин и детей в возрасте до пяти лет сразу же после постановки диагноза. Единая схема приема одной таблетки комбинированного препарата один раз в день теперь рекомендуется всем взрослым, живущим с ВИЧ, в том числе страдающим туберкулезом, гепатитом и другими сопутствующими инфекционными заболеваниями. Дополнительные рекомендации, содержащиеся в руководстве, ставят своей целью помочь программам приблизить службы помощи к месту жительства; ускорить получение результатов тестов; более тесно интегрировать лечение ВИЧ со службами дородовой, противотуберкулезной, наркологической и иной помощи; а также использовать более широкий круг работников здравоохранения для проведения лечения и оказания дальнейшей помощи.

Страны обратились к ВОЗ с просьбой разработать более простое руководство по использованию антиретровирусных препаратов. Я полагаю, что настоящее сводное руководство вносит важный вклад в выполнение этой просьбы. В нем приводятся рекомендации для всех возрастных групп и групп населения. Рекомендации по клиническим вопросам сопровождаются рекомендациями по операционной и программной деятельности, касающимися важнейших аспектов лечения и оказания помощи – от тестирования до охвата и удержания пациентов службами помощи, а также от оказания общей помощи при ВИЧ до ведения сопутствующих заболеваний. Новые рекомендации предлагают внести значительные изменения в программы. Они также требуют большего объема инвестиций. Я лично убеждена в том, что в будущем меры борьбы с ВИЧ будут следовать тенденциям последнего времени, то есть основываться на постоянной готовности развивать достигнутые успехи и решать новые сложные задачи. По оценкам ВОЗ, их воздействие будет беспрецедентно высоким: выполнение этих рекомендаций в глобальном масштабе в период до 2025 года может предотвратить три миллиона случаев смерти в дополнение к тем, которые могут быть предотвращены с помощью руководства 2010 года, а также предупредить примерно 3,5 миллиона новых случаев инфицирования. Такие перспективы – немыслимые всего лишь несколько лет назад – могут придать новый импульс усилиям, направленным на необратимое снижение эпидемии ВИЧ. Я настоятельно призываю страны и их партнеров в области развития воспользоваться этой уникальной возможностью, которая выводит нас на новый этап нашего пути.

Д-р Маргарет Чен Генеральный директор ВОЗ

Исполнительное резюме

ИСПОЛНИТЕЛЬНОЕ РЕЗЮМЕ Настоящее сводное руководство содержит новые рекомендации в отношении диагностики инфекции, вызываемой вирусом иммунодефицита человека (ВИЧ), оказания помощи людям, живущим с ВИЧ, и использования антиретровирусных (АРВ) препаратов для лечения и профилактики ВИЧ-инфекции. Эти рекомендации касаются всех этапов оказания помощи при ВИЧ, включая тестирование, уход и лечение. В данном руководстве не рассматриваются поведенческие, биомедицинские и структурные меры вмешательства, которые не предусматривают использования АРВ-препаратов. В процессе подготовки сводного руководства 2013 года были объединены и сведены воедино рекомендации, содержащиеся в различных руководствах ВОЗ и других документах, включая руководство 2010 года по применению антиретровирусной терапии (АРТ) при ВИЧ-инфекции у взрослых и подростков, у детей грудного и более старшего возраста, а также по лечению беременных женщин, живущих с ВИЧ, и профилактике ВИЧ-инфекции у младенцев. Предоставляются подробные рекомендации в отношении использования АРВ-препаратов во всех возрастных группах среди взрослых лиц, беременных и кормящих грудью женщин, подростков, детей и ключевых групп населения. Данное руководство также ставит своей целью обобщить и обновить рекомендации по клиническим вопросам, по предоставлению услуг и по ведению программ. В руководстве 2013 года отражены важные достижения в области мер борьбы с ВИЧ за последние три года. С 2010 года новые технологии, включая тестирование на клетки CD4 по месту оказания помощи и новые подходы к предоставлению услуг, позволяют обеспечить диверсификацию и децентрализацию при проведении тестирования на ВИЧ и контроля за лечением. Более простые и безопасные схемы АРВ-терапии, предусматривающие прием одной таблетки один раз в день и пригодные для использования в большинстве групп населения разных возрастов, стали более доступными и приемлемыми по цене в странах с низким и средним уровнями дохода. Страны переходят к трехкомпонентным схемам лечения, начинающемуся в более ранние сроки, и использованию более простых программ профилактики передачи ВИЧ-инфекции от матери ребенку (ППМР), в которых основное внимание уделяется долгосрочным мерам охраны здоровья беременных женщин и матерей, живущих с ВИЧ, и профилактике ВИЧ-инфекции у их детей. Широкие преимущества использования АРВ-препаратов для профилактики ВИЧ получают всеобщее признание: помимо улучшения состояния здоровья и продления жизни, АРТ предупреждает передачу ВИЧ половым путем. Предэкспозиционная профилактика ВИЧ с помощью АРВ-препаратов расширяет возможности предупреждения ВИЧ-инфицирования, в то время как постэкспозиционная профилактика ВИЧ продолжает играть важную роль в случае контакта с источником ВИЧ в некоторых группах населения и при разных обстоятельствах, включая жертв сексуального насилия. Хотя уровень охвата АРТ и выполнения рекомендаций ВОЗ 2010 года различен в разных странах, повсеместно наблюдается тенденция к тому, чтобы начинать лечение лиц с ВИЧ в более ранние сроки.

В соответствии с предыдущими рекомендациями ВОЗ, руководство 2013 года основано на подходе общественного здравоохранения в целях дальнейшего расширения использования АРВ-препаратов для лечения и профилактики, принимая во внимание практическую осуществимость и эффективность такого подхода в условиях ограниченности ресурсов. Новые клинические рекомендации, содержащиеся в этом руководстве, способствуют расширению круга лиц, отвечающих критериям проведения АРТ, при этом пороговое содержание клеток CD4, являющееся показанием для начала лечения взрослых, подростков и детей старшего возраста, составляет 500 клеток/мм3 или менее. Первоочередное внимание следует уделять лицам с тяжелым течением или на поздней стадии заболевания, вызванного ВИЧ, а также лицам, у которых количество CD4 составляет 350 клеток/мм3 или менее. В некоторых группах людей рекомендуется начинать проведение АРТ при любом количестве клеток CD4, включая лиц с активной формой туберкулеза (ТБ), живущих с ВИЧ; лиц, коинфицированных ВИЧ и вирусом гепатита B (ВГВ), страдающих тяжелым хроническим заболеванием печени; ВИЧ-позитивных партнеров в серодискордантных парах; беременных и кормящих грудью женщин; а также детей в возрасте до пяти лет. По мере возможности рекомендуется обеспечивать гармонизацию схем АРВ-терапии для взрослых и детей, используя новую предпочтительную схему АРВ-терапии первого ряда. Подчеркивается необходимость прекращения использования ставудина (d4T) в схемах АРВ-терапии первого ряда для взрослых и подростков. В настоящее время рекомендуется определение вирусной нагрузки в качестве предпочтительного метода мониторинга эффективности АРТ и выявления неудачи лечения в дополнение к клиническому и иммунологическому мониторингу лиц, получающих АРТ. В руководстве подчеркивается, что АРВ-препараты следует использовать на всех этапах оказания непрерывной помощи при ВИЧ. Приводятся дополнительные новые рекомендации по проведению ВИЧ-тестирования и консультирования на уровне местных сообществ, а также ВИЧ-тестирования подростков. Помимо новых рекомендаций, представлена краткая информация и ссылки на существующие рекомендации ВОЗ в отношении ВИЧ-тестирования и консультирования, профилактики ВИЧ, общей медицинской помощи людям, живущим с ВИЧ, ведения наиболее распространенных сочетанных инфекций и других сопутствующих заболеваний, а также мониторинга и ведения случаев лекарственной токсичности. Некоторые существующие рекомендации нуждаются в обновлении, а новые рекомендации в ближайшие несколько лет должны пересматриваться по мере получения новых фактических данных. Расширение круга лиц, отвечающих критериям получения АРТ, а также вариантов использования АРВ-препаратов открывает новые возможности для спасения жизней, улучшения результатов лечения и сокращения числа случаев ВИЧ-инфекции, однако ставит новые задачи перед лицами, определяющими политику, и исполнителями во многих странах. Новое практическое руководство 2013 года предоставляет рекомендации для усиления основных аспектов схем непрерывного оказания помощи при ВИЧ и расширения взаимодействия в рамках всей системы здравоохранения. Основное внимание в данном руководстве уделяется также стратегиям, направленным на улучшение показателей удержания пациентов в системе оказания помощи при ВИЧ и строгого соблюдения АРТ, а также децентрализации предоставления АРТ в рамках первичной медико-санитарной помощи, служб охраны материнства и детства, противотуберкулезных клиник и наркологических служб. В данном практическом руководстве также рассматривается значение новых клинических рекомендаций для лабораторных служб и систем закупок и поставок АРВ-препаратов и других материалов.

Исполнительное резюме

В руководстве, специально разработанном для руководителей программ по ВИЧ, рассматриваются такие вопросы, как принятие решений и планирование для стратегического использования АРВ-препаратов в процессах руководства на национальном уровне, эпидемиология ВИЧ, потенциал систем здравоохранения, наличие финансовых ресурсов, а также вопросы этики и соблюдения прав человека. В отношении основных новых рекомендаций рассматриваются вопросы их осуществления, особенно касающиеся руководителей программ. В заключительной главе, касающейся мониторинга и оценки, содержится предварительное руководство в отношении контроля за выполнением новых рекомендаций. Процесс пересмотра для подготовки руководства 2013 года проводился в соответствии с процедурами, установленными Комитетом ВОЗ по обзору руководящих принципов. Новые клинические и практические рекомендации, содержащиеся в руководстве, основаны на системе GRADE (Классификация оценки, разработки и определения весомости рекомендаций) для рассмотрения фактических данных и принятия решений. Клинические, операционные и программные рекомендации разрабатывались с учетом результатов моделирования, консультаций с экспертами и изучения практического опыта отдельных стран. В ходе этого процесса были выявлены пробелы в знаниях для разработки программ будущих научных исследований. Помимо новых рекомендаций, основанных на системе GRADE, в руководстве кратко изложены существующие рекомендации из других руководств ВОЗ. Большинство этих рекомендаций были разработаны с помощью системы GRADE или модификации рейтинга GRADE в отношении силы рекомендаций и качества фактических данных. Настоящее руководство предназначено, в основном, для руководителей программ по ВИЧ, особенно в странах с низким и средним уровнями дохода. Предполагается, что данное руководство будет использоваться при принятии стратегических решений и планировании мер по расширению АРТ в странах. Оно будет являться ценным источником информации для клиницистов и указывать приоритетные направления деятельности для агентств по развитию, международных организаций, неправительственных организаций и других партнеров-исполнителей в ближайшие несколько лет. Руководство 2013 года представляет собой важный шаг на пути к обеспечению всеобщего доступа к АРВ-препаратам для лечения и профилактики ВИЧ, повышая эффективность, действенность и устойчивость программ использования АРВ-препаратов для достижения конечной цели ликвидации эпидемии ВИЧ.

Исполнительное резюме

Краткое содержание новых рекомендаций Новые рекомендации ВОЗ в отношении тестирования на ВИЧ и консультирования, антиретровирусной терапии (АРТ) и предоставления услуг при ВИЧ, подготовленные для руководства 2013 года, кратко изложены в приводимой ниже таблице. В ней также приводятся рекомендации для руководителей программ, представленные в Главе 10. Если рекомендации не изменились по сравнению с руководством по АРТ 2010 года, это отмечено в таблице. Данная таблица не является всеобъемлющей и не включает все рекомендации, содержащиеся в этом руководстве, особенно взятые из других ранее опубликованных руководств ВОЗ. Рекомендации ВОЗ, упомянутые в таблице, содержатся в следующих главах: Глава 5 (ВИЧ-тестирование и консультирование, а также профилактика ВИЧ); Глава 6 (Общая медицинская помощь людям, живущим с ВИЧ); Глава 8 (Ведение наиболее распространенных сочетанных инфекций и других сопутствующих заболеваний); и Раздел 7.4 (Мониторинг и ведение случаев лекарственной токсичности).

Тестирование на ВИЧ и консультирование Тема и группа населения Тестирование по месту жительства Рекомендации При генерализованной эпидемии ВИЧ рекомендуется проводить тестирование на ВИЧ и консультирование по месту жительства, поддерживая контакты со службами профилактики, помощи и лечения, в дополнение к тестированию и консультированию по инициативе поставщиков услуг (настоятельная рекомендация, фактические данные низкого качества). Во всех местах, где происходит эпидемия ВИЧ, рекомендуется проводить тестирование на ВИЧ и консультирование для ключевых групп населения по месту жительства, поддерживая контакты со службами профилактики, помощи и лечения, в дополнение к тестированию и консультированию по инициативе поставщиков услуг (настоятельная рекомендация, фактические данные низкого качества). Рекомендуется проводить тестирование на ВИЧ и консультирование подростков из ключевых групп населения, поддерживая контакты со службами профилактики, помощи и лечения, при всех условиях (генерализованная эпидемия, эпидемия низкого уровня и концентрированная эпидемия) (настоятельная рекомендация, фактические данные очень низкого качества). Рекомендуется проводить тестирование на ВИЧ и консультирование всех подростков при генерализованной эпидемии, поддерживая контакты со службами профилактики, помощи и лечения (настоятельная рекомендация, фактические данные очень низкого качества). Мы предлагаем обеспечить доступность тестирования на ВИЧ и консультирования всех подростков при эпидемии низкого уровня и концентрированной эпидемии, поддерживая контакты со службами профилактики, помощи и лечения (условная рекомендация, фактические данные очень низкого качества). Мы предлагаем проводить консультирование всех подростков в отношении потенциальных преимуществ и рисков, связанных с раскрытием информации об их ВИЧ-статусе, а также предоставлять им возможность определять, следует ли раскрывать эту информацию, и если да, то когда, каким образом и кому, и оказывать поддержку в этом (условная рекомендация, фактические данные очень низкого качества).

Тестирование на ВИЧ и консультирование подростковa

Краткое содержание новых рекомендаций

Когда начинать АРТ у людей, живущих с ВИЧ Тема и группа населения Когда начинать АРТ у взрослых и подростков a Рекомендации АРТ следует назначать в приоритетном порядке всем лицам с тяжелым течением или на поздней стадии заболевания, вызванного ВИЧ (клинические стадии 3 или 4 по классификации ВОЗ), и лицам с количеством CD4 ≤350 клеток/мм3 (настоятельная рекомендация, фактические данные среднего качества) АРТ следует назначать всем ВИЧ-инфицированным лицам с количеством CD4 > 350 клеток/мм³ и ≤500 клеток/мм3, независимо от клинической стадии по классификации ВОЗ (настоятельная рекомендация, фактические данные среднего качества). А РТ следует назначать всем ВИЧ-инфицированным лицам, независимо от клинической стадии или количества CD4, в следующих случаях: • Лица с ВИЧ и активной формой ТБ (настоятельная рекомендация, фактические данные низкого качества). • Лица, коинфицированные ВИЧ и ВГВ, с признаками тяжелого хронического заболевания печени (настоятельная рекомендация, фактические данные низкого качества). • Партнеры с ВИЧ в серодискордантных парах следует предлагать АРТ для снижения передачи ВИЧ неинфицированным партнерам (настоятельная рекомендация, фактические данные высокого качества). Когда начинать АРТ у беременных и кормящих грудью женщин сем беременным и кормящим грудью женщинам с ВИЧ следует В назначать три препарата АРВ (АРТ), которые следует принимать, как минимум, в течение периода, когда имеется риск передачи от матери ребенку. Женщины,] соответствующие критериям проведения АРТ, должны получать такое лечение в течение всей жизни (настоятельная рекомендация, фактические данные среднего качества). По программным и операционным соображениям, особенно при генерализованных эпидемиях, всем беременным и кормящим грудью женщинам с ВИЧ следует назначать АРТ в качестве пожизненного лечения (условная рекомендация, фактические данные низкого качества). В некоторых странах в отношении женщин, не отвечающих критериям проведения АРТ по состоянию здоровья, можно рассматривать возможность прекращения приема АРВ-препаратов после окончания периода, когда имеется риск передачи от матери ребенку (условная рекомендация, фактические данные низкого качества).

Подростками являются лица в возрасте от 10 до 19 лет включительно.

Тестирование на ВИЧ и консультирование (продолжение) Тема и группа населения АРВ и продолжительность грудного вскармливания Рекомендации Сохраняются основные принципы и рекомендации, установленные в 2010 году, в том числе следующие: Национальные или субнациональные органы здравоохранения должны решить, следует ли службам охраны здоровья матери и ребенка, в основном, рекомендовать матерям с установленной ВИЧ-инфекцией либо продолжать грудное вскармливание и получать АРВпрепараты, либо полностью избегать грудного вскармливания ввиду их состояния, и оказывать содействие в этом. В тех случаях, когда национальные органы приняли решение о том, что службы охраны здоровья матери и ребенка будут, в основном, рекомендовать грудное вскармливание и получение АРВ-препаратов в качестве стратегии, которая с наибольшей вероятностью будет давать грудным детям, рожденным матерями с установленной ВИЧ-инфекцией, максимальный шанс на выживание без ВИЧ, и оказывать содействие в этом: атери с установленной ВИЧ-инфекцией (чьи дети не инфицированы М ВИЧ или ВИЧ-статус которых не известен) должны применять исключительно грудное вскармливание своих детей в течение первых шести месяцев жизни, вводя затем соответствующий прикорм, и продолжать грудное вскармливание в течение первых 12 месяцев жизни. Грудное вскармливание следует затем прекращать только при возможности предоставления адекватного и безопасного рациона питания без грудного молока (настоятельная рекомендация, фактические данные высокого качества для первых шести месяцев; фактические данные низкого качества для рекомендаций в отношении 12 месяцев). Когда начинать АРТ у детей РТ следует начинать у всех детей, инфицированных ВИЧ, в возрасте А до 5 лет, независимо от клинической стадии по классификации ВОЗ или количества клеток CD4. • Г рудные дети, которым поставлен диагноз в течение первого года жизни (настоятельная рекомендация, фактические данные среднего качества). • Д ети, инфицированные ВИЧ в возрасте от одного до пяти лет (условная рекомендация, фактические данные очень низкого качества). РТ следует начинать у всех ВИЧ-инфицированных детей в возрасте А от пяти лет и старше с количеством клеток CD4 ≤500 клеток/мм3, независимо от клинической стадии по классификации ВОЗ. • Количество CD4 ≤350 клеток/мм3 (настоятельная рекомендация, фактические данные среднего качества). • Количество CD4 от 350 до 500 клеток/мм3 (условная рекомендация, фактические данные очень низкого качества). РТ следует начинать у всех ВИЧ-инфицированных детей с тяжелым А течением или на поздней стадии симптоматического заболевания (клиническая стадия 3 или 4 по классификации ВОЗ), независимо от возраста и количества CD4 (настоятельная рекомендация, фактические данные среднего качества). РТ следует начинать у всех детей в возрасте до 18 месяцев, которым А был поставлен предположительный клинический диагноз ВИЧ-инфекции (настоятельная рекомендация, фактические данные низкого качества).

Краткое содержание новых рекомендаций

С каких схем АРВ-терапии следует начинать Тема и группа населения Схемы АРВ-терапии первого ряда для взрослых Рекомендации РТ первого ряда должна включать два нуклеозидных А ингибитора обратной транскриптазы (НИОТ) плюс один ненуклеозидный ингибитор обратной транскриптазы (ННИОТ). • В качестве предпочтительной схемы для начала АРТ рекомендуется тенофовир + ламивудин (или эмтрицитабин) + эфавиренз как комбинированный препарат с фиксированными дозами (настоятельная рекомендация, фактические данные среднего качества). • Е сли тенофовир + ламивудин (или эмтрицитабин) + эфавиренз противопоказаны или не имеются в наличии, рекомендуется одна из следующих схем: • зидовудин + ламивудин + эфавиренз • зидовудин + ламивудин + невирапин • тенофовир + ламивудин (или эмтрицитабин) + невирапин (настоятельная рекомендация, фактические данные среднего качества). Странам следует прекратить использование ставудина в схемах первого ряда в связи с его общепризнанной метаболической токсичностью (настоятельная рекомендация, фактические данные среднего качества). АРТ первого ряда для беременных и кормящих грудью женщин и их детей рием комбинированного препарата с фиксированными дозами П тенофовир + ламивудин (или эмтрицитабин) + эфавиренз один раз в день рекомендуется в качестве АРТ первого ряда для беременных и кормящих грудью женщин, включая беременных женщин в первом триместре беременности и женщин детородного возраста. Эта рекомендация касается как пожизненного лечения, так и АРТ, которая назначается для ППМР и затем прекращается (настоятельная рекомендация, фактические данные низкого или среднего качества: фактические данные среднего качества для взрослых людей в целом, но низкого качества для конкретных групп беременных и кормящих грудью женщин и грудных детей). рудные дети, матери которых получают АРТ и осуществляют Г грудное вскармливание, должны получать профилактическое лечение в течение шести недель с ежедневным приемом невирапина. Если дети переведены на альтернативное вскармливание, они должны получать профилактическое лечение в течение четырех- шести недель с приемом невирапина один раз в день (или зидовудина два раза в день). Профилактика грудных детей должна начинаться с рождения или когда воздействие ВИЧ выявлено после родов (настоятельная рекомендация, фактические данные среднего качества для детей, получающих грудное вскармливание; настоятельная рекомендация, фактические данные низкого качества для грудных детей, получающих только альтернативное вскармливание).

С каких схем АРВ-терапии следует начинать (продолжение) Тема и группа населения АРТ первого ряда для детей в возрасте до 3 лет Рекомендации В качестве АРТ первого ряда для всех ВИЧ-инфицированных детей в возрасте до трех лет (36 месяцев), независимо от воздействия ННИОТ, следует использовать схему лечения на основе лопинавира/ ритонавира. Если использовать лопинавир/ритонавир не представляется возможным, лечение следует начинать со схемы на основе невирапина (настоятельная рекомендация, фактические данные среднего качества). В тех случаях, когда осуществляется мониторинг вирусной нагрузки, следует рассмотреть возможность замены лопинавира/ ритонавира на ННИОТ после достижения супрессии виремии (условная рекомендация, фактические данные низкого качества). Д ля грудных детей и детей в возрасте до трех лет, инфицированных ВИЧ, в качестве варианта лечения детей, у которых развивается ТБ во время проведения АРВ-терапии по схеме, содержащей невирапин или лопинавир/ритонавир, рекомендуется абакавир + ламивудин + зидовудин. После окончания курса противотуберкулезного лечения эта схема должна быть прекращена, и следует вновь перейти на первоначальную схему лечения (настоятельная рекомендация, фактические данные среднего качества). ля грудных детей и детей в возрасте до трех лет, Д инфицированных ВИЧ, в качестве основы из двух НИОТ для схемы АРВ-терапии следует использовать абакавир + ламивудин или зидовудин + ламивудин (настоятельная рекомендация, фактические данные низкого качества). АРТ первого ряда для детей в возрасте 3 лет и старше (включая подростков) Д ля ВИЧ-инфицированных детей в возрасте трех лет и старше предпочтительным ННИОТ для лечения первого ряда является эфавиренз, а в качестве альтернативного препарата – невирапин (настоятельная рекомендация, фактические данные низкого качества). Д ля ВИЧ-инфицированных детей в возрасте от трех до десяти лет (или подростков, весящих менее 35 кг), основой из двух НИОТ для схемы АРВ-терапии должна служить одна из приведенных ниже комбинаций в следующем предпочтительном порядке: • а бакавир + ламивудин зидовудин или тенофовир + ламивудин (или эмтрицитабин) • (условная рекомендация, фактические данные низкого качества). Д ля ВИЧ-инфицированных подростков (от 10 до 19 лет), весящих 35 кг или более, основа из двух НИОТ для схемы АРВ-терапии должна соответствовать схемам, применяемым для взрослых, являясь одной из приведенных ниже комбинаций в следующем предпочтительном порядке: • т енофовир + ламивудин (или эмтрицитабин) • з идовудин + ламивудин абакавир + ламивудин • (настоятельная рекомендация, фактические данные низкого качества).

Краткое содержание новых рекомендаций

Мониторинг эффективности АРТ и выявление неудачи лечения Тема и группа населения Все группы населения Рекомендации В качестве предпочтительного метода мониторинга для выявления и подтверждения неудачи лечения АРВ рекомендуется использовать вирусную нагрузку (настоятельная рекомендация, фактические данные низкого качества). Если нет возможности проводить регулярное определение вирусной нагрузки, для выявления неудачи лечения следует использовать количество CD4 и клинический мониторинг (настоятельная рекомендация, фактические данные среднего качества).

АРТ второго ряда: на какую схему АРВ-терапии следует переходить Тема и группа населения На какую схему АРВ следует переходить у взрослых и подростков (включая беременных и кормящих грудью женщин) Рекомендации А РТ второго ряда для взрослых должна включать два нуклеозидных ингибитора обратной транскриптазы (НИОТ) + ингибитор протеазы (ИП), усиленный ритонавиром. Рекомендуется следующая последовательность выбора НИОТ для второго ряда: • П осле неудачного использования схемы первого ряда на основе тенофовира + ламивудина (или эмтрицитабина) в качестве основы из двух НИОТ в схемах второго ряда следует использовать зидовудин + ламивудин. • П осле неудачного использования схемы первого ряда на основе зидовудина или ставудина + ламивудина в качестве основы из двух НИОТ в схемах второго ряда следует использовать тенофовир + ламивудин (или эмтрицитабин). В качестве предпочтительного подхода рекомендуется использовать основу из двух НИОТ в виде комбинированного препарата с фиксированными дозами (настоятельная рекомендация, фактические данные среднего качества). Предпочтительными вариантами усиленного ИП для АРТ второго ряда являются термостабильные комбинации атазанавир/ритонавир и лопинавир/ритонавир (настоятельная рекомендация, фактические данные среднего качества).

АРТ второго ряда: на какую схему АРВ-терапии следует переходить (продолжение) Тема и группа населения На какую схему АРВ следует переходить у детей (включая подростков) Рекомендации П осле неудачного использования схемы первого ряда на основе ННИОТ для АРТ второго ряда рекомендуется использовать усиленный ИП плюс два НИОТ; предпочтительным усиленным ИП является лопинавир/ритонавир (настоятельная рекомендация, фактические данные среднего качества). П осле неудачного использования схемы первого ряда на основе лопинавира /ритонавира у детей в возрасте до трех лет следует продолжать применение схемы первого ряда и принимать меры к обеспечению ее лучшего соблюдения (условная рекомендация, фактические данные очень низкого качества). П осле неудачного использования схемы первого ряда на основе лопинавира/ ритонавира у детей в возрасте трех лет и старше следует переключаться на схему второго ряда, содержащую ННИОТ плюс два НИОТ; предпочтительным ННИОТ является эфавиренз (условная рекомендация, фактические данные низкого качества). П осле неудачного использования схемы первого ряда, содержащей абакавир или тенофовир + ламивудин (или эмтрицитабин), предпочтительной основой из двух НИОТ для АРТ второго ряда является зидовудин + ламивудин (настоятельная рекомендация, фактические данные низкого качества). П осле неудачного использования схемы первого ряда, содержащей зидовудин или ставудин + ламивудин (или эмтрицитабин), предпочтительной основой из двух НИОТ для АРТ второго ряда является абакавир или тенофовир + ламивудин (или эмтрицитабин) (настоятельная рекомендация, фактические данные низкого качества).

АРТ третьего ряда Тема и группа населения Все группы населения Рекомендации В рамках национальных программ следует разработать стратегии проведения АРТ третьего ряда (условная рекомендация, фактические данные низкого качества). С хемы третьего ряда должны включать новые препараты с минимальным риском перекрестной устойчивости к ранее использовавшимся схемам, таким как ингибиторы интегразы и ННИОТ и ИП второго поколения (условная рекомендация, фактические данные низкого качества). При отсутствии новых вариантов использования АРВ-препаратов пациентам, у которых схема второго ряда не дает положительных результатов, следует продолжать лечение по переносимой ими схеме (условная рекомендация, фактические данные очень низкого качества). Особые соображения в отношении детей В случае неудачи лечения второго ряда необходимо рассмотреть возможность применения стратегий, обеспечивающих должное соотношение преимуществ и рисков для детей. Для детей более старшего возраста и подростков, в отношении которых имеется больше вариантов лечения, может быть возможно составить схему АРВ-терапии третьего ряда с использованием новых препаратов, применяемых при лечении взрослых, таких как этравирин, дарунавир и ралтегравир. При отсутствии новых АРВ-препаратов для детей, у которых схема второго ряда не дает положительных результатов, следует продолжать лечение по переносимой ими схеме. В случае прекращения АРТ следует не допускать развития оппортунистических инфекций, облегчать симптомы и устранять боль.

Краткое содержание новых рекомендаций

Осуществление деятельности и предоставление услуг Тема и группа населения Меры обеспечения оптимального соблюдения АРТ Рекомендации С ледует рассмотреть возможность направления сообщений на мобильные телефоны в качестве средства напоминания о необходимости соблюдения АРТ в рамках комплекса мер по обеспечению соблюдения требований (настоятельная рекомендация, фактические данные среднего качества). В условиях генерализованной эпидемии службам охраны здоровья матери и ребенка следует начинать и продолжать проведение АРТ беременным и родившим женщинам и грудным детям, отвечающим соответствующим критериям, обеспечивая направление на лечение и взаимодействие, при необходимости, со службами оказания длительной помощи при ВИЧ и проведения АРТ (настоятельная рекомендация, фактические данные очень низкого качества). ри высоком уровне распространенности ВИЧ и ТБ следует П начинать проведение АРТ среди людей, живущих с ВИЧ, в противотуберкулезных учреждениях, обеспечивая взаимодействие со службами оказания длительной помощи при ВИЧ и проведения АРТ (настоятельная рекомендация, фактические данные очень низкого качества). П ри высоком уровне распространенности ВИЧ и ТБ противотуберкулезное лечение может предоставляться людям, живущим с ВИЧ, в учреждениях по оказанию помощи при ВИЧ, где был поставлен также диагноз ТБ (настоятельная рекомендация, фактические данные очень низкого качества). роведение АРТ следует начинать и продолжать среди людей, П живущих с ВИЧ, отвечающих соответствующим критериям, в местах проведения опиоидной заместительной терапии (ОЗТ) (настоятельная рекомендация, фактические данные очень низкого качества). Децентрализация лечения и помощи Необходимо рассмотреть следующие возможности в отношении децентрализации инициирования и проведения АРТ. нициирование АРТ в больницах при дальнейшем проведении И АРТ в периферийных медицинских учреждениях (настоятельная рекомендация, фактические данные низкого качества). нициирование и проведение АРТ в периферийных медицинских И учреждениях (настоятельная рекомендация, фактические данные низкого качества). нициирование АРТ в периферийных медицинских учреждениях И при дальнейшем проведении терапии по месту жительства (то есть вне учреждений здравоохранения, таких как выездные бригады, медицинские пункты, службы помощи на дому или местные общественные организации) в период между регулярными посещениями клиники (настоятельная рекомендация, фактические данные среднего качества).

Интеграция услуг и обеспечение взаимодействия

Осуществление деятельности и предоставление услуг (продолжение) Тема и группа населения Перераспределение обязанностей Рекомендации К валифицированный неврачебный клинический персонал, акушерки и медсестры могут инициировать проведение АРТ первого ряда (настоятельная рекомендация, фактические данные среднего качества). К валифицированный неврачебный клинический персонал, акушерки и медсестры могут продолжать проведение АРТ (настоятельная рекомендация, фактические данные среднего качества). К валифицированные и работающие под контролем участковые медицинские работники могут отпускать препараты для АРТ в период между регулярными посещениями клиники (настоятельная рекомендация, фактические данные среднего качества).

Рекомендации для руководителей программ Тема и группа населения Рекомендации для руководителей программ Рекомендации При принятии решений в отношении клинических и операционных рекомендаций, рекомендуется, чтобы: национальные органы делали это транспарентным, открытым и обоснованным образом. Этот процесс должен обеспечивать участие широкого круга заинтересованных сторон, включая полноценное участие местных сообществ, затронутых данной проблемой, и учитывать конкретные особенности обсуждаемых рекомендаций; процессе принятия решений принимались во внимание в национальные и местные эпидемиологические данные по ВИЧ, текущие показатели осуществления программы АРТ, а также социально-экономическая, политическая и правовая ситуация, включая бюджетные и кадровые потребности, а также другие последствия для систем здравоохранения. Последнее будет определять, какие вводимые ресурсы и системы имеются в настоящее время и в каких областях требуются дополнительные инвестиции; процессе принятия решений принимались во внимание в вопросы соблюдения этических принципов, справедливости и прав человека, воздействия и экономической эффективности, а также такие аспекты, как благоприятные возможности и риски, связанные с реализацией альтернативных вариантов.

ВВЕДЕНИЕ

1.1 История вопроса и текущая ситуация 38 1.2 Обоснование необходимости составления сводного руководства 39 1.3 Цели 40 1.4 Целевая аудитория 40 1.5 Сфера охвата и компоненты 40 1.5.1 Вводные главы 40 1.5.2 Клинические рекомендации 41 1.5.3 Рекомендации по осуществлению деятельности и предоставлению услуг 41

1.5.4 Рекомендации для руководителей программ 42 1.5.5 Мониторинг и оценка 42

1. ВВЕДЕНИЕ 1.1 История вопроса и текущая ситуация Первое руководство ВОЗ по использованию АРТ при ВИЧ-инфекции у взрослых и подростков было опубликовано в 2002 г. (1), а в 2001 г. и 2004 г. были изданы руководства по использованию АРВ-препаратов для ППМР (2). В обновленных в 2006 г. изданиях руководств (3-5) было введено понятие подхода с позиций общественного здравоохранения, предусматривающего использование упрощенных и гармонизированных схем АРВ-терапии (6). Эти публикации и их обновленные издания, выпущенные в 2010 г. (7-9), послужили важным руководством для стран, расширявших масштабы реализации национальных программ использования АРВ-препаратов за последнее десятилетие. В 2013 г. ВОЗ впервые пересмотрела и объединила эти и другие инструктивно-методические документы, касающиеся АРТ, в единое сводное руководство, в котором рассматриваются вопросы использования АРВ-препаратов для лечения и профилактики ВИЧ во всех возрастных группах и слоях населения на всех этапах оказания непрерывной помощи при ВИЧ. Подготовка обновленного варианта этого руководства велась в конце 2012 г. и начале 2013 года. Даже в наиболее бедных странах в настоящее время имеются более безопасные, простые, эффективные и доступные по стоимости схемы АРВ-терапии, чем когда-либо ранее. Новые стратегии и методы тестирования позволяют проводить более раннюю диагностику ВИЧ в большем числе случаев, при этом появляются новые и более доступные по стоимости технологии для мониторинга лиц, получающих АРТ. Страны переходят к трехкомпонентным схемам лечения, начинающемуся в более ранние сроки, и использованию более простых программ ППМР, в которых основное внимание уделяется долгосрочным мерам охраны здоровья беременных женщин и матерей, живущих с ВИЧ, и профилактике ВИЧ-инфекции у их детей. Важные новые фактические данные показывают, что АРВ-препараты в значительной мере способствуют профилактике передачи ВИЧ-инфекции (10). Хотя уровень охвата АРТ и выполнения рекомендаций ВОЗ 2010 года (7-9) различен в разных странах и все еще сохраняются серьезные пробелы в научных исследованиях, повсеместно наблюдается тенденция к расширению доступа и к тому, чтобы начинать лечение лиц с ВИЧ в более ранние сроки. Расширение круга лиц, отвечающих критериям получения АРТ, а также вариантов использования АРВ-препаратов открывают новые возможности для спасения жизней и снижения передачи ВИЧ, однако это может ставить важные технические, операционные, программные и этические задачи перед лицами, определяющими политику, и исполнителями во многих странах с низким и средним уровнями дохода. Это включает использование стратегического комплекса подходов, обеспечивающих более своевременную диагностику ВИЧ-инфекции как в учреждении здравоохранения, так и по месту жительства. Эффективное направление на лечение и взаимодействие между учреждениями здравоохранения, инновационные децентрализованные подходы к предоставлению услуг АРТ, а также эффективная поддержка и меры, направленные на обеспечение соблюдения режима лечения, также необходимы для удержания пациентов в системе оказания длительной медицинской помощи. Важное значение имеют также надежные и доступные по стоимости средства лабораторного мониторинга гарантированного качества, адекватный кадровый потенциал здравоохранения и бесперебойные поставки лекарственных средств.

1. Введение

На уровне реализации программ страны часто встречаются с трудностями в обеспечении охвата лиц, наиболее нуждающихся в АРВ-препаратах. Они могут сталкиваться с необходимостью сложного выбора при распределении ограниченных ресурсов и установлении программных приоритетов для максимально эффективного использования АРВ-препаратов в целях лечения и профилактики в сочетании с другими методами профилактики ВИЧ. Национальные программы по ВИЧ могут нуждаться в обосновании необходимости увеличения инвестиций в программы АРТ путем оценки издержек и выгод, а также демонстрации того, какое воздействие они оказывают на заболеваемость, смертность и частоту случаев ВИЧ.

1.2 Обоснование необходимости составления сводного руководства

1.2 Обоснование необходимости составления сводного руководства Сводное руководство позволяет получить следующие преимущества. Руководство по использованию АРВ-препаратов предоставляется в рамках непрерывного процесса профилактики, лечения и оказания помощи в связи с ВИЧ. Помимо предоставления рекомендаций по клиническому использованию АРВ-препаратов для лечения, в руководстве рассматриваются другие важные аспекты оказания помощи в связи с ВИЧ. В руководстве рассматриваются вопросы использования АРВ-препаратов во всех возрастных группах и слоях населения. Изданные ранее отдельные руководства ВОЗ по применению АРТ у взрослых и подростков были объединены с руководствами в отношении детей и ППМР, обеспечивая максимально возможную гармонизацию схем применения АРВ-препаратов и методов лечения для всех возрастных групп и слоев населения. Новые и существующие рекомендации гармонизированы. Сведение воедино позволило гармонизировать новые рекомендации с существующими руководствами ВОЗ, сохраняющими свою актуальность. Сведение воедино обеспечивает последовательность подходов и взаимосвязь между деятельностью в различных условиях . Сводные рекомендации способствуют взаимосвязи и обеспечивают последовательность подходов в различных условиях, при которых могут предоставляться АРВ-препараты и соответствующие услуги, включая специализированные службы помощи при ВИЧ, службы первичной помощи, участковые службы, службы охраны здоровья матери и ребенка, противотуберкулезные службы, а также службы помощи лицам, употребляющим наркотики. Обновленные рекомендации будут более актуальными и всесторонними. Сводные рекомендации позволяют каждые два года всестороннее пересматривать основные клинические, операционные и программные аспекты применения АРВ-препаратов в разных группах населения, возрастных группах и условиях деятельности с учетом новых научных знаний и практического опыта.

1.3 Цели Подготовка сводного руководства преследует следующие цели: предоставление обновленных научно обоснованных рекомендаций в отношении применения АРВ-препаратов для лечения и профилактики ВИЧ в рамках непрерывного процесса оказания помощи при ВИЧ с позиции общественного здравоохранения, уделяя особое внимание местам, где система здравоохранения располагает ограниченными возможностями и ресурсами; редоставление рекомендаций в отношении основных вопросов осуществления п доступа к службам борьбы с ВИЧ, усиления непрерывного процесса оказания помощи при ВИЧ и дальнейшей интеграции применения АРВ-препаратов в деятельность систем здравоохранения; и редоставление рекомендаций по принятию решений и планированию программ на п национальном уровне, касающихся адаптации, установления приоритетов, а также выполнения клинических и операционных рекомендаций и мониторинга их выполнения и полученных результатов.

1.4 Целевая аудитория Данное руководство предназначено, в первую очередь, для руководителей национальных программ по ВИЧ. Оно будет представлять интерес также для следующих групп пользователей: члены национальных консультативных советов по лечению и профилактике ВИЧ; руководители национальных программ борьбы с ТБ; уководители программ охраны здоровья матерей, новорожденных и детей, а также р программ репродуктивного здоровья; персонал клинических подразделений и других служб здравоохранения; руководители национальных лабораторных служб; люди, живущие с ВИЧ, и организации на уровне местных сообществ; и еждународные и двусторонние агентства и организации, предоставляющие финансовую м и техническую поддержку программам по ВИЧ в условиях ограниченности ресурсов.

1.5 Сфера охвата и компоненты В данном руководстве рассматриваются клинические, операционные и программные аспекты применения АРВ-препаратов для лечения и профилактики ВИЧ (Рис. 1.1).

1.5.1 Вводные главы Руководство включает несколько вводных глав. Глава 1: История вопроса, текущая ситуация, обоснование, цели руководства и целевая аудитория. Глава 2: Руководящие принципы, лежащие в основе руководства. Глава 3: Методы и процесс подготовки руководства. Глава 4: Формат представления новых рекомендаций.

1. Введение

1.5.2 Клинические рекомендации Рекомендации, содержащиеся в Главах 5, 6 и 7, касаются основных аспектов применения АРВ-препаратов для лечения и профилактики ВИЧ во всех возрастных группах и слоях населения в рамках непрерывного процесса оказания помощи – от постановки диагноза ВИЧ до ведения ухода и лечения. Глава 5: Приводится краткое описание методов тестирования на ВИЧ и консультирования со ссылками на существующее руководство ВОЗ. Кроме того, кратко описаны подходы к использованию АРВ-препаратов для профилактики передачи ВИЧ (предэкспозиционная и постэкспозиционная профилактика ВИЧ и АРВ-препараты для профилактики ВИЧ в серодискордантных парах) в рамках всесторонней комплексной профилактики ВИЧ, со ссылками на существующее руководство. Обращаем внимание на то, что в данном руководстве не рассматриваются поведенческие, структурные и биомедицинские меры вмешательства, которые не предусматривают использования АРВ-препаратов. Глава 6: Приводится краткое описание общей помощи при ВИЧ отдельным лицам с момента постановки диагноза ВИЧ-инфекции до момента начала проведения АРТ, включая установление контактов лиц, у которых диагностирована ВИЧ-инфекция, со службами лечения и оказания помощи при ВИЧ, компоненты общего пакета помощи и подготовку отдельных лиц к началу проведения АРТ. Глава 7: Включает рекомендации по проведению АРТ у взрослых (включая беременных и кормящих грудью женщин), подростков и детей, в том числе обновленные рекомендации, касающиеся большинства населения, в отношении оптимальных сроков начала АРТ (когда начинать); обновленные рекомендации в отношении наиболее эффективных и практически осуществимых схем лечения первого и второго ряда (с чего начинать и на какую схему переходить); обновленные рекомендации в отношении мониторинга эффективности и токсичности АРТ; и обсуждение АРТ третьего ряда. Глава 8: Включает краткое описание подходов к профилактике и ведению наиболее распространенных оппортунистических инфекций, связанных с ВИЧ, других сочетанных инфекций и других сопутствующих заболеваний, со ссылками на существующее руководство ВОЗ.

1.5 Сфера охвата и компоненты

1.5.3 Рекомендации по осуществлению деятельности и предоставлению услуг Глава 9: Включает рекомендации по шести основным областям деятельности и предоставления услуг, в которых необходимо принимать меры для дальнейшего расширения программ АРТ, а также обеспечения их эффективности и устойчивости в рамках всей системы здравоохранения. Этими областями являются: удержание пациентов в системе оказания помощи; соблюдение АРТ; кадровые ресурсы; модели предоставления услуг с уделением особого внимания децентрализации АРТ на уровне первичной медико-санитарной помощи и интеграции АРТ в рамках противотуберкулезных служб, служб дородовой помощи, программ охраны материнства и детства и наркологических служб; лабораторные службы; и управление поставками лекарственных средств.

1.5.4 Рекомендации для руководителей программ Глава 10: Данная глава призвана помочь странам в принятии решений и планировании программ. Процесс реализации предусматривает различные меры политики с учетом ситуации на местах, включая распространенность и динамику развития эпидемии ВИЧ; пути передачи инфекции; организацию и потенциал систем здравоохранения; относительный уровень дохода; и существующий уровень охвата мерами вмешательства. В главе предлагаются меры обеспечения справедливых, всесторонних и транспарентных процессов принятия решений на страновом уровне; обсуждаются параметры для рассмотрения при оценке и адаптации глобальных рекомендаций в отдельных странах; и предлагаются инструменты для калькуляции затрат и планирования. Обсуждаются также вопросы реализации в рамках системы здравоохранения и конкретные основные рекомендации, содержащиеся в руководстве.

1.5.5 Мониторинг и оценка Глава 11: Содержит указания в отношении мониторинга выполнения основных новых рекомендаций, приведенных в данном руководстве. В главе предлагается ряд показателей, которые могут быть использованы для отслеживания выполнения новых рекомендаций, а также показателей для мониторинга эффективности программ в рамках непрерывного процесса оказания помощи. В Главе 11 также рассматриваются возможности, которые открывают новые рекомендации в отношении изучения и усиления систем мониторинга и оценки.

Рис. 1.1 Компоненты сводного руководства Что делать • Тестирование на ВИЧ и консультирование • Профилактика на основе АРВ-препаратов • Общая помощь при ВИЧ • Когда начинать АРТ (АРТ первого ряда) • С какой схемы АРТ начинать • Как осуществлять мониторинг (эффективность АРТ и токсичность) • На какую схему АРТ переходить (АРТ второго ряда) • Ведение коинфекций и сопутствующих заболеваний Как решать что делать, где и когда • Принятие решений (процесс, требуемые данные и основные параметры) • Вопросы осуществления • Полезные инструменты для калькуляции затрат и планирования Мониторинг и оценка Программный Клинический Операционный

Как это делать • Соблюдение режима АРТ • Удержание в рамках помощи • Инновационные модели предоставления услуг (интеграция, децентрализация и перераспределение обязанностей) • Кадровые ресурсы • Лабораторные и диагностические службы • Системы управления закупками и поставками

• Значение новых рекомендаций для мониторинга • Промежуточные и конечные результаты мониторинга для расширения доступа к АРВ- препаратам • Другие аспекты мониторинга (мониторинг лекарственной устойчивости ВИЧ и токсичности АРВ-препаратов) • Усиление систем мониторинга и оценки

РУКОВОДЯЩИЕ ПРИНЦИПЫ

2.1 Вклад в достижение глобальных целей в области здравоохранения 44 2.2 Подход с позиции общественного здравоохранения 44 2.3 Укрепление систем здравоохранения с помощью инноваций и обучения 44 2.4 Повышение эффективности и действенности программ 45 2.5 Соблюдение прав человека и принципа справедливости в отношении здоровья 46 2.6 Выполнение рекомендаций с учетом условий на местах 46

2. РУКОВОДЯЩИЕ ПРИНЦИПЫ 2.1 В клад в достижение глобальных целей в области здравоохранения Осуществление этих рекомендаций будет способствовать обеспечению всеобщего доступа к профилактике, лечению, помощи и поддержке при ВИЧ в соответствии с целями и задачами, сформулированными в Политической декларации по ВИЧ/СПИДу в 2006 году (1) и в Политической декларации по ВИЧ и СПИДу в 2011 году: активизация наших усилий по искоренению ВИЧ и СПИДа (2). Эти рекомендации будут также способствовать достижению конкретных целей сектора здравоохранения в рамках Глобальной стратегии для сектора здравоохранения по ВИЧ/СПИДу, 2011–2015 гг. (3) и Глобального плана устранения новых случаев заражения ВИЧ среди детей до 2015 года и оказания помощи матерям, чтобы они могли оставаться в живых (4). В число основных задач на 2015 год входит сокращение доли ВИЧ-инфицированных молодых людей в возрасте 15-25 лет в два раза по сравнению с 2009 годом; сокращение числа новых случаев ВИЧ-инфицирования детей на 90% по сравнению с 2009 годом; сокращение числа людей, умирающих от причин, связанных с ВИЧ, на 25% по сравнению с 2009 годом; снижение числа случаев смерти матерей от причин, связанных с ВИЧ, в два раза по сравнению с 2009 годом; сокращение числа людей, умирающих от ТБ, в два раза по сравнению с 2004 годом; и предоставление АРТ 15 миллионам человек в странах с низким и средним уровнями дохода. В более долгосрочной перспективе эти рекомендации будут способствовать достижению цели всеобщего охвата услугами здравоохранения, являющейся одним из важнейших элементов повестки дня в области развития на период после 2015 года, и обеспечивать информационную основу направленных на это усилий.

2.2 Подход общественного здравоохранения В соответствии с руководством ВОЗ по ВИЧ с 2002 года эти рекомендации основываются на подходе к расширению масштабов использования АРВ-препаратов для лечения и профилактики ВИЧ с точки зрения общественного здравоохранения (5). Подход с позиции общественного здравоохранения призван обеспечить максимально возможный доступ к высококачественным службам на общепопуляционном уровне на основе упрощенных и стандартизированных подходов, соблюдая баланс между внедрением хорошо зарекомендовавших себя стандартов оказания помощи и тем, что может быть практически реализовано в широких масштабах в условиях ограниченности ресурсов.

2.3 Укрепление систем здравоохранения с помощью инноваций и обучения Рекомендации и инновационные подходы к предоставлению услуг, описанные в настоящем руководстве, должны быть реализованы для усиления непрерывного процесса оказания помощи при ВИЧ и общего укрепления систем здравоохранения, особенно в отношении первичной помощи и долгосрочной помощи.

2. Руководящие принципы

2.4 Повышение эффективности и действенности программ

Службы помощи при ВИЧ во многих местах с высоким бременем ВИЧ-инфекции уже интегрируются в работу учреждений здравоохранения на более низком уровне, в то время как службы ППМР все чаще становятся основными элементами служб охраны здоровья матери и ребенка. Службы помощи при ВИЧ, ТБ, гепатите, наркозависимости и службы по снижению вреда интегрируются в различной степени. По мере того как лица, получающие АРТ, будут становиться старше, а ВИЧ-инфекция становиться хроническим, контролируемым состоянием, усиление интеграции служб помощи при ВИЧ с оказанием помощи в отношении неинфекционных заболеваний будет приобретать все более важное значение. В соответствии с этими тенденциями данные рекомендации способствуют адаптации моделей предоставления услуг, которые усиливают непрерывный процесс оказания помощи при ВИЧ и позволяют своевременно начинать АРТ в различных условиях, обеспечивая, чтобы люди должным образом направлялись для получения помощи, оставались в рамках системы оказания помощи и получали пожизненное лечение. Национальные программы по ВИЧ должны рассмотреть возможность проведения внедренческих исследований для нахождения наилучших путей принятия и адаптации этих рекомендаций с учетом ситуации на местах, а также создания более эффективных и действенных служб.

2.4 Повышение эффективности и действенности программ В условиях ограниченности финансовых ресурсов, конкурирующих приоритетов и ограниченных возможностей систем здравоохранения, страны могут сталкиваться с необходимостью сложного выбора из широкого круга вариантов использования АРВ-препаратов для снижения заболеваемости, смертности и распространения ВИЧ. Эти рекомендации основываются на необходимости дальнейшего повышения и оптимизации эффективности и действенности программ борьбы с ВИЧ в странах с помощью стратегического подхода к использованию АРВ-препаратов, который предусматривает: придание приоритетного значения предоставлению АРВ-препаратов людям, живущим с ВИЧ, которые отвечают критериям проведения лечения и которые наиболее нуждаются в нем; и зучение возможностей усиления воздействия АРВ-препаратов на профилактику ВИЧ за счет более раннего начала лечения в некоторых группах населения; п овышение эффективности и уровня охвата программами АРТ в рамках непрерывного процесса предоставления услуг с помощью стратегического комплекса мер, включая тестирование на ВИЧ гарантированного качества, улучшение показателей соблюдения режима и удержания пациентов в системе оказания помощи, инновационные подходы к предоставлению услуг, интеграцию АРТ при различных условиях, а также усиление взаимосвязей между службами; и п ринятие краткосрочных и долгосрочных мер для оптимизации и гармонизации схем приема препаратов и повышения их доступности по стоимости, а также для разработки и внедрения более приемлемых по стоимости средств диагностики и лабораторных служб по месту оказания помощи.

2.5 Соблюдение прав человека и принципа справедливости в отношении здоровья Доступ к профилактике, лечению, оказанию помощи и поддержки при ВИЧ следует считать важнейшим условием для реализации всеобщего права на здоровье, и настоящие рекомендации должны выполняться с соблюдением основных прав человека и этических принципов. В целом, программы борьбы с ВИЧ должны обеспечивать доступность АРВ-препаратов и соответствующих мер для тех, кто наиболее нуждается в них, включая беременных женщин, детей и ключевые группы населения, а также сведение к минимуму проявлений стигматизации и дискриминации. Информированное согласие – в частности, в отношении тестирования на ВИЧ, а также инициирования АРТ – должно быть получено во всех случаях. Для соблюдения конфиденциальности следует принимать адекватные меры предосторожности. Некоторые страны могут сталкиваться со значительными проблемами этического характера в ходе выполнения этих рекомендаций в условиях нехватки ресурсов и ограниченных возможностей систем здравоохранения. Главной проблемой может быть необходимость уделения приоритетного внимания предоставлению АРТ наиболее тяжело больным и лицам, уже получающим лечение, стремясь одновременно к расширению круга лиц, отвечающих критериям для проведения лечения. Каждая страна должна планировать свои собственные действия для обеспечения того, чтобы текущие программы АРТ не нарушались, а расширенный доступ к ним был справедливым и равноправным.

2.6 Выполнение рекомендаций с учетом условий на местах Выполнение рекомендаций, содержащихся в данном руководстве, должно осуществляться с учетом условий на местах, включая эпидемиологию ВИЧ, наличие ресурсов, организацию и потенциал системы здравоохранения, а также предполагаемую эффективность с точки зрения затрат. Настоятельную рекомендацию – применять конкретный подход к предоставлению услуг – не следует рассматривать как утверждение о предпочтительности этой модели по сравнению с моделью предоставления услуг, уже имеющейся в данной стране.

МЕТОДЫ И ПРОЦЕСС ПОДГОТОВКИ РУКОВОДСТВА 3.1 Обзор 3.2 Источники информации 3.3 Внешнее участие 3.3.1 Группы по разработке рекомендаций и процесс коллегиальной экспертной оценки

03 48 48 48 50 50 51 54 54

3.3.2 Конфликт интересов 3.4 Процесс подготовки рекомендаций 3.5 Другие методы 3.6 Распространение

3. МЕТОДЫ И ПРОЦЕСС ПОДГОТОВКИ РУКОВОДСТВА 3.1 Обзор Сводное руководство 2013 года включает новые рекомендации, существующие рекомендации, а также другие рекомендации, касающиеся всех этапов непрерывного оказания помощи при ВИЧ. В их число входят рекомендации по диагностике ВИЧ, общей помощи при ВИЧ, а также стратегическому применению АРВ-препаратов для лечения и профилактики ВИЧ-инфекции на основе подхода общественного здравоохранения. Новые клинические и практические рекомендации были разработаны в соответствии с процедурами, установленными Комитетом ВОЗ по обзору руководящих принципов (1) и основаны на системе GRADE (Классификация оценки, разработки и определения весомости рекомендаций) (2–11). Большинство рекомендаций, приведенных из существующего руководства, были разработаны с помощью системы GRADE. В нескольких случаях, когда система GRADE не применялась, это указывается в тексте. В главе 10 подход GRADE не использовался, поскольку руководство в отношении программ не содержит каких-либо конкретных рекомендаций.

3.2 Источники информации При разработке новых рекомендаций были использованы следующие источники информации. Систематические обзоры, проведенные по поручению Руководящей группы ВОЗ по подготовке руководства (3) (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/ annexes) по 41 теме с использованием методологии PICO (популяция-вмешательствосопоставление-исход). 41 тема охватывала все этапы непрерывного оказания помощи (9 – когда начинать; 11 – с чего начинать; 4 – мониторинг эффективности лечения; 6 – мониторинг токсичности; 11 – различные аспекты предоставления услуг; и 5 – меры обеспечения соблюдения режима лечения). Руководящая группа ВОЗ по подготовке руководства в рамках консультаций с участием групп по разработке рекомендаций установила важные конечные показатели для оценки клинических данных (смертность, заболеваемость, передача инфекции и серьезные побочные реакции) и для оценки осуществления деятельности и предоставления услуг (смертность, заболеваемость, передача инфекции, доступ, удержание пациентов, вирусная супрессия и соблюдение режима лечения). Проведение систематических обзоров было поручено научным работникам, которые разработали протоколы поиска и провели анализ имеющихся научных данных. При проведении поиска в электронных базах данных (MEDLINE/PubMed, Embase, CENTRAL), базах данных конференций (Aegis, AIDSearch, NLM Gateway и ручные поиски) и регистрах клинических исследований (http://clinicaltrials.gov, www.controlledtrials.com и http://www.pactr.org) использовались ключевые слова и поисковые цепочки. Веб-приложение (http://www.who.int/hiv/pub/guidelines/arv2013/annexes) включает протоколы поиска, полный список вопросов для оценки, а также таблицы GRADE и краткий обзор фактических данных по каждой теме. Стандартизированная таблица фактических данных GRADE использовалась для представления сводной количественной информации о фактических данных и результатах оценки их качества для каждого вопроса PICO по конечным показателям. Для оценки качества фактических данных (4-10) и весомости рекомендаций (11) использовалась система GRADE (Вставка 3.1; веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes).

3. Методы и процесс подготовки руководства

Общественные консультации в отношении ценностей и предпочтений в приоритетных областях руководства проводились с помощью онлайнового интернет-опроса и модерируемых интернет-обсуждений с участием сетей гражданского общества и координируемых Международным альянсом по борьбе с ВИЧ/СПИДом и Глобальной сетью людей, живущих с ВИЧ (GNP+). В рамках специальных рабочих групп проводились также обсуждения опыта работы с беременными женщинами, получающими пожизненную АРТ, в Уганде и Малави, а также вопросов ППМР и АРТ у детей в Южной Африке (веб-приложение http://www.who.int/hiv/pub/guidelines/arv2013/annexes). ве глобальные консультации с общественными структурами и организациями Д гражданского общества по вопросам предоставления услуг на всех этапах непрерывного оказания помощи при генерализованных и концентрированных эпидемиях. Консультации с работниками здравоохранения, работающими с взрослыми и детьми, по вопросам ценностей и предпочтений, связанных с приоритетными областями руководства, проводились с помощью интернет-опроса (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Шестой ежегодный обзор работы Службы ВОЗ по обеспечению средств для лечения и диагностики СПИДа за 2012 год по вопросам использования АРВпрепаратов и диагностических средств в 80 странах с низким и средне-низким уровнями дохода (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Математическое моделирование воздействия и экономической эффективности ранее проводимой АРТ в различных группах населения и условиях на основании данных, полученных в странах с генерализованными и концентрированными эпидемиями (Индия, Кения, Южная Африка, Вьетнам и Замбия), вместе с моделированием различных стратегий мониторинга результатов лечения, было проведено Консорциумом по моделированию эпидемии ВИЧ (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Оценка воздействия с помощью модели Spectrum для оценки возрастающей численности взрослых и детей, отвечающих различным критериям получения АРТ (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). О тчеты об опыте работы в странах были представлены в отношении использования Варианта B+ для ППМР в Малави; применения TDF в схемах АРВ-терапии первого ряда в Замбии; прекращения использования d4T в Зимбабве; и расширения мониторинга вирусной нагрузки в программах организации «Врачи без границ» в южной части Африки. Электронный интернет-опрос конечных пользователей на уровне стран был проведен в целях выявления возможных путей улучшения руководства ВОЗ по АРВ-препаратам в отношении его формата, представления информации и распространения (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes).

3.2 Источники информации

3.3 Внешнее участие 3.3.1 Г руппы по разработке рекомендаций и процесс коллегиальной экспертной оценки Данный процесс проводился при поддержке четырех отдельных внешних групп по разработке рекомендаций (Взрослые люди; Охрана здоровья матери и ребенка; Осуществление деятельности и предоставление услуг; и Программная деятельность, в состав которых входили 108 человек) и внешней группы по проведению коллегиальной экспертной оценки в составе более 100 человек. Членский состав групп соответствовал требованиям процедур ВОЗ по составлению руководств (1). В состав групп входили эксперты по ВИЧ-инфекции, научные работники, методисты по составлению руководств, эпидемиологи, эксперты по правам человека, агентства по вопросам развития, партнеры из системы Организации Объединенных Наций, представители гражданского общества и представители сетей людей, живущих с ВИЧ. Принимались во внимание требования адекватной представленности по географическому и половому признаку. Члены общественной группы отбирались по результатам открытого обращения с просьбой о выдвижении кандидатур. Полный проект руководства был направлен для получения замечаний членам групп по разработке рекомендаций и внешней группы по проведению коллегиальной экспертной оценки.

3.3.2 Конфликт интересов Все члены групп по разработке рекомендаций и Группы по проведению коллегиальной экспертной оценки заполнили формы ВОЗ для декларации интересов (включая участников процессов консультаций и совещаний, поддержки научных исследований и финансовых инвестиций). Из числа членов групп по разработке рекомендации и группы по проведению коллегиальной экспертной оценки 21 и 12 экспертов, соответственно, заявили о своем участии в деятельности фармацевтической промышленности или других консультативных групп или о получении вознаграждения за консультационные услуги, а 23 и 13 экспертов заявили о получении финансовой поддержки от представителей фармацевтической промышленности в виде грантов на научные исследования. В руководстве 2013 года основное внимание уделяется разработке новых или обновленных рекомендаций по использованию АРВ-препаратов у взрослых, подростков, детей и беременных женщин. По мнению Секретариата ВОЗ и сопредседателей всех групп по разработке рекомендаций, важными областями потенциального конфликта интересов могут являться данные об особых взаимоотношениях с одной из фармацевтических компаний или о выполнении важной роли в рамках завершенных, текущих и планируемых испытаний в отношении сроков проведения АРТ или оценки конкретных схем АРВ-терапии. Руководящая группа ВОЗ по подготовке руководства рассмотрела все декларации и не выявила случаев исключительного членства в какой-либо консультативной группе, получения вознаграждения за консультационные услуги или финансовой поддержки в виде гранта на научные исследования только от одной фармацевтической компании. Имелось также дополнительное заявление на совещании групп по подготовке рекомендаций об участии членов в качестве исследователей в испытаниях и научных исследованиях. В целом, Руководящая группа ВОЗ по подготовке руководства и сопредседатели каждой из групп по разработке рекомендаций были удовлетворены тем, что декларации интересов носили транспарентный характер и что не было ни одного случая, требующего исключения участников из обсуждений. Было также отмечено, что в составе различных групп по разработке рекомендаций представлен широкий круг участников, а также то, что большинство членов заявили об отсутствии интересов. Таким образом, все лица, заявившие о наличии интересов, продолжали принимать полноценное участие в совещаниях групп по разработке рекомендаций или группы по проведению коллегиальной экспертной оценки.

3. Методы и процесс подготовки руководства

3.4 Процесс подготовки рекомендаций

3.4 Процесс подготовки рекомендаций В период с ноября 2012 г. по январь 2013 г. в Женеве состоялись четыре совещания групп по разработке рекомендаций (Группы по разработке рекомендаций в отношении осуществления деятельности и предоставления услуг в ноябре 2012 г.; Группы по разработке рекомендаций в отношении взрослых людей и Группы по разработке рекомендаций в отношении охраны здоровья матери и ребенка в декабре 2012 г.; и Группы по разработке рекомендаций в отношении программной деятельности в январе 2013 г.). На этих совещаниях были представлены и обсуждались систематические обзоры, таблицы фактических данных по системе GRADE, а также другая информация, описанная в Разделе 3.2. Они были также размещены на защищенном паролем веб-сайте. Затем предлагаемые рекомендации были рассмотрены с учетом стандартизированной таблицы для принятия решений по каждой теме (Вставка 3.1), включающей следующие элементы: существующие и предлагаемые рекомендации; краткие фактические данные; преимущества и риски; ценности и предпочтения социальных и медико-санитарных работников; требуемые затраты и ресурсы; экономическая эффективность; практическая осуществимость и препятствия для реализации; предлагаемая классификация силы рекомендаций (настоятельные или условные); проблемы и потребности в научных исследованиях; и общее обоснование необходимости рекомендаций. Группы по разработке рекомендаций обсудили как предлагаемые формулировки рекомендаций, так и оценки их силы (настоятельные или условные). Все решения принимались в результате обсуждений и достижения консенсуса в отношении рекомендаций, включая их силу и, в соответствующих случаях, условия их использования. Разногласия разрешались путем обсуждений по электронной почте, телеконференций и изменения проектов рекомендаций и их обоснования. Первоначальные варианты разделов руководства были направлены членам групп по разработке рекомендаций, а их окончательный вариант был представлен на рассмотрение членов групп по разработке рекомендаций и экспертов, проводивших коллегиальную оценку. Замечания, полученные более чем от 100 экспертов, были, по возможности, приняты во внимание и включены в текст пересмотренного руководства.

Вставка 3.1 Процесс оценки качества фактических данных и силы рекомендаций с помощью системы GRADE Начиная с 2008 года ВОЗ пользуется системой GRADE, согласно которой оценка качества фактических данных отделена от оценки силы рекомендаций. Качество фактических данных определяется как степень уверенности в том, что представленные оценки эффекта являются достаточными для обоснования конкретной рекомендации. По классификации GRADE качество фактических данных может быть высоким, средним, низким и очень низким (Таблица 3.1) (4–10). Результаты рандомизированных контролируемых исследований изначально оцениваются как фактические данные высокого качества, однако они могут быть переведены в более низкую категорию по ряду причин, включая риск системной ошибки, непоследовательность результатов разных научных исследований, неточность и систематическую ошибку, связанную с предпочтительной публикацией положительных результатов исследования. Результаты обсервационных (неэкспериментальных) исследований изначально оцениваются как фактические данные низкого качества, однако они могут быть переведены в более высокую категорию, если эффективность лечения очень высока, если множественные исследования дают одинаковые результаты, если данные указывают на зависимость реакции от дозы или если все возможные систематические ошибки будут приводить к занижению оценки воздействия (10). Чем выше качество фактических данных, тем больше вероятность того, что рекомендация будет весомой. Сила рекомендации отражает степень уверенности группы по разработке рекомендаций в том, что желаемый эффект применения этой рекомендации будет перевешивать возможные нежелательные последствия. На силу рекомендации влияют следующие факторы: качество фактических данных, соотношение положительных эффектов и наносимого вреда, ценности и предпочтения, использование ресурсов и реальная осуществимость практических мер (Таблица 3.2). Согласно классификации GRADE, по своей силе рекомендации могут быть двух категорий: “настоятельные” и “условные” (11). В случае настоятельной рекомендации Группа по разработке рекомендаций уверена в том, что желаемый эффект применения этой рекомендации перевешивает нежелательные последствия. В случае условной рекомендации Группа по разработке рекомендаций полагает, что желаемый эффект применения этой рекомендации, вероятно, перевешивает нежелательные последствия, однако Группа по разработке рекомендаций не уверена в том, насколько преимущества и недостатки уравновешивают друг друга. В Таблице 3.3 кратко описано значение настоятельной или условной рекомендации для отдельных лиц, клинического персонала и лиц, определяющих политику. Причинами того, что рекомендация носит условный характер, могут быть: отсутствие фактических данных высокого качества, неточность оценок конечных результатов; непостоянство ценностей и предпочтений отдельных лиц в отношении конечных результатов мер вмешательства; незначительные преимущества; применимость при всех или только при определенных условиях; и положительный эффект может не оправдывать затрат (в том числе затрат на выполнение рекомендации).

3. Методы и процесс подготовки руководства

Таблица 3.1 Уровень качества фактических данных по классификации GRADE Уровень качества фактических данных Высокий Средний Низкий Очень низкий Обоснование Вероятность того, что дальнейшие исследования изменят нашу уверенность в оценке эффекта, очень невелика. Дальнейшие исследования могут существенно повлиять на нашу уверенность в оценке эффекта. Вероятность того, что дальнейшие исследования могут повлиять на оценку эффекта и изменить эту оценку, очень высока. Любая оценка эффекта носит очень неопределенный характер.

3.4 Процесс подготовки рекомендаций

Таблица 3.2 Основные показатели, рассматриваемые при определении силы рекомендаций Показатель Преимущества и риски Обоснование Желательные эффекты (преимущества) следует взвешивать относительно нежелательных эффектов (рисков). Чем больше преимущества перевешивают риски, тем выше вероятность того, что рекомендация будет носить настоятельный характер. Если существует вероятность широкого принятия или высокой оценки рекомендации, она, по-видимому, будет носить настоятельный характер. Если имеются веские основания полагать, что рекомендуемый порядок действий вряд ли будет принят, выше вероятность того, что рекомендация будет условной. Низкий уровень затрат (денежные средства, инфраструктура, оборудование или людские ресурсы) или высокая экономическая эффективность повышают вероятность принятия настоятельной рекомендации. Осуществимость какой-либо меры вмешательства в условиях, когда можно ожидать максимального эффекта, повышает вероятность принятия настоятельной рекомендации.

Ценности и предпочтения (приемлемость) Затраты и финансовые последствия (использование ресурсов) Осуществимость

Таблица 3.3 Значение настоятельных и условных рекомендаций для отдельных лиц, клинического персонала и лиц, определяющих политику Настоятельная рекомендация Отдельные лица Большинство людей на вашем месте желали бы принять рекомендуемый порядок действий и лишь немногие не желали бы этого. Большинству людей следует рекомендовать данный порядок действия. Рекомендация может быть принята как мера политики в большинстве ситуаций. Условная рекомендация Многие люди на вашем месте желали бы принять рекомендуемый порядок действий, но многие не желали бы этого. Будьте готовы помочь отдельным людям принять решение в соответствии с их ценностями. Необходимо широкое обсуждение и участие заинтересованных сторон.

Клинический персонал Лица, определяющие политику

3.5 Другие методы Рекомендации, взятые из существующих руководств. Помимо новых рекомендаций, основанных на системе GRADE, в руководстве кратко представлены соответствующие рекомендации из других руководств ВОЗ. Большинство рекомендаций были разработаны с помощью системы GRADE или альтернативной системы оценки, использовавшейся до 2008 года (до A (настоятельно рекомендуется) до C (по желанию)) и I–IV (уровень фактических данных) (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes). В отношении этих существующих рекомендаций новые обзоры фактических данных не проводились. Рекомендации, требующие обновления, особо отмечены, и планируемые сроки их обновления ясно указаны. В тех случаях, когда проведение систематических обзоров и оценки качества фактических данных по GRADE для обоснования новых рекомендаций не представлялось возможным или целесообразным, проводились качественные обзоры литературы, результаты которых приводятся. Это касается отдельных тем в Главе 9, включая удержание пациентов в рамках системы непрерывного оказания помощи, однако это не привело к подготовке официальных рекомендаций. Руководство для руководителей программ по принятию решений для осуществления программ. В главах 10 и 11 не содержатся рекомендации и не оценивается качество фактических данных, поэтому они не следуют системе GRADE. Проводился описательный обзор литературы в отношении процесса и критериев принятия решений по этическим вопросам на основе фактических данных, обзор соответствующих стратегий ВОЗ и резолюций Всемирной ассамблеи здравоохранения, а также результатов математического моделирования воздействия и экономической эффективности ранее проводимой АРТ в различных группах населения и условиях. Члены группы по разработке рекомендаций провели структурированные обсуждения по установлению приоритетов для основных клинических рекомендаций при различных эпидемических сценариях (в условиях генерализованных и концентрированных эпидемий и при низком, среднем и высоком уровне охвата АРТ).

3.6 Распространение Данное руководство будет распространено в виде печатной публикации и в электронной форме на веб-сайте ВОЗ на шести официальных языках Организации Объединенных Наций. Веб-версия будет включать все приложения. В краткой версии для удобства пользования будут обобщены основные новые и существующие рекомендации. На веб-сайте будет также размещена библиотечная подборка всей вспомогательной документации и фактических данных. Штаб-квартира ВОЗ будет тесто сотрудничать с региональными и страновыми бюро, а также партнерами-исполнителями для обеспечения широкого распространения данного руководства на региональных и субрегиональных совещаниях. Государствам-членам будет оказываться содействие в адаптации данного руководства с учетом национальных условий. Разработана метода проведения оценки выполнения рекомендаций пользователями и препятствий для их эффективного осуществления. Пересмотр данного руководства планируется провести в 2015 году. В случае появления важных новых фактических данных могут быть разработаны временные обновленные рекомендации по техническим и программным вопросам.

СТРУКТУРА РУКОВОДСТВА 4 Непрерывное оказание помощи 4.1 Структура представления новых рекомендаций 4.2 Структура представления некоторых рекомендаций, взятых из существующих руководств 4.3 Как использовать рекомендации для конкретных групп населения 4.3.1 Беременные и кормящие грудью женщины 4.3.2 Подростки 4.3.3 Дети 4.3.4 Ключевые группы населения

04 56 58 58 59 59 61 63 64

4. СТРУКТУРА РУКОВОДСТВА Непрерывное оказание помощи

РАЗДЕЛ 6.2

РАЗДЕЛ 9.3

■■ УДЕРЖАНИЕ ПАЦИЕНТОВ ■■ ПРОФИЛАКТИКА ВИЧ ■■ ОБЩАЯ ПОМОЩЬ ПРИ ВИЧ ■■ ПОДГОТОВКА ЛЮДЕЙ К АРТ ■■ ВЕДЕНИЕ КОИНФЕКЦИЙ И СОПУТСТВУЮЩИХ ЗАБОЛЕВАНИЙ

ТЕСТИРОВАНИЕ НА ВИЧ И КОНСУЛЬТИРОВАНИЕ

■■ СВЯЗЬ СО СЛУЖБАМИ ПОМОЩИ

ОХВАТ СЛУЖБАМИ ПОМОЩИ

РАЗДЕЛ 5.1

РАЗДЕЛ 5.2 РАЗДЕЛ 6.1 РАЗДЕЛ 6.4 РАЗДЕЛЫ 8.1 И 8.2

4. Структура руководства

РАЗДЕЛЫ 9.2 И 9.3

■■ УДЕРЖАНИЕ И СОБЛЮДЕНИЕ РЕЖИМА ЛЕЧЕНИЯ НАЧАЛО АРТ (АРТ ПЕРВОГО РЯДА) АРТ ВТОРОГО И ТРЕТЬЕГО РЯДА

■■ МОНИТОРИНГ ЭФФЕКТИВНОСТИ АРТ ■■ МОНИТОРИНГ ТОКСИЧНОСТИ АРВ-ПРЕПАРАТОВ

РАЗДЕЛЫ 7.1 И 7.2

РАЗДЕЛЫ 7.3 И 7.4

РАЗДЕЛ 7.5

4.1 Структура представления новых рекомендаций

Новые рекомендации в данном руководстве обозначены символом . К ним относятся существующие рекомендации, которые были обновлены по результатам анализа новых фактических данных в рамках процесса подготовки настоящего руководства. В тех случаях, когда первоначальные рекомендации не изменились, это ясно указано. Новые рекомендации представлены в следующем формате, чтобы отражать все результаты анализа фактических данных и обсуждений, проведенных группой по разработке рекомендаций. Р екомендация. Оценка силы рекомендаций и качества фактических данных для новой рекомендации приводится с помощью системы GRADE. История вопроса. Приводится описание предыдущего руководства ВОЗ в этой области и основных изменений, имевших место с момента публикации предыдущей рекомендации. Если рекомендация касается конкретной группы населения, может приводиться краткое описание основных проблем данной группы. О боснование рекомендации и подтверждающие ее фактические данные. Приводится краткое описание новых фактических данных, на которых основана данная рекомендация, а также основные соображения практического и программного характера, лежащие в основе этой рекомендации. К линические аспекты и вопросы, касающиеся реализации. В некоторых случаях перечисляются основные клинические аспекты и вопросы, касающиеся реализации данной рекомендации. Для некоторых основных рекомендаций в Главе 10 представлены результаты обсуждения вопросов реализации, касающихся руководителей программ. О сновные пробелы в научных исследованиях . В некоторых случаях кратко описаны или перечислены важнейшие вопросы, требующие дальнейших исследований, если они непосредственно касаются данных рекомендаций. В конце руководства для каждого раздела приводится список использованной литературы по главам.

новое

4.2 Структура представления некоторых рекомендаций, взятых из существующих руководств В двух главах кратко описаны рекомендации, взятые из существующих руководств ВОЗ: в Главе 5 по тестированию на ВИЧ и консультированию, а также использованию АРВ-препаратов для профилактики; и в Главе 8 по общей помощи при ВИЧ, включая профилактику и ведение коинфекций и сопутствующих заболеваний. Обычно они представлены в следующем формате: И стория вопроса; И сточник(и) рекомендации (рекомендаций); Дополнительные указания (в соответствующих случаях); и Существующая рекомендация (рекомендации). Рекомендации, а также сила рекомендации и качество фактических данных оцениваются по системе GRADE (или с помощью альтернативного метода).

4. Структура руководства

4.3 Как использовать рекомендации для конкретных групп населения Настоящее руководство содержит рекомендации для взрослых, беременных и кормящих грудью женщин, подростков, детей и ключевых групп населения. Группы населения, которых касается каждая рекомендация, ясно указаны и для удобства сопровождаются соответствующим символом. Взрослые Беременные женщины Подростки В Таблицах 4.1– 4.4 также указаны номера глав и разделов, касающихся основных рекомендаций для конкретных групп населения: беременных и кормящих грудью женщин, подростков, детей старшего и грудного возраста, а также ключевых групп населения. В таблицах особо отмечены некоторые темы, которые касаются непосредственно отдельных групп населения. Однако перечисленные темы не являются исчерпывающими, и многие рекомендации и другие разделы руководства касаются нескольких групп населения. Дети Ключевые группы населения

4.3 Как использовать рекомендации для конкретных групп населения

4.3.1 Беременные и кормящие грудью женщины В Таблице 4.1 указано, в каких разделах содержатся основные указания и рекомендации, касающиеся беременных и кормящих грудью женщин.

Таблица 4.1 Основные рекомендации и указания в отношении беременных и кормящих грудью женщин Глава Глава 5: Диагностика ВИЧ и АРВ-препараты для профилактики ВИЧ Тема Консультирование и тестирование на ВИЧ в медицинских учреждениях Консультирование и тестирование на ВИЧ по месту жительства Консультирование и тестирование на ВИЧ к онкретных групп населения: Пары Консультирование и тестирование на ВИЧ конкретных групп населения: Беременные женщины и женщины в послеродовом периоде Консультирование и тестирование на ВИЧ конкретных групп населения: Ранняя диагностика у грудных детей АРТ для профилактики среди серодискордантных пар Глава 6: Установление связей между лицами с диагнозом ВИЧ-инфекции и службами лечения и оказания помощи при ВИЧ Оказание общей помощи людям, живущим с ВИЧ Подготовка к прохождению АРТ людей, живущих с ВИЧ Что можно ожидать от первых месяцев прохождения АРТ Раздел главы Раздел 5.1.2 Раздел 5.1.3 Раздел 5.1.4.1 Раздел 5.1.4.2

Раздел 5.1.4.3 Раздел 5.2.2 Раздел 6.3 Раздел 6.4 Раздел 6.5

Таблица 4.1 (продолжение) Глава Глава 7: Антиретровирусная терапия Тема Когда следует начинать АРТ у беременных и кормящих грудью женщин АРВ-препараты и продолжительность грудного вскармливания Особые аспекты оказания помощи и ведения беременных женщин АРТ первого ряда для беременных и кормящих грудью женщин и АРВ-препараты для их детей Раздел главы Раздел 7.1.2 Раздел 7.1.3 Раздел 7.1.3; Вставка 7.1 Раздел 7.2.2

Мониторинг эффективности АРТ и выявление причин неудачи Раздел 7.3 лечения (включая беременных и кормящих грудью женщин) Мониторинг и замена одних препаратов другими при токсичности АРВ-препаратов (включая беременных и кормящих грудью женщин) АРТ второго ряда для взрослых и подростков (включая беременных и кормящих грудью женщин) АРТ третьего ряда (включая беременных и кормящих грудью женщин) Глава 8: Ведение наиболее распространенных инфекций и сопутствующих заболеваний Глава 9: Рекомендации по осуществлению деятельности и предоставлению услуг Профилактика, скрининг и ведение коинфекций Раздел 7.4 Раздел 7.5.1 Раздел 7.6 Раздел 8.1

Профилактика и ведение других сопутствующих заболеваний Раздел 8.2 и долговременный уход за людьми, живущими с ВИЧ Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Соблюдение АРТ: Беременные и родившие женщины Предоставление АРТ службами дородовой помощи и охраны здоровья матери и ребенка Децентрализация и перераспределение обязанностей Раздел 9.2.1 Раздел 9.4.2.1 Разделы 9.4.3 и 9.5.2

Глава 10: Рекомендации для руководителей программ Глава 11: Мониторинг и оценка Приложения

Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Вопросы реализации в отношении основных рекомендаций: переход к пожизненной АРТ для всех беременных и кормящих грудью женщин Значение новых рекомендаций для мониторинга Приложение 1. Клинические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей Приложение 3. Алгоритмы для рекомендаций 2013 года в отношении беременных и кормящих грудью женщин Приложение 6. Контрольный перечень вопросов для оценки готовности: переход к АРТ для беременных и кормящих грудью женщин Приложение 7. Дозировки рекомендованных АРВ-препаратов для взрослых и подростков (включая беременных и кормящих грудью женщин) Глава 12 Раздел 10. 6 Вставка 10.4 Раздел 11.2

4. Структура руководства

4.3.2 Подростки По определению ВОЗ, подростковый возраст составляет от 10 до 19 лет. В число подростков с ВИЧ входят те, кто выжил после перинатальной инфекции, и вновь инфицированные ВИЧ после начала сексуальной жизни или в результате употребления инъекционных наркотиков, других небезопасных инъекций и переливаний крови. Подростки могут обращаться за помощью в различные учреждения, включая клиники педиатрической и дородовой помощи, а также клиники для взрослых. Поскольку немногие системы здравоохранения предоставляют услуги, конкретно предназначенные для подростков, у них могут возникать трудности в отношении доступа к медицинской помощи и соблюдения режима лечения. В целом, клинические и общие рекомендации для взрослых в этом руководстве применимы и к подросткам. Если рекомендации для подростков приводятся в рамках рекомендаций для детей, это ясно указывается. Имеется четыре конкретные рекомендации в отношении тестирования и консультирования, взятые из дополнительного недавно выпущенного руководства для подростков. В руководстве 2013 года Guidance on HIV testing and counselling for adolescents and care for adolescents living with HIV содержатся рекомендации в отношении тестирования на ВИЧ и консультирования, а также предоставления услуг подросткам (Таблица 4.2).

4.3 Как использовать рекомендации для конкретных групп населения

Таблица 4.2 Основные рекомендации и указания для подростков Глава Глава 5: Диагностика ВИЧ и АРВ-препараты для профилактики ВИЧ Тема Консультирование и тестирование на ВИЧ в медицинских учреждениях Консультирование и тестирование на ВИЧ по месту жительства Консультирование и тестирование на ВИЧ конкретных групп населения: Подростки Глава 6: Установление связей между лицами с диагнозом ВИЧинфекции и службами лечения и оказания помощи при ВИЧ Глава 7: Антиретровирусная терапия Оказание общей помощи людям, живущим с ВИЧ Подготовка к прохождению АРТ людей, живущих с ВИЧ Что можно ожидать от первых месяцев прохождения АРТ Когда следует начинать АРТ у взрослых и подростков АРТ первого ряда для детей в возрасте трех лет и старше (включая подростков) Комбинированное лечение ТБ и ВИЧ-инфекции у детей Мониторинг эффективности АРТ и выявление причин неудачи лечения (включая подростков) Мониторинг и замена препаратов другими при токсичности АРВ-препаратов (включая подростков) Основные взаимодействия АРВ-препаратов (включая подростков) АРТ второго ряда для взрослых и подростков АРТ второго ряда для детей (включая подростков) АРТ третьего ряда (включая подростков) Раздел главы Раздел 5.1.2 Раздел 5.1.3 Раздел 5.1.4.4 Раздел 6.3 Раздел 6.4 Раздел 6.5 Раздел 7.1.1 Раздел 7.2.4 Раздел 7.2.5 Раздел 7.3 Раздел 7.4 Таблица 7.16 Раздел 7.5.1 Раздел 7.5.2 Раздел 7.6

Таблица 4.2 (продолжение) Глава Глава 8: Ведение наиболее распространенных коинфекций и сопутствующих заболеваний Глава 9: Рекомендации по операционной деятельности и предоставлению услуг Глава 10: Рекомендации для руководителей программ Тема Профилактика, скрининг и ведение коинфекций Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ Оказание нутритивной помощи и поддержки подросткам и взрослым, живущим с ВИЧ Раздел главы Раздел 8.1 Раздел 8.2

Раздел 8.2.4.1

Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Соблюдение режима АРТ: Подростки Децентрализация и перераспределение обязанностей Раздел 9.2 Разделы 9.4.3 и 9.5.2

Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Вопросы реализации в отношении основных рекомендаций для руководителей программ: повышение порогового уровня CD4 для начала АРТ у взрослых и подростков с 350 до 500 клеток/mm3 Значение новых рекомендаций для мониторинга Приложение 1. Клинические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей Приложение 2. Алгоритмы для рекомендаций 2013 года в отношении взрослых и подростков Приложение 7 . Дозировки рекомендованных АРВ-препаратов для взрослых и подростков Глава 12 Раздел 10.6; Вставка 10.2

Глава 11: Мониторинг и оценка Приложения

Раздел 11.2

4. Структура руководства

4.3 Как использовать рекомендации для конкретных групп населения

4.3.3 Дети В Таблице 4.3 указано, в каких разделах содержатся основные указания и рекомендации, касающиеся детей (в возрасте до 10 лет).

Таблица 4.3 Основные рекомендации и указания для детей Глава Глава 5: Диагностика ВИЧ и АРВ-препараты для профилактики ВИЧ Глава 6: Установление связей между лицами с диагнозом ВИЧ-инфекции и службами лечения и оказания помощи при ВИЧ Глава 7: Антиретровирусная терапия Тема Консультирование и тестирование на ВИЧ в медицинских учреждениях Консультирование и тестирование на ВИЧ по месту жительства Консультирование и тестирование на ВИЧ конкретных групп населения: Дети грудного и младшего возраста Оказание общей помощи людям, живущим с ВИЧ Подготовка к прохождению АРТ людей, живущих с ВИЧ Раздел главы Раздел 5.1.2 Раздел 5.1.3 Раздел 5.1.4.3 Раздел 6.3 Раздел 6.4

Что можно ожидать от первых месяцев прохождения АРТ

Раздел 6.5

Когда следует начинать АРТ у детей АРТ первого ряда для детей моложе трех лет АРТ первого ряда для детей в возрасте трех лет и старше Комбинированное лечение ТБ и ВИЧ-инфекции у детей Мониторинг эффективности АРТ и выявление причин неудачи лечения (включая детей) Мониторинг и замена препаратов другими при токсичности АРВ-препаратов (включая детей) Основные взаимодействия АРВ-препаратов (включая детей) АРТ третьего ряда (включая детей)

Раздел 7.1.4 Раздел 7.2.3 Раздел 7.2.4 Раздел 7.2.5 Раздел 7.3 Раздел 7.4 Таблица 7.17 Раздел 7.6 Раздел 8.1 Раздел 8.1.7 Раздел 8.2 Раздел 8.2.4.2

Глава 8: Ведение наиболее распространенных коинфекций и сопутствующих заболеваний

Профилактика, скрининг и ведение коинфекций (включая детей) Иммунизация Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ Оказание нутритивной помощи и поддержки детям, живущим с ВИЧ

Глава 9: Рекомендации по операционной деятельности и предоставлению услуг

Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Соблюдение режима АРТ: Дети грудного и младшего возраста Децентрализация и перераспределение обязанностей Раздел 9.2.1 Разделы 9.4.3 и 9.5.2

Таблица 4.3 (продолжение) Глава Глава 10: Рекомендации для руководителей программ Тема Раздел главы

Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Вопросы реализации в отношении основных рекомендаций: расширение масштабов лечения для детей Вопросы реализации в отношении основных рекомендаций: прекращение использования d4T Раздел 10.6; Вставка 10.6 Раздел 10.6; Вставка 10.7. Раздел 11.2

Глава 11: Мониторинг и оценка Приложения

Значение новых рекомендаций для мониторинга Приложение 1. Клинические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей Приложение 4. Алгоритм для рекомендаций 2013 года в отношении детей Приложение 5. Алгоритм для ранней диагностики у грудных детей Приложение 7. Дозировка лекарственных форм АРВ- препаратов для детей, рассчитанная по весу

Глава 12

4.3.4 Ключевые группы населения К категории ключевых групп населения в настоящем руководстве относятся как уязвимые группы населения, так и группы населения повышенного риска. К группам населения повышенного риска относятся мужчины, практикующие секс с мужчинами, трансгендерные лица, потребители инъекционных наркотиков и работники секс-индустрии. Использование АРТ в ключевых группах населения должно следовать принципам и рекомендациям, предназначенным для взрослых. Имеется одна рекомендация в отношении тестирования на ВИЧ по месту жительства, которая касается конкретно ключевых групп населения. В Таблице 4.4 указано, в каких разделах содержатся основные указания и рекомендации, касающиеся ключевых групп населения.

Таблица 4.4 Основные рекомендации и указания для ключевых групп населения Глава Глава 2: Руководящие принципы Глава 5: Диагностика ВИЧ и АРВ-препараты для профилактики ВИЧ Тема Соблюдение прав человека и принципа справедливости в отношении здоровья Консультирование и тестирование на ВИЧ в медицинских учреждениях Консультирование и тестирование на ВИЧ по месту жительства Консультирование и тестирование на ВИЧ конкретных групп населения: Ключевые группы населения Раздел главы Раздел 2.5 Раздел 5.1.2 Раздел 5.1.3 Раздел 5.1.4.5

4. Структура руководства

Таблица 4.4 (продолжение) Глава Глава 6: Установление связей между лицами с диагнозом ВИЧ-инфекции и службами лечения и оказания помощи Глава 7: Aнтиретровирусная терапия Тема Оказание общей помощи людям, живущим с ВИЧ Подготовка к прохождению АРТ людей, живущих с ВИЧ Раздел главы Раздел 6.3 Раздел 6.4

4.3 Как использовать рекомендации для конкретных групп населения

Что можно ожидать от первых месяцев прохождения АРТ Когда следует начинать АРТ у взрослых и подростков (включая ключевые группы населения) АРТ первого ряда для взрослых (включая ключевые группы населения) Мониторинг эффективности АРТ и выявление причин неудачи лечения (включая ключевые группы населения) Мониторинг и замена одних препаратов другими при токсичности АРВ-препаратов (включая ключевые группы населения) АРТ второго ряда для взрослых и подростков (включая ключевые группы населения) АРТ третьего ряда (включая ключевые группы населения)

Раздел 6.5

Раздел 7.1.1 Раздел 7.2.1 Раздел 7.3

Раздел 7.4

Раздел 7.5.1 Раздел 7.5.3 Раздел 8.1 Раздел 8.2 Раздел 8.2.3

Глава 8: Ведение наиболее распространенных коинфекций и сопутствующих заболеваний Глава 9: Рекомендации по операционной деятельности и предоставлению услуг

Профилактика, скрининг и ведение коинфекций Профилактика и ведение распространенных коинфекций и сопутствующих заболеваний Употребление наркотиков и расстройства, связанные с этим Соблюдение режима АРТ: Группы повышенного риска (включая работников секс-индустрии, мужчин, практикующих секс с мужчинами, трансгендерных лиц и потребителей инъекционных наркотиков) АРТ в местах проведения опиоидной заместительной терапии; интеграция и взаимодействие служб Децентрализация и перераспределение обязанностей

Раздел 9.2.1

Раздел 9.4.2.3 Разделы 9.4.3 и 9.5.2

Глава 10: Рекомендации для руководителей программ

Рекомендации в этой главе касаются разных групп населения. Перечисленные темы указывают на некоторые конкретные вопросы. Социально-экономическая, политическая и правовая ситуация Вопросы этики, справедливости и прав человека Вопросы реализации в отношении основных рекомендаций: повышение порогового уровня CD4 для начала АРТ у взрослых с 350 до 500 клеток/mm3 Раздел 10.3.4 Раздел 10.4.1 Раздел 10.6; Вставка 10.2

Таблица 4.4 (продолжение) Глава Раздел 11: Мониторинг и оценка Приложения Тема Значение новых рекомендаций для мониторинга Приложение 1. Клинические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей Приложение 7: Дозировки рекомендованных антиретровирусных препаратов Раздел главы Раздел 11.2

Глава 12

КЛИНИЧЕСКОЕ РУКОВОДСТВО ПО ОКАЗАНИЮ НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

ДИАГНОСТИКА ВИЧ И АРВ-ПРЕПАРАТЫ ДЛЯ ПРОФИЛАКТИКИ ВИЧ 5.1 Консультирование и тестирование на ВИЧ 5.1.1 Введение 5.1.2 Консультирование и тестирование на ВИЧ в медицинских учреждениях 5.1.3 Консультирование и тестирование на ВИЧ по месту жительства

05 68 68 70 71 74 85 85 86

5.1.4 Консультирование и тестирование на ВИЧ конкретных групп населения 5.2 Профилактика ВИЧ за счет приема АРВ-препаратов 5.2.1 Пероральная доконтактная профилактика 5.2.2 АРТ на службе профилактики среди серодискордантных пар

5.2.3 Постконтактная профилактика на случай ВИЧ-инфицирования в процессе профессиональной и непрофессиональной деятельности 86 87

5.2.4 Комбинированная профилактика ВИЧ

Цель этой главы Представить краткий обзор существующих и новых доказательных клинических рекомендаций, описывающих подход с позиции общественного здравоохранения к диагностике ВИЧ-инфекции и обеспечению АРВ-препаратами для нужд профилактики в контексте непрерывного оказания широкого спектра услуг при ВИЧ с упором на страны или территории с ограниченным потенциалом систем здравоохранения и дефицитом ресурсов.

РУКОВОДСТВО ПО ОКАЗАНИЮ 5. КЛИНИЧЕСКОЕ

НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

ДЛЯ ПРОФИЛАКТИКИ ВИЧ 5.1 Консультирование и тестирование на ВИЧ 5.1.1 Введение

ДИАГНОСТИКА ВИЧ И АРВ-ПРЕПАРАТЫ

Доступ населения к услугам по лечению, уходу и профилактике ВИЧ обеспечивается через фильтр консультирования и тестирования на ВИЧ-инфекцию. По имеющимся на сегодняшний день ориентировочным общемировым данным, примерно половина людей, живущих с ВИЧ, не имеют никакого представления о своем ВИЧ-статусе. Те люди, которые зачастую знают об этом, проходят обследование несвоевременно, а существующие неудовлетворительные связи между службами консультирования и тестирования на ВИЧ и организации ухода за инфицированными, равно как и неспособность системы обеспечить их оперативное обследование на соответствие критериям назначения АРТ, приводят к тому, что многие больные приступают к лечению на фоне уже значительно ослабленного иммунитета, что обусловливает неудовлетворительные исходы для здоровья и продолжающуюся передачу ВИЧ-инфекции. Стоящая перед национальной программой по ВИЧ общая цель консультирования и тестирования должна состоять в том, чтобы выявлять как можно больше людей, живущих с ВИЧ, на самых ранних этапах после приобретения ВИЧ-инфекции, соответствующим образом и своевременно направлять их в службы профилактики, ухода и лечения. Лиц, прошедших обследование и оказавшихся неинфицированными, следует направлять в соответствующие службы профилактики, например центры медицинского мужского обрезания в приоритетных странах Африки, расположенных к югу от Сахары, или в службы снижения вреда для потребителей наркотиков, и предложить им пройти повторное обследование позднее. Существуют различные модели предоставления услуг по консультированию и тестированию на ВИЧ для расширения доступности диагностики ВИЧ-инфекции, включая службы проведения обследований на базе лечебно-профилактических учреждений, автономных центров, и широкий выбор вариантов на уровне общины. Детальная информация по этому кругу вопросов представлена в вышедшей в 2012 г. публикации ВОЗ с описанием стратегической рамочной основы консультирования и тестирования на ВИЧ (1). Методы экспресс-диагностики, которыми теперь можно воспользоваться непосредственно у постели больного, расцениваются в качестве важной стратегии в целях расширения доступа, повышения шансов получить готовые результаты в тот же день и создания условий для направления больных в соответствующие специализированные учреждения и организации последующего наблюдения. Странам следует делать конкретный выбор из числа имеющихся перспективных моделей организации медобслуживания для обеспечения справедливого доступа к консультированию и тестированию на ВИЧ с учетом местной специфики, характера эпидемии, экономической эффективности и имеющихся ресурсов.

5. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: диагностика ВИЧ и АРВ-препараты для профилактики ВИЧ

Сделанный таким образом выбор должен способствовать постановке диагноза как можно большему число людей, живущих с ВИЧ, и как можно раньше, чтобы своевременно направить их в центры АРТ. Действующие стратегии должны охватывать лиц, относящихся к наиболее уязвимым слоям населения, подверженных наибольшему риску и оказавшихся среди изгоев общества (Вставка 5.1). Использование единственного метода обследования на ВИЧ-инфекцию является недостаточным; полученный результат должен быть подтвержден в соответствии с процедурами, о которых говорится в пересмотренном руководстве ВОЗ от 2012 г. по стратегиям (алгоритмам) проведения тестирования на ВИЧ (1). Должны быть созданы системы обеспечения качества для сведения к минимуму ложноположительных и ложноотрицательных результатов. Неспособность добиться этого приведет к тому, что людям будут сообщать неверные результаты анализов, что не исключает вероятности возникновения серьезных отдаленных последствий. Меры по обеспечению и улучшению качества одинаково важны для процесса консультирования в целях создания гарантий неизменной приемлемости и эффективности процедур консультирования и тестирования на ВИЧ.

5.1 Консультирование и тестирование на ВИЧ

Вставка 5.1. Консультирование и тестирование на ВИЧ: основополагающие принципы Все формы консультирования и тестирования на ВИЧ должны быть добровольными и придерживаться правила из пяти букв «С» (от англ.): согласие, конфиденциальность, консультирование, корректные результаты тестирования и наличие связи со службами по уходу, лечению и профилактике. Обязательное или принудительное тестирование никогда не будет считаться уместным независимо от того, откуда исходит принуждение – от поставщика медицинских услуг, партнера или члена семьи. Действие нижеследующих основных принципов распространяется на все модели консультирования и тестирования на ВИЧ и на все обстоятельства. Лица, проходящие консультирование и тестирование на ВИЧ, обязаны давать информированное согласие (согласия в устной форме вполне достаточно, и письменное согласие не является обязательным), чтобы обследоваться и получить консультацию. Они должны быть информированы о процедуре консультирования и тестирования на ВИЧ, а также о своем праве отказаться от обследования. Услуги по консультированию и тестированию на ВИЧ являются конфиденциальными, а это значит, что содержание беседы между поставщиком услуг по консультированию и тестированию на ВИЧ и заинтересованным лицом не будет доведено до сведения кого бы то ни было без явно выраженного согласия обследуемого индивидуума. Несмотря на необходимость соблюдения врачебной тайны, последняя, тем не менее, не должна усиливать атмосферу секретности, стигмы или позора. Наряду с другими вопросами консультанты должны затрагивать и такие моменты, как кому еще заинтересованные лица хотели бы сообщить эти сведения и как они хотели бы это сделать. Взаимные доверительные отношения с партнером или членами семьи, а также с другими доверенными лицами и поставщиками медицинских услуг нередко оказываются исключительно благотворными.

Услуги по консультированию и тестированию на ВИЧ должны сопровождаться

адекватной и высококачественной дотестовой информацией (которую в некоторых условиях можно предоставлять в форме группового инструктажа относительно процедур накануне обследования) и послетестовым консультированием. В целях высококачественного консультирования должны быть созданы механизмы обеспечения качества и системы поддерживающего кураторства и наставничества. Поставщики услуг по консультированию и тестированию должны стремиться к проведению высококачественных обследований, и на местах должны быть созданы механизмы обеспечения качества, чтобы гарантированно получать правильные результаты анализов. Система обеспечения качества может включать в себя как внутренние, так и внешние мероприятия и должна предусматривать, если потребуется, оказание поддержки со стороны национальной референс-лаборатории. Взаимодействие со службами профилактики, ухода и лечения должно, при наличии показаний, предусматривать возможности для эффективного направления больных в соответствующие службы последующего наблюдения, включая оказание долговременной помощи в плане профилактики и лечения. При любых используемых формах тестирования и консультирования необходимо обеспечивать соблюдение качества.

5.1.2 Консультирование и тестирование на ВИЧ в медицинских учреждениях Общая информация В рутинной практике ВОЗ рекомендует предлагать посетителям услуги по консультированию и тестированию на ВИЧ в условиях клиники (известные как услуги по консультированию и тестированию, оказываемые по инициативе персонала лечебного учреждения) в качестве результативного и эффективного метода выявления ВИЧ-инфицированных лиц, для которых лечение может оказаться полезным.

Первоисточник для подготовки рекомендаций Р уководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебно-профилактических учреждениях. Женева, Всемирная организация здравоохранения, 2007 г. (http://whqlibdoc.who.int/ publications/2007/9789244595565_rus.pdf) (2).

5.1 Консультирование и тестирование на ВИЧ

Существующие рекомендации (2) В условиях генерализованной эпидемии услуги тестирования и консультирования по инициативе медработников лечебно-профилактических учреждений должны быть рекомендованы всем посетителям (взрослым, подросткам и детям) медицинских учреждений любого профиля, включая службы оказания лечебной и хирургической помощи; кожно-венерологические и противотуберкулезные диспансеры и центры лечения вирусных гепатитов; государственные и частные клиники; амбулаторные и стационарные отделения; услуги, оказываемые мобильными медицинскими бригадами или аутрич-работниками; службы ведения беременных женщин (дородовое наблюдение, планирование семьи и охрана здоровья матери и ребенка); медобслуживание ключевых групп населения; службы охраны здоровья детей грудного и более старшего возраста; и службы охраны репродуктивного здоровья. В условиях концентрированной эпидемии и эпидемии в начальной стадии услуги тестирования и консультирования по инициативе медработников лечебно-профилактических учреждений должны быть рекомендованы во всех медицинских учреждениях следующим категориям населения: в зрослым, подросткам или детям, поступающим в медицинское учреждение с признаками и симптомами или состоянием здоровья, которое может указывать на наличие ВИЧ-инфекции, включая ТБ; и В ИЧ-экспонированным детям, детям, рожденным матерями с установленной ВИЧ-инфекцией, и симптоматическим младенцам и детям. Вопрос об оказании услуг тестирования и консультирования по инициативе медработников лечебно-профилактических учреждений должен ставиться перед посетителями кожно-венерологических и противотуберкулезных диспансеров и центров лечения вирусных гепатитов, женских консультаций и клиник, обслуживающих ключевые контингенты (главным образом мужчин, занимающихся сексом с мужчинами, трансгендерных лиц, секс-работников и потребителей инъекционных наркотиков).

5.1.3 Консультирование и тестирование на ВИЧ по месту жительства Новые рекомендации (2013 г.) новое

новое

В условиях генерализованной эпидемии ВИЧ, наряду с мероприятиями по тестированию и консультированию по инициативе медработников, рекомендуется обеспечивать консультирование и тестирование на ВИЧ по месту жительства во взаимодействии со службами профилактики, ухода и лечения (настоятельная рекомендация, фактические данные низкого качества). В условиях любой эпидемии ВИЧ, наряду с мероприятиями по тестированию и консультированию по инициативе медработников, рекомендуется обеспечивать консультирование и тестирование на ВИЧ ключевых групп населения по месту жительства во взаимодействии со службами профилактики, ухода и лечения (настоятельная рекомендация, фактические данные низкого качества).

Общая информация В этом руководстве представлены расширенные критерии проведения АРТ у живущих с ВИЧ детей, подростков, взрослых и беременных и кормящих грудью женщин. В целях получения максимальной пользы от этих рекомендаций для физического лица и общественного здоровья люди, живущие с ВИЧ, должны проходить диагностическое обследование и получить направление в службы ухода за больными на раннем этапе развития ВИЧ-инфекции. Несмотря на ключевую роль тестирования, проводимого на базе лечебных учреждений, лиц, живущих с ВИЧ, нередко выявляют в условиях клиники на поздней стадии вызванного ВИЧ заболевания, причем некоторые группы населения, в том числе мужчины и подростки и особенно ключевые контингенты, редко обращаются за медико-санитарной помощью. Благодаря организации обследований непосредственно по месту жительства можно решить проблему охвата людей, живущих с ВИЧ, на более ранней стадии прогрессирования заболевания, вызванного ВИЧ, по сравнению с системой тестирования и консультирования по инициативе персонала лечебных учреждений, а также охватить и те группы населения, которые обычно не обращаются за медицинскими услугами. Использование методов экспресс-диагностики на ВИЧ на основании результатов анализа образцов крови, взятых из пальца профессионально подготовленными консультантами и медработниками низшего звена, позволило расширить масштабы консультирования и тестирования на ВИЧ на уровне общины, в том числе на дому и стоянках транспортных средств, в культовых учреждениях, школах и университетах, на рабочих местах и местах скопления ключевых групп населения. Дальнейшее расширение практики проведения тестирования по месту жительства, в дополнение к обследованиям на базе лечебно-профилактических учреждений, является важным моментом в решении вопросов получения исчерпывающих сведений о ВИЧ-статусе и ранней диагностики во взаимодействии со службами обеспечения ухода и лечения. Мероприятия по консультированию и тестированию на ВИЧ по месту жительства включают такие формы консультирования и тестирования на ВИЧ, как организация работы на выезде, подворные обходы, выявление источника инфекции, проведение кампаний и обследований на рабочих местах и в учебных заведениях (1).

Обоснование и подтверждающие фактические данные В основе предложенных рекомендаций лежат фактические данные, а также операционные и программные соображения. В итоге систематизированного обзора было выявлено четыре рандомизированных исследования (3,4) и восемь обсервационных исследований (5–10), в рамках которых проводилась сравнительная оценка тестирования по месту жительства и обследований на базе лечебных учреждений в условиях генерализованной эпидемии (веб-приложение http://www.who.int/hiv/pub/guidelines/arv2013/annexes). В целом, было установлено, что благодаря проведению такой работы на уровне общины удалось улучшить показатели тестирования среди лиц, впервые проходящих диагностическое обследование, а также среди взрослых с количеством CD4 свыше 350 клеток/мм3. Однако частота получения положительных результатов тестирования оказалась выше при проведении обследований на базе медицинских учреждений, чем во многих случаях тестирования по месту жительства. Систематизированный обзор показал, что охват консультированием и тестированием на ВИЧ на районном уровне увеличился в результате организации консультирования и тестирования на ВИЧ по месту жительства (с использованием либо подворных обходов, либо путем организации работы на выезде) в сочетании с консультированием и тестированием на ВИЧ на базе лечебных учреждений.

В итоге дополнительного обзора ситуации с охватом ключевых групп населения было найдено три исследования по сравнительному анализу обследований ключевых групп населения по месту жительства и на базе медицинских учреждений (11–13). Несмотря на повышение спроса на услуги тестирования на уровне общины, доля участников, впервые проходящих обследование на ВИЧ, оказалась сопоставимой при тестировании по месту жительства и на базе лечебных учреждений. Пятнадцать исследований было посвящено анализу потенциальных отрицательных последствий тестирования по месту жительства (10, 14–25). В рамках этих исследований обсуждались не только положительные отклики клиентов, прошедших обследование, но и их опасения. В восьми журнальных статьях сообщалось о том, что меньшинство участников отказались проходить консультирование и обследование на ВИЧ из-за боязни разглашения их статуса или стигмы (10,14–17,21,23,25). На примере этих исследований не было продемонстрировано, что организация обследований на уровне общины способствовала либо уменьшению стигмы или страха, либо возрастанию этих или других отрицательных эмоций. По данным нескольких исследований, посвященных сопоставлению затрат на тестирование одного человека на уровне общины и в условиях лечебного учреждения, оказалось, что расходы на одного обследованного лица были аналогичными в обоих случаях (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Несмотря на то, что в итоге обзора в целом были получены фактические данные очень низкого качества, удалось прийти к общему согласию относительно того, что важнейшие программные достоинства метода консультирования и тестирования на ВИЧ по месту жительства, равно как и результаты оценки полезности, предпочтений, уровня затрат и осуществимости такого подхода, послужили достаточным основанием для Группы по разработке руководства предложить в связи с этим настоятельные рекомендации. Идея тестирования на уровне общины должна быть реализована наряду с принципом консультирования и тестирования по инициативе медработников лечебных учреждений. Есть необходимость в использовании множества подходов, которые могут опираться на вовлечение автономных центров, служб тестирования на дому, выездных бригад аутрич-работников (с охватом рабочих, школ, университетов, специальных кампаний по тестированию населения и массовых мероприятий), а также на использование кампаний борьбы со многими болезнями с учетом эпидемиологической обстановки и специфики социального контекста.

5.1 Консультирование и тестирование на ВИЧ

5.1.4 Консультирование и тестирование на ВИЧ конкретных групп населения 5.1.4.1 Супружеские пары Общая информация Проведенные в нескольких странах исследования показали, что мероприятия по консультированию и тестированию на ВИЧ супружеских пар являются приемлемыми, реально выполнимыми и эффективными. Они позволяют выявлять ВИЧ-позитивных партнеров в серодискордантных парах, которых можно направлять на лечение и оказывать им поддержку в соблюдении предписанного режима терапии. Помимо этого, можно также выявлять супружеские пары с серодискордантными результатами обследования на ВИЧ, для которых профилактическое лечение по поводу ВИЧ может оказаться благотворным. Эти услуги должны предлагаться парам, состоящим в браке и совместно проживающим, парам в добрачном периоде, полигамным союзам и любым другим лицам, поддерживающим партнерские отношения друг с другом. Как и в случае со всеми формами консультирования и тестирования на ВИЧ, должен соблюдаться принцип добровольности при консультировании и тестировании на ВИЧ супружеских пар. Поставщики медицинских услуг обязаны помнить о том, что не исключены случаи проявления насилия между близкими в интимном отношении партнерами, и они должны помогать тем лицам, которым бы не хотелось обследоваться вместе со своими партнерами. Услуги по консультированию и тестированию супружеских пар могут предлагаться в медицинских учреждениях любого профиля, которые занимаются консультированием и тестированием на ВИЧ, включая клиники дородового наблюдения и противотуберкулезные службы. Поддержка в поощрении обследования партнеров людей, живущих с ВИЧ, также является результативным и эффективным методом выявления дополнительного числа живущих с ВИЧ индивидуумов, здоровью которых в дальнейшем такое лечение может принести пользу. Более того, консультирование и тестирование на ВИЧ супружеских пар может оказаться важным вмешательством в плане повышения уровня доступности начала АРТ на раннем этапе и охвата лечением большего числа мужчин. Благодаря семейным формам консультирования и тестирования супружеских пар, в которых один или оба партнера живут с ВИЧ-инфекцией, можно выявить детей, подростков и других членов семей, которым ранее не выставлялся такой диагноз.

Первоисточник для подготовки рекомендаций C ouples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/ publications/2012/9789241501972_eng.pdf) (26). Существующие рекомендации (26) Супружеским парам и партнерам следует предлагать добровольное консультирование и тестирование на ВИЧ наряду с оказанием поддержки ввиду взаимного раскрытия информации (настоятельная рекомендация, фактические данные низкого качества). Супружеским парам и партнерам, обращающимся в клиники дородового наблюдения, следует предлагать добровольное консультирование и тестирование на ВИЧ наряду с оказанием поддержки ввиду взаимного раскрытия информации (настоятельная рекомендация, фактические данные низкого качества). Добровольное консультирование и тестирование на ВИЧ супружеских пар и партнеров наряду с оказанием поддержки ввиду взаимного раскрытия информации следует предлагать индивидуумам с известным ВИЧ-статусом и их партнерам (настоятельная рекомендация, фактические данные низкого качества для всех ВИЧ-инфицированных лиц в условиях любой эпидемии; условная рекомендация, фактические данные низкого качества для ВИЧ-отрицательных лиц в зависимости от уровня распространенности ВИЧ в конкретной стране).

5.1.4.2 Беременные женщины и женщины в послеродовом периоде Общая информация Мероприятия по консультированию и тестированию беременных женщин по инициативе медработников лечебных учреждений во взаимодействии со службами профилактики и ухода необходимы для укрепления здоровья матери и профилактики новых инфекций у детей, что может способствовать реализации стратегии обследования супружеских пар.

5.1 Консультирование и тестирование на ВИЧ

Существующие рекомендации (2) Генерализованная эпидемия Консультирование и тестирование по инициативе медработников лечебных учреждений рекомендуются для женщин в качестве рутинного компонента набора услуг по уходу за больными при посещении клиник дородового наблюдения, родовспомогательных, послеродовых и детских учреждений любого профиля. Повторное тестирование рекомендуется в третьем триместре или во время родов либо вскоре после них ввиду высокого риска приобретения ВИЧ-инфекции в период беременности. Начальная и концентрированная стадии эпидемии Вопрос о консультировании и тестировании по инициативе медработников лечебных учреждений следует рассматривать в отношении беременных женщин. Многие страны считают приоритетными мероприятия по консультированию и тестированию по инициативе медработников лечебных учреждений в рамках дородового наблюдения в качестве ключевого компонента своих усилий по ликвидации вертикальной передачи ВИЧ-инфекции от матери ребенку и эффективно сочетают обследование на ВИЧ со скринингом на сифилис, анализами на гепатиты или другими важнейшими тестами в зависимости от профиля учреждения, а также придают особое значение укреплению базовой системы охраны здоровья матери и ребенка.

5.1.4.3 Дети грудного и более старшего возраста Общая информация ВИЧ-экспонированные младенцы и дети моложе 18 месяцев подлежат обследованию в первые четыре-шесть недель после рождения, чтобы уже ВИЧ-инфицированные лица могли приступить к АРТ. Уровень смертности среди ВИЧ-инфицированных непролеченных детей грудного возраста на первом году жизни очень высокий, что выдвигает на передний план исключительную важность тестирования на ВИЧ на раннем этапе, оперативную выдачу готовых результатов и безотлагательное начало курса лечения. В этой группе населения наличие ВИЧ-инфекции можно наверняка подтвердить только на основании вирусологических методов исследования ввиду присутствия персистирующих материнских антител к ВИЧ в организме ребенка в возрасте 15–18 месяцев. Вирусологические методы диагностики включают в себя реакции на выявление вирусных нуклеиновых кислот (ДНК, РНК ВИЧ или суммарные нуклеиновые кислоты) или антиген p24 ВИЧ. В настоящее время вирусологические исследования главным образом проводятся с использованием образцов сухой капиллярной капли крови (СККК) путем забора проб материала местными учреждениями и с их последующей доставкой и анализом в централизованных лабораториях. Несмотря на улучшение показателей раннего тестирования, по-прежнему остаются нерешенными проблемы доступности, выдачи готовых результатов и начала своевременного лечения младенцев с положительным результатом анализа. Есть надежда, что находящиеся в стадии разработки вирусологические анализы по месту лечения заметно улучшат ситуацию с ранней диагностикой и лечением. Поскольку некоторых детей грудного возраста не удается определить как подвергшихся риску заражения ВИЧ или же они оказываются вне досягаемости для динамического наблюдения в послеродовом периоде, задачи консультирования и тестирования по инициативе медработников лечебных учреждений должны выполняться центрами по уходу за младенцами в целях выявления дополнительного числа случаев. Должны быть созданы условия для постановки окончательного диагноза (или определенного диагноза) ближе к концу периода сохранения риска передачи заразного начала от матери ребенку (периода кормления грудью). Отрицательный анализ на антитела к ВИЧ у младенца с известной экспозицией ВИЧ может сыграть полезную роль для исключения вероятности ВИЧ-инфекции при условии отсутствия продолжающейся экспозиции. (См. Приложение 5 с алгоритмом диагностики ВИЧ у детей, не достигших 18 месячного возраста). Применительно к детям в возрасте 18 месяцев и старше (которые не находятся на грудном вскармливании или отказались от груди, как минимум, за шесть недель до этого) могут использоваться стандартные серологические анализы на ВИЧ, например методы экспресс-диагностики, в целях достоверного определения статуса по ВИЧ-инфекции. ВОЗ рекомендует обеспечивать консультирование и тестирование по инициативе медработников лечебных учреждений для всех детей с недостаточностью питания, больных ТБ, поступивших в стационар или имеющих другие признаки или симптомы ВИЧ-инфекции. Другие подходы, в частности обследование всех детей в рамках программ вакцинопрофилактики детского населения, удалось осуществить в некоторых странах или территориях для повышения вероятности выявления ВИЧ-инфицированных детей. Рекомендации по диагностике ВИЧ-инфекции у детей грудного и более старшего возраста будут пересмотрены в будущем году.

Таблица 5.1 Краткое изложение подходов к рекомендованному обследованию детей грудного возраста (27) Категория Здоровый младенец, подвергшийся риску заражения ВИЧ Необходимое обследование Задача Вирусологическое исследование в возрасте 4–6 недель Диагностирование ВИЧ Действие Начало АРТ при ВИЧ-инфицировании Необходимость вирусологического исследования в случае ВИЧ-экспонирования ВИЧ-серопозитивным лицам показано вирусологическое исследование и длительное последующее наблюдение; ВИЧ-отрицательным, предположительно неинфицированным детям, показано повторное обследование, если они попрежнему находятся на грудном вскармливании Проведение вирусологического исследования, если возраст <18 мес. При наличии реакции – начало мероприятий по уходу за ВИЧ-инфицированным и проведение АРТ

5.1 Консультирование и тестирование на ВИЧ

Постановка серологической Младенец – факт реакции на ВИЧ у матери или экспонирования постановка серологической не известен реакции на ВИЧ у ребенка

Выявление или подтверждение ВИЧ-экспонирования

Здоровый ребенок, подвергшийся риску заражения ВИЧ в 9-месячном возрасте

Постановка серологической реакции на ВИЧ (в конечном итоге – иммунизация, как правило, в 9 мес.)

Выявление младенцев с персистирующими антителами к ВИЧ или реакцией сероконверсии

Ребенок грудного или более старшего возраста с признаками и симптомами ВИЧ- инфекции Здоровый или больной ребенок, оказавшийся серопозитивным в возрасте от >9 мес. до <18 мес. Ребенок грудного или более старшего возраста, отказавшийся от груди целиком и полностью

Постановка серологической реакции на ВИЧ

Подтверждение экспонирования

Вирусологическое исследование

Диагностирование ВИЧ

Повторное исследование по истечении шести недель или позднее после прекращения грудного вскармливания – обычно вирусологическому исследованию предшествует постановка серологической реакции на ВИЧ у ВИЧ-позитивного ребенка и в возрасте <18 мес.

Исключение ВИЧ-инфекции после прекращения экспонирования

Инфицированные младенцы и дети в возрасте <5 лет должны быть охвачены мероприятиями по уходу в связи с ВИЧ, включая АРТ

Первоисточники для подготовки рекомендаций WHO recommendations on the diagnosis of HIV infection in infants and children. Geneva, World Health Guideline on HIV disclosure counselling for children up to 12 years of age. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599085_eng.pdf) (27). Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502863_eng.pdf) (28).

Существующие рекомендации (27) Настоятельно рекомендуется, чтобы все младенцы с неизвестным или неопределенным риском заражения ВИЧ проходили обследование в лечебнопрофилактических учреждениях при рождении или вскоре после этого либо при первом же посещении в послеродовом периоде (обычно на 46 неделе) или в связи с поступлением ребенка по другому поводу в целях установления их статуса по экспозиции ВИЧ (настоятельная рекомендация, фактические данные высокого качества). Настоятельно рекомендуется, чтобы все ВИЧ-экспонированные младенцы проходили вирусологические обследования на ВИЧ в возрасте от четырех до шести недель или при первой же возможности в дальнейшем (настоятельная рекомендация, фактические данные высокого качества). Д ля детей грудного возраста с первичным положительным результатом

вирусологического исследования настоятельно рекомендуется, чтобы АРТ начиналась безотлагательно и, одновременно с этим, следует взять второй образец диагностического материала для подтверждения изначально положительного результата вирусологического исследования. Не откладывайте начало проведения АРТ. Немедленное начало АРТ спасает жизни, и такое лечение не следует переносить на более поздний срок в ожидании готовых результатов подтверждающего анализа (настоятельная рекомендация, фактические данные высокого качества). Настоятельно рекомендуется, чтобы младенцы с признаками и симптомами, указывающими на ВИЧ-инфекцию, проходили серологическое тестирование на ВИЧ, а при положительном (реактивном) результате – в том числе и вирусологическое исследование (настоятельная рекомендация, фактические данные низкого качества). Настоятельно рекомендуется, чтобы практически здоровые ВИЧ-экспонированные младенцы проходили серологическое тестирование на ВИЧ ориентировочно в девятимесячном возрасте (или ко времени последнего сеанса проведения иммунизации). Младенцы с реактивными результатами серологических тестов в девятимесячном возрасте должны проходить вирусологическое обследование в целях выявления ВИЧ-инфицированных детей, которым показана АРТ (настоятельная рекомендация, фактические данные низкого качества). Настоятельно рекомендуется, чтобы дети в возрасте 18 месяцев или старше с

подозрением на ВИЧ-инфекцию или риск заражения ВИЧ проходили серологическое тестирование на ВИЧ в соответствии со стандартным диагностическим алгоритмом постановки серологической реакции на ВИЧ, предназначенным для взрослых (настоятельная рекомендация, фактические данные высокого качества).

Существующие рекомендации (28) Детям школьного возраста следует сообщать их ВИЧ-позитивный статус, а также статус их родителей или лиц, которые заботятся о них; детей более раннего возраста следует информировать об их статусе поэтапно с учетом их когнитивных навыков и эмоциональной зрелости в порядке подготовки к полному раскрытию информации об этом (настоятельная рекомендация, фактические данные низкого качества).

5.1 Консультирование и тестирование на ВИЧ

5.1.4.4 Подростки Общая информация Подростки зачастую недостаточно охвачены медобслуживанием, и во многих программах по ВИЧ им не уделяют должного внимания при неудовлетворительной доступности и востребованности услуг консультирования и тестирования на ВИЧ во взаимодействии со службами профилактики и ухода за больными. В категорию ВИЧ-инфицированных подростков входят лица, дожившие до определенного возраста после заражения в перинатальном периоде, а также лица с вновь приобретенной инфекцией по мере их вступления в активную половую жизнь или из-за воздействия заразного начала вследствие введения наркотиков инъекционным путем, других небезопасных инъекций и переливаний крови. В условиях генерализованной эпидемии многие младенцы, оказавшиеся инфицированными в результате вертикальной передачи, не диагностируются в рамках программ ППМР, и более ранняя диагностика и лечение могли бы пойти им на пользу. Во многих ситуациях девушки-подростки и подростки из ключевых групп населения также уязвимы к ВИЧ-инфекции и могли бы извлечь пользу благодаря доступу к приемлемым и эффективным службам оказания помощи при ВИЧ, включая консультирование и тестирование на ВИЧ. В некоторых случаях в связи с вопросами получения согласия могут возникать проблемы в плане доступности этих служб для подростков, о чем подробно говорится в руководстве ВОЗ от 2013 г. по ведению подростков (29).

Первоисточник для подготовки рекомендаций Guidance on HIV testing and counselling for adolescents and care for adolescents living with HIV. Geneva, World Health Organization, 2013, в печати (29).

Новые рекомендации (2013 г.) (29)

новое

Консультирование и тестирование на ВИЧ во взаимосвязи со службами профилактики, лечения и ухода рекомендовано для подростков из ключевых групп населения при любой ситуации (генерализованная эпидемия, эпидемия в начальной стадии и концентрированная эпидемия) (настоятельная рекомендация, фактические данные очень низкого качества).

новое

Консультирование и тестирование на ВИЧ во взаимосвязи со службами профилактики, лечения и ухода рекомендовано для всех подростков при генерализованной эпидемии (настоятельная рекомендация, фактические данные очень низкого качества). Мы считаем, что консультирование и тестирование на ВИЧ во взаимосвязи со службами профилактики, лечения и ухода должно быть доступно для всех подростков в условиях эпидемии с низким уровнем распространенности ВИЧ и концентрированной эпидемии (условная рекомендация, фактические данные очень низкого качества). Мы считаем, что подростки должны иметь возможность обратиться за консультацией о потенциальной пользе и рисках раскрытия информации о своем ВИЧ-статусе, и им следует оказывать поддержку путем развития и повышения самосознания, чтобы они могли определиться относительно того, стоит ли, когда, каким образом и кому конкретно раскрывать эту информацию (условная рекомендация, фактические данные очень низкого качества).

Обоснование и подтверждающие фактические данные Эти рекомендации были разработаны в соответствии с положениями нового руководства по ведению ВИЧ-инфицированных подростков, опубликованного в 2013 г. ВОЗ, ЮНЕСКО, ЮНФПА, ЮНИСЕФ и Глобальной сетью людей, живущих с ВИЧ/ СПИДом (GNР+), и в их основу были положены результаты систематизированных обзоров фактических данных, консультаций с местным населением для оценки систем ценностей и предпочтений подростков и поставщиков медицинских услуг, а также соображения соответствующей Группы по разработке руководства. В большинстве случаев объем опубликованных фактических данных с рекомендациями по ведению подростков невелик; что касается данного руководства, то большой вес придается мнению, представлениям о пользе и предпочтениям как экспертов по ведению подростков, так и поставщиков медико-санитарной помощи для этой категории населения, а также практическому опыту специалистов на местах. Подробности по этому вопросу изложены в резюме фактических данных к полному тексту Руководства по консультированию и тестированию подростков на ВИЧ, а также по уходу за подростками, живущими с ВИЧ (29).

5.1.4.5 Ключевые группы населения Общая информация Услуги по консультированию и тестированию на ВИЧ стали оказывать ключевым группам населения еще со времени разработки методов обследования на ВИЧ. ВОЗ выпустила руководство по вопросам тестирования для потребителей инъекционных наркотиков в 2006 г, для заключенных и беженцев в 2009 г., для мужчин, практикующих секс с мужчинами, и трансгендерных лиц в 2011 г. и для секс-работников в 2012 году. Для ключевых групп населения, особенно для вовлеченных в преступную деятельность, услуги по консультированию и тестированию на ВИЧ иногда приобретают форму наказания или принуждения. Поэтому, как уже существующие, так и новые рекомендации по консультированию и тестированию на ВИЧ лиц, оказавшихся под воздействием максимального риска, и уязвимых групп, выдвигают на передний план вопросы информированного согласия и конфиденциальности, а также обеспечения того, чтобы аспекты консультирования и тестирования на ВИЧ становились неотъемлемой частью комплексной программы профилактики, ухода и лечения. В опубликованной ВОЗ в 2012 г. стратегической рамочной основе для консультирования и тестирования на ВИЧ (1) кратко изложены методики консультирования и тестирования на ВИЧ всех названных групп и контингентов населения (Таблицы 5.2 и 5.3).

Дополнительные методические материалы Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/77745/1/9789241504744_eng.pdf) (30). Профилактика и лечение ВИЧ-инфекции и инфекций, передаваемых половым путем среди мужчин, практикующих секс с мужчинами, и трансгендерных лиц. Рекомендации с позиции общественного здравоохранения. Женева, Всемирная организация здравоохранения. Пересмотренное издание, 2011 г. (http://whqlibdoc.who.int/ publications/2011/9789241501750_eng.pdf) (31).

Таблица 5.2 Краткое изложение рекомендаций по консультированию и тестированию на ВИЧ на случай генерализованной эпидемии Кого обследовать Когда обследовать Где обследовать Все ЛПУ, включая учреждения первичного звена, амбулаторные терапевтические и хирургические отделения, центры дородового наблюдения и охраны здоровья матери и ребенка, противотуберкулезные диспансеры, центры планирования семьи и кожновенерологические диспансеры Соответствующее руководство ВОЗ

5.1 Консультирование и тестирование на ВИЧ

Все лица, обращающиеся в медицинские учреждения

Интегрировать в систему медобслуживания по любому поводу

Руководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебно-профилактических учреждениях (2)

Партнеры и супружеские пары

До вступления в брак, при беременности, с началом раздельного проживания супругов, новые партнерства и с началом мероприятий по уходу и АРТ ВИЧ-отрицательным представителям серодискордантных пар предлагать повторное тестирование через каждые 6–12 мес. Как можно скорее, как только члену семьи выставлен диагноз

Учреждения первичного звена, центры добровольного консультирования и тестирования, клиники АРТ, центры дородового наблюдения и планирования семьи, на общинном уровне и при организации работы на выезде, на дому

Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26) Сообщение результатов тестирования на ВИЧ-инфекцию и информация о повторном тестировании и консультировании взрослых (32)

Семьи первичных больных

Учреждения первичного звена, клиники АРТ, центры охраны здоровья матери и ребенка и дородового наблюдения, на дому на общинном уровне и при организации работы на выезде

Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Planning, implementing and monitoring home-based HIV testing (33)

Ключевые группы населения: потребители инъекционных наркотиков, мужчины, практикующие секс с Через каждые мужчинами, 6–12 мес. трансгендерные лица, сексработники, заключенные и партнеры лиц, вводящих наркотики инъекционным путем

Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach (30) Prevention and treatment of HIV Учреждения первичного звена, and other sexually transmitted infections among men who have sex кожно-венерологические with men and transgender people: диспансеры при организации recommendations for a public health работы на выезде, включая approach (31) центры по снижению вреда и другие учреждения, Service delivery approaches to оказывающие услуги HIV testing and counselling (HTC): ключевым группам населения a strategic HTC programme framework (1) Сообщение результатов тестирования на ВИЧ-инфекцию и информация о повторном тестировании и консультировании взрослых (32)

Таблица 5.2 (продолжение) Кого обследовать Когда обследовать Где обследовать Соответствующее руководство ВОЗ Руководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебнопрофилактических учреждениях (2) Сообщение результатов тестирования на ВИЧинфекцию и информация о повторном тестировании и консультировании взрослых (32) Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26)

При первом посещении клиники дородового наблюдения Повторное Беременные обследование на женщины и их третьем триместре партнеры мужчины или в перинатальном периоде Предлагать партнерам пройти обследование

Клиники дородового наблюдения, родовспомогательные учреждения, послеродовые отделения

Младенцы и дети в возрасте <18 мес.

Ранняя младенческая диагностика на 4–6 неделе для всех новорожденных, матери которых живут с ВИЧ, или если ВИЧ-статус у матери неизвестен; определение окончательного статуса ВИЧинфицирования у ребенка по истечении 18 мес. и/или после окончания грудного вскармливания Определение ВИЧ-статуса у всех контактов, связанных со здоровьем

Службы охраны здоровья матери и ребенка Детские поликлиники Прививочные пункты

WHO recommendations on the diagnosis of HIV infection in infants and children (27)

Дети

Детские стационары и поликлиники, прививочные пункты

Руководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебно-профилактических учреждениях (2) Сообщение результатов тестирования на ВИЧ-инфекцию и информация о повторном тестировании и консультировании взрослых (32) Guidelines on HIV testing and counselling for adolescents and care and treatment for adolescents living with HIV (29)

Подростки

Интегрировать в систему медобслуживания по любому поводу Ежегодно при сексуальной активности; при появлении новых половых партнеров

Учреждения первичного звена, поликлиники, стационары, центры добровольного консультирования и тестирования, службы доброжелательного отношения к молодежи, центры планирования семьи и кожновенерологические диспансер

Таблица 5.3 Краткое изложение рекомендаций по консультированию и тестированию на ВИЧ в случае начальной и концентрированной эпидемии Кого обследовать Когда обследовать Лица с признаками или симптомами ВИЧ-инфекции Интегрировать в систему медобслуживания по любому поводу Где обследовать Кожновенерологические диспансеры, ПТД, терапевтические отделения, клиники другого профиля Лечебные учреждения, включая учреждения первичного звена, клиники АРТ, ПТД, кожновенерологические диспансеры, центры добровольного консультирования и тестирования Клиники АРТ, центры охраны здоровья матери и ребенка и дородового наблюдения, на дому, непосредственно в общине силами выездных бригад Кожновенерологические диспансеры, услуги аутрич-работников для ключевых групп населения и службы по снижению вреда Соответствующее руководство ВОЗ Руководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебнопрофилактических учреждениях (2) Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples (26) Сообщение результатов тестирования на ВИЧ-инфекцию и информация о повторном тестировании и консультировании взрослых (32)

5.1 Консультирование и тестирование на ВИЧ

Партнеры людей, живущих с ВИЧ

Сразу же, как только появляется возможность выставить диагноз партнеру Предлагать ВИЧ-отрицательным партнерам в серодискордантных парах проходить повторное обследование через каждые 6-12 мес. Как можно скорее, как только члену семьи выставлен диагноз

Семьи первичных больных

Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Planning, implementing and monitoring home-based HIV testing (33) Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in s erodiscordant couples (26) Prevention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach (30) Профилактика и лечение ВИЧ-инфекции и инфекций, передаваемых половым путем, среди мужчин, практикующих секс с мужчинами, и трансгендерных лиц. Рекомендации с позиций общественного здравоохранения (31) Service delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework (1) Сообщение результатов тестирования на ВИЧ-инфекцию и информация о повторном тестировании и консультировании взрослых (32)

Ключевые группы населения: потребители инъекционных наркотиков, мужчины практикующие секс с мужчинами, трансгендерные лица, сексработники

Через каждые 6–12 мес.

Таблица 5.3 (продолжение) Кого обследовать Беременные женщины Когда обследовать Где обследовать Соответствующее руководство ВОЗ Руководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебнопрофилактических учреждениях (2) WHO recommendations on the diagnosis of HIV infection in infants and children (27)

При первом посещении Центры клиники дородового дородового наблюдения наблюдения

Младенцы и дети в возрасте <18 мес.

Ранняя младенческая диагностика на 4–6 неделе для всех новорожденных, матери которых живут с ВИЧ, или если ВИЧ-статус у матери неизвестен; определение окончательного статуса ВИЧ-инфицирования у ребенка по истечении 18 мес. и/или после окончания грудного вскармливания Интегрировать в систему медобслуживания по любому поводу

Службы охраны здоровья матери и ребенка Детские поликлиники Прививочные пункты

Дети, имеющие признаки или симптомы ВИЧ-инфекции или проживающие совместно с ВИЧ-инфицированным членом семьи

Во всех лечебнопрофилактических учреждениях

Руководство по вопросам ВИЧ-тестирования и консультирования по инициативе медицинских работников в лечебнопрофилактических учреждениях (2) Сообщение результатов тестирования на ВИЧ-инфекцию и информация о повторном тестировании и консультировании взрослых (32) Guidelines on HIV testing and counselling for adolescents and care and treatment for adolescents living with HIV (29)

Подростки из ключевых групп населения

Через каждые 6–12 мес.

Службы доброжелательного отношения к молодежи, кожновенерологические диспансеры, работа выездных бригад

5.2 Профилактика ВИЧ за счет приема АРВ-препаратов1 5.2.1 Пероральная доконтактная профилактика Общая информация Пероральная доконтактная химиопрофилактика ВИЧ-инфекции (PrEP) предполагает ежедневный прием АРВ-препаратов не инфицированными ВИЧ лицами, чтобы блокировать приобретение ВИЧ. Клинические испытания ежедневной пероральной PrEP позволили получить фактические данные о ее эффективности в отношении серодискордантных гетеросексуальных супружеских пар (34), мужчин и трансгендерных женщин, практикующих секс с мужчинами (35), гетеросексуальных супружеских пар высокого риска (36), потребителей инъекционных наркотиков (37).

5.2 Профилактика ВИЧ за счет приема АРВ-препаратов

Первоисточник для подготовки рекомендаций uidance on oral pre-exposure prophylaxis (PrEP) for serodiscordant couples, men G and transgender women who have sex with men at high risk of HIV: recommendations for use in the context of demonstration projects. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75188/1/9789241503884_eng.pdf) (38).

Существующие рекомендации (38) Существующие рекомендации ВОЗ (38) ориентированы на использование пероральной PrEP в рамках демонстрационных проектов для серодискордантных пар, а также мужчин и трансгендерных женщин, практикующих секс с мужчинами. Серодискордантные пары. В случае выявления серодискордантных пар, наряду с необходимостью в дополнительных вариантах выбора для них путей профилактики ВИЧ, правомерно рассмотреть вопрос о прохождении ими курса ежедневной PrEP (либо за счет приема TDF, либо комбинированного лечения TDF + FTC) в качестве возможного дополнительного вмешательства для неинфицированного партнера (условная рекомендация, фактические данные высокого качества). Если же PrEP показана ВИЧ-отрицательному партнеру того же пола в мужских серодискордантных парах, то следует назначать комбинированное лечение TDF + FTC, поскольку фактические данные в пользу эффективности и безопасности применительно к проникающему сексу между мужчинами были получены только в связи с этой схемой лечения. М ужчины и трансгендерные женщины. В случае передачи ВИЧ среди мужчин и трансгендерных женщин, практикующих секс с мужчинами, наряду с необходимостью в дополнительных вариантах выбора для них путей профилактики ВИЧ, правомерно рассмотреть вопрос о прохождении ими курса ежедневной PrEP (в частности, комбинированного лечения TDF + FTC) в качестве возможного дополнительного вмешательства (условная рекомендация, фактические данные высокого качества).

В Главе 7 речь идет о других аспектах приема АРВ-препаратов в профилактических целях, включая ППМР.

5.2.2 АРТ на службе профилактики среди серодискордантных пар Первоисточник для подготовки рекомендаций ouples HIV testing and counselling including antiretroviral therapy for treatment and prevention C in serodiscordant couples. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/ publications/2012/9789241501972_eng.pdf) (26).

Существующие рекомендации (26) ВИЧ-инфицированным лицам в серодискордантных парах, приступающим к АРТ ради сохранения собственного здоровья, следует также рекомендовать прохождение АРТ для снижения вероятности передачи ВИЧ неинфицированному партнеру (настоятельная рекомендация, фактические данные высокого качества). ВИЧ-позитивным партнерам с количеством CD4 ≥350 клеток/мм3 в серодискордантных парах следует предлагать прохождение АРТ для снижения вероятности передачи ВИЧ неинфицированным партнерам (настоятельная рекомендация, фактические данные высокого качества).

5.2.3 Постконтактная профилактика на случай ВИЧ-инфицирования в процессе профессиональной и непрофессиональной деятельности Общая информация Постконтактная профилактика сводится к краткосрочной АРТ с целью снизить вероятность приобретения ВИЧ-инфекции после потенциальной экспозиции либо в производственных условиях, либо в процессе полового акта. В рамках сектора здравоохранения мероприятия по постконтактной профилактике должны быть составной частью всеобъемлющего пакета универсальных мер предосторожности, обеспечивающих уменьшение степени воздействия на персонал опасных факторов производственной среды, связанных с инфекцией. Руководство ВОЗ по постконтактной профилактике воздействия заразного начала в условиях производства не пересматривалось с 2006 г., и его предстоит обновить к 2014 году. Рекомендуемый в настоящее время период проведения постконтактной профилактики ВИЧ-инфекции составляет 28 дней, и первую дозу препарата следует принимать как можно скорее в первые 72 часа после экспозиции. В основе выбора конкретных препаратов для постконтактной профилактики должна лежать принятая в стране схема АРВ-терапии первого ряда по поводу ВИЧ. Недавно одобренная рекомендация (39) касается, в частности, постконтактной профилактики в случае изнасилования.

Первоисточник для подготовки рекомендаций esponding to intimate partner violence and sexual violence against women: clinical R and policy guidelines. Geneva, World Health Organization, в печати (39).

5.2 Профилактика ВИЧ за счет приема АРВ-препаратов

Существующие рекомендации (2013 г.) (39) еобходимо поставить вопрос о проведении постконтактной профилактики ВИЧ Н у женщин, обращающихся за помощью в первые 72 часа после изнасилования. Следует приобщать лицо, пережившее акт насилия, к процессу принятия коллективного решения относительно целесообразности прохождения курса постконтактной профилактики по поводу ВИЧ (настоятельная рекомендация, фактические данные очень низкого качества).

5.2.4 Комбинированная профилактика ВИЧ Общая информация Профилактика ВИЧ среди населения нуждается в корректировке на протяжении всей жизни человека, и комбинированный подход помогает людям получать доступ к тем типам профилактических вмешательств, которые наилучшим образом соответствуют их запросам на разных жизненных этапах. Комбинированные подходы могут также обусловить проявление синергических факторов, обладающих более выраженным воздействием по сравнению с единичными мерами вмешательства. Несмотря на то, что АРВ-препаратам принадлежит ключевая роль в профилактике ВИЧ, они должны использоваться в сочетании с соответствующим комплексом мер, которые описаны ниже. Д ругие медико-биологические вмешательства, снижающие уровень риска инфицирования ВИЧ и/или вероятность передачи ВИЧ из расчета на одно событие, которое предполагает контакт с инфекцией, включают следующее: • М ужские и женские презервативы. Мужские презервативы снижают частоту

гетеросексуальной передачи, как минимум, на 80% и обеспечивают защиту в 64% случаев анального секса среди мужчин, практикующих секс с мужчинами (40), если пользоваться ими постоянно и правильно. Имеется не так много данных об эффективности женских презервативов, но фактические данные говорят об их аналогичном профилактическом действии (41).

• П рограммы обмена игл и шприцев напрямую связаны со снижением передачи

ВИЧ при введении наркотиков инъекционным путем (42).

• О пиоидная заместительная терапия метадоном или бупренорфином

является наиболее эффективной формой лечения опиоидной зависимости и сопровождается дополнительной пользой благодаря существенному снижению стереотипов поведения, связанного с риском инфицирования ВИЧ, и вероятности передачи при потреблении инъекционных наркотиков. Опиоидная заместительная терапия также позволяет оказывать поддержку людям, получающим АРТ, в плане соблюдения предписанного режима лечения (43-44). риск приобретения ВИЧ у мужчин до 66% и связано со значительным защитным эффектом на протяжении всей жизни (45).

• Д обровольное мужское обрезание по медицинским показаниям снижает

оведенческие вмешательства снижают частоту событий, связанных П с потенциальной передачей заразного начала, включая следующее. • А дресное информирование и просвещение. Программы, в рамках которых

используются различные коммуникационные подходы, например половое воспитание детей школьного возраста, консультирование сверстников, а также консультирование на уровне общины и межличностное консультирование, что служит цели распространения поведенческих посланий, которые ориентированы на поощрение людей в их стремлении снизить распространенность форм поведения, повышающих риск инфицирования ВИЧ, и способствует утверждению протективных стереотипов поведения (например, более безопасное наркопотребление, отсрочка начала половой жизни, уменьшение частоты незащищенных половых контактов с множеством партнеров, правильное и постоянное пользование мужскими и женскими презервативами и знание ВИЧ-статуса как собственного, так и партнера).

Структурные и поддерживающие вмешательства оказывают свое влияние на

доступность, обращаемость и следование поведенческим и медико-биологическим вмешательствам. Такие меры вмешательства нацелены на важнейшие социальные, юридические, политические и средовые факторы, способствующие циркуляции ВИЧ, и включают в себя правовую и политическую реформу, меры противодействия стигме и дискриминации, поощрение гендерного равенства и предупреждение насилия на основании гендерной принадлежности, развитие экономического потенциала и самосознания, доступность обучения и поддерживающих вмешательств, имеющих целью усилить систему направления больных в специализированные учреждения, приверженность лечению, удержание лиц, охваченных услугами, и мобилизацию общины.

5.2 Профилактика ВИЧ за счет приема АРВ-препаратов

КЛИНИЧЕСКОЕ РУКОВОДСТВО ПО ОКАЗАНИЮ НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

УСТАНОВЛЕНИЕ СВЯЗЕЙ МЕЖДУ ЛИЦАМИ С ДИАГНОЗОМ ВИЧ-ИНФЕКЦИИ И СЛУЖБАМИ ЛЕЧЕНИЯ И ОКАЗАНИЯ ПОМОЩИ ПРИ ВИЧ 6.1 Введение

06 90

6.2 Надлежащая практика установления связей со службами предоставления ухода 90 6.3 Оказание общей помощи людям, живущим с ВИЧ 6.4 Подготовка к прохождению АРТ людей, живущих с ВИЧ 6.5 Что можно ожидать от первых месяцев прохождения АРТ 90 94 94

Цель этой главы Представить обзор по вопросам и вмешательствам, связанным не только с оказанием общей помощи при ВИЧ индивидуумам с момента постановки диагноза ВИЧ-инфекции вплоть до начала прохождения АРТ, включая практику установления связей между лицами с диагнозом ВИЧ-инфекции и службами лечения и оказания помощи при ВИЧ, но и со слагаемыми пакета услуг по оказанию общей помощи и подготовке индивидуумов к прохождению курса АРТ.

РУКОВОДСТВО ПО ОКАЗАНИЮ 6. КЛИНИЧЕСКОЕ

НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

УСТАНОВЛЕНИЕ СВЯЗЕЙ МЕЖДУ ЛИЦАМИ С ДИАГНОЗОМ ВИЧ-ИНФЕКЦИИ И СЛУЖБАМИ ЛЕЧЕНИЯ И ОКАЗАНИЯ ПОМОЩИ ПРИ ВИЧ 6.1 Введение Крайне важно, чтобы люди, живущие с ВИЧ, как можно раньше оказывались в поле зрения служб, обеспечивающих уход за ними. Это позволяет не только заранее оценить их соответствие критериям назначения АРТ и своевременно приступить к прохождению курса АРТ, но и обеспечить доступ к мерам вмешательства для предупреждения дальнейшей передачи ВИЧ, профилактики других инфекций и сопутствующих заболеваний и, тем самым, свести к минимуму шансы оказаться вне системы последующего наблюдения. В вышедшей в 2012 г. публикации ВОЗ с описанием стратегической рамочной основы консультирования и тестирования на ВИЧ (1) особо подчеркивается значимость установления связей между программами консультирования и тестирования на ВИЧ, с одной стороны, и службами профилактики, лечения, ухода за больными и оказания им поддержки, с другой.

6.2 Надлежащая практика установления связей со службами предоставления ухода Вмешательства, имеющие целью улучшение взаимосвязей со службами предоставления ухода за больными, требуют более строгой оценки. Тем не менее, из нескольких систематизированных обзоров и обсервационных исследований следует, что некоторые подходы к надлежащей практике могут служить примером для совершенствования взаимосвязей со службами организации ухода (2–4). К таковым следует отнести интеграцию служб консультирования и тестирования на ВИЧ со службами ухода за больными; определение количества клеток CD4 на месте или безотлагательно при получении готовых результатов в тот же день; оказание помощи с транспортом в тех случаях, когда учреждение, на базе которого проводится АРТ, расположено на большом расстоянии от центра консультирования и тестирования на ВИЧ; подключение аутрич-работников из местного населения к работе по поиску лиц, выпавших из системы последующего наблюдения; обеспечение поддержки со стороны лиц, оказавшихся в таком же положении, или пациентов «со стажем»; и использование таких современных технологий, как передача текстовых сообщений по мобильному телефону.

6.3 Оказание общей помощи людям, живущим с ВИЧ В дополнение к АРТ странам следует сформировать пакет вмешательств по оказанию общей помощи при ВИЧ людям, живущим с ВИЧ, для снижения частоты передачи ВИЧ, профилактики заболеваний и повышения качества их жизни. Не все живущие с ВИЧ люди отвечают критериям назначения АРТ, а среди тех, кто этим критериям соответствует, не у всех будет возможность немедленно получить доступ к АРТ. Другие же будут склонны отложить прохождение АРТ на более поздний срок. Регистрация желающих получать помощь позволяет обеспечивать тщательный клинический и лабораторный мониторинг и заранее оценивать соответствие критериям получения АРТ и своевременно ее начинать, а также имеет целью минимизировать число выпавших из системы последующего наблюдения. Многие виды вмешательства,

6. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: установление связей между лицами с диагнозом ВИЧ-инфекции и службами лечения и оказания помощи при ВИЧ

связанные с уходом за больными, сохраняют свою актуальность на всех этапах оказания непрерывной помощи, в частности когда речь идет о ВИЧ-экспонированных индивидуумах и людях, живущих с ВИЧ, до начала и в период прохождения АРТ. Общая помощь включает в себя элементарную профилактику ВИЧ, укрепление здоровья людей, живущих с ВИЧ, а также скрининг, профилактику и ведение связанных с ВИЧ коинфекций и сопутствующих заболеваний. ВОЗ выпустила краткое руководство по оказанию общей помощи и проведению профилактических вмешательств (5–7), а в 2008 г. рекомендовала пакет из 13 профилактических вмешательств для взрослых и подростков, живущих с ВИЧ в странах и территориях с ограниченными ресурсами (5). Сюда входит следующее: (1) психосоциальное консультирование и поддержка; (2) раскрытие информации и уведомление партнера; (3) профилактическое лечение котримоксазолом (ПЛК); (4) консультирование, скрининг и профилактическое лечение ТБ; (5) предупреждение наиболее распространенных микозов; (6) профилактика инфекций, передающихся половым путем, и оказание поддержки в удовлетворении потребностей охраны репродуктивного здоровья, включая предупреждение и скрининг на рак шейки матки; (7) малярия (котримоксазол, надкроватные сетки и профилактика малярии среди беременных женщин); (8) выборочные управляемые инфекции; (9) питание; (10) планирование семьи; (11) ППМР; (12) программы обмена игл и шприцев для потребителей инъекционных наркотиков; и (13) водоснабжение, санитария и гигиена. Содержание пакета общей помощи будет меняться в зависимости от типа эпидемии, пострадавшей части населения и уровня распространенности сочетанных инфекций, других сопутствующих заболеваний и состояний здоровья. В Таблице 6.1 дается обзор слагаемых пакета услуг по оказанию общей помощи людям, живущим с ВИЧ. В Разделе 8.1 кратко представлены ключевые рекомендации, заимствованные из существующих руководств ВОЗ по проведению скрининга и химиопрофилактики и определению сроков назначения АРТ с учетом наиболее распространенных коинфекций, сопутствующих заболеваний и других состояний здоровья.

6.3 Оказание общей помощи людям, живущим с ВИЧ

Таблица 6.1 Обзор ключевых элементов оказания общей непрерывной помощи при ВИЧ людям, живущим с ВИЧ Услуги При постановке диагноза ВИЧ Перед При включении в началом состав группы АРТ лиц для ухода за ними ✓ ✓ Стабильное состояние на фоне получения АРТ При неудаче в лечении и переходе на другую схему АРВ-терапии Комментарий и перекрестные ссылки Приложение 1

Общие виды помощи Определение ✓ клинической стадии заболевания по классификации ВОЗ Наличие ✓ беременности Планирование семьи и контрацепция ППМР Поддержка ✓ при раскрытии информации и уведомлении партнера

✓

Раздел 8.2.6.1 Разделы 7.1.2 и 7.2.2 Раздел 5.1.4

✓

Таблица 6.1 (продолжение) Услуги При постановке диагноза ВИЧ Перед При включении в началом состав группы АРТ лиц для ухода за ними ✓ ✓ Стабильное состояние на фоне получения АРТ ✓ При неудаче в лечении и переходе на другую схему АРВ-терапии ✓ Комментарий и перекретные ссылки Раздел 5.2.4

Консультирование ✓ по вопросам снижения риска и использования комбинированных подходов к профилактике ВИЧ Проведение скрининга в целях профилактики и ведения сопутствующей патологии и неинфекционных заболеваний Проведение скрининга и решение проблем, связанных с психическим здоровьем и употреблением веществ, вызывающих зависимость Психосоциальное консультирование и поддержка ✓

✓

Раздел 8.2.1

✓

Разделы 8.2.2 и 8.2.3

Общие виды помощи Купирование боли и симптомов Оценка состояния питания и консультирование Оценка состояния ✓ питания, динамики роста и развития у детей и подростков Питание детей грудного и более старшего возраста ✓ ✓ ✓ ✓ ✓ Раздел 8.2.5 Раздел 8.2.4 Разделы 7.1.3 и 8.2.4

✓

Таблица 6.1 (продолжение) Перед При включении началом АРТ в состав группы лиц для ухода за ними Профилактика и лечение коинфекций Услуги При постановке диагноза ВИЧ Профилактическое лечение котримоксазолом Активное выявление случаев ТБ Профилактическая терапия изониазидом Скрининг на криптококковую инфекцию и профилактика микозов Скрининг на вирусные гепатиты B и C Предупреждение малярии (надкроватные сетки, обработанные инсектицидами, и средства профилактики) Скрининг на инфекции, передающиеся половым путем Профилактика и скрининг на рак шейки матки Проведение оценки на предмет управляемых инфекций Подготовка индивидуумов к прохождению АРТ Подготовительные мероприятия, оценка ситуации и оказание поддержки в соблюдении предписанного режима Медикаментозная терапия в настоящее время ✓ ✓ ✓ Стабильное состояние на фоне получения АРТ При неудаче в лечении и переходе на другую схему АРВтерапии ✓ Комментарий и перекрестные ссылки

6.3 Оказание общей помощи людям, живущим с ВИЧ

✓

Раздел 8.1.1 Раздел 8.1.2 Раздел 8.1.2 Раздел 8.1.3

✓ ✓

✓ ✓ ✓

✓

✓ ✓

✓ ✓ ✓

✓ ✓

Раздел 8.1.4 Раздел 8.1.5

✓

Раздел 8.1.6

✓

Раздел 8.1.7 Раздел 8.1.7 Раздел 6.4

✓

Разделы 6.4 и 9.2

✓

Раздел 7.4.6

6.4 Подготовка к прохождению АРТ людей, живущих с ВИЧ Прежде чем больные должны приступить к прохождению АРТ, очень важно подробно обсудить с ними их стремление и готовность начать АРТ, схему лечения АРВ-препаратами, их дозировки и расписание приема препаратов, вероятные выгоды и возможные побочные эффекты, а также необходимые посещения в порядке последующего наблюдения и мониторинга. При ведении детей с ВИЧ в этой беседе должно непосредственно участвовать лицо, осуществляющее уход за ребенком, и при этом следует обсудить вопрос о раскрытии информации об их ВИЧ-статусе (см. Главу 5). Повторное тестирование всех людей, живущих с ВИЧ, является надлежащей практикой для обеспечения корректной диагностики ВИЧ-инфекции. Перед началом курса АРТ следует всегда принимать во внимание состояние питания, любые сопутствующие заболевания и потенциально взаимодействующие лекарственные средства с точки зрения возможных противопоказаний и коррекции дозы того или иного препарата. Окончательное решение дать свое согласие или отказаться от АРТ зависит от конкретного индивидуума или человека, ухаживающего за ним или за нею, и если они предпочтут отложить начало АРТ на более поздний срок, то к этому вопросу следует вернуться снова при последующих визитах. При наличии проблем с психическим здоровьем, наркопотреблением или проблем иного характера, которые являются серьезным препятствием в плане соблюдения предписанного режима лечения, следует обеспечить оказание соответствующей поддержки и на регулярной основе проводить повторную оценку готовности приступить к АРТ. Большой набор информационных материалов для пациентов, равно как и поддержка на уровне общины и со стороны лиц одного круга, могут содействовать тому, чтобы человек выразил свою готовность и принял решение о начале лечения. Люди, приступающие к курсу лечения, и ухаживающие за ними лица должны понимать, что изначально предложенная схема АРВ-терапии раскрывает для них наиболее благоприятные возможности для эффективного подавления вирусной нагрузки и восстановления иммунитета, и что для успешного проведения АРТ от них требуется точное соблюдение назначенного режима лекарственного лечения. Их следует информировать о том, что многие побочные эффекты являются временными или поддаются купированию, и что в отношении проблематичных АРВ-препаратов нередко допускается замена одних препаратов на другие. (см. Раздел 9.2, в котором говорится о стратегиях в поддержку соблюдения предписанной схемы АРВ-терапии). Людей, получающих АРТ, и ухаживающих за ними лиц следует также регулярно опрашивать о том, принимают ли больные другие лекарственные средства, в том числе лечебные средства из трав и питательные добавки. Лицам, получающим АРТ, следует отдавать себе отчет в том, что за счет действия АРВ-препаратов снижается риск передачи ВИЧ, но при этом они не способны защитить других людей от приобретения инфекции. Им следует рекомендовать защищенный секс (включая использование презервативов) наряду с воздержанием от других действий высокого риска, например от взаимного обмена инъекционным инструментарием, во избежание передачи ВИЧ другим людям.

6.5 Что можно ожидать от первых месяцев прохождения АРТ Несмотря на то, что АРТ обязывает человека проходить этот курс лечения пожизненно, первые шесть месяцев от начала лечения особенно важны. Стоит рассчитывать на клиническое и иммунологическое улучшение и подавление популяции вирусов тогда, когда индивидуумы соблюдают режим АРТ, однако на этом фоне могут проявиться оппортунистические инфекции и/или воспалительный синдром восстановления иммунитета (ВСВИ), а также ранние побочные действия лекарственных средств, например лекарственная гиперчувствительность, особенно в первые три месяца прохождения АРТ. АРТ значительно снижает смертность в целом, но в то же время показатели смертности самые высокие в первые три месяца от начала АРТ. Эти осложнения встречаются чаще всего, когда у приступающих к АРТ людей заболевание, вызванное ВИЧ, уже приобрело прогрессирующий характер на фоне иммунодефицита в тяжелой форме и протекающих коинфекций и/или сопутствующих заболеваний, очень низкого уровня гемоглобина, низкого индекса массы тела и крайне низкого количества клеток CD4 или выраженной недостаточности питания (8,9).

Восстановление количества клеток CD4 У большинства взрослых и детей количество клеток CD4 увеличивается с началом проведения АРТ и первыми признаками восстановления иммунитета. Как правило, такое увеличение отмечается в течение первого года лечения, стабилизируется при выходе показателей на плато и затем продолжает нарастать на протяжении второго года (10). Однако подавление иммунитета в тяжелой форме может продолжаться у некоторых индивидуумов, когда не происходит существенного увеличения количества клеток CD4 на фоне лечения, особенно у лиц с очень низким количеством клеток CD4 на момент начала АРТ. Неудачная попытка добиться некоторого восстановления количества клеток CD4 должна настораживать медицинского работника относительно потенциальных проблем с соблюдением режима или отсутствия первичного ответа на АРТ, и следует рассмотреть вопрос о целесообразности продолжения курса профилактики оппортунистических инфекций, например профилактического лечения котримоксазолом.

6.5 Что можно ожидать от первых месяцев прохождения АРТ

Воспалительный синдром восстановления иммунитета (ВСВИ) ВСВИ представляет собой спектр клинических признаков и симптомов, которые предположительно ассоциируются с восстановлением напряженности иммунитета за счет ответа на проведение АРТ. Это общепризнанное явление, которое наблюдается у 10%–30% лиц, приступающих к АРТ, обычно в течение первых 4–8 недель от начала лечения (11,12). Синдром может проявляться в двух разных формах: по типу парадоксального ВСВИ, когда оппортунистическую инфекцию или опухоль диагностируют до начала формирования ответа на лечение благодаря АРТ, но затем, с началом проведения АРТ, течение такой патологии ухудшается; или по типу демаскирующего ВСВИ, когда одновременно с началом АРТ запускается патологический процесс, который до проведения АРТ клинически не проявляется. Это состояние следует иметь в виду только тогда, когда его картину невозможно объяснить новой инфекцией, ожидаемым характером течения известной инфекции или лекарственной токсичностью. Его клинический спектр весьма разнообразен, и ВСВИ регистрировался в связи со многими разными инфекциями, опухолями и неинфекционными состояниями (11,12). Наиболее серьезные и жизнеугрожающие формы проявления парадоксального ВСВИ связаны с ТБ, криптококкозом, саркомой Капоши и с опоясывающим лишаем. БЦЖ-ассоциированный ВСВИ (локализованный и системный) может присутствовать у младенцев с ВИЧ-инфекцией в странах и территориях, где иммунизация БЦЖ проводится в плановом порядке. Основными факторами риска являются: низкое количество клеток CD4+ (<50 клеток/мм3) на момент начала АРТ, диссеминированные оппортунистические инфекции или опухоли и укороченный период лечения оппортунистических инфекций до начала проведения АРТ (11,12). ВСВИ, как правило, самокупируется, и прерывание АРТ показано в редких случаях, но больные могут нуждаться в ободрении ввиду затянувшихся симптомов во избежание прекращения лечения или неудовлетворительного соблюдения режима АРТ. Важнейшие шаги по снижению вероятности развития ВСВИ включают в себя следующее: более ранняя диагностика ВИЧ и начало АРТ, прежде чем количество клеток CD4 упадет ниже 200 клеток/мм3; усовершенствованный скрининг на оппортунистические инфекции до проведения АРТ, особенно на возбудители ТБ и криптококкоза; и оптимальное ведение оппортунистических инфекций до начала АРТ. Сроки проведения АРТ у людей с оппортунистическими инфекциями требуют сбалансированного подхода к оценке повышенного риска развития ВСВИ, когда лечение начинают на раннем этапе, в противовес продолжающейся высокой смертности, когда АРТ откладывают на более поздний срок. В Главе 8 кратко представлены существующие рекомендации ВОЗ по определению оптимальных сроков проведения АРТ среди больных ТБ (см. Раздел 8.1.2) и по ведению криптококковой инфекции (см. Раздел 8.1.3) с учетом фактических данных рандомизированных клинических исследований.

КЛИНИЧЕСКОЕ РУКОВОДСТВО ПО ОКАЗАНИЮ НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

АНТИРЕТРОВИРУСНАЯ ТЕРАПИЯ 7.1 Когда следует начинать АРТ 7.1.1 Когда следует начинать АРТ у взрослых и подростков 7.1.2 Когда следует начинать АРТ у беременных и кормящих грудью женщин 7.1.3 АРВ-препараты и продолжительность грудного вскармливания 7.1.4 Когда следует начинать АРТ у детей 7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда) 7.2.1 АРТ первого ряда для взрослых 7.2.2 АРТ первого ряда для беременных и кормящих грудью женщин и АРВ-препараты для их детей 7.2.3 АРТ первого ряда для детей в возрасте до трех лет 7.2.4 АРТ первого ряда для детей в возрасте трех лет и старше (включая подростков) 7.2.5 Комбинированное лечение ТБ и ВИЧ-инфекции у детей 7.3 Мониторинг эффективности АРТ и выявление причин неудачи лечения 7.3.1 Лабораторный мониторинг до и после начала АРТ 7.3.2 Мониторинг эффективности АРТ и выявление причин неудачи лечения 7.4.1 Основополагающие принципы 7.4.2 Основные типы проявления токсичности АРВ-препаратов 7.4.3 Мониторинг токсичности TDF 7.4.4 Мониторинг токсичности других АРВ-препаратов 7.4.5 Замена одних препаратов другими при лекарственной токсичности АРТ 7.4.6 Основные взаимодействия АРВ-препаратов 7.5 На какую схему АРВ-терапии следует переходить (АРТ-терапии второго ряда) 7.5.1 АРТ второго ряда для взрослых и подростков 7.5.2 АРТ второго ряда для детей (включая подростков) 7.6 АРТ третьего ряда

07 98 99 108 114 119 124 125 129 137 142 146 148 148 149 156 156 159 161 161 162 165 166 170 173

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ 156

Цель этой главы Представить обновленные, доказательные клинические рекомендации наряду с описанием подхода с позиции общественного здравоохранения к проведению АРТ в контексте оказания непрерывной помощи при ВИЧ с упором на страны и территории с ограниченными материальными и кадровыми ресурсами.

К ЛИНИЧЕСКОЕ РУКОВОДСТВО ПО ОКАЗАНИЮ 7. НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

АНТИРЕТРОВИРУСНАЯ ТЕРАПИЯ 7.1 Когда следует начинать АРТ

Раннее начало лечения ассоциируется с клинической пользой и выгодами с точки зрения профилактики ВИЧ, улучшением показателей выживаемости и снижением частоты встречаемости ВИЧ-инфекции на уровне общины. Группа по разработке руководства от 2013 г. рекомендует национальным программам по ВИЧ обеспечивать проведение АРТ всем людям с подтвержденным диагнозом ВИЧ с количеством лимфоцитов CD4 в пределах 500 клеток/мм3 или менее, назначая АРТ в приоритетном порядке лицам с тяжелым течением заболевания или на его поздней стадии (см. Приложение 1) или с количеством CD4 на уровне 350 клеток/мм3 или ниже. Кроме того, АРТ рекомендуется начинать лицам с активной формой ТБ и коинфекцией ВГВ при тяжелом хроническом заболевании печени, всем беременным и кормящим грудью женщинам с ВИЧ, всем живущим с ВИЧ детям моложе пяти лет и всем индивидуумам, поддерживающим серодискордантные отношения, независимо от количества клеток CD4 (Таблица 7.1).

Таблица 7.1 Краткое изложение рекомендаций относительно того, когда следует начинать АРТ у взрослых, подростков, беременных и кормящих грудью женщин, а также у детей Популяция Рекомендация АРТ следует начинать, если количество CD4 ≤500 клеток/мм3 Начало проведения АРТ в приоритетном порядке у всех лиц с тяжелым течением или на поздней стадии заболевания, вызванного ВИЧ (клинические стадии 3 или 4 по классификации ВОЗ), или с количеством CD4 ≤350 клеток/мм3 Взрослые и подростки (≥10 лет) АРТ следует начинать независимо от клинической стадии заболевания по классификации ВОЗ или количества клеток CD4 Активная форма ТБ Коинфекция ВГВ с признаками тяжелого хронического заболевания печени Беременные и кормящие грудью женщины с ВИЧ Партнеры с ВИЧ в серодискордантных парах (для снижения риска передачи ВИЧ) АРТ следует начинать, если количество CD4 ≤500 клеток/мм3 Начало проведения АРТ в приоритетном порядке у всех детей с тяжелым течением или на поздней стадии заболевания, вызванного ВИЧ (клинические стадии 3 или 4 по классификации ВОЗ), или с количеством CD4 ≤350 клеток/мм3 АРТ следует начинать независимо от количества клеток CD4 К линическая стадия 3 или 4 по классификации ВОЗ Активная форма ТБ

Дети в возрасте ≥5 лет

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

7.1 Когда следует начинать АРТ

Популяция

Рекомендация АРТ следует начинать у всех независимо от клинической стадии заболевания по классификации ВОЗ или количества клеток CD4 Начало проведения АРТ в приоритетном порядке у всех ВИЧ-инфицированных детей в возрасте 1–2 лет или с тяжелым течением/на поздней стадии заболевания, вызванного ВИЧ (клинические стадии 3 или 4 по классификации ВОЗ), или с количеством CD4 ≤750 клеток/мм3 или <25% в зависимости от того, какая из этих величин окажется меньше АРТ следует начинать у всех детей грудного возраста независимо от клинической стадии заболевания по классификации ВОЗ или количества клеток CD4

Дети в возрасте 1–5 летa

Младенцы <1 годаa a

Начало проведения АРТ всем ВИЧ-инфицированным детям младше 18 месяцев с предположительным клиническим диагнозом ВИЧ-инфекции.

7.1.1 Когда следует начинать АРТ у взрослых и подростков Новые рекомендации РТ следует назначать в приоритетном порядке всем лицам с тяжелым А течением или на поздней, клинически очевидной стадии заболевания, вызванного ВИЧ (клинические стадии 3 или 4 по классификации ВОЗ), и лицам с количеством CD4 ≤350 клеток/мм3 (настоятельная рекомендация, фактические данные среднего качества). РТ следует назначать всем ВИЧ-инфицированным лицам с количеством А CD4 >350 клеток и ≤500 клеток/мм3 независимо от клинической стадии по классификации ВОЗ (настоятельная рекомендация, фактические данные среднего качества)a. РТ следует назначать всем ВИЧ-инфицированным лицам независимо от А клинической стадии или количества клеток CD4 в следующих ситуациях: • Л ица с ВИЧ и активной формой ТБ (настоятельная рекомендация, фактические данные низкого качества). • Л ица, коинфицированные ВИЧ и ВГВ, и с признаками тяжелого хронического заболевания печениb (настоятельная рекомендация, фактические данные низкого качества). • П артнеры с ВИЧ в серодискордантных парах следует предлагать АРТ для снижения передачи ВИЧ неинфицированным партнерам (настоятельная рекомендация, фактические данные высокого качества). • Б еременным и кормящим грудью женщинам с ВИЧ (см. Раздел 7.1.2 с рекомендациями). a

новое

меется недостаточный объем фактических данных и/или благоприятный профиль по критерию риски-выгоды в поддержку И начала АРТ при количестве лимфоцитов CD4 >500 клеток/мм3 или независимо от количества клеток CD4 или клинической стадии по классификации ВОЗ в следующих ситуациях: индивидуумы с ВИЧ старше 50 лет, индивидуумы с ВИЧ-1, инфицированные или коинфицированные ВИЧ-2, индивидуумы с ВИЧ, коинфицированные ВГС, и ключевые группы населения с ВИЧ и высоким риском передачи заразного начала (например, потребители инъекционных наркотиков, мужчины, практикующие секс с мужчинами, трансгендерные лица и секс-работники). Порядок назначения курса АРТ этим контингентам населения должен соответствовать тем же принципам и рекомендациям, как и в случае с другими категориями взрослых с ВИЧ. b Имеется недостаточный объем фактических данных и/или благоприятный профиль по критерию риски-выгоды в поддержку проведения АРТ у любого человека со смешанной инфекцией ВИЧ и ВГВ и количеством лимфоцитов CD4 >500 клеток/мм3 или независимо от количества клеток CD4 или клинической стадии по классификации ВОЗ. Поэтому назначение АРТ независимо от количества клеток CD4 рекомендовано лицам с признаками тяжелого хронического заболевания печени, которые подвержены наибольшему риску прогрессирования болезни печени и смертности от нее. В отношении лиц без признаков тяжелого хронического заболевания печени порядок назначения курса АРТ должен соответствовать тем же принципам и рекомендациям, как и в случае с другими категориями взрослых.

100

Таблица 7.2 Краткое изложение рекомендаций относительно того, когда следует начинать АРТ у взрослых и подростков Когда следует начинать АРТ у взрослых и подростков Целевая группа населения Тяжелая/поздняя стадия развития ВИЧ-инфекции (клиническая стадия 3 или 4 по классификации ВОЗ) ВИЧ-инфекция (клиническая стадия 1 или 2 по классификации ВОЗ) Рекомендация АРТ следует начинать у всех индивидуумов независимо от количества клеток CD4 АРТ следует начинать, если количество CD4 ≤500 клеток/мм3 (в приоритетном порядке при CD4 ≤350 клеток/мм3) АРТ следует начинать у всех индивидуумов с активной формой ТБ независимо от количества клеток CD4 a (Рекомендации от 2010 г. остаются неизменными (2)) АРТ следует начинать у всех индивидуумов с количеством CD4 ≤500 клеток/мм3 и независимо от количества клеток CD4 на фоне тяжелого хронического заболевания печениb АРТ следует начинать всем ВИЧ-инфицированным партнерам независимо от количества клеток CD4 (для снижения риска передачи ВИЧ неинфицированному партнеру) (Действующая с 2012 года рекомендация (49))

Заболевание ТБ

Коинфекция гепатита

ВИЧ-серодискордантные пары

В первую очередь должно быть начато лечение по поводу ТБ, по окончании которого как можно скорее следует приступить к АРТ (и это должно произойти в первые восемь недель от начала курса лечения ТБ). У лиц с количеством CD4 менее чем 50 клеток/мм 3 АРТ следует обеспечить в течение двух недель от начала курса лечения ТБ (см. Раздел 8.1.2). Тяжелое хроническое заболевание печени включает в себя цирроз и терминальную стадию печеночной недостаточности и подразделяется на стадии компенсации и декомпенсации. Декомпенсированный цирроз определяется как развитие клинически очевидных осложнений на фоне портальной гипертензии (асцит, варикозное кровоизлияние и печеночная энцефалопатия) или печеночной недостаточности (желтухи).

Общая информация Начиная с 2002 г. руководство ВОЗ по АРТ дорабатывалось с учетом неуклонно возрастающего объема накопленных фактических данных в поддержку более раннего начала АРТ (1). В Руководстве ВОЗ от 2010 г. по ведению взрослых и подростков (2) было рекомендовано назначать АРТ всем индивидуумам (в том числе беременным женщинам) с количеством CD4 ≤350 клеток/мм3 независимо от клинической стадии по классификации ВОЗ, а также лицам с тяжелым течением заболевания, вызванного ВИЧ, или на его поздней стадии (клинические стадии 3 или 4 по классификации ВОЗ) независимо от количества клеток CD4. В основе этой настоятельной рекомендации лежат фактические данные среднего качества, полученные в результате рандомизированных контролируемых испытаний (3,4) и обсервационных исследований (5–8) и указывающие на то, что начало проведения АРТ при таком пороговом уровне клеток CD4 или ниже обеспечивало

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

101

снижение смертности, степени прогрессирования заболевания (включая ТБ), показателя вертикальной передачи ВИЧ и частоты тяжелых неблагоприятных проявлений. Данные математического имитационного моделирования также говорят о том, что назначение АРТ на более раннем этапе способно повлиять на передачу ВИЧ как половым, так и вертикальным путем, если имеет место высокий уровень охвата терапией и полная приверженность лечению (9). Для лиц с активной формой ТБ или коинфекцией ВГВ, требующей лечения по поводу ВГВ, в руководстве от 2010 г. (2) рекомендуется приступать к АРТ независимо от количества клеток CD4. Глобальный охват АРТ лиц, которые соответствуют установленным критериям согласно рекомендациям от 2010 г. (CD4 ≤350 клеток/мм3), составил 54% или более 8 миллионов человек, по состоянию на конец 2011 г. (10), однако показатели охвата варьируются в зависимости от того или иного региона в диапазоне от 15% до 68% (11). Лишь в 9 странах с низким и средним уровнями дохода охват превысил 80%-ный уровень, в 68 странах зарегистрированный охват был меньше 50%. Вместе с тем, изменения в проводимой странами политике оказались весьма значительными. Выборочное обследование, недавно проведенное в 92 странах (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/ annexes), показало, что более чем 90% стран при принятии решений о начале АРТ стали руководствоваться пороговым уровнем клеток CD4 в пределах 350 клеток/мм3 или менее, и несколько других стран передвинули свои пороговые величины по CD4 в сторону более 350 клеток/мм3. Медианное количество клеток CD4 на момент начала АРТ, хотя и повышается, было намного меньше 350 клеток/мм3 почти во всех территориях, в том числе в странах с высоким уровнем дохода (12,13), причем запоздалая явка больных для прохождения курса лечения ассоциируется с высокими показателями ранней смертности и неудовлетворительным удержанием больных в системе ухода за ними (6,14). Во многих ситуациях остаются нерешенными такие серьезные проблемы, как повышение уровня знаний о ВИЧ-статусе, укрепление взаимосвязей между службами тестирования и организации ухода за больными, обеспечение оптимального долговременного удержания больных в программе лечения и соблюдение предписанного режима.

7.1 Когда следует начинать АРТ

Обоснование и подтверждающие фактические данные Начиная с 2010 г. получаемые фактические данные и опыт программной деятельности, как и прежде, свидетельствовали о целесообразности сдвига соотношения между рисками и выгодами в сторону более раннего назначения курса АРТ. Дополнительные фактические данные также подтверждают, что непролеченная ВИЧ-инфекция может ассоциироваться с развитием нескольких не предопределяющих диагноз СПИДа состояний (включая сердечно-сосудистые болезни, заболевание почек, болезнь печени, несколько типов рака и нейрокогнитивные нарушения) (15–17), а также то, что начало проведения АРТ на более раннем этапе снижает частоту таких событий и улучшает показатели выживаемости. Новые фактические данные (18) также говорят о том, что АРТ существенно снижает вероятность передачи инфекции половым путем в серодискордантных парах с ВИЧ, но не во всех исследованиях отмечались выгоды в плане выживаемости. В то же время более удобные и менее токсичные схемы лечения стали более доступными наряду с продолжающимся падением стоимости АРВ-препаратов. Дискуссия по вопросу о конкретных ранних сроках начала АРТ все еще продолжается, и Группа по разработке руководства в рамках подготовки этих рекомендаций уделила пристальное внимание оценке потенциальной выгоды и ущерба на уровне индивида и сообщества. Назначение в приоритетном порядке курса АРТ лицам с симптоматическим и бессимптомным заболеванием, вызванным ВИЧ, при количестве лимфоцитов CD4 ≤350 клеток/мм3 Выгоды от проведения АРТ оказываются наибольшими при ведении лиц с симптоматической формой ВИЧ-обусловленного заболевания или лиц с более

102

низким количеством клеток CD4. Группа по разработке руководства от 2013 г. не стала пересматривать весомость и качество фактических данных в поддержку этой рекомендации в руководстве по АРТ от 2010 года (2). Фактические данные среднего качества в итоге проведения двух рандомизированных контролируемых испытаний и нескольких обсервационных исследований подтверждают, что начало проведения АРТ при количестве лимфоцитов CD4 ≤350 клеток/мм3 значительно снижает уровень смертности, степень прогрессирования болезни и встречаемость оппортунистических заболеваний, особенно ТБ и не предопределяющих диагноз СПИДа состояний (2). Назначение курса АРТ при количестве лимфоцитов CD4 в диапазоне от 350 до 500 клеток/мм3 Анализ по критерию риск-выгода в связи с обоснованием целесообразности начала проведения АРТ при количестве лимфоцитов CD4 в диапазоне от 350 до 500 клеток/мм3 был предметом дискуссии в связи с подготовкой данного руководства. Группа по разработке руководства согласилась с тем, что в основе степени воздействия на вероятность передачи ВИЧ лежат убедительные фактические данные. Качество фактических данных в поддержку клинической пользы от более раннего назначения АРТ классифицировалось как среднее по системе GRADE, поскольку в данном случае для обоснования главным образом использовались обсервационные данные, преимущественно представленные странами с высоким уровнем дохода. Группа по разработке руководства настоятельно рекомендовала проведение АРТ на более раннем этапе с точки зрения подхода в интересах общественного здоровья. В ситуациях, когда проведение рекомендаций в жизнь вызывает беспокойство, Группа по разработке руководства предложила предпринять операционные исследования на этапе внедрения, чтобы оценить такие контекстуальные факторы, как осуществимость, установление связей с соответствующими службами и удержание больных в программе лечения, соблюдение предписанного режима и распределение ресурсов. В основу рекомендации о назначении АРТ при количестве CD4 в диапазоне от 350 до 500 клеток/мм3 лежит систематизированный обзор, наряду с профилями оценки фактических данных по системе GRADE (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/ annexes), в рамках которого проводилась оценка качества и весомости фактических данных, полученных в итоге 21 обсервационного исследования (8,19–39) и трех рандомизированных контролируемых испытаний (3,18,40) с регистрацией показателей заболеваемости и смертности, а также иммунологических и вирусологических исходов. Они показали, что начало проведения АРТ при количестве лимфоцитов CD4 >350 клеток/мм3 по сравнению с курсом лечения при количестве CD4 ≤350 клеток/мм3 обеспечивало уменьшение риска прогрессирования заболевания в клиническую форму СПИДа и/или смерть, ТБ, развитие не предопределяющего диагноз СПИДа заболевания, а также повышение вероятности восстановления иммунитета. Несмотря на то, что ни в одном из исследований не фигурировали предположения об индивидуальном ущербе здоровью в связи с АРТ, эти исследования проводились в течение короткого времени. Сводный анализ обсервационных исследований показал, что неуклонное снижение риска летального исхода при назначении АРТ на более раннем этапе, по данным 13 исследований (21–23,26,29–31,34–39), и уменьшение риска прогрессирования заболевания в клиническую форму СПИДа или наступления смерти, по данным 9 исследований (21,23,26,27,30,33,34,36,39) и 3 рандомизированных контролируемых испытаний (3,18,40), наряду с низким уровнем неоднородности элементов исследований, основываются на фактических данных среднего качества в поддержку более ранних сроков проведения терапии. Дальнейший анализ на уровне подгрупп свидетельствовал о снижении риска смертности при пороговом уровне лимфоцитов CD4 для назначения АРТ в пределах 500 клеток/мм3. Воздействие на динамику восстановления иммунитета было непостоянным и классифицировалось как основанное на фактических данных низкого или очень низкого качества (20,24,28). По данным двух исследований не было выявлено статистически

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

103

значимой разницы в вероятности подавления репликации вирусов (<500 копий/мл), риске вирусологической неудачи и повышении вирусной нагрузки одновременно с началом лечения при более высоком или более низком количестве клеток CD4 (20,36). В связи с проведением сводного анализа результатов двух рандомизированных контролируемых испытаний (3,18) речь шла о фактических данных низкого качества в поддержку назначения АРТ при повышенных пороговых величинах по количеству CD4 для снижения смертности, прогрессирования заболевания или комбинированного летального исхода и/или прогрессирования патологического состояния и (по данным одного испытания) риска развития не предопределяющего диагноз СПИДа заболевания. Риск развития тяжелых неблагоприятных проявлений существенно не отличался, однако риск Категории 3 или 4, судя по лабораторно подтвержденным отклонениям от нормыii, оказался повышенным в одном рандомизированном контролируемом испытании (40). Ввиду того, что лечение больных, включенных в ветвь исследования SMART с задержкой назначения курса терапии (3), начиналось с падения количества CD4 ниже 250 клеток/мм3 (а не 350 клеток/мм3), качество фактических данных, свидетельствующих о клинической пользе, ранжировалось как низкое по причине расхождения результатов и отсутствия прямолинейности. В итоге отдельно проведенного систематизированного обзора (41) были найдены одно рандомизированное контролируемое испытание (18) и два обсервационных исследования (42,43), в рамках которых отмечалось снижение риска заболевания ТБ в ситуациях, когда индивидуумы приступали к прохождению АРТ с количеством CD4 более 350 клеток/мм3. Курс АРТ также снижает вероятность рецидива ТБ примерно на 50% (44). Согласно данным динамических моделей, начало проведения АРТ при более 350 клеток/мм3 способно обеспечить более существенное снижение уровня заболеваемости туберкулезом среди населения (45). И наконец, в результате одного рандомизированного контролируемого испытания удалось получить фактические данные высокого качества (18), которые говорят о том, что более ранние сроки назначения АРТ могут заметно снизить риск передачи заразного начала половым путем ВИЧ-отрицательным половым партнерам. Кроме того, этот вывод подтверждается вторичными конечными результатами одного испытания, согласно которым благодаря получению АРТ вероятность передачи ВИЧ половым путем от ВИЧ-инфицированных партнеров снижается на 92% (46). Затраты и экономическая эффективность Группа по разработке руководства проанализировала объем затрат путем математического имитационного моделирования ситуации, а также эпидемиологические выгоды от назначения АРТ при количествах CD4 ≤350 клеток/мм3 и ≤500 клеток/мм3 и в отношении всех взрослых пациентов с ВИЧ независимо от количества клеток CD4. Эти модели говорят о том, что расширение критериев соответствия условиям проведения АРТ до ≤500 клеток/мм3 могло бы обеспечить получение ощутимых выгод для здоровья и оказаться экономически эффективным в условиях как генерализованной, так и концентрированной эпидемии; повышение расходов на проведение АРТ на более раннем этапе может быть отчасти компенсировано за счет снижения последующих затрат (например, благодаря сокращению периода пребывания в стационаре и повышению продуктивности) и предупреждения новых случаев инфицирования ВИЧ (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes). Однако эти выгоды зависят от высоких показателей тестирования и охвата лечением, неуклонного соблюдения предписанного режима терапии и высоких уровней удержания больных в системе ухода за ними. Построенные модели также показывают, ii

7.1 Когда следует начинать АРТ

Лабораторно подтвержденными отклонениями от нормы Категории 3 и 4 принято считать тяжелые неблагоприятные побочные реакции на медикаментозное лечение, которые, как правило, требуют отмены АРВ-препаратов вплоть до стабилизации состояния пациента и их замены на альтернативное лекарственное средство (см. веб-приложение www.who.int/hiv/pub/guidelines/arv2013/ annexes).

104

что вследствие несения основной доли затрат в связи с внедрением в полном объеме руководства по АРТ от 2010 г. (2) (назначение АРТ при количестве CD4 ≤350 клеток/мм3) дополнительные расходы в связи с переходом на использование критерия назначения АРТ в зависимости от количества клеток CD4 с ≤350 клеток/мм3 на ≤500 клеток/мм3 относительно невелики, особенно если в странах уже насчитывается значительное число получающих АРТ и живущих с ВИЧ людей с количеством лимфоцитов CD4 менее 350 клеток/ мм3. Эти результаты моделирования согласуются с рекомендацией по проведению АРТ в приоритетном порядке у ВИЧ-инфицированных взрослых и подростков с количеством CD4 ≤350 клеток/мм3. Вместе с тем, финансовые последствия на региональном и страновом уровнях следует более детально проанализировать, так как в странах наблюдаются разные уровни охвата терапией, и могут иметь место свои соображения относительно затрат в зависимости от местной специфики и имеющихся ресурсов. Потенциальный ущерб Не все обсервационные исследования неизменно продемонстрировали положительное воздействие курса АРТ на более раннем этапе на уровень смертности и частоты встречаемости не обусловленных СПИДом событий, связанных с хроническим воспалением и продолжающейся репликацией вирусов, и для оценки потенциального вреда и пользы потребуется более длительное последующее наблюдение. Долгосрочный профиль безопасности АРТ и воздействие более раннего назначения терапии на формирование лекарственной устойчивости и токсичности также нуждаются в пристальном мониторинге. Осуществимость Судя по данным ведения когорт и осуществления национальной программы, численность нуждающихся в лечении людей может увеличиться вплоть до 25%, если в основе критерия набора больных будет лежать количество лимфоцитов CD4, увеличенное с ≤350 клеток/ мм3 до ≤500 клеток/мм3 (47,48) (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/ annexes). Тем не менее, отечественный опыт также показал, что переход на более высокий пороговый уровень по количеству CD4 для назначения АРТ необязательно приводит к значительному немедленному увеличению числа людей, фактически получающих доступ к лечению без соответствующего повышения спроса на услуги консультирования и тестирования на ВИЧ, установление более тесных связей со службами оказания помощи, мониторинг адекватного лечения и на оказание постоянной поддержки в соблюдении предписанного режима терапии. Внедрение рекомендаций по поводу назначения АРТ индивидуумам с ВИЧ с количеством CD4 в диапазоне от 350 до 500 клеток/мм3 может потребовать дополнительные кадровые ресурсы, создания инфраструктуры и выделения финансовых средств. В Главе 10 эти вопросы рассматриваются более подробно. Назначение АРТ независимо от количества клеток CD4 ВИЧ-позитивные партнеры в ВИЧ-серодискордантных парах iii Результаты исследования HPTN052 (18) со всей очевидностью говорят в пользу использования АРТ в целях профилактики передачи ВИЧ среди ВИЧ-серодискордантных пар. Поэтому Группа по разработке руководства одобрила рекомендации, предложенные в руководстве ВОЗ от 2012 г. по консультированию и тестированию на ВИЧ, включая проведение АРТ у серодискордантных пар для лечения и профилактики (49), с тем чтобы половому партнеру с ВИЧ из такой пары обязательно предлагали курс АРТ независимо от количества клеток CD4.

iii

ВИЧ-серодискордантная пара это такая пара, в которой один из половых партнеров является ВИЧ-позитивным, а другой – ВИЧотрицательным. Несмотря на то, что у одного из партнеров в настоящее время отрицательная реакция на ВИЧ, это не означает, что данный партнер обладает иммунитетом или защитой от заражения ВИЧ в будущем.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

105

Лечение активной формы ТБ iv В 2010 г. ВОЗ рекомендовала назначать АРТ всем людям с ВИЧ и активной формой ТБ независимо от количества клеток CD4, причем сначала следует пролечивать ТБ, а затем как можно скорее приступать к прохождению АРТ (в течение первых восьми недель от начала терапии). Группа по разработке руководства проанализировала фактические данные, полученные в итоге трех рандомизированных клинических испытаний и свидетельствующие о том, что люди с диагнозом ТБ и тяжелой формой иммунодефицита (количество CD4 ≤50 клеток/мм3), которые начинают курс АРТ раньше восьми недель, с клинической точки зрения получают выгоду по сравнению с имеющими отсрочку в лечении более чем на восемь недель (50–52), а также одобрила рекомендации от 2010 года. Осуществление на практике рекомендаций по ведению ВИЧ и ТБ можно облегчить путем интеграции соответствующих служб (Глава 9). ВИЧ и коинфекция ВГВ с признаками тяжелого хронического заболевания печени v Коинфекция ВИЧ оказывает свое влияние практически на каждый аспект естественного течения инфекции ВГВ. Ее последствия включают в себя повышенные уровни хронизации; в меньшей степени спонтанное купирование ВГВ; ускоренное прогрессирование фиброза печени наряду с повышением риска цирроза и печеночно-клеточного рака; более высокую смертность, связанную с заболеванием печени, и пониженный ответ на АРВ-терапию (53–56). Заболевание печени превратилось в ведущую причину летального исхода у лиц со смешанной инфекцией ВИЧ и ВГВ (57,58). В руководстве ВОЗ по проведению АРТ от 2010 года (2) рекомендовано назначать АРТ всем индивидуумам со смешанной инфекцией ВИЧ и ВГВ, которым показано лечение по поводу инфекции ВГВ (определяемой как хроническая активная форма гепатита) независимо от количества клеток CD4 или клинической стадии по классификации ВОЗ. Однако из-за отсутствия рутинного скрининга на ВГВ большинство людей не подозревают о своем статусе по ВГВ. Более того, имеет место ограниченный доступ к дорогостоящим диагностическим методикам стадирования заболевания печени (биопсия печени, транзиторная эластография, ДНК-ВГВ и сывороточные маркеры), необходимым для выявления хронической активной формы заболевания печени и определения критериев назначения лечения по поводу ВГВ. В результате проведения метаанализа (59) и анализа на уровне подгруппы в рамках рандомизированного контролируемого испытания (60) были получены фактические данные низкого качества комплексного воздействия АРТ на связанную с функцией печени заболеваемость и смертность среди индивидуумов с сочетанной инфекцией ВИЧ и ВГВ, но в этих исследованиях не анализировалась выгода от назначения АРТ при более высоких параметрах CD4. В целом, по мнению Группы по разработке руководства, было получено недостаточно фактических данных и/или данных о подходящем профиле соотношения между риском и выгодой в поддержку назначения АРТ всем лицам с коинфекцией ВИЧ и ВГВ с количеством CD4 >500 клеток/мм3 или независимо от количества клеток CD4 или стадии болезни печени. Также существуют риски, связанные с началом проведения АРТ в более ранние сроки (гепатотоксичность, воспалительный синдром восстановления иммунитета и реактивация воспалительного процесса в печени). iv

7.1 Когда следует начинать АРТ

Активная форма ТБ подразумевает наличие инфекции ТБ, проявляющейся в определенной симптоматике и клиническом проявлении болезни. Под латентной туберкулезной инфекцией имеется в виду инфекция ТБ, на фоне которой у человека отсутствуют какие-либо симптомы или клинические проявления болезни. Не у всех людей со скрытой туберкулезной инфекцией возникнет заболевание ТБ, но у людей с ВИЧ риск прогрессирования инфекции в заболевание очень высок.

Тяжелое хроническое заболевание печени сопровождается циррозом и терминальной стадией заболевания печени и классифицируется как протекающее в стадии компенсации и декомпенсации. Декомпенсированный цирроз определяется как развитие клинических осложнений портальной гипертензии (асцит, варикозное кровоизлияние и печеночная энцефалопатия) или недостаточность функции печени (желтуха).

106

Тем не менее, Группа по разработке руководства не рекомендует назначать АРТ всем людям с сочетанной инфекцией ВИЧ и ВГВ независимо от количества клеток CD4 у лиц с признаками тяжелого хронического заболевания печени, подверженных наибольшему риску прогрессирования болезни печени и смертности. Термин «тяжелое хроническое заболевание печени» использовался вместо понятия хронической активной формы гепатита (как об этом сказано в руководстве от 2010 г.), поскольку он является более доступным для понимания и использования на практике на основании исключительно клинических критериев. В ситуациях, когда невозможно обеспечить проведение АРТ у всех индивидуумов с ВИЧ с количеством CD4 ≤500 клеток/мм3, следует рассмотреть вопрос о предпочтительном диагностировании и пролечивании лиц с коинфекцией ВИЧ и ВГВ. Как следует из руководства ВОЗ от 2010 г. по проведению АРТ (2), результаты одного рандомизированного контролируемого исследования говорят о целесообразности использования по меньшей мере двух препаратов, обладающих специфической активностью против ВГВ (TDF + 3TC или FTC), применительно к более выраженному ответу на вирусную нагрузку и снижению вероятности развития лекарственной устойчивости у возбудителя ВГВ (61,62). Принципиально важные пробелы в научных исследованиях в этой области включают в себя необходимость пополнения объема данных о воздействии АРТ на связанные с заболеванием печени исходы у ВГВ-коинфицированных лиц, проживающих в странах с ограниченными ресурсами, а также об относительном влиянии АРТ у людей с количеством CD4 >500 клеток/мм3 и заболеванием печени на ранней стадии. Контингенты населения, для которых не предложена конкретная новая рекомендация Группой по разработке руководства не были найдены фактические данные и/или данные о подходящем профиле соотношения между риском и выгодой в поддержку рекомендаций для назначения АРТ при количестве CD4 >500 клеток/мм3 или независимо от количества клеток CD4 или при клинической стадии по классификации ВОЗ у нижеперечисленных групп населения. ВИЧ-инфицированные индивидуумы в возрасте 50 лет и старше Объединенный анализ данных ведения 13 когорт из стран Европы и Северной Америки указывал на наличие повышенного риска смерти и прогрессирования болезни у людей с ВИЧ старше 50 лет (26). Однако эти данные не были стратифицированы по количеству клеток CD4 и не служат основанием для назначения АРТ этой группе населения с количеством CD4 >500 клеток/мм3. Индивидуумы с ВИЧ-2 Отсутствие рандомизированных исследований по проблеме лечения лиц с ВИЧ-2 затрудняет процесс определения оптимальных сроков назначения АРТ для данной группы. В итоге систематизированного обзора (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/ annexes) были проанализированы обсервационные данные по 15 исследованиям, и не было выявлено статистически значимой разницы между началом проведения АРТ с количеством CD4 ≤350 клеток/мм3 и >350 клеток/мм3 применительно к таким исходам, как смертность, прогрессирование заболевания, рост количества клеток CD4, формирование вирусологического ответа и риск развития лекарственной устойчивости. Качество фактических данных было классифицировано как низкое или очень низкое при наличии серьезного риска систематической ошибки и расхождения результатов (малочисленные события) для всех этих исходов. Индивидуумы с сочетанной инфекцией ВИЧ и ВГС Обсервационные исследования показали, что коинфекция ВИЧ и ВГС ускоряет прогрессирование связанного с ВГС фиброза печени и приводит к росту показателя встречаемости заболевания печени в терминальной стадии (63) и к смертности (63–65).

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

107

Существуют последовательные, но низкокачественные обсервационные данные, характеризующие суммарные выгоды от назначения АРТ с точки зрения смертности и прогрессирования заболевания печени у лиц с сочетанной инфекцией ВИЧ и ВГС, о чем говорят фактические данные метаанализа (66) и результаты обзора девяти когортных исследований, в рамках которых изучалась взаимосвязь между АРТ и фиброзом печени, указывающая на то, что АРТ ассоциируется со снижением частоты прогрессирования фиброза печени, хотя это заключение не анализировалось по количеству клеток CD4 (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Группа по разработке руководства одобрила содержание особого примечания в руководстве от 2010 г. (2) о том, что практика назначения АРТ лицам с коинфекцией ВГС должна следовать тем же принципам, что и в случае с моноинфекцией ВИЧ. Из-за отсутствия фактических данных проведение АРТ, независимо от количества клеток CD4, не было рекомендовано. В ситуациях с ограниченной доступностью методов анализа на антитела на ВГС и определения РНК, средств диагностики для стадирования заболевания печени (например, биопсия), возможностей для лечения ВГС и определенных групп населения, таких как потребители инъекционных наркотиков, возникают проблемы при диагностике и лечении активно протекающей инфекции ВГС. Однако ограниченный доступ к средствам тестирования на ВГС или лечения и/или высокая частота инфицирования ВГС не должны препятствовать проведению АРТ. Намеченное на 2014 год руководство ВОЗ по ведению гепатитов будет включать подробные методические рекомендации по скринингу, лечению и организации ухода за больными ВГС. Лица с сочетанной инфекцией ВИЧ и ВГС, получающие АРТ и лекарственное лечение по поводу ВГС, нуждаются в пристальном мониторинге ввиду потенциального взаимодействия лекарственных средств и повышенного риска токсичности препаратов, входящих в схемы лечения ВГС (например, интерферон, рибавирин и более современные средства прямого действия) и АРВ-терапии. Ключевые группы населения Расширение масштабов АРВ-терапии в целях профилактики ВИЧ-инфекции или снижения частоты случаев передачи ВИЧ среди ключевых групп населения являлось предметом анализа в рамках исследований на уровне сообщества, экологических исследований и математических моделей (67–79). Результаты некоторых из этих исследований свидетельствовали о снижении вирусной нагрузки в сообществе при наличии или отсутствии связанного с этим снижения частоты встречаемости ВИЧ при неизменно высоком уровне охвата АРТ или стремительно расширяющейся доступности АРТ. Вместе с тем, Группа по разработке руководства пришла к выводу о том, что нет достаточных фактических данных в пользу рекомендуемого назначения АРТ в более ранние сроки для ключевых групп населения независимо от количества клеток CD4. Проведение АРТ среди ключевых групп населения должно соответствовать тем же общим принципам и рекомендациям, как и в случае остальной части взрослого населения и подростков с ВИЧ.

7.1 Когда следует начинать АРТ

Клинические соображения В Разделе 10.6 (Контрольный список 10.3) рассматриваются практические аспекты, касающиеся замены пороговой величины 350 клеток/мм3 по количеству лимфоцитов CD4 на 500 клеток/мм3, что принципиально важно для руководителей программ.

Основные пробелы в научных исследованиях Необходимо проводить дальнейшие исследования, чтобы иметь более полное представление о клинических преимуществах и недостатках назначения АРТ в более ранние сроки. В настоящее время в рамках двух крупных рандомизированных испытаний анализируются оптимальные сроки назначения АРТ, и его результаты ожидаются в

108

2014-2015 годах. Исследование START (Оптимальные сроки проведения антиретровирусной терапии) с охватом взрослых в возрасте 18 лет и старше, ранее не получавших АРВ-препараты, посвящено сопоставлению безотлагательного назначения АРТ лицам с количеством лимфоцитов CD4 более 500 клеток/мм3 и отсроченного начала проведения АРТ до тех пор, пока не произойдет падения лимфоцитов CD4 до уровня ниже 350 клеток/мм3 или не возникнет событие, связанное со СПИДом (80). Исследование TEMPRANO (Ранняя антиретровирусная терапия и/или Раннее профилактическое лечение изониазидом туберкулеза у ВИЧ-инфицированных взрослых – ANRS 12136) имеет целью сравнить выгоды и риски назначения АРТ, согласно положениям руководства ВОЗ от 2010 г. (≤350 клеток/мм3) (2), с выгодами и рисками безотлагательного проведения АРТ у взрослых с количеством CD4 >350 клеток/мм3 в Кот-д’Ивуаре (81). Результаты этих исследований будут положены в основу будущих рекомендаций ВОЗ. Другие приоритетные научные изыскания нацелены на выяснение частоты встречаемости тяжелых неблагоприятных проявлений вследствие более интенсивного воздействия АРТ и на проведение оценки приемлемости и востребованности АРТ, приверженности лечению и долгосрочного удержания в программе ухода за больными, которые приступают к АРТ с повышенными уровнями лимфоцитов CD4, а также величины профилактической пользы от безотлагательного проведения АРТ среди ключевых групп населения.

7.1.2 К огда следует начинать АРТ у беременных и кормящих грудью женщин Новые рекомендации сем беременным и кормящим грудью женщинам с ВИЧ следует назначать В три АРВ-препарата (АРТ), которые следует принимать, как минимум, в течение периода, когда сохраняется риск передачи от матери ребенку. Женщины, соответствующие критериям проведения АРТ, должны получать такое лечение в течение всей жизни (настоятельная рекомендация, фактические данные среднего качества). о программным и операционным соображениям, особенно при П генерализованных эпидемиях, всем беременным и кормящим грудью женщинам с ВИЧ следует назначать АРТ в качестве пожизненного лечения (условная рекомендация, фактические данные низкого качества). некоторых странах в отношении женщин, не отвечающих критериям В проведения АРТ по состоянию здоровья, можно рассматривать возможность прекращения приема АРВ-препаратов после окончания периода, когда сохраняется риск передачи от матери ребенку (условная рекомендация, фактические данные низкого качества). новое

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

109

Таблица 7.3 Варианты программной деятельности в связи с АРТ для ППМР Вариант национальной программы ППМР Назначение пожизненной АРТ всем беременным и кормящим грудью женщинам (“Вариант B+”) Назначение пожизненной АРТ только беременным и кормящим грудью женщинам, отвечающим критериям получения такого лечения (“Вариант B”) a

7.1 Когда следует начинать АРТ

Беременные и кормящие грудью женщины с ВИЧ Независимо от клинической стадии по классификации ВОЗ или количества клеток CD4 Начало и продолжение АРТ после родов и прекращения грудного вскармливания Отвечающие критериям леченияa Начало АРТ и ее продолжение после родов и прекращения грудного вскармливания b Не отвечающие критериям леченияa Начало АРТ и ее отмена после родов и прекращения грудного вскармливания b c

ВИЧ-экспонированный младенец

Грудное вскармливание 6-недельный курс профилактического лечения младенца с введением NVP 1 раз в день

Альтернативное вскармливание 4–6-недельный курс профилактического лечения младенца с введением NVP 1 раз в день (или AZT 2 раза в день)

оличество CD4≤500 клеток/мм3 или клиническая стадия заболевания 3 или 4 на период начала АРТ или в соответствии с К национальным руководством. b Больные, у которых, судя по клиническим или лабораторным критериям, отмечается неудача лечения во время беременности или грудного вскармливания, подлежат обследованию по поводу назначения терапии второго ряда. c В случае грудного вскармливания АРТ следует отменить по истечении одной недели после завершения кормления грудью. В случае альтернативного вскармливания АРТ следует отменить после родов.

Общая информация АРВ-препараты используются для беременных и кормящих грудью женщин с ВИЧ главным образом в интересах охраны здоровья матери и в целях профилактики инфицирования ребенка, оказавшегося под воздействием заразного начала. Это также может быть связано с выгодами в плане предупреждения передачи ВИЧ половым путем. В руководстве ВОЗ от 2010 г. по ППМР (82) рекомендуется пожизненная АРТ для женщин, отвечающих критериям назначения лечения (на основании критериев соответствия от 2010 г. с учетом количества CD4 ≤350 клеток/мм3 или наличия клинической стадии развития заболевания 3 или 4 по классификации ВОЗ), а также профилактическое лечение АРВ-препаратами в целях ППМР женщин с ВИЧ, не отвечающих критериям проведения лечения. Для тех, кто не соответствует установленным критериям, были рекомендованы две схемы профилактического лечения: «Вариант A» – AZT для матери в период беременности, одноразовая доза NVP (sd-NVP) плюс AZT и 3TC для матери на момент родов и продолжение терапии в течение одной недели после родов; и «Вариант B» – тройная комбинация АРВ-препаратов для матери в период беременности и в течение всего периода грудного вскармливания. Профилактический курс лечения рекомендовано начинать уже с 14-ой недели гестации, и в обоих вариантах курс профилактики для младенца с приемом NVP

новое

110

или AZT в перинатальном периоде должен занимать от четырех до шести недель независимо от того, кормит ли мать ребенка грудью или нет. Из оперативных соображений странам было рекомендовано руководствоваться отечественным подходом к выбору своего варианта АРВ-терапии в целях ППМР. В целях ускорения стремительного глобального расширения масштабов АРТ и ППМР в странах с дефицитом ресурсов следует обеспечивать осуществление справедливого доступа к АРТ для беременных женщин и достижение глобальной цели элиминации новых детских инфекций и сохранения жизни матерей (83), а также продолжать работу по упрощению, стандартизации и гармонизации рекомендаций. В 2011 г. в Малави был внедрен в практику новый подход к проведению пожизненной АРТ у всех беременных и кормящих грудью женщин с ВИЧ независимо от количества клеток CD4 или клинической стадии, обычно именуемого как «Вариант B+» (84–86). В апреле 2012 г. ВОЗ выпустила обновление к программе (87), в котором говорится о некоторых оперативных преимуществах Варианта B и формирующейся стратегии в связи с Вариантом B+. В руководстве от 2013 г. рекомендовано назначение курса АРТ (одна упрощенная схема лечения комбинацией из трех препаратов) для всех беременных и кормящих грудью женщин с ВИЧ в период сохраняющегося риска вертикальной передачи ВИЧ от матери ребенку, а также продолжение пожизненной АРТ либо для всех женщин, либо для женщин, отвечающих установленным критериям, ради сохранения их здоровья. Вариант A уже больше не рекомендуется для использования.

Обоснование и подтверждающие фактические данные Преимущества стандартизованной схемы АРВ-терапии для всех беременных и кормящих грудью женщин с ВИЧ Несмотря на то, что имеющиеся данные по-прежнему говорят, что профилактические схемы, согласно Вариантам A и B, характеризуются аналогичной эффективностью в условиях проведения клинических испытаний (88–92), из-за сложностей реализации Варианта A во многих странах не удалось добиться расширения масштабов ППМР. Эти сложности проявляются в разных подходах к составлению схем лечения и профилактики; требованиях к измерению количества клеток CD4 для определения критериев назначения терапии и конкретного типа схемы лечения; переходах с одной схемы на другую в дородовом, родовом и послеродовом периодах; необходимости дополнительного приема матерями после родов «шлейфа» из АРВ-препаратов; и удлиненном профилактическом лечении NVP у детей грудного возраста. В отличие от этого, организация лечения по оптимизированной схеме АРВ-терапии первого ряда с включением препаратов с фиксированными дозами TDF + 3TC (или FTC) + EFV (см. Раздел 7.2.2) для всех беременных и кормящих грудью женщин с ВИЧ ассоциируется с важными программными и клиническими преимуществами, включая следующее. Простота осуществления. Такая же упрощенная схема АРВ-терапии предлагается всем беременным женщинам (независимо от «критериев соответствия» проводимому лечению) и продолжается в период беременности, в родах и после них. Г армонизированные схемы. Оптимизированная схема первого ряда с включением комбинированных препаратов с фиксированными дозами может быть приведена в соответствие с положениями руководства по АРТ у небеременных взрослых женщин. Возросший охват АРТ. Благодаря этому создаются гарантии для того, чтобы у женщин с ослабленным иммунитетом, у которых нет доступа к тестированию для определения количества клеток CD4, была возможность безотлагательно получать соответствующую АРТ.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

111

• П реимущества ввиду вертикальной передачи. Обеспечивается охват АРТ в целях максимальной профилактики младенческих инфекций. • П ольза с точки зрения охраны здоровья матери. Момент прогрессирования заболевания в процессе лечения можно отсрочить (93). П риемлемость. Обзоры, проведенные в связи с этим руководством, в целом свидетельствовали о явных предпочтениях сообществ и приемлемости этого подхода. В ыгоды с точки зрения передачи половым путем. АРТ обеспечит снижение частоты передачи ВИЧ-инфекции половым партнерам половым путем (18). Группой по разработке руководства также были рассмотрены суммарные фактические данные, полученные в итоге систематизированного обзора 21 обсервационного исследования (19–39) и 3 рандомизированных контролируемых испытаний (3,18,40), которые использовались при оценке сроков назначения АРТ у взрослых (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes; см. Раздел 7.1.1). Рекомендация относительно проведения АРТ в более широком масштабе у беременных и кормящих грудью женщин основывается на осознании того, что для стран с дефицитом ресурсов доступен лишь ограниченный перечень вариантов АРВ-терапии. В ней также отдается должное необходимости достижения баланса между преимуществами проведения АРТ у беременных и кормящих грудью женщин и возможными рисками токсичности АРВ-препаратов для организма матери, плода и младенца в период беременности и грудного вскармливания. Среди других вопросов, обсуждавшихся Группой по разработке руководства, можно назвать такие, как затраты; экономическая эффективность и бремя для системы здравоохранения (94,95); аспекты, связанные с соблюдением предписанного режима и удержанием в программе лечения (96), лекарственная устойчивость при ВИЧ, неэффективность АРТ и перспективы создания будущих вариантов лечения; и обеспечение доступности лечения для всех людей, которые удовлетворяют критериям назначения терапии в соответствии с положениями действующего руководства. Пожизненная АРТ в сравнении с отменой АРТ после исчезновения риска передачи ВИЧ от матери ребенку Рекомендация по поводу назначения пожизненной АРТ всем беременным и кормящим грудью женщинам с ВИЧ или продолжения АРТ только теми, кто соответствует критериям проведения лечения ради сохранения здоровья женщины, является условной с учетом эпидемиологической обстановки и программной деятельности в стране, а также по причине отсутствия убедительных фактических данных о воздействии и эффективности реализации пожизненной АРТ в полном объеме для всех беременных и кормящих грудью женщин. В условиях генерализованной эпидемии и при ограниченной доступности методов определения количества CD4, ограниченных возможностях для тестирования партнеров, большой продолжительности грудного вскармливания или высоких показателях фертильности очевидны преимущества пожизненного назначения АРТ всем беременным и кормящим грудью женщинам с ВИЧ. Это обеспечит максимальный охват всех нуждающихся в лечении ради сохранения их здоровья, предотвратит прекращение и возобновление приема препаратов при повторных беременностях, не допустит на раннем этапе передачу инфекции от матери ребенку при будущих беременностях, снизит риск передачи ВИЧ партнерам в ВИЧ-серодискордантных парах и укрепит здоровье матери. С введением в практику нового порогового уровня по количеству CD4 ≤500 клеток/мм3, чтобы отвечать установленным критериям, примерно 60% ВИЧ-инфицированных беременных женщин будут соответствовать критериям проведения лечения ради сохранения их здоровья (97). Несмотря на отсутствие надежных количественных оценок, не исключено, что, по меньшей мере, еще 10%–20% женщин будут отвечать критериям назначения терапии по истечении ближайших двух лет после родов.

7.1 Когда следует начинать АРТ

112

В странах с концентрированной эпидемией, в которых доступность методов тестирования для определения количества клеток CD4 находится на высоком уровне, существуют адекватные возможности для назначения АРТ беременным и кормящим грудью женщинам, отвечающим критериям проведения лечения, регистрируются низкие показатели рождаемости, и/или матерям с ВИЧ не рекомендуется грудное вскармливание, следует рассмотреть вопрос об отмене АРВ-препаратов у женщин, не соответствующих критериям АРТ, после завершения периода существования риска передачи заразного начала от матери ребенку. Независимо от этого подхода необходимо предпринимать специальные меры и поддерживающие инициативы в целях не только оптимизации приверженности лечению, особенно в период грудного вскармливания, в связи с которым в рамках многих программ последующее наблюдение проводится неудовлетворительно, но и обеспечения эффективных контактов со службами долгосрочной терапии. В Главе 10 даны дополнительные методические рекомендации для национальных программ по принятию решений, касающихся назначения пожизненной АРТ и отмены АРТ (Вставка 10.4). Эпиднадзор за повышенной токсичностью АРВ-препаратов в целях определения степени их воздействия в течение всего периода беременности и кормления грудью играет важнейшую роль при оценке безопасности этого подхода к ведению женщин, плода и ребенка. Это особенно актуально ввиду того, что все большее число женщин, уже получающих АРТ, становятся беременными, что обусловливает гораздо более высокие уровни воздействия АРВ-препаратов на раннем этапе гестации (см. Разделы 7.2.2 «С каких схем АРВ-терапии следует начинать» и 7.4 «Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ»). Кроме того, важно проводить исследования процессов внедрения, чтобы ликвидировать многие пробелы в знаниях, связанные с пожизненным проведением АРТ. Переход от руководства от 2010 г. к руководству от 2013 г. Новое руководство от 2013 г. рекомендует странам, внедряющим на данном этапе Вариант терапии A в соответствии с положениями руководства от 2010 г. (82), перейти (при соответствующем планировании) на назначение АРТ всем беременным и кормящим грудью женщинам с ВИЧ; в руководстве от 2013 г. Вариант A уже больше не рекомендуется для использования. Страны, постепенно переходящие на Вариант B, а также те, которые в настоящее время внедряют его в практику, должны принимать во внимание достоинства и недостатки проведения пожизненной АРТ у всех беременных и кормящих грудью женщин с учетом местной специфики.

Клинические соображения В Разделе 10.6 (Вопросы осуществления в отношении основных рекомендаций, Вставка 10.4) обсуждаются клинические соображения и аспекты осуществления, относящиеся к компетенции руководителей программ в их стремлении постепенно перейти на схему пожизненной АРТ у всех беременных и кормящих грудью женщин. Разработан набор инструментов для решения организационных вопросов в связи с переходом на пожизненную АРТ у беременных и кормящих грудью женщин (98), включая контрольный перечень вопросов по оценка готовности (Приложение 6).

Основные пробелы в научных исследованиях Группа по разработке руководства обратила особое внимание на необходимость проведения дальнейших научных исследований в поддержку новых рекомендаций, а также в целях информационного обеспечения решений, касающихся программной деятельности, и стимулирования оптимального осуществления. Важнейшие пробелы в научных изысканиях включают в себя следующее.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

113

Эпиднадзор за токсичностью АРВ-препаратов. Необходимы дополнительные научные исследования по проблеме безопасности и приемлемости пожизненной АРТ у беременных и кормящих грудью женщин и их детей, особенно в условиях как низкой обеспеченности ресурсами, когда случаи недостаточного питания и сопутствующих заболеваний являются более распространенными, чем в богатых ресурсами странах, так и ограниченного потенциала для проведения мониторинга. Нужны более качественные данные о показателях состояния здоровья матерей, исходах ведения беременности (например, мертворождение, низкая масса тела при рождении и недоношенность), пороки развития и показатели состояния здоровья детей грудного и раннего возраста (см. Вставку 7.2). Исходы для здоровья матери и ребенка. Актуальность проведения научных изысканий продиктована необходимостью более точного определения отдаленных исходов ведения с точки зрения как вероятности передачи вируса от матери ребенку в конце периода грудного вскармливания, так и охраны здоровья матери. Помимо краткосрочных исходов (например, воздействие на частоту передачи инфекции от матери ребенку в раннем периоде, который в настоящее время принято приравнивать к шести неделям), оценки отдаленных исходов АРТ у матерей исключительно важны для измерения следующих итоговых показателей: частота передачи на завершающем этапе грудного вскармливания и выживаемости на фоне отсутствия ВИЧ-инфекции; состояние здоровья матери и ребенка, инфицированных и не инфицированных ВИЧ; удержание больных в программе ухода за ними (в отношении лиц как с низким, так и с высоким количеством клеток CD4); долгосрочный успех АРТ первого ряда; и развитие лекарственной устойчивости при ВИЧ. Приверженность больных и их удержание в программе лечения. Научные исследования необходимы для определения путей оптимизации приемлемости, приверженности лечению и удержания в программе АРТ беременных и кормящих грудью женщин, в том числе женщин, приступающих к пожизненной АРТ и не отвечающих ныне действующим критериям назначения терапии ради сохранения своего здоровья. Одинаково важны и такие исследования, как изучение систем здравоохранения и анализ мер вмешательства на уровне общины для оптимизации курса пожизненной АРТ у беременных и кормящих грудью женщин с ВИЧ, а также потенциальное влияние разных стратегий назначения АРТ на разные контингенты населения.

7.1 Когда следует начинать АРТ

114

7.1.3 АРВ-препараты и продолжительность грудного вскармливания Рекомендации Сохраняются основные принципы и рекомендации, установленные в 2010 г., в том числе следующие: Национальные и субнациональные органы здравоохранения должны решить, следует ли службам охраны здоровья матери и ребенка главным образом рекомендовать матерям с установленной ВИЧ-инфекцией либо продолжать грудное вскармливание и получать АРВ-препараты, либо полностью избегать грудного вскармливания ввиду их состояния, и оказывать содействие в этом. В тех случаях, когда национальные органы приняли решение о том, что службы охраны здоровья матери и ребенка будут главным образом рекомендовать грудное вскармливание и получение АРВ-препаратов в качестве стратегии, которая с наибольшей вероятностью будет давать грудным детям, рожденным матерями с установленной ВИЧ-инфекцией, максимальный шанс на выживание без ВИЧ, и будут оказывать содействие в этом. атери с установленной ВИЧ-инфекцией (чьи дети не инфицированы ВИЧ или М ВИЧ-статус которых неизвестен) должны применять исключительно грудное вскармливание своих детей в течение первых 6 месяцев жизни, вводя затем соответствующий прикорм, и продолжать грудное вскармливание в течение первых 12 месяцев жизни. Грудное вскармливание следует затем прекращать только при возможности предоставления адекватного и безопасного рациона питания без грудного молока (настоятельная рекомендация, фактические данные высокого качества для первых 6 месяцев; фактические данные низкого качества в отношении рекомендации 12 месяцев).

Общая информация Основная цель рекомендаций ВОЗ, касающихся ВИЧ и вскармливания детей грудного возраста, состоит в улучшении показателей свободной от ВИЧ выживаемости младенцев, оказавшихся под воздействием ВИЧ-инфекции. Сюда входит снижение риска передачи ВИЧ через грудное молоко, главным образом за счет приема АРВ-препаратов, не допуская при этом случаи недостаточности питания и повышения риска серьезных инфекций у детей грудного и более старшего возраста вследствие небезопасной практики кормления. В рекомендациях ВОЗ от 2010 г. отмечалось что АРВ-препараты следует назначать либо матери, либо младенцу в течение всего периода грудного вскармливания для снижения риска передачи ВИЧ после родов (82,99). В странах, где грудное вскармливание было рекомендовано на фоне приема АРВ-препаратов, суть действовавшей рекомендации заключалась в том, чтобы женщины с ВИЧ «продолжали вскармливать ребенка грудью в первые 12 месяцев жизни» и «прекращали только тогда, когда взамен грудного молока обеспечивался адекватный и безопасный режим питания» (99) . В основу этой рекомендации были положены фактические данные о том, что именно в первые 12 месяцев жизни грудное вскармливание приносит максимальную пользу для профилактики смертности от диареи, пневмонии и недостаточности питания, а также о том, что при лечении АРВ-препаратами риск передачи ВИЧ младенцам через грудное молоко остается на низком уровне (100,101). В то время были некоторые сомнения относительно приверженности матерей курсу АРВ-лечения в целях профилактики, а также их способности давать АРВ-препараты своим вскармливаемым грудью детям в

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

115

течение достаточно длительного времени, то есть вплоть до достижения ими возраста 18 или 24 месяцев. Следовательно, имела место неопределенность относительно уровня защиты от передачи ВИЧ-инфекции детей на грудном вскармливании по истечении 12 месяцев. И наконец, был накоплен ограниченный объем данных о потенциальных неблагоприятных событиях среди младенцев, оказавшихся под продолжительным (хотя и в небольших дозах) воздействием АРВ-препаратов, поступающих в организм вместе с грудным молоком (102–104). Начиная с 2010 года принятые на страновом уровне рекомендации по соответствующей продолжительности грудного вскармливания для женщин с ВИЧ и их грудных детей (когда рекомендуется грудное вскармливание) варьировались в диапазоне от 12 до 18 месяцев; в некоторых случаях этот период не уточняется. Данные по охвату АРВ-лечением и соблюдению предписанного режима во время грудного вскармливания и эффективным послеродовым динамическим наблюдением за парами «мать-младенец» по-прежнему остаются ограниченными. При возрастающих масштабах дородового охвата лечением АРВпрепаратами в рамках программ ППМР относительная доля инфицированных младенцев на грудном вскармливании может увеличиваться вследствие неадекватного охвата лечением АРВ-препаратами в период грудного вскармливания, что выдвигает на передний план значимость эффективной стратегии профилактики в послеродовом периоде. Вариант проведения пожизненной АРТ у всех беременных женщин с ВИЧ независимо от количества клеток CD4 или клинической стадии (Раздел 7.1.2) поднимает вопрос о том, стоит ли этим матерям ограничивать продолжительность грудного вскармливания. Таким образом, Группа по разработке руководства рассмотрела вопрос о целесообразности (ввиду получения ВИЧ-инфицированными беременными женщинами пожизненной АРТ независимо от количества клеток CD4 или клинической стадии) следования рекомендации по продолжительности грудного вскармливания в непрерывном режиме в первые 12 месяцев жизни или рекомендации, не предусматривающей ограничение продолжительности грудного вскармливания. Группой по разработке руководства был поставлен вопрос о пересмотре этой рекомендации в свете потенциальных операционных выгод от удлинения периода грудного вскармливания, включая: у прощение и гармонизацию рекомендаций для матерей с ВИЧ и их грудных детей с рекомендациями для матерей без ВИЧ, благодаря чему, по-видимому, можно будет сделать более понятными для восприятия населением санитарно-просветительские сообщения и улучшить практику вскармливания детей грудного возраста на уровне сообщества в целом; и у меньшение стигмы и возможное повышение приемлемости этого подхода среди матерей и сообществ. В конечном счете, Группа по разработке руководства приняла решение не вносить изменения в рекомендации от 2010 г. по ВИЧ и вскармливанию грудных детей.

новое

7.1 Когда следует начинать АРТ

Обоснование решения в пользу того, чтобы не пересматривать рекомендации ВОЗ от 2010 г. в отношении ВИЧ и вскармливания детей грудного возраста В целом, не были получены новые фактические данные в поддержку пересмотра рекомендации от 2010 года. Главное опасение по поводу поощрения неограниченного грудного вскармливания среди матерей с ВИЧ сводилось к тому, что матери могут уклоняться от соблюдения предписанного режима АРТ на протяжении всего периода кормления грудью, подвергая своих детей риску передачи ВИЧ-инфекции. Несмотря на то, что это условие актуально в

116

любое время нахождения младенца на грудном вскармливании, оно приобретает особую значимость после достижения ребенком 12-месячного возраста. До этого возраста грудное вскармливание обеспечивает основную защиту для ребенка от летального исхода по причине диареи, пневмонии и недостаточности питания. Хотя грудное вскармливание и продолжает приносить большую пользу для здоровья младенца после достижения 12-месячного возраста, снижение показателей смертности от указанных состояний становится не столь значимым. В рекомендациях ВОЗ отмечается, что в отдельных случаях без грудного вскармливания матери могут не суметь обеспечить безопасный и адекватный режим питания для своих детей старше 12 месяцев, и в таких ситуациях кормление грудью должно быть продолжено. Однако на текущий момент времени не имеется фактических данных в поддержку этого подхода в принципе, в том числе на основании дополнительного риска передачи ВИЧ и данных эпиднадзора за токсичностью АРВ-препаратов, чтобы исключить возможные неблагоприятные исходы для здоровья грудного ребенка, связанные с АРВ-терапией.

Клинические соображения по оказанию поддержки живущим с ВИЧ матерям в кормлении грудью Ключевые клинические и практические соображения относительно использования АРВ-препаратов в период грудного вскармливания включают в себя следующее: п ослеродовая профилактика у младенцев не теряет своей актуальности: грудные дети матерей, получающих АРТ и практикующих грудное вскармливание, должны проходить шестимесячный профилактический курс лечения с ежедневным приемом NVP (Раздел 7.2.2); с ледует иметь в виду конкретные меры вмешательства (например, интегрированное динамическое наблюдение, предусматривающее услуги по иммунизации и контрольные посещения здорового ребенка) в целях улучшения послеродового наблюдения за парами «мать-ребенок», что нередко является слабым звеном в большинстве программ; и я сное и эффективное информирование общины и пользователей о пользе грудного вскармливания на фоне приема АРВ-препаратов и учет местной специфики при определении продолжительности грудного вскармливания. Кроме того, Группа по разработке руководства обратила особое внимание на необходимость оказания поддержки в усилении мониторинга за проявлениями потенциальности токсичности в результате длительного воздействия АРВ-препаратов (например, дозорный учрежденческий мониторинг за когортами детей грудного возраста в течение первых двух лет жизни), затем в следующие 3-5 лет и в ходе дальнейшего мониторинга по мере внедрения новых препаратов для проведения оценки влияния АРВ-терапии на неврологические показатели, состояние функции почек и развития скелета ребенка.

Основные пробелы в научных исследованиях р иск передачи заразного начала в послеродовом периоде в контексте АРТ при меняющейся продолжительности грудного вскармливания и в разных условиях программной деятельности; к ратко- и долгосрочные исходы ведения грудного ребенка, связанные с длительным воздействием низких дозировок АРВ-препаратов (особенно EFV и TDF) через грудное молоко, включая неврологические показатели, статус питания (в том числе по микронутриентам), метаболизм и развитие костной ткани; и м еры вмешательства в целях улучшения приверженности лечению АРВ-препаратами в послеродовом периоде во время грудного вскармливания, а также уточнение роли

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

117

пожизненной АРТ у всех беременных женщин и родильниц с точки зрения соблюдения режима приема АРВ-препаратов в период грудного вскармливания, что позволит женщинам с ВИЧ кормить ребенка грудью без каких-либо ограничений по времени.

7.1 Когда следует начинать АРТ

Вставка 7.1 Особые соображения по уходу за беременными женщинами и их ведению (См. также веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes)

Первоисточники для подготовки методических рекомендаций: P regnancy, childbirth, postpartum and newborn care: a guide for essential practice. Geneva, World Health Organization, 2006 (www.who.int/reproductivehealth/publications/ maternal_perinatal_health/924159084X/en/index.html). G uidance on global scale-up of the prevention of mother-to-child transmission of ВИЧ. Geneva, World Health Organization, 2007 (www.who.int/hiv/pub/mtct/pmtct_ scaleup2007/en/index.html). I MAI/IMPAC clinical training for integrated PMTCT services. Geneva, World Health Organization, 2013 (www.who.int/hiv/topics/mtct/training/en).

Общие методологические принципы Б еременные женщины с ВИЧ должны получать, по меньшей мере, минимальный пакет услуг, предусматривающих рекомендуемое количество дородовых посещений и наблюдений во время беременности, а также должны учитываться такие дополнительные вмешательства, как скрининг на инфекции, передающиеся половым путем, оказание нутритивной поддержки и консультирование по вопросам питания грудного ребенка и планированию семьи. С уществует высокий уровень риска передачи ВИЧ в период родовой деятельности и родов. Это риск можно свести к минимуму, руководствуясь несколькими ключевыми принципами и методиками, включая усиление роли рекомендуемых посещений клиники дородового наблюдения, особенно при ведении женщин из групп высокого риска в конце третьего триместра; поощрение ведения родов в условиях учреждений квалифицированным и опытным акушерским персоналом; отказ от необоснованного использования инструментальных методов и разрыва плодного пузыря путем использования партограммы для мониторинга разных периодов родов; и неинвазивная назогастральная аспирация и смывание пятен крови с тела новорожденного.

Дополнительные меры по снижению вероятности передачи ВИЧ включают в себя следующее: М еры по раннему выявлению матерей с ВИЧ и обеспечению АРВ-препаратов как для матери, так и для новорожденного имеют важнейшее значение. М атерям, поступающим по поводу родов с неизвестным ВИЧ-статусом, должен быть проведен экспресс-анализ на ВИЧ непосредственно в родах или сразу после этого.

118

Вставка 7.1 (продолжение) П ри выявлении женщин с положительным результатом тестирования АРВпрепараты следует назначать и матери, и ребенку в соответствии с действующими рекомендациями по лечению и с учетом удлиненного курса профилактики у младенца (см. Раздел 7.2.2). М едицинским работникам необходимо следовать универсальным мерам предосторожности при ведении всех родов, в том числе и матерей с ВИЧ. С ледует прилагать особые усилия к тому, чтобы оказание родовспомогательной помощи проходило в духе всемерной поддержки и без проявлений стигматизации. Н есмотря на очевидность того, что кесарево сечение предохраняет от передачи ВИЧ, ВОЗ не рекомендует это делать в странах с ограниченными ресурсами, особенно при отсутствии АРВ-препаратов или в случае высокой вирусной нагрузки, обусловленной ВИЧ-инфекцией; по большей части кесарево сечение рекомендуется по акушерским и другим медицинским показаниям. Если женщины с ВИЧ и женщины с неизвестным ВИЧ-статусом рожают вне лечебных учреждений, то следует содействовать их медицинскому освидетельствованию на базе центра охраны здоровья матери и ребенка как можно раньше после родов и начинать или продолжать соответствующие вмешательства по поводу ВИЧ. Обеспечение динамического наблюдения, взаимосвязей со службами по уходу, лечению и оказанию послеродовой помощи особенно важно для женщин с ВИЧ и их ВИЧ-экспонированных грудных детей. Оказание первичной помощи ребенку со стороны медработников обычно приурочивают к первому сеансу иммунизации на четвертой-шестой неделе, включая закрепление безопасной практики питания, проведение оценки охвата АРВ-терапией и диагностическое обследование ребенка на раннем этапе. В идеальном случае последующая помощь матери должна быть оказана в те же сроки и должна включать послеродовой медосмотр, консультирование по планированию семьи, обзор схемы АРВ-терапии и оказание поддержки в соблюдении предписанного режима.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

119

7.1.4 Когда следует начинать АРТ у детей Новые рекомендации новое

7.1 Когда следует начинать АРТ

РТ следует начинать у всех детей, инфицированных ВИЧ, в возрасте до пяти А лет независимо от клинической стадии по классификации ВОЗ или количества клеток CD4. • Г рудные дети, которым поставлен диагноз в течение первого года жизни (настоятельная рекомендация, фактические данные среднего качества) • Дети, инфицированные ВИЧ в возрасте от одного года до пяти лет (условная рекомендацияa, фактические данные очень низкого качества). АРТ следует начинать у всех ВИЧ-инфицированных детей в возрасте от пяти лет и старше с количеством клеток CD4 ≤500 клеток/мм3 независимо от клинической стадии по классификации ВОЗ • к оличество CD4 ≤350 клеток/мм3 (настоятельная рекомендация, фактические данные среднего качества) • количество CD4 от 350 до 500 клеток/мм3 (условная рекомендацияb, фактические данные очень низкого качества). АРТ следует начинать у всех ВИЧ-инфицированных детей с тяжелым течением или на поздней стадии симптоматического заболевания (клиническая стадия 3 или 4 по классификации ВОЗ) независимо от возраста и количества CD4 (настоятельная рекомендация, фактические данные среднего качества). АРТ следует начинать у всех детей в возрасте до 18 месяцев, которым был поставлен предположительный клинический диагноз c ВИЧ-инфекции (настоятельная рекомендация, фактические данные низкого качества)

Эта рекомендация является условной ввиду отсутствия фактических данных в поддержку раннего начала терапии в этой возрастной группе, но с этим подходом ассоциируются существенные программные преимущества в условиях с ограниченным доступом к иммунологическому тестированию, высоким бременем вызванного ВИЧ заболевания у детей и низким охватом АРТ среди детей, поскольку упрощение критериев соответствия для назначения АРТ, по-видимому, повысит уровни охвата АРТ среди ВИЧ-инфицированных детей и улучшит их показатели состояния здоровья. В приоритетном порядке АРТ следует давать детям, не достигшим двухлетнего возраста, независимо от клинической стадии по классификации ВОЗ или количества клеток CD4, ввиду более высокого риска смертности, а также детям в возрасте от двух до пяти лет на поздней стадии развития болезни (клинические стадии развития ВИЧ-инфекции 3 и 4 по классификации ВОЗ) или при количестве лимфоцитов CD4 ≤750 клеток/мм3 или <25% в зависимости от того, какой из этих параметров окажется ниже), независимо от клинической стадии по классификации ВОЗ (настоятельная рекомендация, фактические данные очень низкого качества) (105). Эта рекомендация является условной ввиду отсутствия фактических данных по этой группе населения в поддержку индивидуальной пользы в результате начала проведения АРТ на более раннем этапе; однако этот подход должен обеспечить значительные программные преимущества в условиях с высоким уровнем охвата детского населения АРТ и необходимости согласования программной деятельности с рекомендациями по назначению АРВ-препаратов для взрослых. Если эта рекомендация не будет одобрена, то курс АРТ следует назначать при клинических стадиях развития ВИЧ-инфекции 3 и 4 по классификации ВОЗ или при количестве лимфоцитов CD4 ≤350 клеток/мм3, независимо от клинической стадии по классификации ВОЗ (настоятельная рекомендация, фактические данные очень низкого качества) (105).

новое

См. веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes

120

Таблица 7.4 Краткое изложение рекомендаций относительно того, когда следует начинать АРТ у детей Возраст Младенцы (<1 года) От 1 года до менее чем 5 лет Когда следует начинать Следует обеспечить лечение всех детей Следует обеспечить лечение всех детей (в приоритетном порядке, это дети в возрасте ≤2 лет или при клинической стадии 3 или 4 по классификации ВОЗ или количестве CD4 ≤750 клеток/мм³ или <25%) При клинической стадии 3 или 4 по классификации ВОЗ или количестве CD4 ≤500 клеток/мм3 (в приоритетном порядке, при CD4 ≤350 клеток/мм³)

От 5 лет и старше

Общая информация Дети грудного и раннего возраста подвержены исключительно высокому риску по неблагоприятным исходам ведения ВИЧ-инфекции. При отсутствии какого-либо вмешательства умирает до 52% детей, не дожив до двухлетнего возраста (106). К пяти годам риск смертности и прогрессирование заболевания ввиду отсутствия лечения снижается до уровней, сопоставимых с показателями у молодых взрослых (107,108). Наращивание масштабов реализации программ ранней диагностики у грудных детей повысило шансы выявления ВИЧ-инфицированных младенцев, однако ситуация с назначением АРТ на раннем этапе для тех, у кого была обнаружена инфекция, остается неудовлетворительной. Большинство ВИЧ-инфицированных детей, отвечающих критериям проведения АРТ, все еще остаются не пролеченными, и уровень охвата АРТ среди детей значительно отстает от соответствующих показателей среди взрослых (28% против 57% во всем мире в 2011 году) (11). Диагностика и удержание в программе лечения детей, оказавшихся под воздействием ВИЧ, и ВИЧ-инфицированных детей в системе ухода за ними также сопряжены с уникальными проблемами по причине их зависимости от лица, проявляющего о них заботу. Показатель выхода из-под динамического наблюдения был особенно высоким в рамках оказания непрерывной помощи (109) наряду с существованием действительно непростой проблемы удержания в программе детей, за которым организован уход в связи с ВИЧ, но которые еще не соответствуют критериям назначения АРТ. На основании операционных и программных доводов некоторые страны уже внедряют в практику тактику безотлагательного проведения АРТ у детей моложе пяти лет. (110,111). В Руководстве ВОЗ от 2010 года клинические и иммунологические критерии соответствия назначения АРТ детям старше пяти лет увязаны к критериями, которые распространяются на взрослых (то есть проведение лечение при клинической стадии болезни 3 или 4 по классификации ВОЗ или при количестве CD4 ≤350 клеток/мм3) (105). В них также рекомендуется пролечивать всех ВИЧ-инфицированных детей младше двух лет независимо от клинического или иммунологического статуса. В отношении детей в возрасте от двух до пяти лет было рекомендовано приступать к лечению тех из них, у кого наблюдается клиническая стадия болезни 3 или 4 по классификации ВОЗ или определяется количество лимфоцитов CD4 <25% или ≤750 клеток/мм3 (105).

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

121

В результате проведенного в 2013 г. обзора фактических данных, а также с учетом оперативных соображений, достоинств и предпочтений, высказанных поставщиками медико-санитарной помощи, имеющиеся рекомендации были пересмотрены с позиции их упрощения и расширения списка показаний для лечения детей, включая назначение АРТ всем детям вплоть до пятилетнего возраста и повышение порогового уровня по количеству CD4 для начала проведения АРТ до ≤500 клеток/мм3 у детей в возрасте 5 лет и старше, что согласуется с соответствующим новым пороговым уровнем применительно к взрослым.

7.1 Когда следует начинать АРТ

Обоснование и подтверждающие фактические данные В основу этих рекомендаций были положены ощутимые оперативные и программные преимущества, обеспеченные за счет упрощения критериев назначения АРТ, несмотря на нехватку клинических выгод в поддержку проведения лечения независимо от количества клеток CD4 или клинической стадии после завершения периода младенчества. По аналогии с этим, в интересах программной деятельности и с учетом того, что прогрессирование болезни у детей в возрасте пяти лет и старше сопоставимо с такой динамикой у молодых взрослых, большая значимость придавалась приведению предложенных критериев назначения АРТ в соответствие с теми, которые распространяются на взрослых. Фактические данные в поддержку повышения возрастного порога до пяти лет для раннего проведения АРТ На основании количества клеток CD4 и клинической стадии ВОЗ можно выделить тех детей, которые подвергаются повышенному риску прогрессирования болезни и смерти. Предшествующие рекомендации основывались на обсервационных исследованиях, которые указывали на то, что непролеченные дети на втором году жизни продолжают находиться под воздействием высокого риска смертности и заболеваемости по сравнению с детьми без ВИЧ (106). Полученные кривые выживаемости детей подсказывают, что смертность среди детей старше двух лет и с количеством CD4 свыше 25% составляет примерно 1–2% в год (107,108). В итоге систематизированного обзора удалось найти только одно рандомизированное клиническое испытание PREDICT (112) с информацией по этому вопросу (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). В состав выборки для этого испытания было включено 300 детей (возраст 1–12 лет, медианный возраст – 6,4 года) с количеством CD4 более 15% и без признаков клинической стадии болезни C по классификации CDC, причем они прошли рандомизацию по группам с безотлагательным или отсроченным началом лечения до того момента, чтобы довести уменьшение количества лимфоцитов CD4 до уровня ниже 15%. Такие показатели, как свободная от СПИДа выживаемость, неврологические исходы и параметры роста, не отличались между собой в зависимости принадлежности к той или иной группе (113). Кроме того, был проведен анализ путем моделирования причинно-следственных связей с использованием проспективных данных, собранных в рамках Южноафриканской сети IeDEA по ведению 5732 детей в возрасте 24–59 месяцев, ранее не получавших АРТ (медианный возраст – 3,3 года) и имевших количество клеток CD4 с превышением существующих пороговых уровней для соответствия установленным критериям в пределах 25% или 750 клеток/мм3 (114) (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Результаты этого исследования не говорили в пользу преимуществ в плане выживаемости за счет проведения лечения в этой группе населения на раннем этапе, однако значительная доля детей в этом возрастном диапазоне быстро переходила в состояние соответствия действующим критериям, поскольку у большинства детей с количеством лимфоцитов CD4 на уровне 750 клеток/мм3 или выше на момент включения в программу ухода за ними пороговые величины по CD4 для назначения курса лечения были достигнуты в течение трех лет. Точнее говоря, в случае 32% из этой подсовокупности когорты не удавалось выходить на пороговые уровни по соответствию установленным критериям по истечении одного года, а в случае 60% – по истечении двух лет.

122

Операционные и программные преимущества Несмотря на меньший риск прогрессирования болезни у детей в возрасте 2–5 лет по сравнению с детьми моложе двух лет при наличии фактических данных низкого качества, Группа по разработке руководства подчеркнула значимость оперативных и программных преимуществ благодаря удалению барьера по количеству клеток CD4 для начала проведения терапии у детей моложе пяти лет. Ожидается, что назначение терапии всем детям моложе пяти лет должно упростить процедуру лечения детского контингента и облегчить процесс существенного расширения охвата АРТ детей раннего возраста. Хотя этот подход и не оценивался с позиции отдельного исхода лечения, программные данные говорят о том, что удается выходить на более лучшие показатели удержания пациентов в программе среди детей, получающих АРТ, чем среди тех, для кого организован уход, но не назначена АРТ (109). Повышение уровней охвата АРТ и проведение адресных мероприятий среди этой категории детей в целях обеспечения ухода за ними ввиду ВИЧ-инфекции может также упростить задачу организации лечения в связи с другими предотвращаемыми причинами смертности среди детей моложе пяти лет. Этот подход, по-видимому, будет ассоциироваться с небольшим увеличением бремени для ныне действующих систем (115). Следует отметить, что случаи несвоевременной диагностики все еще имеют место, и большая доля детей с выявленной ВИЧ-инфекцией уже соответствовала бы установленным критериям назначения АРТ на основании принятых в 2010 г. рекомендаций. Достоинства и предпочтения на уровне сообщества Судя по всему, расширение масштабов назначения АРТ с охватом каждого ребенка моложе пяти лет воспринимается положительно. Проведенная оценка достоинств и предпочтений людей, живущих с ВИЧ, лиц, обеспечивающих уход за больными, и провайдеров медицинских услуг для детей с ВИЧ показала, что начало лечения в более ранние сроки является предпочтительным, так как оно, как представляется, облегчает проявление заботы о ребенке в семье, предотвращает выход из-под динамического наблюдения и улучшает приверженность лечению (116). Вместе с тем, не исключается риск сопротивления этому, если лечение у детей раннего возраста начинается заблаговременно и соблюдение режима оказывается неудовлетворительным или лекарственное обеспечение является недостаточным; это особенно актуально применительно к самым маленьким детям, когда гармонизация детских лекарственных форм и форм для взрослых представляется особенно трудной задачей. Тем не менее, получаемые при этом выгоды с точки зрения лечения, по видимому, перевешивают эти риски. В тех случаях, когда доступность методов иммунологического тестирования ограничена, наряду с высоким бременем заболеваемости ВИЧ у детей и низким охватом АРТ детского населения, смягчение критериев назначения курса АРТ может значительно улучшить общие показатели состояния здоровья у детей с ВИЧ (117). Национальным программам следует определиться с тем, как наилучшим образом обеспечить внедрение этой рекомендации и определить целесообразность следования рекомендации относительно всеобщего охвата лечением всех детей моложе пяти лет или постановки во главу угла принципа всеобщего лечения грудных детей, не достигших годовалого возраста и применения на практике клинических и иммунологических критериев к детям в возрасте от одного года до пяти лет. При расширении масштабов назначения АРТ независимо от клинического или иммунологического статуса в период после младенчества для всех детей моложе пяти лет в приоритетном порядке, следует заниматься лечением детей моложе двух лет, поскольку они подвергаются повышенному риску смерти и стремительного прогрессирования болезни. Помимо этого, расширение диапазона связанных с АРТ услуг потребует создание гарантий для удержания больных в программе ухода за ними и должно соизмеряться с параллельным расширением масштаба вмешательств в поддержку приверженности лечению.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

123

Фактические данные в поддержку повышения порогового уровня CD4 до 500 клеток/мм3 Критерии назначения АРТ детям в 5-летнем возрасте и старше такие же, как и в случае взрослых. Несмотря на наличие ограниченного объема данных для оценки клинического эффекта от пролечивания детей с количеством лимфоцитов CD4 в интервале от 350 до 500 клеток/мм3 при том, что польза от приема АРВ-препаратов для профилактики передачи половым путем не является одним из факторов для этой группы населения, с этим походом связаны программные преимущества, получаемые за счет гармонизации названных критериев и критериев для взрослых. Это может оказаться наиболее целесообразным в условиях с высоким уровнем охвата АРТ. Как в случае со взрослыми, в приоритетном порядке следует обеспечивать лечение детей с количеством CD4 ≤350 клеток/мм3, поскольку они подвергаются наибольшему риску прогрессирования заболевания. Коинфекция ВИЧ и ВГВ По данным небольших когортных исследований, в рамках которых как ВИЧ, так и ВГВ являются эндемическими по своей природе, регистрируемые уровни заболеваемости хроническим ВГВ у детей с ВИЧ варьируются в диапазоне от 1% до 49% (118). Инфекцию ВГВ нередко приобретают в младенческом или раннем детском возрасте и, в отличие от взрослых, она может находиться в фазе иммунологической толерантности в течение всего периода детства и отрочества. К сожалению, естественное течение этой патологии у детей с ВИЧ еще плохо изучено, и все еще предстоит оценить выгоды от назначения АРТ этим детям на более раннем этапе. Клинические соображения по расширению масштабов проведения АРТ среди детей В Разделе 10.6 рассматриваются соображения по поводу аспектов осуществления, относящихся к компетенции руководителей программ (см. Вставку 10.6). Дополнительным важным соображением для клиницистов и других поставщиков медицинских услуг в плане решения вопросов осуществления является расширение показаний для начала проведения АРТ у детей моложе пяти лет независимо от клинического или иммунологического статуса, в связи чем отпадает необходимость в определении количества клеток CD4 для обоснования курса лечения в этой возрастной группе и отсрочке назначения АРТ в условиях отсутствия доступа к тестированию на CD4. Однако наличие методов тестирования на CD4, включая определение исходного количества и процентного содержания клеток CD4, по-прежнему является важным для обеспечения соответствующего мониторинга хода лечения в отсутствие контроля вирусной нагрузки.

7.1 Когда следует начинать АРТ

Основные пробелы в научных исследованиях Нужны дополнительные данные для определения потенциальных клинических выгод и степени воздействия раннего назначения АРТ на заболеваемость детей моложе пяти лет, а также на формируемый иммунологический и вирусологический ответ с течением времени. Требует дальнейшего изучения влияние курса АРТ на более раннем этапе на удержание больных в программе ухода за ними, приверженность лечению и развитие потенциальной лекарственной устойчивости при ВИЧ у детей с менее запущенной формой заболевания. Также необходимы данные в поддержку обоснования оптимального подхода к началу проведения АРТ у детей с сочетанной ВГВ-инфекцией.

124

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда) При назначении АРТ первого ряда рекомендуется использовать упрощенные, менее токсичные и более удобные схемы лечения в виде комбинированных препаратов с фиксированными дозами. Однократное ежедневное лечение по схеме с включением основы из одного нетимидинового НИОТ (TDF + FTC или TDF + 3TC) и одного ННИОТ (EFV) принято считать предпочтительными вариантами для взрослых, подростков и детей старше трех лет. Для детей моложе трех лет схема на основе ИП представляется предпочтительной (Таблица 7.5).

Таблица 7. Краткое описание схем АРВ-терапии первого ряда для взрослых, подростков, беременных и кормящих грудью женщин, а также детей АРТ первого ряда Взрослые (включая беременных и кормящих грудью женщин и взрослых с коинфекцией ТБ и ВГВ) Предпочтительные схемы первого ряда Альтернативные схемы первого рядаa b AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + NVP TDF + 3TC (или FTC) + EFV AZT + 3TC + EFV Подростки (от 10 до 19 лет) ≥35 кг AZT + 3TC + NVP TDF + 3TC (или FTC) + NVP ABC + 3TC + EFV (или NVP) ABC + 3TC + NVP AZT + 3TC + EFV Дети от 3 лет до менее чем 10 лет и подростки <35 кг ABC + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + EFV TDF + 3TC (или FTC) + NVP Дети в возрасте <3 лет ABC или AZT + 3TC + LPV/r ABC + 3TC + NVP AZT + 3TC + NVP

В отношении подростков следует прекратить дальнейшее назначение d4T в качестве препарата выбора в составе схемы лечения первого ряда и ограничить его применение лишь в особых случаях, когда другие АРВ-препараты не могут быть использованы, и допускать вероятность его приема по возможности в течение максимально короткого промежутка времени при тщательном динамическом наблюдении. В отношении детей назначение d4T допустимо исключительно в ситуациях, когда возникают подозрения или получены подтверждения по поводу токсичности AZT и есть проблемы с доступностью ABC или TDF. Период лечения этим препаратом должен быть как можно короче. См. Вставку 10.7 с методическими рекомендациями, касающимися постепенного отказа от назначения d4T. При особых обстоятельствах допускается использование ABC или усиленных ИП (ATV/r, DRV/r, LPV/r).

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

125

7.2.1 АРТ первого ряда для взрослых Новые рекомендации А РТ первого ряда должна включать два нуклеозидных ингибитора обратной транскриптазы (НИОТ) плюс один ненуклеозидный ингибитор обратной транскриптазы (ННИОТ) • В качестве предпочтительной схемы для начала АРТ рекомендуется TDF + 3TC (или FTC) + EFV как комбинированный препарат с фиксированными дозами (настоятельная рекомендация, фактические данные среднего качества). • Если TDF + 3TC (или FTC) + EFV противопоказаны или не имеются в наличии, рекомендуется одна из следующих схем: • • • AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + NVP (настоятельная рекомендация, фактические данные среднего качества). новое

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

транам следует прекратить использование d4T в схемах первого ряда в С связи с его общепризнанной метаболической токсичностью (настоятельная рекомендация, фактические данные среднего качества).

Таблица 7.6 Краткое описание схем АРВ-терапии первого ряда для взрослыхa АРТ первого ряда для взрослых (включая беременных и кормящих грудью женщин и лиц с коинфекцией ТБ и ВГВ) Предпочтительные схемы Альтернативные схемы Особые обстоятельства a

TDF + 3TC (или FTC) + EFV AZT + 3TC + EFV (или NVP) TDF + 3TC (или FTC) + NVP Схемы, содержащие ABC, d4T и усиленные ИП b

новое

Информацию по подросткам см. в Разделе 7.2.4, в котором речь идет об АРТ первого ряда для детей в возрасте 3 лет и старше, куда включены ВИЧ-инфицированные подростки (в возрасте 10 лет и старше). Следует прекратить дальнейшее назначение d4T в качестве препарата выбора в составе схемы лечения первого ряда и ограничить его применение лишь в особых случаях. Период лечения этим препаратом по мере возможности должен быть максимально коротким и предусматривать тщательное динамическое наблюдение.

Особыми обстоятельствами могут быть ситуации, при которых предпочтительные или альтернативные схемы могут оказаться недоступными или неподходящими из-за значительных токсических проявлений, предполагаемых лекарственных взаимодействий, проблем с закупками и организацией поставок препаратов или по другим причинами.

126

Общая информация В Руководстве ВОЗ от 2010 года по АРТ (2) было рекомендовано первоначально включать в схему АРТ у никогда ранее не лечившихся взрослых один из ННИОТ (либо NVP, либо EFV) плюс два НИОТ, одним из которых должен быть 3TC (или FTC), а другим – AZT или TDF. В руководстве подчеркивается, насколько важно воздерживаться от назначения d4T как предпочтительного варианта для схем первого ряда по причине хорошо известной митохондриальной токсичности этого препарата, используя схемы с потенциально меньшей токсичностью и более подходящие для большинства людей, предпочтительно в виде комбинированных препаратов с фиксированными дозами при наличии клинических, операционных и программных достоинств. Рекомендуемые схемы обладали более удачными, по сравнению с d4T, профилями токсичности, но считались сопоставимыми с точки зрения действенности, так как не были получены фактические данные в пользу того, что в вирусологическом отношении AZT превосходит d4T, AZT превосходит TDF, TDF превосходит d4T или ABC, или EFV превосходит NVP. Постепенный отказ от назначения d4T в качестве предпочтительного варианта для АРТ первого ряда был неоднозначный. Если некоторые страны добились быстрого и ощутимого прогресса в этом плане, то другие придерживались постепенного подхода к проблеме, например, отказ от назначения d4T только для людей, впервые приступающих к АРТ, или неиспользование d4T у беременных женщин (веб-приложение www.who.int/hiv/pub/ guidelines/arv2013/annexes). ВОЗ (119,120) выступает за более доступный по затратам и эффективный подход к лечению, в том числе более простые схемы АРВ-терапии, предусматривающие однократный ежесуточный прием всего одной таблетки. В руководстве от 2013 года поощряется дальнейшее упрощение системы организации АРТ путем сокращения количества предпочитаемых схем первого ряда и повышения роли схем лечения, которые применимы к самым разным контингентам населения.

Обоснование и подтверждающие фактические данные Переход на схему TDF + 3TC (или FTC) + EFV в качестве предпочтительного варианта терапии первого ряда В итоге систематизированного обзора сравнительной оценки шести схем лечения были получены фактические данные среднего качества, указывающие на то, что однократный суточный прием комбинации TDF + 3TC (или FTC) + EFV реже ассоциируется с тяжелыми неблагоприятными проявлениями и обладает более выраженным вирусологическим и терапевтическим ответом по сравнению с другими схемами приема препаратов один или два раза в день (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Дополнительный систематизированный обзор показал, что по сравнению с лицами, принимающими EFV, получающие NVP люди в два раза чаще склонны прекращать терапию из-за неблагоприятных проявлений (121). Группой по разработке руководства был также проведен обзор опубликованного метаанализа и доработанного анализа (122,123), который не свидетельствовал о повышении риска возникновения пороков развития на фоне приема EFV по сравнению с другими АРВ-препаратами, назначаемыми в первом триместре беременности (122). Фармакологическая сопоставимость 3TC и FTC очевидна (123). Схема TDF + 3TC (или FTC) + EFV ассоциируется с хорошим потенциалом для гармонизации лечения среди разных групп населения: комбинированные препараты TDF/FTC или TDF/3TC являются предпочтительным вариантом на основе НИОТ для людей с коинфекцией ВИЧ и ВГВ и могут использоваться у людей с сочетанной инфекцией ТБ и у беременных женщин. EFV относится к категории предпочтительных ННИОТ для людей с ВИЧ и ТБ (фармакологическая совместимость с

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

127

противотуберкулезными препаратами), а также с коинфекцией ВИЧ и ВГВ (более низкий риск гепатотоксичности) и может использоваться у беременных женщин, в том числе у женщин в первом триместре беременности. Если нет возможности использовать TDF + 3TC (или FTC) + EFV, то в качестве альтернативных схем первого ряда ранее не получавшим АРТ пациентам могут быть предложены ННИОТ-содержащие схемы приема препаратов один или два раза в день (AZT + 3TC + EFV, AZT + 3TC + NVP, а также TDF + 3TC (или FTC) + NVP). Несмотря на предположительно эквивалентные варианты, они обладают потенциальными преимуществами по сравнению с предпочтительными схемами терапии. Использование других препаратов, таких как ABC и усиленных ИП, является приемлемым в качестве возможных резервных вариантов в особых ситуациях, но они не рекомендуются в качестве предпочтительных альтернативных вариантов с позиции принципов оптимизации назначения АРВ-препаратов. NVP у беременных женщин Как и прежде, существуют опасения по поводу повышенного, по сравнению с EFV, риска возникновения неблагоприятных проявлений на фоне приема NVP, а также относительно использования NVP у женщин с ВИЧ и количеством лимфоцитов CD4 более 250 клеток/мм3, притом что по данным некоторых исследований отмечается повышение относительного риска развития тяжелых реакций со стороны печени и кожных покровов у беременных женщин, получающих NVP при повышенном количестве клеток CD4 (124–126). Из обновленного в 2013 г. (134) систематизированного обзора (127) следует, что риск развития NVP-ассоциированной токсичности у беременных женщин говорит о повышенной частоте неблагоприятных проявлений, но она не выше частоты встречаемости таких проявлений среди взрослой части населения в целом. Следует отметить наличие недостаточно убедительных фактических данных в поддержку теории о том, что беременные женщины с ВИЧ и высоким уровнем клеток CD4 подвержены повышенному риску развития неблагоприятных проявлений по сравнению с населением с ВИЧ в целом. К числу важных соображений следует отнести необходимость во вводном дозировании NVP при его первичном назначении, а также тот факт, что его не выпускают в виде комбинированного препарата с фиксированными дозами вместе с TDF + 3TC (или FTC). Поэтому NVP следует использовать с осторожностью у беременных женщин и женщин с вероятностью развития беременности и только по результатам рассмотрения риска и выгод и доступных альтернатив (см. Раздел 7.3.2). Альтернативы назначению NVP, например ABC и усиленные ИП, являются допустимыми, но ими следует воспользоваться только при отсутствии NVP в наличии. Использование альтернативных схем и постепенный отказ от назначения d4T Рекомендуемые в настоящее время такие альтернативные схемы, как AZT вместо TDF или NVP вместо EFV (Таблица 7.5) сопоставимы по своей терапевтической эффективности, но имеют потенциальные клинические и программные недостатки по сравнению с предпочтительными вариантами. В отношении лиц, у которых уже достигнута стабилизация клинического состояния за счет пролечивания по альтернативной схеме, при отсутствии противопоказаний можно рассмотреть возможность продолжения курса лечения по этой же схеме на основании положений национального руководства или перейти на предпочтительные варианты, чтобы упростить организацию лечения, сократить расходы, улучшить переносимость, усилить приверженность лечению и содействовать улучшению процесса чередования схем терапии. В особых обстоятельствах приемлемыми для этой цели являются такие препараты, как ABC и усиленные ИП, но их следует назначать только тогда, когда нет других вариантов. Следует воздерживаться от дальнейшего использования d4T-содержащих схем и резервировать этот препарат исключительно для тех случаев, когда нет возможности

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

128

воспользоваться другими АРВ-препаратами, а продолжительность приема этого препарата должна быть по возможности короткой и предполагать тщательный мониторинг. В условиях, при которых схемы на основе d4T все еще используются в качестве предпочтительного варианта для начала проведения АРТ, следует проводить в жизнь план постепенного отказа от назначения d4T, отдавая при этом предпочтение использованию схем первого ряда на основе TDF (2,128,129). В Разделе 10.6 (Вставка 10.7) приводятся итоги дальнейшей дискуссии по вопросу постепенного вывода d4T из практики ведения больных. Токсичность TDF Данные систематизированного обзора по проблеме токсичности TDF (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes) указывают на то, что TDF обладает низким уровнем нефротоксичности в кратко- и среднесрочной перспективе, особенно у людей с фоновым заболеванием почек или факторами риска по развитию этой патологии. Проспективные когортные данные говорят о том, что TDF ассоциируется с умеренным понижением функции почек (по результатам измерения снижения расчетной скорости клубочковой фильтрации) (130,131) и уменьшением минеральной плотности костной ткани, однако клиническая значимость и размах этих побочных эффектов, особенно при длительной терапии, требуют более глубокого изучения. Кроме того, нужны дальнейшие научные исследования, чтобы установить целесообразность рутинного лабораторного скрининга и мониторинга токсичности TDF, или же его следует проводить только среди таких групп высокого риска, как лица с гипертензией и диабетом, или среди тех, кто получает усиленные ИП. Поскольку нефротоксичность TDF обычно проявляется в дисфункции почечных канальцев, анализы состояния функции клубочков не дают прямой количественной оценки, и никакой другой простой тест не способен выявить токсические поражения почечных канальцев. В Разделе 7.4 приводится продолжение этой дискуссии. Фактические данные говорят о том, что общее улучшение функции почек вследствие АРТ может компенсировать риск проявления токсичности TDF у лиц с ВИЧ, не страдающих вторичным заболеванием почек. Инфекция ВИЧ-2 Систематизированный обзор вариантов лечения у индивидуумов с ВИЧ-2 (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes) позволил отнести фактические данные, полученные в итоге проведения всех обсервационных исследований, к категории очень низкого качества при наличии серьезного риска систематической ошибки, непоследовательности и расхождения результатов. Ввиду природной резистентность ВИЧ-2 к ННИОТ никогда ранее не получавшие такого лечения люди со смешанной инфекцией ВИЧ-1 и ВИЧ-2 должны проходить лечение по схеме, содержащей три НИОТ (TDF + 3TC (или FTC) + AZT или AZT + 3TC + ABC), или усиленной ритонавиром ИП плюс два НИОТ. Если используется схема на основе ИП, то предпочтительным вариантом для терапии первого ряда должен быть LPV/r, поскольку его будут закупать в странах и территориях с низким уровнем дохода как для лечения взрослых по схеме второго ряда, так и для лечения детей по схеме первого ряда. Препараты SQV/r и DRV/r относятся к альтернативным вариантам лечения усиленными ИП, но они не существуют в форме термостабильных комбинированных препаратов с фиксированными дозами.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

129

7.2.2 АРТ первого ряда для беременных и кормящих грудью женщин и АРВ препараты для их детей Новые рекомендации новое

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

П рием комбинированного препарата с фиксированными дозами TDF + 3TC (или FTC) + EFV один раз в день рекомендуется в качестве АРТ первого ряда для беременных и кормящих грудью женщин, включая беременных женщин в первом триместре беременности и женщин детородного возраста. Эта рекомендация касается как пожизненного лечения, так и АРТ, которая назначается для ППМР и затем прекращается (настоятельная рекомендация, фактические данные низкого или среднего качества: фактические данные среднего качества для взрослой части населения в целом, но низкого качества для таких конкретных групп населения, как беременные и кормящие грудью женщины и дети грудного возраста). рудные дети, матери которых получают АРТ и осуществляют грудное Г вскармливание, должны получать профилактическое лечение в течение шести недель с ежедневным приемом NVP. Если дети переведены на альтернативное вскармливание, они должны получать профилактическое лечение в течение четырех-шести недель с приемом NVP один раз в день (или AZT два раза в день). Профилактика у грудных детей должна начинаться с рождения или когда воздействие ВИЧ выявлено после родов (настоятельная рекомендация, фактические данные среднего качества для детей, получающих грудное вскармливание; настоятельная рекомендация, фактические данные низкого качества для грудных детей, получающих только альтернативное вскармливание). Примечание: В связи с рекомендациями по профилактике у детей грудного возраста приведенные оценки и рекомендации по системе GRADE заимствованы из руководства от 2010 г., и они не анализировались Группой по разработке руководства при составлении настоящего руководства.

Общая информация В руководстве ВОЗ по ППМР от 2010 года (82) было рекомендовано делать выбор из четырех разных схем для лечения беременных и кормящих грудью женщин с ВИЧ, которые нуждались в АРТ ради сохранения своего здоровья: AZT + 3TC или TDF + 3TC (или FTC) плюс либо NVP, либо EFV. Ввиду опасений по поводу повышенного риска токсичности NVP у беременных женщин с более высоким количеством клеток CD4 (132–134) в состав рекомендуемых схем для беременных женщин, которым не было показано лечение в целях поддержания собственного здоровья и которые получали тройную комбинацию АРВ-препаратов для ППМР, включали AZT + 3TC или TDF + 3TC (или FTC) + EFV в качестве предпочтительных схем на основе ННИОТ. В состав альтернативных схем в основном включали AZT + 3TC плюс либо LPV/r, либо ABC, а не NVP. Несмотря на то, что было рекомендовано назначать TDF и EFV, данные об их безопасности для использования в период беременности и грудного вскармливания имелись лишь в ограниченном объеме. В руководстве ВОЗ от 2010 года (82) также было рекомендовано назначать курс доконтактной химиопрофилактики в период от четырех до шести недель с введением детской формы NVP (или AZT) для всех новорожденных от матерей, которые получали тройную комбинацию АРВ-препаратов в целях лечения или профилактики. Было рекомендовано ежедневное профилактическое лечение NVP младенцев в течение всего периода грудного вскармливания, если мать не получала лечения по схеме из трех АРВ-препаратов. новое

130

На примере клинических испытаний было показано, что курс химиопрофилактики у грудных детей имеет особое значение для ППМР на тот случай, когда мать прошла неполный курс лечения АРВ-препаратами или не принимала их вовсе в дородовом периоде и когда не было достигнуто подавления репликации вирусов (135–137). Это продолжает оставаться рекомендуемым компонентом схем ППМР в странах с достаточными ресурсами в качестве дополнительной защиты от воздействия ВИЧ во время родовой деятельности, даже когда матери получают АРТ в период беременности и когда мать не вскармливает ребенка грудью (138). Данные, положенные в основу этой рекомендации, не менялись с 2010 года.

Обоснование и подтверждающие фактические данные В руководстве от 2013 г. подчеркивается значимость упрощения и гармонизации терапии первого ряда. Рекомендуется схема однократного ежедневного лечения комбинированными препаратами с фиксированными дозами с введением TDF в качестве предпочтительного НИОТ и EFV в качестве предпочтительного ННИОТ в сочетании с 3TC или FTC у всех взрослых, в том числе у беременных и кормящих грудью женщин, в качестве предпочтительной схемы в целях улучшения показателей состояния здоровья и содействия приверженности лечению и организации закупок лекарственных средств (см. Раздел 7.2.1 и веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes). Идеальная схема первого ряда для беременных и кормящих грудью женщин с ВИЧ не является затратной; она доступна в форме комбинированных препаратов с фиксированными дозами; безопасна как для беременных и кормящих грудью женщин, так и для их детей; хорошо переносится; предусматривает низкий уровень требований к мониторингу и характеризуется низким профилем лекарственной устойчивости; сопоставима с другими лекарственными средствами при оказании клинической помощи; и гармонизирована с рекомендациями для взрослых небеременных женщин. Схема лечения в составе TDF + 3TC (или FTC) + EFV доступна в форме комбинированного препарата с фиксированными дозами для однократного ежедневного приема и рекомендована в качестве схемы первого ряда для взрослых благодаря своей простоте, приемлемости по затратам (с 2010 г. стоимость лечения заметно снизилась) и эффективности против ВГВ. Фактор безопасности имеет жизненно важное значение для беременных и кормящих грудью женщин и их детей, а также для женщин, которые могут забеременеть в будущем. Несмотря на то, что данные об использовании EFV и TDF у беременных женщин попрежнему ограничены, начиная с 2010 г. удалось получить дополнительные сведения и обеспечить дополнительные гарантии в пользу рекомендуемого курса лечения TDF + 3TC (или FTC) + EFV в качестве АРВ-схемы первого ряда для беременных и кормящих грудью женщин (122,139,140). В Разделах 7.3.1 и 7.5.2 приводится подробная информация по обоснованию в целом рекомендуемой схемы первого ряда, включая вопросы токсичности и мониторинга. Безопасность приема EFV при беременности Ранее полученные данные говорят о том, что пороки развития, включая анэнцефалию, офтальмомикрию и расщепление неба у приматов под воздействием EFV в утробе самки (141), а также отдельные выборочные истории болезни и ретроспективные клинические данные о дефектах нервной трубки у человека (142) стали поводом для опасений относительно назначения EFV в первом триместре беременности или же не беременным женщинам с потенциалом деторождения. Управление по контролю качества пищевых продуктов и лекарственных препаратов США и Европейское агентство по лекарственным средствам не рекомендуют назначать EFV в первом триместре беременности, а также женщинам с потенциалом деторождения при условии, когда потенциальные выгоды не перевешивают потенциальные риски; вместе с тем, недавно Британская ассоциация по ВИЧ

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

131

пересмотрела свою рекомендацию, согласно которой допускается использование EFV в первом триместре (143). Поскольку риск возникновения дефектов нервной трубки ограничивается первыми пятьюшестью неделями развития беременности и ввиду того, что при беременности эта патология распознавалась редко на ранней стадии, особенно в странах и территориях с ограниченными ресурсами, всякий потенциальный риск дефектов нервной трубки на фоне приема EFV будет в первую очередь проявляться у женщин, ставших беременными еще при прохождении курса лечения EFV. Результаты оценки проспективно собранных данных при ведении больных людей представляются обнадеживающими; в итоге обновленного систематизированного обзора и метаанализа, включая Регистр антиретровирусной терапии во время беременности (47,134), были зафиксированы исходы ведения 1502 живорожденных от женщин, получавших EFV в первом триместре, и не обнаружено ни роста суммарной статистики пороков развития, ни повышения настороженности в отношении EFV по сравнению с воздействием других АРВпрепаратов в период беременности (140). При единственном случае выявленного дефекта нервной трубки его расчетная распространенность, по данным систематизированного обзора, продолжает сохраняться на уровне примерно 7 на 10 000 населения (0,07%), что сопоставимо с оценочными данными в пределах 0,02% 0,2% среди населения США в целом (138). B силу того, что дефекты нервной трубки относятся к числу относительно редко встречающихся событий и прослеживаются лишь ограниченные сведения об экспозиции терапии в Регистре антиретровирусной терапии во время беременности и в рамках метаанализов, ныне имеющиеся данные вполне достаточны для того, чтобы исключить потенциальный повышенный риск более чем в три раза или до 0,21% (более ограниченный объем данных, приведенных в руководстве от 2010 г., был достаточен для исключения 10-кратного увеличения риска). Несмотря на то, что Группа по разработке руководства обратила особое внимание на необходимость получения более качественных данных о ситуации с пороками развития, ее члены выразили уверенность в том, что этот потенциально низкий показатель следует соизмерять с программными преимуществами и клинической пользой от назначения EFV в целях профилактики ВИЧ-инфекции у грудных детей и охраны здоровья матери. Безопасность приема NVP при беременности: (см. Раздел 7.2.1) Безопасность приема TDF при беременности и в период грудного вскармливания Потенциальная обеспокоенность по поводу безопасности TDF ассоциируется с нефротоксичностью препарата (Раздел 7.4.3), неблагоприятными исходами ведения новорожденного и влияниями на минеральную плотность костной ткани. В результате систематизированного обзора была проведена оценка токсичности воздействия TDF на состояние плода во время беременности (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes). Согласно данным Регистра антиретровирусной терапии во время беременности, распространенность пороков развития в целом под влиянием TDF в первом триместре составила 2,4% в выборке численностью 1612 живорожденных и не отличалась от фонового уровня в США. Ограниченные по объему исследования свидетельствовали об отсутствии различий в темпах роста плода при сопоставлении младенцев, оказавшихся и не оказавшихся под воздействием TDF (144,145). TDF обладает ограниченной способностью проникновения в грудное молоко, что ограничивает его потенциальную токсичность для ребенка на грудном вскармливании. Однако не проводилось каких-либо исследований воздействия TDF на кормящих грудью женщин, у которых во время грудного вскармливания обычно происходит разрежение кости, которое стабилизируется с окончанием лактации. В настоящее время проводится очередная серия исследований профиля безопасности TDF применительно к состоянию костной ткани и функции почек при беременности и грудном вскармливании и у матери, и у ребенка. Ежедневный однократный прием TDF + 3TC (или FTC) + EFV по схеме с фиксированными дозами прост и удобен, а гармонизация рекомендаций для беременных и не беременных

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

132

женщин позволяет облегчить задачу управления системой поставок. На основании полученных данных и практического опыта Группа по разработке руководства пришла к выводу о том, что явные преимущества этой схема для беременных и кормящих грудью женщин (и женщин с потенциалом деторождения) перевешивают потенциальные риски (см. Раздел 7.5.2). Профилактика у грудных детей

Таблица 7.7 Упрощенные рекомендации по дозированию при профилактическом лечении детей грудного возраста (адаптировано по материалам (82)) Возраст младенца От рожденияa до 6 недельb Масса тела при рождении 2000−2499 г Масса тела при рождении ≥2500 г > От >6 недель до 6 месяцевc > От >6 месяцев до 9 месяцев От >9 месяцев до прекращения грудного вскармливания a

Суточная дозировка 10 мг один раз в день 15 мг один раз в день 20 мг один раз в день 30 мг один раз в день 40 мг один раз в день

Младенцам с массой тела <2000 г следует назначать дозы из расчета мг/кг; предлагаемая начальная доза соответствует 2 мг/кг один раз в день. Рекомендуемый период – 6 недель, но в ситуациях с альтернативным вскармливанием может быть рассмотрена возможность лечения в течение 4 недель.

При особых обстоятельствах должен быть рассмотрен вопрос о режиме дозирования для возраста старше 6 недель при удлинении периода дозирования до 12 недель. Этими обстоятельствами могут быть случаи, когда матери удалось пройти лишь ограниченный курс АРТ при маловероятном подавлении вирусной нагрузки, или когда младенец классифицируется как ВИЧэкспонированный сразу после рождения и находится на грудном вскармливании (Таблица 7.8). В основе этого лежит дозировка, необходимая для противодействия экспозиции среди детей грудного возраста, в количестве >100 нг/мл при минимальных коррекциях указанной дозы.

Упрощенные рекомендации по дозированию при профилактическом лечении детей грудного возраста: AZT (рекомендовано только в тех случаях, когда в рацион питания вводится прикорм) Возраст младенца От рожденияa до 6 недель Масса тела при рождении 2000−2499 г a Масса тела при рождении ≥2500 г a

Суточная дозировка 10 мг два раза в день 15 мг два раза в день

Младенцам с массой тела <2000 г следует назначать дозы из расчета мг/кг; предлагаемая начальная доза соответствует 2 мг/кг два раза в день.

Не было получено каких-либо новых данных, на основании которых требовался бы пересмотр рекомендаций по химиопрофилактике у грудных детей. Для младенцев на грудном вскармливании рекомендована схема приема детской формы NVP в течение шести недель; неизменными остаются рекомендации по ведению младенцев, находящихся на альтернативном вскармливании и подлежащих лечению детской формой NVP или AZT от четырех до шести недель. Если токсичность детской формы NVP требует отмены этого

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

133

препарата или если же детской формы NVP нет в наличии, то вместо нее можно назначить прием детской формы 3TC. По данным нескольких исследований (146,147), без всякого риска для химиопрофилактики у младенцев в период грудного вскармливания можно использовать 3TC. Несмотря на то, что Группой по разработке руководства в официальном порядке не проводился обзор этой тактики, ее члены рассмотрели целый ряд сценариев, согласно которым вполне приемлемым может оказаться более продолжительный период химиопрофилактики у грудных детей. Поскольку может потребоваться несколько недель или даже месяцев для того, чтобы курс АРТ у матери обеспечивал подавление репликации вирусов и чтобы исключить вероятность передачи инфекции в последовом периоде младенцу на грудном вскармливании в течение этого времени или когда кормящая грудью мать приступает к курсу АРТ буквально на завершающем этапе беременности (к примеру, менее чем за четыре недели до родов), непосредственно в родах или после них, правомерно рассмотреть вопрос о продлении курса профилактического лечения детской формой NVP до 12 недель. Химиопрофилактика у младенцев также играет важную роль, если кормящая грудью мать прерывает курс АРТ в период грудного вскармливания, так как это обстоятельство подвергает ее ребенка повышенному риску передачи заразного начала в послеродовом периоде. В таких ситуациях уместно поставить вопрос о ежедневном приеме детской формы NVP на то время, когда мать прерывает АРТ, и о продолжении предложенного лечения еще в течение шести недель от момента возобновления матерью своей АРТ (или в течение еще одной недели после завершения периода грудного вскармливания в зависимости от того, что наступит раньше). В Таблице 7.8 дано краткое описание целого набора сценариев профилактического лечения у матери и грудного ребенка.

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

Таблица 7.8 Краткое описание курса профилактического АРВ-лечения матери и ребенка для разных клинических сценариев Сценарий Матери поставлен диагноз ВИЧ-инфекции в период беременностиc,d Матери поставлен диагноз ВИЧ-инфекции во время родов или сразу после них, и она планирует кормить ребенка грудью Матери поставлен диагноз ВИЧ-инфекции во время родов или сразу после них, и она планирует альтернативное вскармливание АРВпрофилактика у материa Начало АРТ у матери АРВпрофилактика у младенцаb NVPc Продолжительность АРВ-профилактики у младенца 6 недель c

Начало АРТ у матери

NVP

6 недель; вероятность продления этого срока до 12 недель

Направление матери в службу по оказанию помощи при ВИЧ для обследования и назначения лечения

NVPc

6 недель c

134

Таблица 7.8 (продолжение) Сценарий АРВпрофилактика у материa АРВпрофилактика у младенцаb Продолжительность АРВ-профилактики у младенца Постановка ПЦР в целях ранней диагностики ВИЧ у младенца, а затем безотлагательное назначение 6-недельного курса лечения NVP – высока вероятность продления этого срока до 12 недель Постановка ПЦР на ВИЧ согласно национальным рекомендациям по ранней диагностике у детей грудного возраста; без назначения ребенку курса АРВ-профилактики; начало лечения, если младенец окажется инфицированным

Установлено, что ребенок подвергался риску воздействия ВИЧинфекции после родов (по результатам определения антител к ВИЧ у младенца или у матери) и находится на грудном вскармливании

Начало АРТ у матери

NVP

Установлено, что ребенок подвергался риску воздействия ВИЧинфекции после родов (по результатам определения антител к ВИЧ у младенца или у матери) и не находится на грудном вскармливании

Направление матери в службу по оказанию помощи при ВИЧ для обследования и назначения лечения

Без приема препарата

Мать получает АРТ, но прерывает ее на фоне кормления ребенка грудью (например, по причине токсичности препаратов, истощения их запасов или отказа продолжать лечение) a

Определение альтернативной схемы АРВ-терапии или решения; консультирование по поводу продолжения АРТ без перерыва в лечении

NVP

До 6 недель после возобновления АРТ у матери или до 1 недели после прекращения грудного вскармливания

В идеальном случае следует определить количество клеток CD4 у матери непосредственно перед началом или вскоре после назначения АРТ; необходимо руководствоваться требованиями действующего в стране руководства относительно проведения АРТ – должна ли она быть пожизненной или подлежит отмене после исчезновения риска передачи заразного начала. b Если принимаемый ребенком NVP вызывает токсическую реакцию или же запаса NVP не имеется, то вместо него можно использовать 3TC. c Если мать пользуется альтернативным вскармливанием, то вместо детской формы NVP можно использовать детскую форму AZT; если есть документированные данные о подавлении вирусной нагрузки в организме матери накануне родов благодаря приему АРТ и при использовании альтернативного вскармливания, допускается назначение ребенку 4-недельного курса АРВ профилактики. d Если известно, что мать приступила к прохождению АРТ менее чем за 4 недели до родов, допускайте вероятность продления периода лечения детской формой NVP до 12 недель, если такие младенцы находятся на грудном вскармливании.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

135

Альтернативные схемы по причине токсичности, непереносимости или отсутствия доступа к рекомендуемым схемам Лечение AZT рекомендовано в качестве альтернативного НИОТ для небеременных женщин, страдающих непереносимостью к TDF или не имеющих возможности принимать этот препарат. Учитывая большой массив данных о безопасности и эффективности лечения AZT у беременных и кормящих грудью женщин, можно сказать, что AZT также рекомендован как альтернативный НИОТ для беременных и кормящих грудью женщин. Для не беременных женщин, страдающих непереносимостью к EFV или не имеющих возможности принимать этот препарат, рекомендуемым альтернативным ННИОТ является NVP. Однако из-за того, что АРТ (тройная комбинация АРВ-препаратов) теперь рекомендована для беременных и кормящих грудью женщин независимо от количества клеток CD4, сохраняются опасения по поводу использования NVP у женщин с повышенным уровнем клеток CD4. Несмотря на то, что в руководстве от 2010 г. (2,82) утверждается, что польза от NVP перевешивает риск для женщин с количеством CD4 в пределах от 250 до 350 клеток/мм3, данные о профиле безопасности этого препарата для женщин с количеством лимфоцитов CD4 ≥350 клеток/мм3 являются ограниченными, и обнаружение жизнеугрожающей гепатотоксичности NVP при его использовании в целях профилактики профессионального заражения ВИЧ у лиц без ВИЧ-инфекции повышают уровень беспокойства по поводу его использования у лиц с повышенным количеством клеток CD4. Однако недавно проведенный систематизированный анализ риска NVP-ассоциированной токсичности у беременных женщин (134) (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes) говорит о том, что частота неблагоприятных проявлений не превышает соответствующий уровень среди взрослой части населения в целом. Более того, данные о взаимосвязи между токсичностью NVP и повышенным уровнем клеток CD4 весьма противоречивы, и риск значительной гепатотоксичности в большинстве исследований составляет около 3% (121). Имеющиеся данные указывают на то, что переход на лечение NVP тех лиц, которые уже проходили курс терапии и у которых имело место подавление репликации вирусов, не ассоциируется с повышением токсичности даже на фоне перестройки иммунной системы. И наконец, альтернативой замены EFV на NVP будет один из ИП, который является рекомендуемой терапией второго ряда и является более дорогостоящим по сравнению с препаратами класса ННИОТ. В результате, Группа по разработке руководства пришла к выводу, что суммарная выгода от замены NVP при ведении беременных или кормящих грудью женщин при редком стечении обстоятельств, когда имеет место непереносимость EFV, перевешивает потенциальные риски.

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

Клинические соображения Важнейшее значение для ППМР имеет поддержание цепочки поставок препаратов и обеспечение бесперебойного предоставления АРТ матерям и АРВ-препаратов грудным детям в период беременности и грудного вскармливания. Все службы охраны здоровья матери и ребенка, предоставляющие услуги ППМР, должны располагать потенциалом для инициирования, проведения и мониторинга постоянной АРВ-терапии для матерей и грудных детей.

Основные пробелы в научных исследованиях Эпиднадзор за токсичностью АРВ-препаратов. Необходимо продолжать научные исследования для оценки кратко- и долгосрочного воздействия EFV, TDF и других АРВ-препаратов на беременных и кормящих грудью женщин, а также на детей во внутриутробном периоде и после рождения, включая мониторинг пороков развития и других неблагоприятных исходов беременности, а также оценку воздействия TDF на почки и кости как у женщин, так и у ВИЧ-экспонированных грудных детей.

136

Приемлемость EFV для АРТ первого ряда. Требуются дальнейшие исследования для определения уровня непереносимости EFV, а также необходимости перехода на альтернативную схему первого ряда и того, как следует оказывать поддержку при введении альтернативных схем первого ряда в рамках программ для беременных и кормящих грудью женщин. Профилактика у детей грудного возраста. Необходимы данные более высокого качества в отношении оптимальной продолжительности профилактического лечения детей грудного возраста, матери которых получают АРТ, особенно если мать начинает получать АРТ на поздней стадии беременности или в послеродовой период, в связи с чем вирусная супрессия у нее отсутствует в период родов или начала грудного вскармливания. Для облегчения приема препаратов новорожденными и грудными детьми необходимо разработать улучшенные лекарственные формы NVP, которые легче принимать. Оптимальная тактика ведения грудных детей, оказавшихся под воздействием ВИЧ в период грудного вскармливания Важно установить в какой мере перинатального воздействия ВИЧ удалось избежать в дородовой период, а также определить уровень сероконверсии матери, надлежащие стратегии послеродового скрининга грудных детей на воздействие ВИЧ и оптимальные стратегии проведения тестирования и профилактики. Отмена АРТ на основе ННИОТ (использование «шлейфа»). В связи с длительным периодом полувыведения EFV (и NVP), при резком прекращении лечения на основе ННИОТ возникает риск развития устойчивости к ННИОТ. В отношении женщин, которые желают или должны прекратить АРТ на основе EFV по причине токсичности или других состояний, необходимы дополнительные данные для того, чтобы определить, следует ли использовать «шлейф» из НИОТ для снижения этого риска. Изучение данных фармакокинетического моделирования при подготовке настоящего руководства указывает на то, что если в схеме на основе НИОТ используется TDF, такой «шлейф» может не потребоваться, однако если схема на основе НИОТ включает AZT, рекомендуется использовать «шлейф» в течение двух недель (период полувыведения EFV дольше, чем NVP).

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

137

7.2.3 АРТ первого ряда для детей в возрасте до трех лет Новые рекомендации новое

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

качестве АРТ первого ряда для всех ВИЧ-инфицированных детей в возрасте до В трех лет (36 месяцев) независимо от воздействия ННИОТ следует использовать схему лечения на основе LPV/r. Если использовать LPV/r не представляется возможным, лечение следует начинать со схемы на основе NVP (настоятельная рекомендация, фактические данные среднего качества). В тех случаях, когда осуществляется мониторинг вирусной нагрузки, следует рассмотреть возможность замены LPV/r на ННИОТ после достижения супрессии виремии (условная рекомендация, фактические данные низкого качества). Особое примечание: По результатам рандомизированного контролируемого испытания, согласующимся с использованием этого подхода (148,161), под подавлением репликации вирусов имеется в виду вирусная нагрузка ≤400 копий/мм 3 в целях вычленения группы детей, которым с большей степенью вероятности можно без всякого риска назначить NVP вместо LPV/r. Использование более высокой точки отсечения по вирусной нагрузке для определения подавления репликации вирусов не было предметом изучения в контексте этой стратегии.

Д ля грудных детей и детей в возрасте до трех лет, инфицированных ВИЧ, в качестве варианта лечения детей, у которых развивается ТБ во время проведения АРВ-терапии по схеме, содержащей NVP или LPV/r, рекомендуется ABC + 3TC + AZT. После окончания курса противотуберкулезного лечения эта схема должна быть отменена, и следует вновь перейти на первоначальную схему (настоятельная рекомендация, фактические данные среднего качества). Д ля грудных детей и детей в возрасте до трех лет, инфицированных ВИЧ, в качестве основы из двух НИОТ для схемы АРВ-терапии следует использовать ABC или AZT + 3TC (настоятельная рекомендация, фактические данные низкого качества).

Таблица 7.9 Краткое описание схем АРВ-терапии первого ряда для детей в возрасте до трех лет Предпочтительные схемы Альтернативные схемы Особые обстоятельстваe ABCa или AZT + 3TC + LPV/rb ABCa или AZT + 3TC + NVPc d4Td + 3TC + LPV/r d4Td + 3TC + NVP На основании общего принципа использования нетимидиновых аналогов в схемах первого ряда и тимидиновых аналогов в схемах второго ряда назначение ABC следует, по мере возможности, считать НИОТ предпочтительными препаратами. Эта рекомендация была разработана Рабочей группой CHAIN. Следует тщательным образом продумывать вопросы, касающиеся наличия и стоимости препаратов. b Согласно рекомендациям Управления по контролю качества пищевых продуктов и лекарственных препаратов США, следует избегать назначения жидкой пероральной формы LPV/r при лечении недоношенных детей (рожденных за месяц или более до ожидаемого срока родов) не раньше, чем через 14 дней после предполагаемого срока, а в случае доношенных новорожденных – не раньше, чем в 14-дневном возрасте. Дозировки для детей моложе 6 недель следует рассчитывать на основании площади поверхности тела (Приложение 3). c На завершающем этапе разработки этих методических рекомендаций Управление по контролю качества пищевых продуктов и лекарственных препаратов США одобрило назначение EFV детям в возрасте от 3 месяцев до 3 лет с массой тела более 3,5 кг. Ввиду наличия ограниченного объема данных для обоснования оптимального режима лечения названным препаратом в этой возрастной группе члены Группы по разработке руководства согласились с тем, чтобы сохранить NVP в качестве рекомендуемого ННИОТ для детей в возрасте до 3 лет. По мере получения дополнительных данных ВОЗ подготовит дополнительные методические указания на этот счет. a

новое

138

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья Вследствие наличия ограниченного числа вариантов для детей в возрасте до 3 лет, d4T по-прежнему входит в состав группы рекомендуемых НИОТ, однако его использование должно ограничиваться ситуациями, при которых возникают подозрения или подтверждается токсичность к AZT и исключается возможность назначения ABC. Продолжительность лечения этим препаратом должна быть ограничена до минимально возможного короткого периода. Во Вставке 10.7 даны методические рекомендации, касающиеся постепенного отказа от назначения d4T. e Особыми обстоятельствами могут быть ситуации, при которых предпочтительные или альтернативные схемы могут оказаться недоступными или неподходящими из-за значительных токсических проявлений, предполагаемых лекарственных взаимодействий, проблем с закупками и организацией поставок препаратов или по другим причинами. d

Общая информация Оптимизация АРТ первого ряда у детей в возрасте до трех лет имеет важнейшее значение для достижения эффективного и быстрого подавления репликации вируса в условиях высокой вирусной нагрузки и быстрого роста ребенка. Альтернативные подходы к лечению могут потребоваться при ограниченном наличии препаратов в надлежащих лекарственных формах, долгосрочной токсичности АРВ-препаратов, сложности обеспечения соблюдения режима лечения, а также возможности ранее существовавшей резистентности вируса в результате воздействия АРВ-препаратов для ППМР. У детей младшего возраста с ВИЧ, получавших ННИОТ для ППМР, наблюдается выраженная вирусная резистентность (150), что снижает эффективность АРТ первого ряда с использованием NVP (151,152). По этой причине в руководстве ВОЗ 2010 года (105) для детей в возрасте до 24 месяцев, принимавших ранее ННИОТ, рекомендовалось использовать схему лечения на основе LPV/r. Для детей младшего возраста, не получавших ННИОТ или статус которых не известен, рекомендовалась схема на основе NVP (105). В отношении этой возрастной группы имеются новые фактические данные, которые указывают на преимущество схемы на основе LPV/r, независимо от воздействия ППМР (153,154). Были также изучены несколько стратегий для решения проблем, связанных с использованием схем на основе LPV/r или для предоставления эффективных альтернативных схем в условиях, когда применение LPV/r неосуществимо или проблематично ввиду высокой распространенности ТБ (веб-приложение www.who.int/hiv/ pub/guidelines/arv2013/annexes).

Обоснование и подтверждающие фактические данные Эта рекомендация основывается на фактических данных о преимуществе схемы на основе LPV/r для детей младшего возраста с учетом возможностей ее применения. Эффективность схемы на основе LPV/r для лечения детей грудного и раннего возраста Систематический обзор двух рандомизированных исследований (153,154) показывает, что риск прекращения лечения и вирусологической неудачи или смерти у детей в возрасте до 36 месяцев ниже, если их лечение начинается со схемы на основе LPV/r, а не NVP. Было показано, что в возрасте 24 недель LPV/r превосходил NVP, независимо от воздействия ННИОТ для ППМР (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Кроме того, данные эпиднадзора за лекарственной устойчивостью среди детей в возрасте до 18 месяцев (149,155) также указывают на поддающийся обнаружению уровень резистентности к ННИОТ даже среди детей, ранее не получавших АРВ-препараты для ППМР или статус воздействия на которых не известен, что может свидетельствовать о том, что предыдущее воздействие в рамках ППМР может не являться точным показателем для выявления детей с повышенным риском устойчивости ВИЧ к ННИОТ. Известно, что LPV/r обладает лучшим профилем резистентности, обеспечивающим защиту от селекции резистентности к НИОТ, не оказывая отрицательного влияния на использование других ИП в схемах второго ряда (156,157–159). Кроме того, потенциальным преимуществом является значительное снижение частоты случаев малярии среди детей, получающих

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

139

лечение на основе LPV/r, как показало недавно проведенное рандомизированное исследование, в котором сравнивалось использование LPV/r по сравнению с NVP или EFV среди детей в Уганде, получавших комбинацию препаратов артеметер + люмефантрин для лечения приступов малярии (160). Осуществимость назначения LPV/r в условиях ограниченности ресурсов Применение схемы лечения на основе LPV/r у детей грудного возраста и в возрасте до трех лет в некоторых местах с ограниченными ресурсами может быть сложной задачей. Существующая форма LPV/r в виде сиропа требует наличия холодовой цепи на всех этапах до пункта выдачи. Сироп имеет неприятный вкус, что может привести к несоблюдению режима лечения, о чем свидетельствуют результаты изучения ценностей и предпочтений среди работников здравоохранения. Кроме того, не известен риск метаболических осложнений среди детей, начинающих прием LPV/r на ранних этапах жизни. LPV/r также требует больших затрат, а его применение в сочетании с противотуберкулезной терапией является сложной задачей. Для решения этих проблем предлагаются альтернативные подходы. В рамках недавно проведенного рандомизированного клинического исследования (148,161) и продолжающегося рандомизированного клинического исследования (162) была проведена оценка стратегии начала лечения с использованием LPV/r с последующей заменой этого препарата на ННИОТ (NVP или EFV). Целью таких стратегий щадящего применения ИП является снижение воздействия LPV/r, упрощение подхода к продолжению лечения и использование терапии на основе ИП для АРТ второго ряда. Безопасность и эффективность этого подхода были подтверждены в ходе изучения детей с устойчивой вирусологической супрессией, достигнутой после получения терапии первого ряда на основе LPV/r, особенно при отсутствии устойчивости ВИЧ к ННИОТ до начала АРТ (148,161). Однако этот подход может также усложнить программы лечения и потребовать доступа к вирусологическому мониторингу. Таким образом, эта стратегия может быть реально применима только в местах, где имеется возможность тестирования на вирусную нагрузку и/или генотип. В условиях, где ни один из этих подходов не может быть осуществим или доступен по стоимости, эффективной альтернативой является схема на основе NVP, особенно принимая во внимание наличие двух- и трехкомпонентных комбинированных препаратов с фиксированными дозами. По данным недавно проведенного рандомизированного контролируемого исследования, хорошие вирусологические результаты (в 83% случаев вирусная нагрузка составляла менее 400 копий/мл на протяжении 3,7 лет, независимо от возраста) могут быть получены, если начинать лечение детей с ABC, 3TC и одного из ННИОТ (163). EFV не использовался в этой возрастной группе, однако в период завершения подготовки этого руководства Управление по контролю качества пищевых продуктов и лекарственных препаратов США выдало разрешение на использование этого препарата у детей в возрасте от 3 месяцев до 3 лет, масса тела которых составляет не менее 3,5 кг. Дозировки для этой группы населения приводятся в Приложении 7, а рекомендации в отношении наилучших путей использования этого препарата в качестве альтернативы для LPV/r или NVP будут представлены после получения дополнительных данных. Подбор препаратов класса НИОТ При выборе препаратов класса НИОТ следует стремиться к созданию надежной и устойчивой основы, которая обеспечивает минимальную токсичность, минимальную стоимость и максимальную осуществимость. Имеются лишь ограниченные фактические данные (164) прямых сравнительных исследований, которые можно использовать для подбора препаратов класса НИОТ (AZT или ABC) в сочетании с 3TC для трехкомпонентной схемы АРВ-терапии. Однако выбор НИОТ первого ряда влияет на АРТ второго ряда, и известно, что неудачное применение AZT приводит к накоплению мутаций резистентности к аналогам тимидина, что снижает восприимчивость к ABC или TDF в последующей схеме

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

140

лечения (если имеются две или более мутаций резистентности к аналогам тимидина). Риск того, что это произойдет, выше при использовании схемы на основе ННИОТ; использование AZT в рамках схемы на основе LPV/r, таким образом, может являться не столь проблематичным. Напротив, устойчивость ВИЧ к ABC не приводит к резистентности к аналогам тимидина и сохраняет или даже усиливает чувствительность ВИЧ к AZT и d4T для применения в схемах второго ряда (159). Хотя ABC может быть предпочтительным препаратом для обеспечения последовательной АРТ (159,165) и гармонизации со схемами для детей более старшего возраста, доступность этого препарата ограничена в условиях ограниченности ресурсов. Кроме того, стоимость ABC может являться значительным препятствием для его применения во многих странах, особенно в сочетании с LPV/r. Ожидается, что более полные данные о сравнительной эффективности ABC и AZT будут получены по результатам проводимых в настоящее время исследований (166). С 2010 года ВОЗ рекомендует постепенно прекращать использование d4T в связи с известной долгосрочной токсичностью этого препарата. Однако в условиях, когда использование AZT может быть нежелательно в связи с риском анемии (например, в эндемичных по малярии районах) и где ABC отсутствует в наличии, использование d4T остается возможным в рамках ограниченных вариантов лечения для этой возрастной группы. d4T также сохраняет важное значение при подозреваемой или подтвержденной токсичности AZT и когда не может применяться ABC. Однако продолжительность лечения этим препаратом следует, по возможности, сократить до минимума. Рекомендации по прекращению использования d4T приводятся во Вставке 10.7. При подготовке этих рекомендаций Группа по разработке руководства уделяла особое внимание следующим аспектам: в ажное значение эффективных схем первого ряда, в отношении которых имеются фактические данные о наличии лучшего вирусологического ответа, о чем свидетельствуют рандомизированные контролируемые исследования в этой возрастной группе; н еобходимость принятия мер в связи с ростом фактических данных об устойчивости ВИЧ к ННИОТ среди детей в возрасте до 18 месяцев, особенно с учетом рекомендации проводить лечение беременных женщин с помощью схем на основе EFV для ППМР; ж елательность наличия одной предпочтительной схемы для детей в возрасте до 3 лет при предоставлении альтернативных стратегий, которые остаются менее дорогостоящими, сохраняют возможности применения схем второго ряда и являются более осуществимыми; о жидание разработки новых лекарственных форм в ближайшие несколько лет (капсулы с покрытыми частицами или пакеты с порошками, содержащие LPV/r); и спользование нетимидиновых аналогов в схемах первого ряда для сохранения эффективности AZT в схемах второго ряда и для гармонизации схем для детей более старшего возраста и для взрослых, принимая во внимание наличие дополнительных расходов; в ыявление подгруппы детей, у которых можно успешно применять альтернативные стратегии, чтобы сохранить ИП для использования в АРТ второго ряда, на что указывают результаты рандомизированного исследования; и н ахождение контролируемой схемы, такой как ABC + 3TC + AZT, для использования при сопутствующей противотуберкулезной терапии, которая может обеспечивать сохранение хорошей клинической и иммунологической эффективности после вирусологической супрессии при стандартной АРТ.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

141

Клинические соображения В Разделе 10.6 (Вопросы реализации в отношении основных рекомендаций, Вставка 10.6) обсуждаются вопросы реализации, касающиеся руководителей программ. Важным вопросом, который должны принимать во внимание клинический персонал и другие работники здравоохранения, является использование LPV/r у детей младшего возраста. Если клинический персонал ожидает возникновения значительных трудностей в отношении хранения или применения LPV/r, можно рассмотреть возможность использования NVP (особенно, комбинированного препарата на основе NVP с фиксированными дозами). Кроме того, следует избегать перорального приема LPV/r в жидкой форме недоношенными младенцами или доношенными младенцами в возрасте до 14 дней (167). Дозировки для детей в возрасте до шести недель могут быть рассчитаны на основе площади поверхности тела (Приложение 3).

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

Основные пробелы в научных исследованиях Необходимо более полно изучить в условиях, выходящих за рамки клинических испытаний, какое влияние оказывают новые подходы к ППМР на характер резистентности у детей, инфицируемых ВИЧ, несмотря на прием АРВ-препаратов для ППМР. Кроме того, требуются дополнительные фактические данные для оптимального подбора НИОТ и подтверждения безопасности схем, включающих EFV в качестве варианта первого ряда или в рамках щадящих стратегий применения ИП при отсутствии возможностей тестирования на вирусную нагрузку или генотипирования. Необходимы также исследования для более полного изучения долгосрочных метаболических последствий использования схем на основе LPV/r для детей грудного и младшего возраста.

142

7.2.4 АРТ первого ряда для детей в возрасте трех лет и старше (включая подростков) Новые рекомендации новое

Д ля ВИЧ-инфицированных детей в возрасте трех лет и старше (в том числе для подростков) предпочтительным ННИОТ для лечения первого ряда является EFV, а в качестве альтернативного препарата – NVP (настоятельная рекомендация, фактические данные низкого качества). Особое примечание: При определении возможностей выбора ННИОТ для терапии первого ряда национальные программы должны учитывать характеристики дозирования EFV (один раз в сутки) и NVP (два раза в сутки), а также то, как это согласуется со схемами на основе НИОТ. Например, лучшим выбором может быть NVP, если рекомендуемой схемой является прием комбинированного препарата с фиксированными дозами два раза в сутки.

Д ля ВИЧ-инфицированных детей в возрасте трех лет и старше, но младше 10 лет (или для подростков с весом менее 35 кг) основой из двух НИОТ для схемы АРВ-терапия служить одна из приведенных ниже комбинаций в следующем предпочтительном порядке: • ABC + 3TC • AZT или TDF + 3TC (или FTC) (условная рекомендация, фактические данные низкого качества). собое примечание: Следует принимать во внимание относительные преимущества ABC по О сравнению с TDF и AZT для этой группы населения. Окончательные фактические данные для какой-либо предпочтительной рекомендации отсутствуют, и каждый из вариантов имеет свои риски и преимущества. ABC может приниматься один раз в сутки, имеется для разных возрастных групп в виде комбинированного препарата с фиксированными дозами с 3TC и сочетается с TDF с точки зрения резистентности (168). AZT широко используется и имеется в наличии в виде двух- и трехкомпонентных комбинированных препаратов с фиксированными дозами с NVP, однако принимается два раза в сутки и может вызывать тяжелую анемию. TDF недавно был разрешен к применению у детей (169), и его преимуществом является прием один раз в сутки. Однако лекарственные формы TDF для детей имеются не везде, опыт применения TDF у детей является ограниченным и существуют опасения в отношении долгосрочных последствий, связанных с токсическим воздействием на кости (170,171). В пользу принятия TDF в качестве рекомендации на национальном уровне свидетельствуют следующие соображения: в национальных программах TDF применяется для взрослых и беременных женщин, и имеются соответствующие формы комбинированных препаратов TDF с фиксированными дозами для детей.

Д ля ВИЧ-инфицированных подростков (от 10 до 19 лет включительно), весящих 35 кг или более, основа из двух НИОТ для схемы АРВ-терапия должна соответствовать схемам, применяемым для взрослых, являясь одной из приведенных ниже комбинаций в следующем предпочтительном порядке: • TDF + 3TC (или FTC) • AZT + 3TC • ABC + 3TC (настоятельная рекомендация, фактические данные низкого качества). Особое примечание: Комбинированные препараты с фиксированными дозами, содержащие TDF, в настоящее время имеются в виде таблеток без делений для взрослых для приема один раз в сутки. При массе тела 35 кг или более дозировки TDF в двух- и трехкомпонентных комбинированных препаратах с фиксированными дозами для взрослых и дозировки EFV в трехкомпонентных комбинированных препаратах с фиксированными дозами для взрослых допустимы для использования у подростков. При особых обстоятельствах допускается использование ABC или усиленных ИП.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

143

Таблица 7.10 Краткое описание рекомендуемых схем АРВ-терапии первого ряда для детей и подростков Дети в возрасте от 3 до менее 10 лет и подростки <35 кг Предпочтительная схема ABCa + 3TC + EFV ABC + 3TC + NVP AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + EFV TDF + 3TC (или FTC) + NVP d4Tb + 3TC + EFV d4Tb + 3TC + NVP Подростки (возраст от 10 до 19 лет) ≥35 кг TDF + 3TC (или FTC) + EFVa

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

Альтернативные схемы

AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + NVP ABC + 3TC + EFV ABC + 3TC + NVP

Особые обстоятельстваc a

Эти рекомендации применимы к детям и подросткам, приступающим к прохождению АРТ первого ряда. Дети и подростки, которые уже пролечиваются по ABC-содержащим схемам, вместо ABC могут без всякого риска принимать TDF, если это продиктовано программными соображениями. Детям и подросткам, которые проходят лечение по d4T-содержащим схемам без признаков неэффективной терапии, можно безопасно назначать ABC или TDF вместо d4T. Несмотря на отсутствие прямых доказательств, так же допускается возможность замены AZT на ABC или TDF, чтобы упростить и гармонизировать схемы лечения в разных возрастных группах. Включение TDF в первоначальные схемы АРВ-терапии для детей с коинфекцией ВГВ создает потенциальные преимущества с точки зрения уменьшения вероятности селекции устойчивых к 3TC штаммов ВИЧ, которые могут ограничить возможности выбора вариантов лечения ВГВ в будущем. b Использование d4T должно ограничиваться ситуациями, при которых возникают подозрения или подтверждается токсичность к AZT, а ABC или TDF оказываются недоступными. Продолжительность лечения этим препаратом должна быть ограничена до минимально возможного короткого периода. Во Вставке 10.7 даны методические рекомендации, касающиеся постепенного отказа от назначения d4T. c Особыми обстоятельствами могут быть ситуации, при которых предпочтительные или альтернативные схемы могут оказаться недоступными или неподходящими из-за значительных токсических проявлений, предполагаемых лекарственных взаимодействий, проблем с закупками и организацией поставок препаратов или по другим причинами.

Общая информация Несмотря на расширение доступа к ранней диагностике у грудных детей и широкое наличие нескольких комбинированных препаратов с фиксированными дозами для детей, уровень охвата АРТ детей значительно отстает от уровня охвата взрослых. Рекомендации в отношении лечения детей должны быть легко осуществимыми на всех уровнях системы здравоохранения, включая уровень первичной медико-санитарной помощи, всеми службами, предоставляющими услуги АРТ, а не только педиатрами. В Руководстве ВОЗ 2010 года в отношении проведения АРТ у детей в возрасте трех лет и старше (105) рекомендуется начинать со схемы, содержащей NVP или EFV, в сочетании со схемой на основе НИОТ. Рекомендуемыми схемами на основе НИОТ, в порядке их предпочтительности, являлись 3TC + AZT или 3TC + ABC или 3TC + d4T. Для подростков с ВГВ предпочтительной основной схемой являлась TDF + FTC или 3TC. Новые рекомендации в Руководстве 2013 года основаны на новых фактических данных о предпочтительных НИОТ и ННИОТ для использования в этой группе детей.

новое

Обоснование и подтверждающие фактические данные Управление по контролю качества пищевых продуктов и лекарственных средств США (172) и Европейское агентство по лекарственным средствам (173) разрешили использование TDF для детей в возрасте старше двух лет, что дает возможность использовать одну схему лечения для взрослых и детей. Гармонизация рекомендаций в отношении лечения детей со схемами для взрослых может расширить доступ детей к АРТ. К другим преимуществам

144

TDF относятся возможность комбинирования этого препарата с 3TC и EFV для создания эффективной схемы приема препаратов один раз в сутки для детей (169). Кроме того, тот факт, что устойчивость ВИЧ к TDF – в частности K65R – может усиливать антивирусный эффект AZT и может сделать TDF хорошим выбором для терапии первого ряда с точки зрения последовательного применения НИОТ в схемах первого и второго ряда (165,174–176). Однако опыт применения TDF у детей младшего возраста является ограниченным, и хотя известно, что TDF уменьшает минеральную плотность костной ткани, не ясно, является ли это воздействие постоянным и как оно может повлиять на характер развития в будущем и на риск переломов, что указывалось в исследовании ценностей и предпочтений работников здравоохранения. Кроме того, лекарственные формы TDF для детей не являются широко доступными, и в настоящее время отсутствуют TDF-содержащие комбинированные препараты с фиксированными дозами для детей. ABC обладает многими преимуществами TDF (прием один раз в сутки и положительный профиль резистентности), однако, в отличие от TDF, ABC более тщательно исследован у детей, и обычно он лучше переносится. ABC имеется также в виде комбинированных препаратов с фиксированными дозами для детей, однако его стоимость значительно выше. Кроме того, у людей с HLA-B*5701 он может вызывать гиперчувствительность с летальным исходом; хотя он очень редко встречается среди африканских детей, он может поражать до 3%– 4% детей европеоидной и азиатской рас (177). Данные систематического обзора, проведенного на основе обсервационных исследований, показывают, что профиль краткосрочной токсичности и вирусологический ответ у EFV лучше, чем у NVP (121,178). У большинства детей, получающих в настоящее время АРТ, схема лечения включает NVP, в то время как для взрослых в качестве предпочтительного ННИОТ все чаще выбирается EFV. Основная причина этого расхождения связана относительной доступностью NVP или EFV в составе комбинированных препаратов с фиксированными дозами для детей или взрослых. Для детей, состояние которых хорошо контролируется и остается стабильным при использовании схем, содержащих NVP, не требуется замена NVP на EFV, однако EFV является лучшим выбором для тех, кто начинает получать АРТ с использованием других препаратов для приема один раз в сутки. При подготовке этих рекомендаций Группа по разработке руководства обращала особое внимание на следующее: использование эффективных схем первого ряда; у добство приема один раз в сутки и использования комбинированных препаратов с фиксированными дозами в тех случаях, когда это возможно; и спользование нетимидиновых аналогов – ABC или TDF – в схемах первого ряда для максимального повышения эффективности AZT в АРТ второго ряда; и п редоставление рекомендаций в отношении лечения для детей более старшего возраста и подростков, согласованных с рекомендациями для взрослых.

Клинические соображения по расширению масштабов АРТ у детей В Разделе 10.6 (Вопросы реализации в отношении основных рекомендаций, Вставка 10.6) обсуждаются вопросы реализации, касающиеся руководителей программ. Важным вопросом, который должны принимать во внимание клинический персонал и другие работники здравоохранения, является: нужно ли вносить изменения в схемы лечения детей, клиническое состояние которых является стабильным, и как это делать. По мере того как дети взрослеют, появляются новые комбинированные препараты с фиксированными дозами и программы переходят на использование других схем первого ряда. Возможность изменения схем АРВ-терапии для людей, у которых достигнута стабилизация клинического состояния, может рассматриваться в целях упрощения проведения лечения и гармонизации используемых схем АРВ-терапии. Вопросы, касающиеся упрощения и гармонизации АРТ для детей при отсутствии неэффективного лечения в анамнезе, приводятся в Таблице 7.11.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

145

Таблица 7.11 Соображения, касающиеся упрощения и гармонизации АРТ для детей при отсутствии неэффективного лечения в анамнезеa по любой схеме Схема, содержащая: Методические указания Переключение с d4T на соответствующий возрасту НИОТ согласно схеме, рекомендованной в рамках национальной программы Вносить изменения не нужно, но стоит рассмотреть вопрос о замене LPV/r на NVP или EFV, если наблюдается устойчивый вирусологический ответ на LPV/r Отдельные достоинства нижение риска С токсичности, связанной с d4T ожет способствовать М соблюдению режима лечения за счет приема однократной суточной дозы (если выбор сделан в пользу ABC или TDF) ожет способствовать М соблюдению режима лечения за счет улучшения вкусовых качеств и использования комбинированных препаратов с фиксированными дозами в более удобных формах расфасовки (таблетки с насечками для отрыва и однократного суточного приема) нижение риска С метаболических изменений Вносить изменения не нужно, но можно рассмотреть вопрос о переходе на ABC или TDF ожет способствовать М соблюдению режима лечения за счет приема однократной суточной дозы (если в схему входит EFV) ожет снизить риск М обострения анемии Вносить изменения не нужно, но можно рассмотреть вопрос о переходе на TDF, особенно для подростков с массой тела более 35 кг Вносить изменения не нужно, но, возможно, стоит рассмотреть вопрос о переходе на EFV, особенно с 3-летнего возраста Программные преимущества риведение в П соответствие со схемами для взрослых

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

d4T

П риведение в соответствие со схемами для взрослых Р езервирование ИП для АРТ второго ряда Н ет необходимости в соблюдении требований холодовой цепи нижение стоимости С препарата риведение в П соответствие со схемами для взрослых

LPV/r

AZT

ABC

огут использоваться М комбинированные препараты с фиксированными дозами (если в схему также входит EFV) ожет способствовать М соблюдению режима лечения за счет приема однократной суточной дозы (если схема предусматривает сочетание с ABC или TDF)

П риведение в соответствие со схемами для взрослых

NVP

П риведение в соответствие со схемами для взрослых

Определяются на основании принимаемых странами критериев неудачи лечения.

146

Основные пробелы в научных исследованиях Для изучения долгосрочной эффективности и безопасности TDF, ABC и EFV, а также рекомендованных комбинаций необходимы дальнейшие исследования. Требуются дополнительные данные о воздействии TDF на костную ткань, рост и нефротоксичность у детей и подростков, особенно при недостаточности питания и задержке роста. Неблагоприятные явления, связанные с приемом EFV в подростковый период, например воздействие на центральную нервную систему, требуют изучения для обеспечения безопасной гармонизации со схемами лечения для взрослых. Системы эпиднадзора за токсичностью, созданные наряду со службами АРТ на дозорных участках, могут предоставлять данные для лучшего понимания частоты и клинической значимости случаев развития токсичности

7.2.5 Комбинированное лечение ТБ и ВИЧ-инфекции у детей ТБ является одной из наиболее распространенных оппортунистических инфекций среди детей с ВИЧ. Таким образом, важное значение имеет выбор схем, совместимых с противотуберкулезной терапией. Взаимодействие между рифампицином и LPV/r или NVP означает, что комбинированное лечение детей в возрасте до трех лет является сложной задачей, однако предварительные результаты недавно проведенного крупного рандомизированного контролируемого исследования (163) по изучению АРТ у детей свидетельствуют об эффективности трехкомпонентной нуклеозидной схемы лечения которая, несмотря на ограниченный объем данных в отношении одновременной противотуберкулезной терапии, представляет собой приемлемый вариант для детей, которые нуждаются в противотуберкулезной терапии, уже получая АРТ (Таблица 7.12). Рекомендуемые схемы лечения детей с диагнозом ТБ и начинающих получать АРТ соответствуют рекомендациям 2010 года и приводятся в Таблице 7.12, вместе с общими указаниями в отношении выбора схем комбинированного лечения ВИЧ и ТБ.

Таблица 7.12 Краткое описание рекомендуемых схем АРВ-терапии для детей, которым показано лечение ТБ Рекомендуемые схемы для детей и подростков, приступающих к АРТ на фоне лечения ТБ a b Два НИОТ + NVP таким образом, чтобы доза соответствовала 200 мг/м2 или Тройная комбинация НИОТ (AZT + 3TC + ABC)c Два НИОТ + EFV или Тройная комбинация НИОТ (AZT + 3TC + ABC)c

До 3 лет

3 года и старше

Рекомендуемая схема для детей грудного и более старшего возраста, приступающих к лечению ТБ на фоне получения АРТa Ребенок, пролечиваемый по стандартной схеме на основе ННИОТ (два НИОТ + EFV или NVP) Продолжение приема NVP таким образом, чтобы доза соответствовала 200 мг/м2 или Тройная комбинация НИОТ (AZT + 3TC + ABC)c Если ребенок уже получает EFV, то следует продолжать ту же схему Если ребенок получает NVP, то следует перейти на EFV или Тройная комбинация НИОТ (AZT + 3TC + ABC)c

До 3 лет

3 года и старше

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

147

7.2 С каких схем АРВ-терапии следует начинать (схемы АРТ первого ряда)

Рекомендуемая схема для детей грудного и более старшего возраста, приступающих к лечению ТБ на фоне получения АРТa Тройная комбинация НИОТ (AZT + 3TC + ABC)c или Вместо LPV/r следует назначить NVP таким образом, чтобы доза соответствовала 200 мг/м2 или Следует продолжать прием LPV/r; необходимо продумать вопрос о дополнительном включении RTV в схему для достижения полной терапевтической дозыd Если в анамнезе ребенка нет сведений о неэффективности лечения по схеме на основе ННИОТ: То следует произвести замену на EFV e Ребенок, пролечиваемый по стандартной схеме на основе ИП (два НИОТ + LPV/r) 3 года и старше или Тройная комбинация НИОТ (AZT + 3TC + ABC)c или Следует продолжать прием LPV/r; необходимо продумать вопрос о дополнительном включении RTV в схему для достижения полной терапевтической дозыd Если в анамнезе ребенка имеются сведения о неэффективности лечения по схеме на основе ННИОТ: Тройная комбинация НИОТ (AZT + 3TC + ABC)c или Следует продолжать прием LPV/r и продумать вопрос о дополнительном включении RTV в схему для достижения полной терапевтической дозыd Следует предусмотреть возможность консультирования с экспертами для составления схемы лечения препаратами второго ряда a

До 3 лет

Следует обеспечить оптимальное дозирование рифампицина на основании нового руководства по определению дозировок (см. веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Замена АРВ-препаратов производится на основании схемы АРВ-терапии с учетом возраста и согласно рекомендованной в масштабе страны АРТ первого ряда.

новое

Тройную комбинацию НИОТ рекомендуется назначать только на период противотуберкулезного лечения; соответствующую возрасту схему на основе ИП или ННИОТ следует возобновить по мере завершения курса лечения на основе рифампицина. Если руководствоваться результатами выборочного обследования ARROW (163), то эту схему следует считать предпочтительным вариантом для детей моложе трех лет, пролечиваемых на момент начала лечения ТБ по схеме на основе LPV/r. Управление по контролю качества пищевых продуктов и лекарственных препаратов США одобрило назначение EFV детям в возрасте от 3 месяцев до 3 лет с массой тела более 3,5 кг, что представляет собой потенциальную альтернативу принципу лечения тройной комбинацией НИОТ. Схема лечения на основе EFV детей моложе 3 лет, как и прежде, не рекомендована, так как необходимо получить данные фармакокинетики, чтобы убедиться в том, что параллельный прием рифампицина не приводит к падению концентраций препарата ниже терапевтического уровня. Тройную терапию НИОТ следует также считать предпочтительной схемой для детей старше 3 лет при неэффективном лечении по схеме на основе ННИОТ в анамнезе. Следует повышать дозировку RTV до тех пор, пока она не станет такой же, как и в случае LPV в мг в соотношении 1:1. Переключение на EFV следует рассматривать как предпочтительный вариант (179), и к приему EFV можно будет вернуться после завершения курса противотуберкулезной терапии, создавая предпосылки для упрощения и гармонизации схем лечения АРВ-препаратами, предназначенными для детей более старшего возраста.

d e

148

7.3 М ониторинг эффективности АРТ и выявление причин неудачи лечения 7.3.1 Лабораторный мониторинг до и после начала АРТ Клиническая оценка и лабораторные тесты играют важнейшую роль в оценке состояния отдельных лиц до начала АРТ и последующем мониторинге эффективности их лечения и возможной токсичности АРВ-препаратов. В Таблице 7.13 приводятся рекомендуемые лабораторные тесты для скрининга и мониторинга ВИЧ, а также подходы к проведению скрининга на коинфекции и неинфекционные заболевания.

Таблица 7.13 Рекомендуемые и желательные лабораторные исследования при диагностике ВИЧ-инфекции и мониторинге АРТ Этап ведения ВИЧ-инфекции Рекомендуемые Серологическое тестирование на ВИЧ, подсчет количества клеток CD4 Диагностика ВИЧ-инфекции Желательные (при наличии возможности) Серологическая реакция на ВГВ (HBsAg)a Серологическая реакция на ВГС Скрининг на криптококковый антиген, если количество CD4 ≤100 клеток/мм3 b Скрининг на инфекции, передающиеся половым путем Обследование на ведущие неинфекционные и сопутствующие заболеванияc

Скрининг на ТБ Динамическое наблюдение на этапе до назначения АРТ Подсчет клеток CD4 (через каждые 6–12 месяцев) Подсчет клеток CD4

Назначение АРТ

Определение уровня гемоглобина на фоне приема AZTd Тест на беременность Измерение артериального давления Анализ мочи с помощью индикаторной полоски на гликозурию и определение расчетной скорости клубочковой фильтрации (рСКФ) и сывороточного креатинина на фоне приема TDFe Определение уровня аланинаминотрансферазы на фоне приема NVP f Анализ мочи с помощью индикаторной полоски на гликозурию и определение сывороточного креатинина на фоне приема TDFc

Получение АРТ

Подсчет клеток CD4 (через каждые 6 месяцев) Анализ вирусной нагрузки вследствие ВИЧ (на 6 месяцев от начала АРТ и через каждые 12 месяцев в дальнейшем) Подсчет клеток CD4 Анализ вирусной нагрузки вследствие ВИЧ

При неудаче в лечении

Серологическая реакция на ВГВ (HBsAg)a (до перехода на другую схему АРВтерапии, если такое тестирование не проводилось или если результат был изначально отрицательным)

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

149

По мере возможности, определение HBsAg имеет целью выявление лиц с коинфекцией ВИЧ и ВГВ, которым показана АРТ по схеме, содержащей TDF. b Может проводиться в ситуациях с высоким уровнем распространенности криптококковой антигенемии (>3%) (180). c Возможно обследование на наличие хронических состояний, которые могут повлиять на тактику проведения АРТ, например на гипертензию и другие сердечно-сосудистые заболевания, диабет и ТБ. d Среди детей и взрослых с высоким риском неблагоприятных проявлений, связанных с приемом AZT (низкое количество клеток CD4 или низкий ИМТ). e Среди лиц с высоким риском неблагоприятных проявлений, связанных с приемом TDF: сопутствующее заболевание почек, принадлежность к возрастной группе, низкий ИМТ, диабет, гипертензия и параллельное использование усиленного ИП или потенциально нефротоксичных препаратов. f Среди лиц с высоким риском неблагоприятных проявлений, связанных с приемом NVP, например ранее не получавшие АРТ пациенты, ВИЧ-инфицированные женщины с количеством CD4 >250 клеток/мм3 и коинфекцией ВГС. Однако печеночные ферменты обладают низкой прогностической ценностью для мониторинга токсичности NVP. a

7.3 Мониторинг эффективности АРТ и выявление причин неудачи лечения

7.3.2 Мониторинг эффективности АРТ и выявление причин неудачи в лечении Новые рекомендации новое

В качестве предпочтительного метода мониторинга для выявления и подтверждения неудачи АРВ-лечения рекомендуется использовать вирусную нагрузку (настоятельная рекомендация, фактические данные низкого качества). Если нет возможности проводить регулярное определение вирусной нагрузки для выявления неудачи лечения следует использовать количество CD4 и клинический мониторинг (настоятельная рекомендация, фактические данные среднего качества). Особые примечания: Неудача лечения определяется как постоянно выявляемая вирусная нагрузка, превышающая 1000 копий/мл (то есть проведение двух последовательных определений вирусной нагрузки с интервалом три месяца с оказанием поддержки в соблюдении режима лечения в период между определениями) не ранее, чем через шесть месяцев после начала использования АРВ-препаратов. Вирусная нагрузка обычно определяется в плазме; однако некоторые технологии использования цельной крови в качестве исследуемого образца, такие как лабораторные исследования с использованием сухих капель капиллярной крови и тестирование по месту оказания помощи, являются ненадежными в отношении этого нижнего порогового уровня, и если используются такие методы, следует устанавливать более высокие пороговые уровни. Вирусную нагрузку следует определять вскоре после начала АРТ (через 6 месяцев) и затем не реже, чем через каждые 12 месяцев для выявления неэффективности лечения. Если нет возможности регулярно проводить тестирование на вирусную нагрузку, для определения неудачи лечения следует использовать количество CD4 и клинический мониторинг с проведением, при возможности, целенаправленного определения вирусной нагрузки для подтверждения вирусологической неудачи.

новое

Общая информация Мониторинг лиц, получающих АРТ, имеет важное значение для обеспечения успеха лечения, выявления проблем с соблюдением режима лечения и определения того, следует ли переходить на другие схемы АРВ-терапии в случае неудачи и на какие схемы переходить. До 2010 года руководства ВОЗ по АРТ рекомендовали использовать клинические результаты и количество CD4 для регулярного мониторинга эффективности действия АРВ-препаратов. Однако определение вирусной нагрузки как более чувствительного и раннего индикатора неудачи лечения получает все большее признание и является золотым стандартом для мониторинга эффективности применения АРВ-препаратов в странах с высоким уровнем дохода. В Руководстве ВОЗ 2010 года рекомендовалось, чтобы страны рассмотрели возможность постепенного введения тестирования на вирусную нагрузку для мониторинга

150

эффективности АРТ и использовали пороговый уровень вирусной нагрузки выше 5000 копий/мл у лиц, соблюдающих режим лечения и не имеющих других причин для наличия повышенной вирусной нагрузки (таких, как взаимодействие лекарственных средств, плохая всасываемость и сопутствующие заболевания). Однако большинство программ АРТ в условиях ограниченности ресурсов все еще не имеют доступа к тестированию на вирусную нагрузку и продолжают полагаться на данные клинического и иммунологического мониторинга. Это ограниченное использование мониторинга вирусной нагрузки считается одной из главных причин того, что изменение схем АРВ-терапии в условиях ограниченности ресурсов происходило реже, чем ожидалось.

Обоснование и подтверждающие фактические данные Хотя данные клинических исследований по изучению положительного влияния определения вирусной нагрузки на показатели выживаемости носят ограниченный характер, оно может служить ранним индикатором неудачи лечения, и в руководстве 2013 года настоятельно рекомендуется использовать его для выявления вирусологической неудачи и/или подтверждения неудачи в лечении людей с признаками клинической и/ или иммунологической неудачи (Таблица 7.14). Поскольку в нескольких клинических и эпидемиологических исследованиях показано, что риск передачи ВИЧ является очень низким, если вирусная нагрузка ниже 1000 копий/мл (181), Группа по разработке руководства также рекомендовала снизить пороговый уровень вирусной нагрузки для определения неудачи лечения с 5000 копий/мл до 1000 копий/мл.

Таблица 7.14 Предложенные ВОЗ определения понятий клинической, иммунологической и вирусологической неудачи лечения для принятия решения о переходе на другие схемы АРВ-терапии Неудача Определение Взрослые и подростки Новое или рецидивирующее клиническое событие, свидетельствующее о тяжелой форме иммунодефицита (состояние в клинической стадии 4 по классификации ВОЗ)a по истечении 6 месяцев эффективного лечения Дети Новое или рецидивирующее клиническое событие, свидетельствующее о тяжелой форме иммунодефицита (состояние в клинической стадии 3 или 4, за исключением ТБ, по классификации ВОЗ) по истечении 6 месяцев эффективного лечения Комментарии

Клиническая неудача

Необходимо разграничивать это состояние и воспалительный синдром восстановления иммунитетаb, который протекает на фоне проведения АРТ У взрослых определенные состояния в клинической стадии 3 по классификации ВОЗ (ТБ легких и тяжелые бактериальные инфекции) также указывают на неудачу в леченииa

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

151

7.3 Мониторинг эффективности АРТ и выявление причин неудачи лечения

Неудача

Определение Взрослые и подростки Количество клеток CD4 снижается до исходного уровня (или ниже) или Устойчивые уровни CD4 ниже 100 клеток/мм3

Комментарии Без сопутствующей или свежей инфекции возникает транзиторное снижение количества клеток CD4 Согласно данным систематизированного обзора, клинические и иммунологические критерии ВОЗ обладают низкой чувствительностью и прогностической ценностью положительного результата при выявлении лиц с иммунологической неудачей (182). Прогнозируемая величина, по-видимому, будет даже ниже при начале АРТ на более раннем этапе и неэффективном лечении с повышенным количеством клеток CD4. На данном этапе не существует предложенного альтернативного определения неудачи в лечении, равно как и выверенного альтернативного определения иммунологической неудачи Не была определена оптимальная пороговая величина для определения вирусологической неудачи и необходимости перехода на другую схему АРТ

Иммунологическая неудача

Дети Младше 5 лет Устойчивые уровни CD4 ниже 200 клеток/мм3 или <10% Старше 5 лет Устойчивые уровни CD4 ниже 100 клеток/мм3

Вирусологическая неудача

Вирусная нагрузка в плазме крови соответствует более 1000 копиям/мл по результатам двух последовательных измерений вирусной нагрузки спустя 3 месяца при оказании поддержки в соблюдении режима лечения

Человек должен проходить курс АРВ-терапии, как минимум, в течение 6 месяцев, прежде чем можно утверждать, что та или иная схема оказалась неэффективной При оценке вирусной нагрузки с использованием СККК и технологий экспрессанализа непосредственно у постели больного следует ориентироваться на более высокую пороговую величину

новое

См. Приложение 1 с перечнем клинических состояний, связанных с тяжелым течением или поздней стадией заболевания, вызванного ВИЧ. b В Разделе 6.1 обсуждается вопрос о воспалительном синдроме восстановления иммунитета. a

152

Вирусологический мониторинг (вирусная нагрузка) в сравнении с иммунологическим (CD4) и клиническим мониторингом (клиническое стадирование по классификации ВОЗ) Основным аргументом в пользу того, чтобы рекомендовать мониторинг вирусной нагрузки в качестве предпочтительного подхода по сравнению с иммунологическим и клиническим мониторингом является предоставление на ранней стадии более точной информации о неэффективности лечения и о необходимости перехода на препараты второго ряда, что снижает накопление мутаций, связанных с лекарственной устойчивостью и улучшает клинические результаты. Определение вирусной нагрузки может также помочь отличить неэффективность лечения от несоблюдения режима лечения (183) и может служить косвенным показателем риска передачи инфекции на популяционном уровне (76). Имеются лишь ограниченные данные, свидетельствующие о каких-либо дополнительных преимуществах мониторинга вирусной нагрузки по сравнению с количеством CD4 и/или клиническим мониторингом в отношении выживаемости лиц с ВИЧ, получающих АРТ. В ходе систематического обзора были выявлены три рандомизированных исследования по изучению вирусологического мониторинга в сравнении с иммунологическим и клиническим мониторингом (184–186) (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes). По сравнению с иммунологическим и/или клиническим мониторингом добавление мониторинга вирусной нагрузки не было связано со снижением смертности. В одном из этих исследований (185) не было установлено значительных различий в частоте случаев клинических неудач, переходов на схемы второго ряда и мутаций резистентности. В одном из когортных исследований с использованием моделирования среди взрослых также было установлено, что добавление вирусологического мониторинга к клиническим и/или иммунологическим критериям не приводило к различиям в показателях смертности или частоты новых СПИД-определяющих заболеваний (187). Хотя рандомизированные контролируемые исследования еще не продемонстрировали наличие преимуществ мониторинга вирусной нагрузки в плане выживаемости, продолжительность последующих наблюдений была ограниченной (менее пяти лет), в связи с чем требуется более длительное наблюдение для изучения долгосрочного воздействия на показатели выживаемости, профиль резистентности и передачу ВИЧ. В ходе систематического обзора были получены фактические данные среднего качества о том, что существующие рекомендации ВОЗ, касающиеся иммунологического и клинического мониторинга для выявления неудачных результатов лечения, обладают низкой чувствительностью и низкой прогностической ценностью для определения случаев вирусологической неудачи среди взрослых (187–200) (веб-приложение www.who.int/hiv/ pub/guidelines/arv2013/annexes). Это означает, что многие люди, у которых была выявлена вирусологическая неудача, фактически имеют адекватную вирусологическую супрессию, в связи с чем имеется риск того, что они будут неправильно классифицированы как не получающие эффективного лечения и будут неоправданно переведены на лечение второго ряда. В ходе дополнительного систематического обзора с использованием данных для детей также были получены фактические данные среднего качества о том, что иммунологические критерии (201–204) имеют низкую чувствительность и положительную прогностическую значимость для случаев вирусологической неудачи у детей. Иммунологический мониторинг в сравнении с клиническим мониторингом При отсутствии возможности проводить мониторинг вирусной нагрузки, рекомендуется клинический мониторинг и мониторинг CD4 (205). Хотя в ходе систематического обзора двух рандомизированных контролируемых исследований (184,206) были получены фактические данные среднего качества в отношении преимуществ мониторинга СВ4 и клинического мониторинга в отношении показателей смертности и заболеваемости по сравнению с рутинным клиническим мониторингом среди взрослых, получающих АРТ, основное внимание в этих исследованиях уделялось CD4 и клиническому мониторингу среди лиц,

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

153

которые начинали получать АРТ при количестве CD4 ниже 200 клеток/мм3 (веб-приложение www.who.int/hiv/pub/guidelines/arv2013/annexes). Существующие иммунологические и клинические критерии могут обладать низкой чувствительностью и специфичностью для выявления случаев неудач лечения среди людей, начинающих получать АРТ при более высоких уровнях CD4, в связи с чем необходимо установить более точные иммунологические критерии для этих людей. Рутинный мониторинг в сравнении с целенаправленным мониторингом вирусной нагрузки для выявления неудачи лечения Определение вирусной нагрузки следует проводить регулярно (каждые 6-12 месяцев) для выявления случаев неудачи лечения в более ранние сроки и более точно. В местах с ограниченным доступом к тестированию на вирусную нагрузку следует применять стратегию целенаправленного мониторинга вирусной нагрузки для подтверждения неудачи лечения, подозреваемой на основании иммунологических или клинических критериев (Таблица 7.14), чтобы избежать неоправданного перехода на АРТ второго ряда. Целенаправленный мониторинг вирусной нагрузки требует меньше затрат, чем определение вирусной нагрузки на регулярной основе, однако, как и клинический, так и иммунологический мониторинг, он может приводить к задержкам в переходе на АРТ второго ряда, что может впоследствии увеличивать риск прогрессирования заболевания, селекции резистентности к АРВ-препаратам и передачи ВИЧ. Пороговый уровень для определения вирусологической неудачи Оптимальный пороговый уровень для определения вирусологической неудачи и для изменения схем АРВ-терапии не был установлен. В качестве обоснования для порогового уровня 1000 копий/мл были использованы два источника фактических данных. Во-первых, «всплески» вирусной нагрузки или перемежающаяся виремия низкого уровня (50–1000 копий/мл) могут иметь место при эффективном лечении, но быть связаны с повышенным риском неудачи лечения, если виремия низкого уровня не носит устойчивого характера (207). Во-вторых, клинические и эпидемиологические исследования показывают, что риск передачи ВИЧ и прогрессирования заболевания является очень низким при уровне вирусной нагрузки ниже 1000 копий/мл (181,208,209). Большинство имеющихся и разрабатываемых в настоящее время платформ для определения вирусной нагрузки в крови и плазме обладают хорошей диагностической точностью при этом нижнем пороговом уровне. Однако чувствительность сухих капель капиллярной крови для определения вирусной нагрузки при использовании такого порогового уровня может быть снижена (210,211). Таким образом, программы, использующие технологию сухих капель капиллярной крови для оценки уровня вирусной нагрузки, могут рассмотреть возможность сохранения высокого порогового уровня (3000–5000 копий/мл) до тех пор, пока не будет установлена чувствительность при более низких пороговых уровнях (212–214).

7.3 Мониторинг эффективности АРТ и выявление причин неудачи лечения

154

Рис. 7.1 Стратегии определения вирусной нагрузки в целях выявления или подтверждения неудачи лечения и перехода на другую схему АРВ-терапии у взрослых, подростков и детей Целенаправленный мониторинг вирусной нагрузки (подозреваемая клиническая или иммунологическая неудача) Регулярный мониторинг вирусной нагрузки (ранее выявление вирусологической неудачи)

Анализ на вирусную нагрузку

Вирусная нагрузка >1000 копий/мл

Обследование на наличие проблем с соблюдением режима лечения

Повторный анализ на вирусную нагрузку по истечении 3–6 месяцев

Вирусная нагрузка ≤1000 копий/мл

Вирусная нагрузка >1000 копий/мл

Продолжение терапии первого ряда

Переход на терапию второго ряда

Особые соображения в отношении детей Целью данного руководства является гармонизация подходов к мониторингу для детей с подходами, рекомендованными для взрослых. По мере того как дети будут начинать АРТ в более ранние сроки и при более высоких уровнях CD4, использование мониторинга вирусной нагрузки для выявления случаев неудачи лечения и несоблюдения режима лечения будет приносить все более положительные результаты. Кроме того, определение вирусной нагрузки может способствовать осуществлению стратегий лечения для сохранения возможности использования вариантов второго ряда по мере роста детей (например, переход от LPV/r к одному из ННИОТ после стабилизации уровня вирусологической супрессии) (см. Раздел 7.2.3).

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

155

Фактические данные, полученные в рамках одного рандомизированного контролируемого исследования, проведенного в нескольких странах (включая США, европейские страны, Бразилию и Таиланд), PENPACT1 (158), показывают, что изменение схемы лечения при низких пороговых уровнях вирусной нагрузки не приводит к улучшению клинических и вирусологических результатов, но сводит к минимуму развитие лекарственной устойчивости ВИЧ, особенно в отношении НИОТ, если используется схема на основе ННИОТ. В этих условиях рекомендуется согласование с пороговыми уровнями вирусной нагрузки, рекомендованными для взрослых. Однако результаты определения вирусной нагрузки в первые шесть месяцев после начала АРТ следует интерпретировать с осторожностью, так как детям грудного и младшего возраста может потребоваться больше времени для достижения вирусологической супрессии в связи с более высоким исходным уровнем вирусной нагрузки. Рекомендация начинать АРТ для всех детей в возрасте до пяти лет независимо от клинических и иммунологических критериев означает, что определение количества клеток CD4 не требуется для начала АРТ. Однако в тех случаях, когда возможности мониторинга вирусной нагрузки ограничены или отсутствуют, мониторинг CD4 – включая определение исходного уровня и CD4 в процентном отношении для детей в возрасте до 5 лет – будет продолжать иметь важное значение для мониторинга эффективности лечения. Как и у взрослых, отсутствие возможностей определять вирусную нагрузку или CD4 не должно препятствовать назначению АРТ для детей. Результаты недавно завершенного исследования показывают, что показатели смертности и прогрессирования заболевания при клиническом мониторинге и лабораторном мониторинге сопоставимы, особенно в первый год лечения (163).

7.3 Мониторинг эффективности АРТ и выявление причин неудачи лечения

Клинические соображения по расширению масштабов определения вирусной нагрузки В Разделе 10.6 (Вопросы реализации в отношении основных рекомендаций, Вставка 10.3) обсуждаются клинические вопросы и вопросы реализации, касающиеся руководителей программ. Дополнительные вопросы реализации для клинического персонала и работников здравоохранения включают следующие. Д оступ к АРТ должен являться наиболее приоритетной задачей. Отсутствие лабораторных тестов для мониторинга эффективности лечения не должно являться препятствием для начала АРТ. У становление приоритетов. Если возможности определения вирусной нагрузки ограничены, следует обеспечить их постепенное расширение с помощью целенаправленного подхода для подтверждения эффективности лечения. Это может быть особенно важно для групп населения, получающих АРВ-препараты для сокращения числа случаев передачи ВИЧ, таких как беременные и кормящие грудью женщины, а также серодискордантные пары, для которых устойчивая супрессия вирусной нагрузки имеет важнейшее значение для обеспечения эффективности стратегии.

156

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ 7.4.1 Основополагающие принципы Н аличие возможностей лабораторного мониторинга не требуется для начала АРТ. Д ля лиц, получающих АРТ, можно использовать лабораторный мониторинг безопасности и токсичности на основании симптомов.

7.4.2 Основные типы проявления токсичности АРВ-препаратов В Руководстве ВОЗ 2010 года по АРТ рекомендовалось проводить лабораторный мониторинг безопасности и токсичности схем АРВ-терапии на основании симптомов. В то же время рекомендовалось (но не в виде обязательного требования) проведение нескольких лабораторных тестов для мониторинга токсичности АРВ-препаратов для конкретных групп высокого риска с использованием определенных препаратов. В Таблице 7.15 приводится описание основных типов токсичности и соответствующих факторов риска для основных АРВ-препаратов. Подход к мониторингу токсичности препаратов на основе симптомов требует проведения дальнейших исследований для оптимизации лечения. Необходимы дополнительные данные о том, требуется ли проведение регулярного или периодического лабораторного мониторинга в отношении конкретных типов токсичности (таких, как мониторинг функции почек при приеме TDF) для всех лиц или только при наличии повышенного риска.

Таблица 7.15 Типы проявления токсичности, связанной с действием АРВ-препаратов первого, второго и третьего ряда АРВпрепарат Основные типы токсичности Факторы риска Предлагаемая тактика ведения Если в состав АРТ первого ряда входит ABC, то вместо этого препарата следует назначить TDF или AZT или d4T Если в состав АРТ второго ряда входит ABC, то вместо этого препарата следует назначить TDF

ABC

Реакция Присутствие гена HLA-B*5701 гиперчувствительности

Отклонения от нормы на электрокардиограмме (удлинение интервала PR)

Предшествующее поражение проводящей системы Параллельный прием других препаратов, которые могут удлинять интервал PR

ATV/r

Непрямая гипербилирубинемия (клинические проявления желтухи) Почечнокаменная болезнь и риск недоношенности

LPV/r или DRV/r. Если противопоказаны усиленные ИП, а ННИОТ в составе АРТ Фоновое заболевание печени первого ряда оказались Сочетанная инфекция ВГВ и ВГС неэффективными, то следует рассмотреть вопрос Параллельный прием о назначении ингибиторов гепатотоксичных препаратов интегразы Факторы риска неизвестны

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

157

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ

АРВпрепарат

Основные типы токсичности Анемия, нейтропения, миопатия, липоартрофия или липодистрофия

Факторы риска

Предлагаемая тактика ведения

AZT

Исходная анемия или Если в состав АРТ первого ряда нейтропения входит AZT, то вместо этого Количество CD4 ≤200 клеток/мм3 препарата следует назначить TDF или ABC ИМТ >25 (или масса тела >75 кг) Если в состав АРТ второго ряда Лактоцидоз или входит AZT, то вместо этого тяжелая гепатомегалия Продолжительное экспонирование по аналогам препарата следует назначить d4T с гиперстеатозом нуклеозидов Более старший возраст Количество CD4 ≤200 клеток/мм3 Параллельный прием изониазида или ddL

d4T

Если в состав АРТ первого ряда входит d4T, то вместо этого препарата следует назначить TDF или AZT, или ABC Если в состав АРТ второго ряда ИМТ >25 (или масса тела >75 кг) входит d4T (после приема TDF Лактоцидоз или или ABC в составе АРТ первого тяжелая гепатомегалия Продолжительное ряда), то вместо него следует с гиперстеатозом, экспонирование по аналогам назначить AZT острый панкреатит нуклеозидов Периферическая нейропатия, липоартрофия или липодистрофия Если в состав АРТ второго ряда входит DRV/r, то следует Гепатотоксичность рассмотреть вопрос о его замене на ATV/r или LPV/r Если же этот препарат входит в состав АРТ третьего ряда, то Тяжелые кожные Аллергия на имеется только ограниченное реакции и реакции сульфаниламидные препараты число вариантов гиперчувствительности Непрерывное токсическое действие на Депрессия или другое центральную нервную психическое расстройство (в предшествующем периоде или систему (например, на начальном этапе лечения) патологические сны, депрессия или Дневная дозировка спутанность сознания) Фоновое заболевание печени – сочетанная инфекция ВГВ и ВГС Гепатотоксичность Параллельный прием NVP. Если у человека гепатотоксичного препарата непереносимость к обоим Конвульсии Судороги в анамнезе ННИОТ, следует назначить усиленные ИП Реакция гиперчувствительности, синдром СтивенсаДжонсона Потенциальный риск врожденных дефектов Факторы риска неизвестны нервной трубки (очень низкий риск у человека) (122,140) Гинекомастия у мужчин Тяжелые кожные Имеется ограниченное число реакции и реакции Неизвестно вариантов гиперчувствительности Фоновое заболевание печени Сочетанная инфекция ВГВ и ВГС Параллельный прием гепатотоксичных препаратов

DRV/r

новое

EFV

ETV

158

Таблица 7.15 (продолжение) АРВпрепарат Основные типы токсичности Факторы риска Лица с предшествующим поражением проводящей системы Предлагаемая тактика ведения

Отклонения от нормы на электрокардиограмме (удлинение интервалов PR Параллельный прием других препаратов, и QT, торсады) которые могут обусловить удлинение интервала PR Врожденный синдром длинного интервала QT Гипокалиемия Удлинение интервала QT Параллельный прием препаратов, которые могут обусловить удлинение интервала QT Фоновое заболевание печени Гепатотоксичность Сочетанная инфекция ВГВ и ВГС Параллельный прием гепатотоксичных препаратов Панкреатит Поздняя стадия заболевания, вызванного ВИЧ

Если в состав АРТ первого ряда у детей входит LPV/r, следует назначать соответствующие возрасту ННИОТ (NVP детям моложе 3 лет и EFV детям от 3 лет и старше). ATV можно назначать детям старше 6 лет Если в состав АРТ второго ряда у взрослых входит LPV/r, то следует назначать ATV/r или DRV/r. Если усиленные ИП противопоказаны и человека постигла неудача при лечении ННИОТ в составе АРТ первого ряда, то следует рассмотреть вопрос о назначении ингибиторов интегразы

LPV/r

Риск недоношенности, липоартрофия или метаболический синдром, Факторы риска неизвестны дислипидемия или тяжелая диарея Фоновое заболевание печени Сочетанная инфекция ВГВ и ВГС Параллельный прием гепатотоксичных препаратов Гепатотоксичность NVP Количество CD4 >250 клеток/мм3 у женщин Количество CD4 >400 клеток/мм3 у мужчин Первый месяц прохождения лечения (если не используется начальная доза) Тяжелая кожная реакция и реакция Факторы риска неизвестны гиперчувствительности (синдром Стивенса-Джонсона) EFV. Если у человека непереносимость к обоим ННИОТ, следует назначить усиленные ИП

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

159

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ

АРВпрепарат

Основные типы токсичности

Факторы риска

Предлагаемая тактика ведения

RAL

Параллельный прием других препаратов, которые Имеется ограниченное число Острый некроз скелетных повышают риск миопатии и вариантов мышц, миопатия, миалгия острого некроза скелетных мышц Фоновое заболевание почек Более старший возраст ИМТ <18.5 (или масса тела <50 кг) Дисфункция почечных канальцев, синдром Фанкони Непролеченный сахарный диабет Непролеченная гипертензия Если в состав АРТ первого ряда входит TDF, то вместо этого препарата следует назначить AZT или d4T, или ABC

TDF (169) Снижение минеральной плотности костной ткани

Параллельный прием нефротоксичных препаратов или усиленного Если в состав АРТ второго ряда ИП входит TDF (после приема d4T + AZT в составе АРТ первого Остеомаляция и патологический перелом в ряда), то его следует заменить на ABC или ddL анамнезе Факторы риска по остеопорозу или потере костной массы Продолжительное воздействие аналогов нуклеозидов Ожирение

Лактоцидоз или тяжелая гепатомегалия с гиперстеатозом

Обострение гепатита B (реактивация Отмена TDF из-за его воспалительного процесса токсичности в печени)

Следует назначить альтернативный препарат для лечения гепатита B (например, энтекавир)

7.4.3 Мониторинг токсичности TDF Нефротоксичность TDF характеризуется нарушением функции клеток проксимальных почечных канальцев, которое может быть связано с острой почечной недостаточностью или хронической болезнью почек (130). По данным систематического обзора (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes) ни в одном из исследований не сравнивались надлежащим образом стратегии мониторинга для лиц, получающих TDF, такие как регулярный мониторинг токсичности по сравнению с оказанием помощи без мониторинга или с несистематическим мониторингом в случае наличия предполагаемой необходимости по клиническим показаниям. Результаты одного клинического исследования (исследование DART), в котором проводилось сравнение клинического и лабораторного мониторинга, показали, что у лиц, получающих TDF, выше риск снижения расчетной скорости клубочковой фильтрации, однако риск развития почечной недостаточности при медиане периода наблюдения пять лет (фактические данные низкого качества) не увеличивается.

160

В нескольких обсервационных когортных исследованиях сообщалось, что прием TDF был связан с повышенным риском хронической болезни почек. Однако период воздействия TDF во всех трех исследованиях считался слишком коротким для того, чтобы указывать на усиление долгосрочного риска почечной недостаточности, переломов костей или изменений в распределении жировой клетчатки. Необходимо провести оценку наилучшего параметра для мониторинга нефротоксичности, связанной с TDF; в то же время проведение лабораторного мониторинга с использованием креатининовой пробы не является обязательным для назначения лечения с применением TDF. Лицам с повышенным риском (людям пожилого возраста или страдающим болезнью почек, длительным диабетом или неконтролируемой гипертонией одновременно с приемом усиленного ИП или нефротоксичных препаратов) все же рекомендуется выявлять наличие почечной недостаточности и ограничивать ее дальнейшее прогрессирование. Высокая частота случаев глюкозурии была также обнаружена у лиц без диабета, которым была проведена биопсия для выявления нефротоксичности TDF с повышенным уровнем креатинина в сыворотке, по сравнению с принимающими TDF лицами с нормальной скоростью клубочковой фильтрации, позволяя предполагать, что анализ на гликозурию с помощью индикаторной полоски может являться экономически эффективным скрининговым тестом на наличие серьезных повреждений почек, вызванных TDF (215). Снижение минеральной плотности костной ткани, связанное с приемом TDF, наблюдалось у детей, хотя неясно, как снижение минеральной плотности костной ткани может повлиять на структуру роста в будущем или на риск переломов костей. Кроме того, необходимо определить точный и практически осуществимый метод измерения минеральной плотности костной ткани, при этом сохраняется значительная неопределенность в отношении наилучшего метода мониторинга костной токсичности, связанной с приемом TDF, у детей. Проведение двухэнергетической рентгеновской абсорбциометрии в большинстве мест не представляется возможным, однако рекомендуется осуществлять тщательный мониторинг роста детей при получении ими лечения TDF (169).

Клинические соображения П роведение лабораторного мониторинга не является обязательным требованием при назначении лечения TDF. Р егулярный контроль артериального давления можно проводить для оценки состояния в отношении гипертонии. А нализ мочи с помощью индикаторной полоски можно использовать для выявления гликозурии или тяжелой нефротоксичности TDF у лиц без диабета, принимающих схемы лечения, содержащие TDF. Е сли имеется возможность регулярного проведения креатининовой пробы, до начала приема схем с содержанием TDF следует определить расчетную скорость клубочковой фильтрацииa исходного уровня. Н е следует начинать прием TDF, если расчетная скорость клубочковой фильтрации ниже 50 мл/ мин, при длительном диабете, неконтролируемой гипертонии и почечной недостаточности. У детей, принимающих TDF, следует осуществлять мониторинг роста.

Для оценки следует использовать формулы Кокрофта-Голта (CG) или модификации диеты при почечной болезни (MDRD). Онлайновый калькулятор имеется на веб-сайте http://nephron.com/cgi-bin/CGSI.cgi.

Формула CG: рСКФ = (140 – возраст) X (вес в кг) X 0,85 (для женщин)/(72 X креатинин в мг%). Формула MDRD: рСКФ = 175 X сывороточный креатинин–1,154 X возраст– 0,203 X 1,212 (для пациентов черной расы) X 0,742 (для женщин).

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

161

Основные пробелы в научных исследованиях Требуются дополнительные данные о том, как лучше всего осуществлять мониторинг функции почек у людей, получающих схемы лечения, содержащие TDF (должен ли мониторинг токсичности в группах повышенного риска быть регулярным или целенаправленным при приеме альтернативных препаратов людьми с повышенным риском). Кроме того, необходимы дополнительные данные для того, чтобы понять частоту и клиническую значимость снижения минеральной плотности костной ткани у детей. Для этой группы населения следует определить более точные и доступные по стоимости методы мониторинга остеотоксичности.

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ

7.4.4 Мониторинг токсичности других АРВ-препаратов AZT Прием AZT связан с риском гематологической токсичности, в связи с чем перед началом АРТ рекомендуется измерять уровень гемоглобина, особенно у взрослых и детей с низкой массой тела, низким количеством CD4 и поздней стадией заболевания, вызванного ВИЧ. Лицам с ВИЧ и тяжелой анемией при оценке исходного состояния (уровень гемоглобина ниже 7,0 г/дл) следует избегать приема AZT в качестве терапии первого ряда.

NVP Лабораторные измерения показателей активности ферментов печени имеют очень низкую прогностическую ценность в отношении схем, содержащих NVP. Однако, при наличии возможности, рекомендуется проводить мониторинг ферментов печени, особенно у женщин с ВИЧ, у которых количество клеток CD4 превышает 250 клеток/мм3, а также у людей с ВИЧ, коинфицированных ВГВ или ВГС. Более подробная информация о безопасности применения NVP у лиц с высокими показателями CD4 приводится в Разделе 7.2.1.

EFV Основным типом токсичности EFV являются побочные эффекты, оказывающие воздействие на центральную нервную систему, которые обычно проходят через несколько недель. Однако в некоторых случаях они могут сохраняться на протяжении нескольких месяцев или постоянно. Несмотря на опасения в отношении потенциального риска тератогенности, связанной с приемом EFV во время беременности, в рамках недавно проведенного метаанализа не было выявлено общего увеличения частоты случаев врожденных пороков при приеме EFV в первый триместр беременности по сравнению с другими АРВ-препаратами (122). Более подробная информация о безопасности приема EFV беременными женщинами приводится в Разделе 7.3.2.

7.4.5 Замена одних препаратов другими при лекарственной токсичности АРТ В случае лекарственной токсичности и в целях недопущения взаимодействия лекарственных препаратов может потребоваться смена схемы лекарственного лечения или одного препарата. Рекомендации в отношении мониторинга определенных типов токсичности АРВ-препаратов приводится в Разделах 7.4.3 и 7.4.4.

Клинические соображения З атягивание сроков замены или перехода на другие препараты при наличии серьезных побочных эффектов может нанести вред и отрицательно повлиять на соблюдение режима лечения, что приводит к развитию лекарственной устойчивости и неэффективности лечения.

162

Е сли необходимо прервать прием препаратов, например при серьезных и угрожающих жизни побочных эффектах, связанных с токсичностью, важно принимать во внимание разные периоды полувыведения АРВ-препаратов. Например, если требуется прекратить прием препарата ННИОТ, следует использовать поэтапный подход путем продления использования схемы лечения на основе НИОТ на две или три недели. В качестве альтернативного варианта ННИОТ можно временно заменить усиленным ИП.

7.4.6 Основные взаимодействия АРВ-препаратов Провайдеры медицинских услуг должны быть знакомы со всеми препаратами, которые принимают люди с ВИЧ, при назначении АРТ, а также с новыми препаратами, которые назначаются дополнительно при проведении лечения. Имеется несколько основных областей взаимодействий препаратов (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes). В руководстве ВОЗ по лечению ТБ рассматриваются основные вопросы, касающиеся ведения случаев коинфицирования ТБ и ВИЧ (216). Основной противопоказанной комбинацией лекарственных средств является рифампицин и ИП. Если люди, коинфицированные ТБ и ВИЧ, получают усиленный ИП, может потребоваться замена рифампицина на рифабутин. Если рифабутин отсутствует в наличии, на протяжении лечения ТБ можно использовать LPV/r и SQV/r в случае увеличения усиленной дозы RTV или удвоения стандартной дозы LPV/r (см. Раздел 7.6.1). Для детей следует также рассмотреть возможность использования трехкомпонентной схемы НИОТ (такой, как AZT + 3TC + ABC). В лечении ВГС часто используются рибавирин и пегинтерферон альфа-2а. Прием этих препаратов вместе с AZT часто связан с повышенным риском развития анемии и печеночной декомпенсации. Людям, коинфицированным ВГС и ВИЧ и получающим AZT, может потребоваться перейти на TDF. Для лечения грибковых инфекций часто используются итраконазол и кетоконазол. Исследования показали, что NVP может снижать концентрации этих противогрибковых препаратов до субтерапевтических уровней. Для обеспечения адекватного лечения грибковых инфекций у людей с ВИЧ могут использоваться альтернативные противогрибковые препараты (такие, как флуконазол). Для лечения неосложненной малярии, вызванной Plasmodium falciparum, ВОЗ рекомендует комбинированную терапию на основе артемизинина (217). Одним из вариантов комбинированной терапии на основе артемизинина является артесунат и амодиахин. EFV повышает концентрации амодиахина, и его прием связан со значительным увеличением уровня печеночных трансаминаз. Для предупреждения случаев тяжелой токсичности у людей с ВИЧ можно использовать альтернативные схемы комбинированной терапии на основе артемизинина (такие, как артеметер плюс люмефантрин, артесунат плюс мефлохин или артесунат плюс сульфадоксин-пириметамин). Для лечения опиоидной зависимости ВОЗ рекомендует метадон и бупренорфин (218). Одновременный прием EFV снижает концентрации метадона. Впоследствии это может привести к развитию синдрома отмены и повысить риск возврата к употреблению опиоидов. Следует осуществлять тщательный мониторинг в отношении людей, получающих метадон и EFV, и может потребоваться корректировка дозы метадона для тех, кто испытывает синдром отмены опиоидов. АРВ-препараты могут либо снижать, либо усиливать биодоступность стероидных гормонов в гормональных контрацептивах (219). Имеется ограниченный объем данных, указывающих на возможность лекарственных взаимодействий между многими АРВ-препаратами (особенно некоторыми ННИОТ и ИП, усиленными RTV) и гормональными контрацептивами на основе эстрогенов. Эти взаимодействия могут изменять безопасность и эффективность

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

163

как гормональных контрацептивов, так и АРВ-препаратов. Если женщины, получающие АРТ, принимают решение начать и продолжать использование гормональных контрацептивов, рекомендуется постоянно использовать презервативы и другие методы контрацепции как для профилактики передачи ВИЧ, так и для компенсирования возможного снижения эффективности гормональной контрацепции. Одновременное использование усиленных ИП и ННИОТ с некоторыми антигистаминными препаратами (такими, как астемизол и терфенадин) связано с тяжелыми и угрожающими жизни реакциями, например сердечной аритмией. К альтернативным антигистаминным препаратам относятся лоратидин и цетиризин. ВОЗ рекомендует прием статинов людьми, у которых десятилетний сердечно-сосудистый риск превышает 30% (220). Прием усиленных ИП может увеличивать концентрации ловастатина и симвастатина. Повышенные концентрации могут усиливать риск развития серьезных побочных эффектов, таких как миопатия (включая рабдомиолиз). Для предупреждения тяжелой токсичности у людей с ВИЧ следует использовать альтернативные препараты, применяемые при гиперлипидемии.

7.4 Мониторинг и замена одних препаратов другими при лекарственной токсичности АРТ

Таблица 7.16 Основные взаимодействия АРВ-препаратов и предлагаемая тактика ведения таких случаевa АРВпрепарат AZT Основные взаимодействия Рибавирин и пегилированный интерферон альфа-2а Рифампицин Ловастатин и симвастатин Усиленные ИП (ATV/r, LPV/r) Гормональная контрацепция на основе эстрогена Метадон и бупренорфин Астемизол и терфенадин TDF Амодиахин Метадон EFV Гормональная контрацепция на основе эстрогена Астемизол и терфенадин Рифампицин NVP a

Предлагаемая тактика ведения Схема первого ряда: вместо AZT следует назначить TDF Схема второго ряда: вместо AZT следует назначить d4T Вместо рифампицина следует назначить рифабутин Следует правильно подобрать дозу ИП или перейти на три НИОТ Следует назначить альтернативный препарат для лечения дислипидемии (например, правастатин) Следует воспользоваться альтернативными или дополнительными методами контрацепции В зависимости от ситуации следует правильно подобрать дозы метадона и бупренорфина Следует назначить альтернативное антигистаминное средство Следует мониторировать почечную функцию Следует назначить альтернативное антималярийное средство В зависимости от ситуации следует правильно подобрать дозу метадона Следует воспользоваться альтернативными или дополнительными методами контрацепции Следует назначить альтернативное антигистаминное средство Вместо NVP следует назначить EFV Следует назначить альтернативное противогрибковое средство (например, флуконазол)

Итраконакол и кетоконазол

Эта таблица была составлена с использованием схем лекарственных взаимодействий, которые были разработаны Ливерпульским университетом и с которыми можно ознакомиться в онлайновом режиме на сайте www.hiv-druginteractions.org. Более всеобъемлющая таблица взаимодействий АРВ-препаратов представлена в виде отдельного веб-приложения (www.who.int/hiv/pub/guidelines/arv2013/annexes).

164

Вставка 7.2 Эпиднадзор за проявлениями токсичности АРВ-препаратов ВОЗ поручила проведение систематических обзоров в отношении конкретных типов токсичности, связанной с основными АРВ-препаратами, а также стратегий лабораторного мониторинга для обобщения и обновления методических рекомендаций (140,169). Результаты этих обзоров указывают на сохраняющиеся пробелы в фактических данных относительно возможного усиления риска токсичности, связанного с длительным приемом АРВ-препаратов, использованием АРВ-препаратов во время беременности и грудного вскармливания, детьми, подростками и группами населения с соответствующими факторами риска, а также в отношении лабораторного мониторинга для выявления токсичности. Имеющиеся фактические данные ограничиваются исследованиями, проведенными в рамках ограниченной выборки или небольшой продолжительности. Важное значение имеет мониторинг использования АРВ-препаратов в странах с ограниченными ресурсами, где проявления токсичности могут принимать иной характер в связи с экологическими или поведенческими факторами, распространенностью других заболеваний и использованием АРВ-препаратов в сочетании с другими лекарственными средствами. Осуществление эпиднадзора за проявлениями токсичности даст возможность получить фактические данные о конкретных типах токсичности, повысить уровень доверия к приему препаратов, выявить группы населения с факторами риска и разработать планы профилактических стратегий. Группа по разработке руководства предложила ВОЗ усилить деятельность по эпиднадзору за проявлениями токсичности в основных областях. К этим областям относятся возможное усиление риска токсичности, связанной с длительным использованием АРВ-препаратов, нефротоксичность и остеотоксичность, связанные с использованием TDF у взрослых и детей, безопасность использования схем, содержащих EFV и TDF, во время беременности и грудного вскармливания, а также использование TDF среди детей, подростков и групп населения с соответствующими факторами риска. Еще одной важной областью исследований является разработка лабораторных показателей для мониторинга функции почек у лиц, принимающих TDF. При поддержке ВОЗ было уже начато проведение нескольких мероприятий по эпиднадзору за проявлениями токсичности, используя стандартизированные подходы на дозорных участках в условиях ограниченности ресурсов. В Кот-д’Ивуаре в настоящее время проводится систематический эпиднадзор для мониторинга нефротоксичности, связанной с TDF в схемах первого и второго ряда, с проведением оценки потребностей в лабораторном мониторинге на трех дозорных участках. Аналогичный подход осуществляется в настоящее время во Вьетнаме для оценки нефротоксичности, связанной с приемом TDF, а также токсического воздействия на центральную нервную систему, связанную с приемом EFV, у людей, использующих АРВ-препараты для профилактики ВИЧ-инфицирования, таких как серодискордантные пары. В Лаосской Народно-Демократической Республике осуществляется мониторинг за анемией, связанной с AZT, и гиперчувствительностью, связанной с NVP, используя подход целенаправленного и систематического эпиднадзора. В Малави в рамках программы эпиднадзора будет осуществляться мониторинг роста детей, а также вестись наблюдение за матерями, кормящими грудью и получающими TDF. При наличии возможностей, для оценки безопасности АРВ-препаратов и других лекарственных средств при беременности, а также факторов риска неблагоприятных исходов беременности, включая последствия для здоровья матери, преждевременные роды, мертворождения, низкую массу тела при рождении

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

165

7.5 На какую схему АРВ-терапии следует переходить (АРТ второго ряда)

и пороки развития, рекомендуется создание регистра беременных, включая программу эпиднадзора за врожденными пороками. ВОЗ, Чрезвычайный план Президента США для оказания помощи в связи со СПИДом, Центры США по контролю и профилактике заболеваний и Национальные институты здравоохранения США поддерживают создание регистров беременных, получающих АРВ-препараты, а также проведение эпиднадзора за врожденными пороками на дозорных участках в Малави, Южной Африке и Уганде для крупномасштабной оценки использования схем, содержащих EFV, беременными женщинами. Эпиднадзор за проявлениями токсичности АРВ-препаратов будет способствовать лучшему пониманию долгосрочных рисков, связанных с токсичностью АРТ, и оптимизации применения АРВ-препаратов для лечения и профилактики ВИЧ во всех группах населения.

7.5 На какую схему АРВ-терапии следует переходить (АРТ второго ряда) Использование комбинации усиленного ИП + двух НИОТ рекомендуется в качестве предпочтительной стратегии АРТ второго ряда для взрослых, подростков, а также для детей, если в АРТ первого ряда использовались схемы, содержащие ННИОТ. Для детей, получающих АРТ первого ряда с использованием схемы на основе ИП, рекомендуется переход на ННИОТ или продолжение использования схемы на основе ИП, в зависимости от возраста (Таблица 7.17).

Таблица 7.17 Краткое описание предпочтительных схем АРВ-терапии для взрослых, подростков, беременных женщин и детей АРТ второго ряда Взрослые и подростки (в возрасте ≥10 лет), включая беременных и кормящих грудью женщин Если использовалась схема первого ряда, в состав которой входили ННИОТ Если Дети использовалась схема первого ряда, в состав которой входил ИП a

Предпочтительные схемы AZT + 3TC + LPV/r a AZT + 3TC + ATV/r a

Альтернативные схемы TDF + 3TC (или FTC) + ATV/r TDF + 3TC (или FTC) + LPV/r ABC + 3TC + LPV/rb TDF + 3TC (или FTC) + LPV/rb

ABC + 3TC + LPV/rb Никаких изменений в используемой схеме первого рядаc AZT (или ABC) + 3TC + EFV

<3 лет от 3 лет до моложе 10 лет

AZT (или ABC) + 3TC + NVP

ABC (или TDF) + 3TC + NVP

В особых ситуациях DRV/r может использоваться как альтернативный ИП и SQV/r; в настоящее время ни один из этих препаратов не является доступным в виде термостабильного комбинированного препарата с фиксированными дозами, однако в настоящее время разрабатывается термостабильный комбинированный препарат с фиксированными дозами DRV + RTV. Детям старше шести лет допускается назначение ATV/r в качестве альтернативы LPV/r.

b c

За исключением случаев, когда неудача лечения объясняется недостаточно строгим соблюдением предписанного режима из-за неприятных вкусовых ощущений при приеме LPV/r.

166

7.5.1 АРТ второго ряда для взрослых и подростков Новые рекомендации новое

РТ второго ряда для взрослых должна включать два нуклеозидных ингибитора А обратной транскриптазы (НИОТ) + ингибитор протеазы (ИП), усиленный ритонавиром. • Рекомендуется следующая последовательность выбора НИОТ для второго ряда: • П осле неудачного использования схемы первого ряда на основе TDF + 3TC (или FTC) в качестве основы из двух НИОТ в схемах второго ряда следует использовать AZT + 3TC. • П осле неудачного использования схемы первого ряда на основе AZT или d4T + 3TC в качестве основы из двух НИОТ в схемах второго ряда следует использовать TDF + 3TC (или FTC). • В качестве предпочтительного подхода рекомендуется использовать основу из двух НИОТ в виде комбинированного препарата с фиксированными дозами (настоятельная рекомендация, фактические данные среднего качества). редпочтительными вариантами усиленного ИП для АРТ второго ряда являются П термостабильные комбинации ATV/r и LPV/r (настоятельная рекомендация, фактические данные среднего качества).

Таблица 7.18 Краткое описание предпочтительных схем АРВ-терапии второго ряда для взрослых и подростков Целевая группа населения Взрослые и подростки (≥10 лет) Беременные женщины Предпочтительная схема второго рядаa Если в состав АРТ первого ряда входил d4T или AZT Если в состав АРТ первого ряда входил TDF

TDF + 3TC (или FTC) + ATV/r или LPV/r AZT + 3TC + ATV/r или LPV/r

Для взрослых и подростков рекомендованы одинаковые схемы лечения Если доступен рифабутин Стандартные ИП-содержащие схемы в соответствии с рекомендациями для взрослых и подростков Те же основные препараты класса НИОТ в соответствии с рекомендациями для взрослых и подростков плюс двойная доза LPV/r (то есть LPV/r 800 мг/200 мг два раза в день) или стандартная доза LPV наряду с правильно подобранной дозой RTV (то есть LPV/r 400 мг/400 мг два раза в день)

Коинфекция ВИЧ и ТБ

Если рифабутин не доступен

Коинфекция ВИЧ и ВГВ a

AZT + TDF + 3TC (или FTC) + (ATV/r или LPV/r)

качестве запасных вариантов выбора НИОТ можно назначить ABC или ddI, но при этом усложняется вся схема В и повышается стоимость лечения без очевидных клинических преимуществ. В особых ситуациях DRV/r может использоваться как альтернативный ИП и SQV/r, однако ни один из этих препаратов не является доступным в виде термостабильного комбинированного препарата с фиксированными дозами, хотя в настоящее время разрабатывается термостабильный комбинированный препарат с фиксированными дозами DRV + RTV.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

167

Общая информация В Руководстве ВОЗ 2010 года рекомендовалось включать в схемы лечения второго ряда для взрослых усиленный ИП плюс два НИОТ (в зависимости от препаратов, использованных при лечении первого ряда). В этом руководстве придавалось большое значение использованию более простых схем второго уровня, в идеале термостабильных лекарственных форм и комбинированных препаратов с фиксированными дозами (по возможности, для приема один раз в сутки). За исключением рекомендаций для людей с ВИЧ и ТБ, рекомендации 2013 года не отличаются от рекомендаций 2010 года.

7.5 На какую схему АРВ-терапии следует переходить (АРТ второго ряда)

Обоснование и подтверждающие фактические данные Варианты ИП для АРТ второго ряда Поскольку желательно, чтобы АРТ первого ряда была основана на ННИОТ, для терапии второго ряда рекомендуются схемы, основанные на ИП. Из всех вариантов ИП предпочтительными являются ATV/r и LPV/r. Альтернативным вариантом является DRV/r, однако в настоящее время он отсутствует в виде комбинированного препарата с фиксированными дозами, хотя один такой препарат находится в стадии разработки. Другие ИП (FPV/r, IDV/r и SQV/r) отсутствуют в виде термостабильных комбинированных препаратов с фиксированными дозами и/или их прием связан с большим количеством принимаемых таблеток или высокой частотой побочных эффектов. Группа по разработке руководства особо подчеркнула важное значение упрощения АРТ второго ряда путем сокращения количества принимаемых таблеток и ограничения числа предпочтительных схем второго ряда, которые могут быть использованы в разных группах населения (взрослые, подростки, дети, беременные женщины и лица, коинфицированные ТБ, ВГВ и ВГС). Использованию менее токсичных, более удобных и более эффективных термостабильных комбинированных препаратов с фиксированными дозами также придавалось важное значение. По результатам систематического обзора (веб-приложение www.who.int/hiv/pub/guidelines/ arv2013/annexes) данных шести клинических исследований, в которых сравнивались препараты, используемые для АРТ второго ряда (ATV/r, LPV/r и DRV/r), был сделан вывод об отсутствии фактических данных для изменения рекомендаций, содержащихся в руководстве 2010 года (221–226). Эти исследования указывают на наличие фактических данных низкого или очень низкого качества (переведенных в более низкую категорию по классификации GRADE, в основном, по причине косвенного характера и неточности) в отношении использования ATV/r или DRV/r (один раз в сутки) вместо LPV/r (два раза в сутки) или наоборот в качестве предпочтительных вариантов усиленных ИП. В одном исследовании среди лиц, получающих АРТ, ATV/r считался сопоставимым с LPV/r (221). В исследовании среди лиц, ранее не проходивших АРТ, вирусологический ответ и показатели удержания пациентов у ATV/r были лучше, чем у LPV/r (224). В двух исследованиях у лиц, получавших схемы лечения, включающие DRV/r, вирусологический ответ и показатели удержания пациентов также были лучше, чем у получавших LPV/r, как в группах лиц, ранее не проходивших АРТ, так и проходивших АРТ ранее (222,226). DRV/r использовался для терапии второго ряда в странах с высоким уровнем дохода. Однако два важных фактора в настоящее время препятствуют использованию DRV/r в качестве предпочтительного варианта в настоящем руководстве. Этими факторами являются высокая стоимость и отсутствие термостабильного комбинированного препарата с фиксированными дозами. Необходимы дополнительные исследования для обеспечения лучшего понимания стратегии последовательного использования ИП в терапии второго и третьего ряда. Дополнительным аргументом в пользу сохранения обоих ИП в качестве равноправных вариантов являются разные профили

новое

168

лекарственной токсичности ATV/r и LPV/r, противопоказания к использованию ATV/r и рифампицина, а также отсутствие одобрения ВОЗ в отношении его использования у детей в возрасте до шести лет (Таблица 7.19). Группа по разработке руководства рекомендовала использовать DRV/r в качестве предпочтительного препарата третьего ряда. Однако можно рассмотреть возможность его использования в качестве альтернативы LPV/r или ATV/r для терапии второго ряда, особенно при наличии комбинированных препаратов с фиксированными дозами по конкурентоспособным ценам.

Основа ННИОТ Группа по разработке руководства подтвердила обоснованность принятой в 2010 году рекомендации в отношении последовательного использования препаратов в соответствии с принципами оптимизации АРТ (в частности, наличием комбинированных препаратов с фиксированными дозами и переносимостью), а также с учетом риска мутаций резистентности, на основании НИОТ, применявшихся в схеме первого ряда. Если в рамках неэффективной схемы первого ряда использовался один из тимидиновых аналогов НИОТ (AZT или d4T), в схеме второго ряда следует использовать TDF. Если в схеме первого ряда использовался нетимидиновый аналог (то есть TDF), в АРТ второго ряда следует использовать AZT. Другие препараты НИОТ, такие как ABC и ddI, являются допустимыми в качестве резервных вариантов при особых обстоятельствах, однако они не рекомендуются в качестве предпочтительных альтернативных вариантов, так как не обладают конкретными преимуществами, и при этом усложняется вся схема и повышается стоимость лечения. Для лиц, коинфицированных ВИЧ и ВГВ, схема лечения которых первого ряда содержала TDF + 3TC (или FTC), следует продолжать использовать эти НИОТ в схемах второго ряда для подавления ВГВ и снижения риска реактивация воспалительного процесса в печени, независимо от выбранной схемы второго ряда, которой должна быть AZT + TDF + 3TC (или FTC) + усиленный ИП. Для людей с активной формой ТБ, получающих рифампицин, все усиленные ИП в стандартных дозах противопоказаны в связи с лекарственными взаимодействиями и значительным снижением концентраций ИП в плазме (227–230). В этой ситуации могут использоваться LPV/r и SQV/r со скорректированной суперусиленной дозой RTV (LPV/r 400 мг/400 мг два раза в сутки или SQV/r 400 мг/400 мг два раза в сутки) или удвоением суточной дозы LPV/r (LPV/r 800 мг/200 мг два раза в сутки), однако это связано с более высокими уровнями токсичности и требует проведения тщательного клинического и лабораторного мониторинга. Рекомендация использовать LPV/r 800 мг/ 200 мг два раза в сутки основана на фактических данных, классифицированных как имеющих низкое качество, и это связано с уровнем токсичности, аналогичным уровню при приеме LPV/r 400 мг/ 400 мг два раза в сутки (230,231). Однако этот вариант может быть менее сложным и более осуществимым, поскольку LPV/r широко доступен в качестве единичной лекарственной формы, в отличие от RTV. В то же время, если вместо рифампицина используется рифабутин, все усиленные ИП могут приниматься одновременно в своих стандартных дозировках (Таблица 7.19).

Клинические соображения Упрощение клинических и программных аспектов может быть обеспечено путем последовательного перехода от АРТ первого ряда к АРТ второго ряда. Если схемы, основанные на AZT или d4T, неэффективны, следует использовать схему второго ряда с приемом компонентов усиленного ИП и НИОТ (таких, как TDF + 3TC (или FTC) + ATV/r) один раз в сутки. При неэффективности схемы, основанной на TDF, следует использовать схему приема компонентов ИП и НИОТ (таких, как AZT + 3TC + LPV/r) два раза в сутки.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

169

Основные пробелы в научных исследованиях Несколько проводимых в настоящее время исследований, в которых сравниваются разные препараты и классы АРВ-препаратов (232–236), предоставят дополнительные данные о соответствующих схемах второго ряда, включая щадящее и ограниченное использование НИОТ (получение результатов ожидается после 2014 года). Необходимо дальнейшее изучение роли DRV в схемах второго и третьего ряда (оптимальные дозировки для взрослых и детей, прием один или два раза в сутки, комбинированные препараты с фиксированными дозами вместе с другими усиленными препаратами и ингибиторами интегразы и стратегии чередования). В настоящее время проводятся несколько исследований по изучению индукционного и поддерживающего лечения с использованием монотерапии ИП/r для поддерживающего лечения. Следует также изучить возможность включения рифабутина в состав комбинированных препаратов с фиксированными дозами для лечения ТБ.

7.5 На какую схему АРВ-терапии следует переходить (АРТ второго ряда)

Таблица 7.19 Сравнительный анализ: ATV/r, LPV/r и DRV/r Основные параметры Согласованность со схемами лечения детей Количество таблеток в день (стандартная дозировка в виде комбинированного препарата с фиксированными дозами) Удобство в использовании (схема приема один раз в день по сравнению с приемом дважды в день) Безопасность при беременности Непереносимость со стороны желудочно-кишечного тракта (диарея) Наличие других форм выпуска препарата (в виде термостабильного комбинированного препарата с фиксированными дозами) Использование наряду со схемой противотуберкулезного лечения с включением рифампицина Гипербилирубинемия Дислипидемия Потенциал для снижения стоимости в будущем Доступность в странах (регистрационный статус) Наличие генерических препаратов a b

ATV/r Нетa

LPV/r Да

DRV/r Нетb

от 2 до 4

Один раз в день Да Не часто

Два раз в день

Один или два раза в день Да Не часто

Да Распространенное явление

Да

Нетd

Нет + ± Низкий Низкая Да

Даc – + Низкий Высокая Да

Нет – ± Высокий Низкая Нет

Одобрено только для детей в возрасте >6 лет. Одобрено только для детей в возрасте >3 лет. c Только при условии использования в повышенных дозировках. d В настоящее время разрабатывается термостабильный КПФД.

170

7.5.2 АРТ второго ряда для детей (включая подростков) Новые рекомендации новое

осле неудачного использования схемы первого ряда на основе ННИОТ для П АРТ второго ряда рекомендуется использовать усиленный ИП плюс два НИОТ; предпочтительным усиленным ИП является LPV/r (настоятельная рекомендация, фактические данные среднего качества). осле неудачного использования схемы первого ряда на основе LPV/r у П детей в возрасте до 3 лет следует продолжать применение схемы первого ряда и принимать меры к обеспечению ее лучшего соблюдения (условная рекомендация, фактические данные очень низкого качества). осле неудачного использования схемы первого ряда на основе LPV/r у детей П в возрасте 3 лет и старше следует переключиться на схему второго ряда, содержащую ННИОТ плюс два НИОТ; предпочтительным ННИОТ является EFV (условная рекомендация, фактические данные низкого качества). осле неудачного использования схемы первого ряда, содержащей ABC или TDF П + 3TC (или FTC), предпочтительной основой из двух НИОТ для АРТ второго ряда является AZT + 3TC (настоятельная рекомендация, фактические данные низкого качества). осле неудачного использования схемы первого ряда, содержащей AZT или d4T П + 3TC (или FTC), предпочтительной основой из двух НИОТ для АРТ второго ряда является ABC или TDF + 3TC (или FTC) (настоятельная рекомендация, фактические данные низкого качества).

Таблица 7.20 Краткое описание рекомендуемых схем АРТ первого и второго ряда для детей (включая подростков) Дети (включая подростков) Схема АРВ-терапии первого ряда ABC + 3TC + LPV/r AZT + 3TC + LPV/r ABC + 3TC + LPV/r AZT + 3TC + LPV/r ABC + 3TC + EFV (илиNVP) Все возрастные группы TDFb + 3TC (или FTC) + EFV (илиNVP) AZT + 3TC + EFV (или NVP) Схема АРВ-терапии второго ряда

Схема первого ряда на основе LPV/r Схема первого ряда на основе ННИОТ a

До 3-х лет От 3-х лет и старше

Без измененийa AZT + 3TC + EFV ABC или TDFb + 3TC + EFV AZT + 3TC + LPV/rc ABC или TDF + 3TCc (или FTC) + LPV/rc

екомендуется не вносить каких-либо изменений, если только речь не идет о прогрессировании заболевания Р на поздней стадии или о недостаточной приверженности назначенному лечению, в частности из-за неприятных вкусовых ощущений при приеме LPV/r. В этом случае следует рассмотреть возможность перехода на схему второго ряда на основе NVP. В качестве альтернативы допускается пролечивание по схеме на основе EFV с учетом недавно одобренного назначения EFV детям младше 3-х лет. Вместе с тем, необходимы дополнительные данные для обоснования оптимального режима лечения EFV у этой группы населения. b Допускается назначение TDF детям исключительно старше 2-х лет. c Детям старше 6 лет вместо LPV/r допускается назначение ATV/r.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

171

Общая информация Разработка рекомендаций в отношении сильнодействующих и эффективных схем второго ряда для детей грудного и более старшего возраста связана с особыми трудностями в связи с отсутствием опыта их применения в условиях ограниченности ресурсов и наличия ограниченных вариантов лекарственных форм. Это подчеркивает необходимость выбора сильнодействующих и эффективных схем первого ряда и обеспечения устойчивости результатов и действенности путем оптимизации соблюдения режима лечения. В руководстве ВОЗ 2010 года была рекомендована схема, основанная на ИП, усиленном RTV, в комбинации с двумя НИОТ в качестве лечения второго ряда для детей, у которых схема, состоящая из двух НИОТ плюс один ННИОТ, оказалась неэффективной (105). Для детей грудного и младшего возраста, получающих ННИОТ в рамках ППМР и начинающих получать схему АРТ первого ряда на основе ИП, для лечения второго ряда было рекомендовано использовать два новых НИОТ и один ННИОТ, поскольку он являлся единственным имеющимся новым классом препаратов. Текущие рекомендации в настоящее время лучше подкреплены данными клинических исследований у детей (156,158,237) и данными обсервационных исследований (157). Группа по разработке руководства также рассмотрела операционные и программные вопросы, включая наличие термостойких лекарственных форм и комбинированных препаратов с фиксированными дозами для детей.

7.5 На какую схему АРВ-терапии следует переходить (АРТ второго ряда)

Обоснование и подтверждающие фактические данные После рассмотрения данных для взрослых и детей и изучения таких факторов, как наличие термостабильных комбинированных препаратов с фиксированными дозами, оптимальная суточная дозировка, гармонизация схем со схемами для взрослых, высокая стоимость и наличие альтернативных вариантов, основные рекомендации, содержащиеся в руководстве 2010 года, были подтверждены. Для детей, у которых схема первого ряда на основе LPV/r оказалась неэффективной, ННИОТ остается единственным новым классом препаратов, который может быть принят. Рандомизированные данные для детей более старшего возраста (158) косвенно подтверждают безопасность использования схемы второго ряда на основе ННИОТ, однако сохраняются опасения относительно использования этого подхода для детей грудного и младшего возраста. Исходя из субоптимальных результатов применения схем на основе NVP (и ограниченности имеющихся данных в отношении использования EFV) у детей в возрасте до трех лет (153,154) и возможности быстрого повторного возникновения ВИЧ, устойчивых к ННИОТ, предполагается, что схемы второго ряда на основе ННИОТ будут иметь ограниченную продолжительность использования в этой возрастной группе (238). Появляются все новые данные о том, что у детей младшего возраста, у которых схемы на основе LPV/r были неэффективны, селекция основных мутаций резистентности к ИП происходит редко и накопление мутаций аналогов тимидина носит очень ограниченный характер (156,237,239,240). В этих условиях и при отсутствии надежных альтернативных вариантов второго ряда, таких как схемы, включающие DRV/r, Группа по разработке руководства рекомендовала в качестве поддерживающего лечения для детей в возрасте до трех лет прием LPV/r до достижения трехлетнего возраста, несмотря на неудачу лечения. Однако следует рассматривать возможность более быстрого перехода на другую схему в ситуациях, когда неудача вызвана несоблюдением режима лечения в связи с неприятным вкусом LPV/r или при прогрессировании заболевания, вызванного ВИЧ. В таких случаях детей в возрасте до трех лет следует переводить на схему, основанную на NVP, при этом следует осуществлять тщательных мониторинг для обеспечения адекватного соблюдения режима лечения.

новое

172

Для детей, начинающих АРТ первого ряда со схемы на основе ННИОТ, для терапии второго ряда по прежнему рекомендуется схема на основе ИП. Предпочтительным препаратом является LPV/r, однако можно рассмотреть возможность использования ATV/r и DRV/r, если будут созданы более приемлемые лекарственные формы. Несмотря на профиль токсичности и ограниченную роль при коинфицировании ТБ и ВИЧ, ATV/r является перспективной альтернативой использованию LPV/r для детей в возрасте старше шести лет. ATV/r имеет некоторые преимущества по сравнению с LPV/r, включая более низкую стоимость и возможность приема один раз в сутки. DRV/r является предпочтительным вариантом ИП после неудачи лечения LPV/r или ATV/r и будет иметь важное значение в качестве препарата третьего ряда или в лечении второго ряда для детей младшего возраста, у которых лечение первого ряда с использованием LPV/r было неэффективно. Однако ATV/r в настоящее время лицензирован только для использования у детей в возрасте старше шести лет, а DRV/r – у детей старше трех лет. Ни ATV/r, ни DRV/r в настоящее время не имеются в виде совместной формы комбинированного препарата с фиксированными дозами для детей. Рабочая группа по АРВ-препаратам для детей определила надлежащие дозировки обоих препаратов, используя существующие весовые категории ВОЗ в пересчете на основе существующих комбинированных таблеток с фиксированными дозами для взрослых. Для разработки адекватных лекарственных форм для детей срочно необходимы валидационные исследования. Использование неусиленных ИП (таких, как фосампренавир (FPV), DRV и ATV) и других ИП (таких, как IDV/r, SQV/r, FPV/r и TPV/r) связано со сниженной вирусологической супрессией, приемом большого количества таблеток и/или высокой частотой побочных эффектов, в результате чего они не рекомендуются (241). Следует отметить, что RTV в жидкой форме требует хранения в холодильнике, имеет неприятный вкус, характеризуется значительной желудочно-кишечной интолерантностью и плохо переносится детьми грудного и более старшего возраста. Термостабильная форма LPV/r в виде 100-мг комбинированной таблетки с фиксированными дозами для детей переносится лучше, однако она не подлежит делению или дроблению; многие дети испытывают трудности в проглатывании этой таблетки целиком. В ближайшее время ожидается получение результатов проводимого рандомизированного исследований о том, можно ли принимать LPV/r один раз в сутки (242). Приемлемой альтернативой представляется создание новых термостабильных форм для детей в виде заполненных гранулами капсул, которые будут доступны в ближайшем будущем (165,243). Последовательность чередования НИОТ определялась на основе принципов оптимизации для АРВ-препаратов и необходимости максимизации противовирусной активности, несмотря на селекцию мутаций резистентности. Если в неэффективной схеме первого ряда использовался тимидиновый аналог НИОТ (AZT или d4T), в схеме второго уровня следует использовать ABC или TDF. Если в неэффективной схеме первого ряда использовался аналог НИОТ (ABC или TDF), в схеме второго ряде следует использовать AZT. Дополнительные преимущества использования ddI в схемах второго ряда неясны; предпочтительным вариантом является продолжение приема 3TC, несмотря на вероятность наличия резистентности к 3TC. Резистентность ВИЧ к 3TC с мутацией M184V может снижать репликацию вируса и вызывать, в некоторой степени, повторную чувствительность к AZT или TDF, хотя эти данные основаны на исследованиях in vitro.

Основные пробелы в научных исследованиях Требуются дополнительные фактические данные для обоснования выбора схем второго ряда для детей младшего возраста, у которых схема первого ряда на основе LPV/r была неэффективной. Для создания эффективных альтернативных вариантов в будущем важное значение имеют валидационные исследования для оценки упрощенных дозировок комбинированных препаратов ATV/r и DRV/r с фиксированными дозами. Следует также изучить инновационные стратегии второго ряда, такие как ИП + ингибиторы интегразы или индукционное и поддерживающее лечение с использованием монотерапии ИП/r у детей.

7. Клиническое руководство по оказанию непрерывной помощи на всех ее этапах: антиретровирусная терапия

173

7.6 АРТ третьего ряда New recommendations новое

7.6 АРТ третьего ряда

В рамках национальных программ следует разработать стратегии проведения АРТ третьего ряда (условная рекомендация, фактические данные низкого качества). С хемы третьего ряда должны включать новые препараты с минимальным риском перекрестной устойчивости к ранее использовавшимся схемам, таким как ингибиторы интегразы и ННИОТ и ИП второго поколения (условная рекомендация, фактические данные низкого качества). П ри отсутствии новых АРВ-вариантов пациентам, у которых схема второго ряда не дает положительных результатов, следует продолжать лечение по переносимой ими схеме (условная рекомендация, фактические данные очень низкого качества).

Общая информация В 2010 году ВОЗ разработала рекомендации в отношении АРТ третьего ряда в условиях ограниченности данных, касающихся стратегий третьего ряда. Хотя число исследований новых препаратов невелико, данные когортных исследований указывают на высокий уровень смертности среди людей, у которых АРТ второго ряда была неэффективной (245).

Обоснование и подтверждающие фактические данные Группа по разработке руководства поддержала рекомендации, содержащиеся в руководстве ВОЗ 2010 года. При этом Группа по разработке руководства подчеркнула важное значение сбалансированного сочетания необходимости в разработке стратегий АРТ третьего ряда с необходимостью расширения доступа к АРТ первого ряда и второго ряда. Она признала также, что многие страны испытывают финансовые трудности, которые ограничивают возможности использования схем третьего ряда. Имеются данные рандомизированных контролируемых исследований в отношении DRV/r, этравирина (ETV) и ралтегравира (RAL), однако большинство исследований проводились в странах с хорошо обеспеченными ресурсами или в странах со средним или высоким уровнями дохода. Взятые вместе, эти данные свидетельствуют об эффективности этих препаратов среди пациентов, получавших ранее АРТ в течение длительного времени. Согласно опубликованным данным объединенного анализа подгрупп, использование DRV/r плюс оптимизированного фонового режима (ОФР), выбранного с помощью генотипирования и фенотипирования, продемонстрировало более высокие результаты, чем в контрольной группе (усиленный ИП + ОФР, где усиленный ИП выбирался исследователем) среди лиц, получавших ранее АРТ в течение длительного времени (222). Было также показано, что DRV/r не уступает LPV/r среди получавших ранее АРТ людей через 96 недель (223). Среди лиц с ограниченными вариантами лечения, комбинация RAL + ОФР обеспечивала получение более высоких результатов вирусологической супрессии, чем только ОФР в течение, как минимум, 96 недель (246,247). Аналогичным образом, комбинация ETV + OBR обеспечивала вирусологическую супрессию и улучшение иммунологического ответа в большей степени, чем только ОФР через 96 недель (248). Среди людей, инфицированных ВИЧ с множественной лекарственной устойчивостью, для которых число остающихся вариантов лечения было невелико, комбинация RAL, ETV и DRV/r показала хорошую переносимость и сопровождалась вирусологической супрессией схожей с той, которую можно ожидать среди людей, ранее не получавших лечения (249,250).

новое

174

Данные сообщений о пострегистрационных наблюдениях указывают на более высокую частоту случаев гиперчувствительности к ETV, чем сообщалось ранее (251). Комбинация ETV + RAL не получила разрешения на использование у лиц в возрасте до 16 лет. Имеются ограниченные данные об использовании этих новых препаратов у детей грудного и более старшего возраста, включая очень ограниченный объем данных о фармакокинетике и безопасности.

Особые соображения в отношении детей В случае неудачи лечения второго ряда необходимо рассмотреть возможность применения стратегий, обеспечивающих должное соотношение преимуществ и рисков для детей. Для детей более старшего возраста и подростков, в отношении которых имеется больше вариантов лечения, может быть составлена АРВ-схема третьего ряда с использованием новых препаратов, применяемых при лечении взрослых, таких как ETV, DRV и RAL (подробные сведения о лечении детей этими препаратами даны в веб-приложении www.who.int/hiv/pub/guidelines/arv2013/annexes). При отсутствии новых АРВ-препаратов для детей, у которых схема второго ряда не дает положительных результатов, следует продолжать лечение по переносимой ими схеме. В случае прекращения АРТ следует не допускать развития оппортунистических инфекций, облегчать симптомы и устранять боль.

Клинические соображения Критерии для выявления случаев неэффективности АРТ второго ряда являются теми же, что и для выявления неэффективности АРТ первого ряда. Спрос на схемы второго и третьего ряда будет возрастать по мере расширения доступа к тестам для определения вирусной нагрузки и дальнейшего расширения масштабов АРТ первого ряда. Хотя желательно разработать стратегию в отношении доступа к АРТ третьего ряда, это не должно сокращать возможности доступа к назначению АРТ первого ряда. Стоимость препаратов, применение которых возможно в АРТ третьего ряда, таких как DRV, ETV и RAL, недостаточно хорошо изучена в условиях ограниченности ресурсов, однако можно ожидать, что она будет выше, чем препаратов для схем первого и второго ряда.

Основные пробелы в научных исследованиях Дополнительная информация для проведения АРТ второго и третьего ряда в условиях ограниченности ресурсов, требуется во многих областях, включая мониторинг важнейших конечных результатов для людей, получающих АРТ второго ряда, изучение возможностей приема один раз в сутки DRV/r и RAL в качестве альтернативы схем АРТ второго ряда на основе НИОТ, а также разработка термостабильных лекарственных форм DRV/r. Необходимы исследования в области фармакологического надзора, включая изучение долгосрочной безопасности и возможных лекарственных взаимодействий с препаратами, применяемыми для лечения ТБ, малярии, гепатита и опиоидной заместительной терапии. По мере расширения эпидемии в странах с низким и средним уровнями дохода, необходимо безотлагательное проведение пилотных исследований по осуществлению АРТ третьего ряда в условиях, где системы здравоохранения обладают ограниченным потенциалом и ресурсами.

КЛИНИЧЕСКОЕ РУКОВОДСТВО ПО ОКАЗАНИЮ НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

ВЕДЕНИЕ НАИБОЛЕЕ РАСПРОСТРАНЕННЫХ КОИНФЕКЦИЙ И СОПУТСТВУЮЩИХ ЗАБОЛЕВАНИЙ

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций 176 8.1.1 Профилактическое лечение котримоксазолом 176 8.1.2 Туберкулез 178 8.1.3 Криптококковая инфекция 185 8.1.4 Вирусные гепатиты B и C 187 8.1.5 Малярия 187 8.1.6 Инфекции, передающиеся половым путем, и рак шейки матки 189 8.1.7 Вакцины для людей, живущих с ВИЧ 191 8.2 Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ 191 8.2.1 Скрининг на неинфекционные заболевания и уход за больными 191 8.2.2 Охрана психического здоровья 192 8.2.3 Употребление наркотиков и расстройства, связанные с этим 192 8.2.4 Оказание нутритивной помощи и поддержки 193 8.2.5 Паллиативная помощь: симптоматическое лечение и уход за умирающими больными 195 8.2.6 Другие соответствующие общие принципы организации помощи 195

Цель этой главы Представить краткое изложение отдельных существующих клинических рекомендаций и соответствующих исходных документов по вопросам профилактики и ведения наиболее распространенных коинфекций и сопутствующих заболеваний в контексте преемственности оказания комплексной помощи ВИЧ-инфицированным с упором на страны и территории с дефицитом материальных и кадровых ресурсов.

176

8. КЛИНИЧЕСКОЕ РУКОВОДСТВО ПО ОКАЗАНИЮ

ВЕДЕНИЕ НАИБОЛЕЕ РАСПРОСТРАНЕННЫХ КОИНФЕКЦИЙ И СОПУТСТВУЮЩИХ ЗАБОЛЕВАНИЙ Введение Различные коинфекции, сопутствующие заболевания и другие состояния здоровья являются весьма распространенными среди людей, живущих с ВИЧ, и имеют свои последствия для их лечения и ухода за больными, включая определение сроков лечения и выбор конкретных АРВ-препаратов. В этом разделе представлен краткий обзор наиболее распространенных и важных состояний здоровья. В нем резюмированы отобранные ключевые рекомендации, заимствованные из уже существующих руководств ВОЗ и смежных материалов, с упором на вопросы скрининга, профилактики и определения сроков проведения АРТ в связи с этими состояниями; в данном случае речь не идет об их более комплексном ведении. По соответствующим методическим рекомендациям даются первоисточники и электронные ссылки, включая базу фактических данных и обоснование в поддержку разных рекомендаций. Весомость рекомендаций и качество фактических данных классифицируются либо с помощью системы GRADE (настоятельные или условные рекомендации и высокое, среднее, низкое и очень низкое качество фактических данных), либо с помощью альтернативной системы ранжирования, которая использовалась до 2008 г. (от A (настоятельно рекомендуется) до C (по усмотрению)) и уровни I–IV (по степени доказательности). В некоторых случаях даются лишь первоисточники и ссылки на веб-сайты. Эти рекомендации не анализировались или обсуждались в процессе разработки руководства от 2013 г., но были включены в текст сводного руководства, когда затрагивались вопросы организации ухода при ВИЧ и лечения АРВ-препаратам.

НЕПРЕРЫВНОЙ ПОМОЩИ НА ВСЕХ ЕЕ ЭТАПАХ:

8.1 П рофилактика, скрининг и ведение наиболее распространенных коинфекций 8.1.1 Профилактическое лечение котримоксазолом Общая информация Профилактическое лечение котримоксазолом (ПЛК) следует осуществлять в качестве неотъемлемой части пакета услуг, связанных с ведением ВИЧ-инфекции. Существующие рекомендации относятся к началу проведения ПЛК среди взрослых, подростков, беременных женщин и детей в целях профилактики пневмоцистной пневмонии, токсоплазмоза и бактериальных инфекций, а также касаются пользы химиопрофилактики малярии и отмены ПЛК.

Первоисточник для подготовки рекомендаций uidelines on co-trimoxazole prophylaxis for HIV-related infection among children, adolescents and G adults: recommendations for a public health approach. Geneva, World Health Organization, 2006 (www.who.int/hiv/pub/plhiv/ctx/en/) (1).

Эти рекомендации предстоит обновить в 2014 году.

8. клиническое руководство по оказанию непрерывной помощи на всех ее этапах: ведение наиболее распространенных коинфекций и сопутствующих заболеваний

177

Основные отобранные существующие рекомендации В Таблице 8.1 представлен соответствующий набор рекомендаций. По поводу методологии, которая использовалась при ранжировании качества фактических данных, следует обращаться к веб-приложению (www.who.int/hiv/pub/guidelines/arv2013/annexes).

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Таблица 8.1 Критерии назначения, отмены и мониторинга профилактической терапии котримоксазолом в соответствии с Руководством ВОЗ от 2006 г. Возраст ВИЧэкспонированные младенцы Критерии назначения Всем, начиная с 4–6-недельного возраста (A-III) Критерии отменыa Вплоть до прекращения риска передачи ВИЧ или исключения вероятности ВИЧинфекции (A-I) Дозировка котримоксазола См. Приложение 7 Подход к мониторингу Клинический с периодичностью в 3 месяца (A-III)

<1 года

Всем b (A-II)

Вплоть до наступления См. 5-летнего возраста Приложение 7 независимо от CD4% или клинических симптомов c (A-IV) или никогда (A-IV) Никогда (A-IV) См. Приложение 7 Клинический с периодичностью в 3 месяца (A-III)

1–5 лет

Клинические стадии заболевания 2, 3 и 4 по классификации ВОЗ независимо от CD4% или Любая стадия заболевания по классификации ВОЗ и при CD4 <25% (A-I) или Всем b (C-IV)

≥5 лет, Любая стадия включая заболевания по взрослых классификации ВОЗ и при количестве CD4 <350 клеток/ мм 3 (A-III) d или При стадии 3 или 4 по классификации ВОЗ независимо от уровня CD4 (A-I) или Всем b (C-III) a

Никогда (A-IV) или когда количество CD4 ≥350 клеток/мм3 по истечении 6 мес АРТe (C-IV) или при CD4 ≥200 клеток/мм3 по истечении 6 мес. АРТc (B-I)

См. Приложение 7: при <30 кг 960 мг в день

Клинический с периодичностью в 3 месяца(A-III)

Следует также принимать решение об отмене, если у человека синдром Стивенса-Джонсона, тяжелое заболевание печени, тяжелая анемия, тяжелая панцитопения или отрицательный ВИЧ-статус. Противопоказания к профилактическому лечению котримоксазолом: сильная аллергия на сульфаниламидные препараты; тяжелое заболевание печени, тяжелое заболевание почек и недостаточность глюкозо-6-фосфатдегидрогеназы (Г6ФД). b Во всех случаях, независимо от пропорции CD4 или клинической стадии, в территориях с высокой распространенностью ВИЧ, высокой младенческой смертностью вследствие инфекционной заболеваемости и ограниченной инфраструктуры здравоохранения c Если в основном назначается в целях профилактики пневмоцистной пневмонии или токсоплазмоза. d Некоторые страны могут руководствоваться пороговым значением по количеству CD4-лимфоцитов <200 клеток/мм 3. e

В ситуациях с высоким уровнем распространенности бактериальных инфекций или малярии.

178

8.1.2 Туберкулез Общая информация Среди людей, живущих с ВИЧ, заболевание ТБ является наиболее часто встречающейся жизнеугрожающей оппортунистической инфекцией и ведущей причиной смерти. АРТ следует назначать всем ВИЧ-инфицированным лицам с активной формой заболевания ТБ. Центры, обеспечивающие уход за ВИЧинфицированными, обязаны руководствоваться предложенной ВОЗ Стратегией трех «И» (от англ.): интенсивное выявление случаев ТБ, профилактическое лечение изониазидом (ПЛИ) и инфекционный контроль при любом обращении в лечебное учреждение.

Первоисточники для подготовки рекомендаций П олитика ВОЗ в отношении сотрудничества в области ТБ/ВИЧ: руководящие принципы для национальных программ и других заинтересованных сторон. Женева, Всемирная организация здравоохранения, 2012 г. (http://whqlibdoc.who.int/ publications/2012/9789244503003_rus.pdf) (2). Б ыстрое внедрение диагностического теста Xpert MTB/RIF: технические и операционные рекомендации. Вопросы практического применения. Женева, Всемирная организация здравоохранения, 2011 г. (http://whqlibdoc.who.int/ publications/2011/9789241501569_rus.pdf) (21).

Дополнительные методические материалы G uidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. Geneva, World Health Organization, 2011 (www.who.int/tb/challenges/hiv/ICF_IPTguidelines/en/index.html). HO policy on TB infection control in health-care facilities, congregate settings W and households. Geneva, World Health Organization, 2009 (www.who.int/tb/ publications/2009/9789241598323/en). reatment of tuberculosis: guidelines for national programmes. 4th ed. Geneva, World T Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241547833_ eng.pdf). mproving the diagnosis of and treatment of smear-negative pulmonary and extrapulmonary I TB among adults and adolescents: recommendations for HIV prevalent and resourceconstrained settings. Geneva, World Health Organization, 2007 (www.who.int/hiv/pub/tb/ pulmonary/en/). ecommendations for investigating contact of persons with infectious tuberculosis in lowR and middle-income countries. Geneva World Health Organization, 2012 (http://apps.who. int/iris/bitstream/10665/77741/1/9789241504492_eng.pdf). uidelines for the programmatic management of drug-resistant tuberculosis. Geneva World G Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501583_ eng.pdf). hildhood tuberculosis guidelines. Geneva, World Health Organization, forthcoming C (expected 2013).

179

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Основные отобранные существующие рекомендации Выявление случаев заболевания ТБ и противотуберкулезное лечение зрослые и подростки, живущие с ВИЧ, должны проходить скрининг на ТБ В согласно клиническому алгоритму; у лиц с проявлениями любого из таких симптомов, как кашель, лихорадка, потеря веса или ночная потливость, может быть активная форма ТБ, и они подлежат обследованию на ТБ и другие заболевания (Рис. 8.1) (настоятельная рекомендация, фактические данные среднего качества) (2). детей, живущих с ВИЧ, при проявлениях любого из таких симптомов, как У плохая прибавка в весе ребенка, лихорадка или кашель в текущем периоде или контакт с больным ТБ в анамнезе, может быть ТБ, и они подлежат обследованию на ТБ и другие патологические состояния. Если в результате обследования ТБ не выявлен, то таким детям следует предложить пройти профилактический курс лечения изониазидом независимо от их возраста (Рис. 8.2) (настоятельная рекомендация, фактические данные низкого качества) (2). ольные ТБ с известным ВИЧ-позитивным статусом, а также больные ТБ, Б проживающие в территориях с высокой распространенностью ВИЧ, должны проходить, по меньшей мере, шестимесячный курс лечения рифампицином (настоятельная рекомендация, фактические данные высокого качества). птимальная периодичность приема очередной дозы препарата является О ежесуточной в течение интенсивной фазы и фазы продолжения лечения (настоятельная рекомендация, фактические данные высокого качества) (2). ест-система Xpert MTB/RIF должна использоваться в качестве исходного Т диагностического теста у лиц с подозрением на ВИЧ-ассоциированный ТБ или ТБ с множественной лекарственной устойчивостью (настоятельная рекомендация) (21).

180

Основные отобранные существующие рекомендации Профилактическое лечение изониазидом (ПЛИ) (2) зрослые и подростки, живущие с ВИЧ, должны проходить обследование в В соответствии с клиническим алгоритмом; у лиц без проявлений любого из таких симптомов, как кашель в текущем периоде, лихорадка, потеря веса или ночная потливость, активная форма ТБ представляется маловероятной, и им следует предлагать ПЛИ (настоятельная рекомендация, фактические данные среднего качества). П родолжительность ПЛИ • В зрослые и подростки, живущие с ВИЧ, с неизвестной или положительной пробой с внутрикожным введением туберкулина (ТКП) и с маловероятной активной формой ТБ должны проходить, как минимум, шестимесячный курс ПЛИ в рамках всеобъемлющего пакета услуг по оказанию помощи при ВИЧ. Курс ПЛИ следует назначать таким индивидуумам независимо от степени подавления иммунитета, а также лицам, получающим АРТ, всем, кто проходил лечение по поводу ТБ ранее, и беременным женщинам (настоятельная рекомендация, фактические данные высокого качества). • В зрослые и подростки, живущие с ВИЧ, с неизвестным или положительным ТКП- статусом и с маловероятной активной формой ТБ должны проходить, как минимум, 36-месячный курс ПЛИ. Курс ПЛИ следует назначать таким индивидуумам независимо от степени подавления иммунитета, а также лицам, получающим АРТ, всем, кто проходил лечение по поводу ТБ ранее, и беременным женщинам (условная рекомендация, фактические данные среднего качества). остановка ТКП не является обязательной для начала ПЛИ у людей, живущих П с ВИЧ (настоятельная рекомендация, фактические данные среднего качества). Люди, живущие с ВИЧ и имеющие положительную ТКП, оказываются в более выигрышном положении в результате ПЛИ; ТКП может использоваться тогда, когда целесообразно выявлять таких индивидуумов (настоятельная рекомендация, фактические данные высокого качества). рохождение курса ПЛИ людьми, живущими с ВИЧ, не приводит к повышению П риска развития устойчивой к изониазиду формы ТБ. Поэтому опасения по поводу развития устойчивости к INH не должны быть препятствием при организации ПЛИ (настоятельная рекомендация, фактические данные среднего качества). детей, живущих с ВИЧ и не имеющих проблем с плохой прибавкой в весе, У лихорадкой или кашлем в текущем периоде, активная форма ТБ маловероятна (настоятельная рекомендация, фактические данные низкого качества). Дети старше 12 месяцев, живущие с ВИЧ и вряд ли имеющие активную форму ТБ на основании результатов скрининга на характерные симптомы, а также не находящиеся в контакте с больным ТБ, должны проходить шестимесячный курс ПЛИ (10 мг/кг/день) в рамках всеобъемлющего пакета услуг по профилактике и оказанию помощи при ВИЧ (настоятельная рекомендация, фактические данные среднего качества).

181

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Из числа живущих с ВИЧ детей моложе 12 месяцев только тем детям, которые находятся в контакте с больным ТБ и прошли освидетельствование на ТБ (на основании результатов обследований), следует назначать шестимесячный курс ПЛИ, если по результатам оценки у них не выявлено заболевание ТБ (настоятельная рекомендация, фактические данные низкого качества). Все живущие с ВИЧ дети после успешного завершения курса лечения по поводу ТБ должны принимать изониазид еще в течение следующих шести месяцев (условная рекомендация, фактические данные низкого качества).

Рис. 8.1 Алгоритм скрининга на ТБ среди взрослых и подростков, живущих с ВИЧ в странах и территориях с высокой распространенностью ВИЧ-инфекции и ограниченными ресурсами Взрослые и подростки с ВИЧa Скрининг на ТБ при наличии любого из следующих симптомов:b кашель в текущем периоде лихорадка потеря веса ночная потливость Нет Обследование на противопоказания к ПЛИc Нет Назначить ПЛИ Да Отсрочить ПЛИ Да Обследование на ТБ и другие заболеванияd Другой диагноз Приступить к адекватному лечению и поставить вопрос о ПЛИ Не ТБ Наблюдать и поставить вопрос о ПЛИ ТБ Начать лечение ТБ

Проводить регулярный скрининг на ТБ при каждом контакте с медработником или при обращении в лечебное учреждение Каждый взрослый и подросток подлежит обследованию на соответствие критериям прохождения антиретровирусной терапии. Мерам инфекционного контроля следует уделять приоритетное внимание для снижения вероятности передачи Mycobacterium tuberculosis во всех типах учреждений, на базе которых проводится лечение. b При наличии соответствующей аппаратуры может быть проведено рентгенологическое исследование органов грудной клетки, но это необязательно с точки зрения отнесения пациентов к группам больных ТБ и не больных ТБ. В странах и территориях с высокой распространенностью ВИЧ и, в частности, с высоким уровнем распространенности ТБ среди людей, живущих с ВИЧ (например, более 10%), следует тщательно рассмотреть вопрос о целесообразности внедрения других чувствительных методов обследований. c Перечень противопоказаний включает в себя следующее: активная форма гепатита (острый или хронический), регулярное и тяжелое алкогольное опьянение и симптомы периферической нейропатии. Наличие ТБ в анамнезе и протекающая беременность не должны быть противопоказаниями к началу ПЛИ. Хотя проба с внутрикожным введением туберкулина и не является обязательной для назначения ПЛИ, в отдельных ситуациях допускается ее постановка в рамках скрининга на соответствие установленным критериям. d Обследования на ТБ должны проводиться согласно существующему национальному руководству. a

182

Рис. 8.2 Алгоритм скрининга на ТБ среди живущих с ВИЧ детей старше одного года Ребенок старше 12 мес. и живущий с ВИЧa Скрининг на ТБ при наличии любого из следующих симптомов: плохая прибавка в весе ребенкаb лихорадка кашель в текущем периоде контакт с больным ТБ в анамнезе Нет Обследование на противопоказания к ПЛИc Нет Назначить ПЛИ Да Отсрочить ПЛИ Да

Обследование на ТБ и другие заболеванияd Другой диагноз Приступить к адекватному лечению и поставить вопрос о ПЛИ Не ТБ Наблюдать и поставить вопрос о ПЛИ ТБ Начать лечение ТБ

Проводить регулярный скрининг на ТБ при каждом контакте с медработником или при обращении в лечебное учреждение сем детям, не достигшим годовалого возраста, должно быть обеспечено ПЛИ, если в их анамнезе имеются сведения о В семейном контакте с больным ТБ. b Под плохим увеличением массы тела подразумевается (1) зарегистрированная потеря в весе или очень низкая масса тела (соответствующая возрасту масса менее 3 по Z-шкале), (2) недостаточный вес (соответствующая возрасту масса менее 2 по Z-шкале), (3) подтвержденная потеря в весе (>5%) со времени последнего посещения или (4) сглаживание кривой роста. c Перечень противопоказаний включает в себя следующее: активная форма гепатита (острый или хронический) и симптомы периферической нейропатии. Наличие ТБ в анамнезе не должно быть противопоказанием к началу ПЛИ. Хотя проба с внутрикожным введением туберкулина и не является обязательной для назначения ПЛИ, в отдельных ситуациях допускается ее постановка в рамках скрининга на соответствие установленным критериям. d Обследования на ТБ должны проводиться согласно существующему национальному руководству. a

Инфекционный контроль Общая информация Лица, живущие с ВИЧ, подвергаются высокому риску приобретения туберкулезной инфекции при нахождении в лечебно-профилактических учреждениях и местах массового скопления людей. Национальные программы борьбы с ТБ и национальные программы по ВИЧ должны обеспечивать общее руководство процессом осуществления программ инфекционного контроля в рамках противотуберкулезных мероприятий. В каждом медицинском учреждении должен быть свой план мероприятий по контролю за распространением туберкулезной инфекции, в котором предусмотрены административные меры, мероприятия по контролю за состоянием окружающей среды и меры индивидуальной защиты для снижения вероятности передачи возбудителей ТБ в условиях лечебного учреждения и в местах массового скопления людей, а также мероприятия по эпиднадзору за случаями заболевания ТБ среди персонала (Вставка 8.1). Среди ВИЧ-инфицированных медицинских работников должна проводиться АРТ и ПЛИ при условии их соответствия установленным критериям.

183

Первоисточники для подготовки рекомендаций W HO policy on TB infection control in health-care facilities, congregate settings and households. Geneva, World Health Organization, 2009 (www.who.int/tb/ publications/2009/9789241598323/en) (3). uidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health G Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf) (4). П олитика ВОЗ в отношении сотрудничества в области ТБ/ВИЧ: руководящие принципы для национальных программ и других заинтересованных сторон. Geneva, World Health Organization, 2012 (www.who.int/tb/publications/2012/tb_hiv_policy_9789241503006/en) (2). Childhood tuberculosis guidelines. Geneva, World Health Organization, forthcoming (expected 2013) (5).

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Вставка 8.1. Краткое изложение рекомендаций, касающихся основных мер инфекционного контроля (3) Административные меры (внутриучрежденческий комитет и протоколы по санитарно-эпидемиологическому контролю) Система сортировки больных для выявления лиц с подозрением на ТБ Р азделение потоков пациентов с подозрением на ТБ или с подтвержденным диагнозом ТБ П равила кашля и респираторная гигиена Э кспресс-диагностика с помощью тест-системы Xpert MTB/RIF (при своевременном лечении активного ТБ) (настоятельная рекомендация, фактические данные низкого качества). Медицинские работники и лица, ухаживающие за больными Эпиднадзор и информация П акет услуг по ведению ВИЧ-позитивных работников (АРТ и профилактическое лечение изониазидом) С редства индивидуальной защиты (защитные маски-респираторы, параметры которых соответствуют или превышают стандарты N95) П еревод живущих с ВИЧ медработников в места с низким риском (настоятельная рекомендация, фактические данные высокого качества). Контроль за состоянием окружающей среды Система вентиляции (механической) Система вентиляции (естественной) У льтрафиолетовое бактерицидное облучение с помощью ламп, подвешенных к потолку внутри помещений (настоятельная рекомендация, фактические данные низкого качества). Индивидуальные меры П ребывание как можно дольше на открытом воздухе П равила кашля С он в отдельной постели при положительном мазке мокроты И збегать мест массового скопления людей и пребывания в общественном транспорте при положительном мазке мокроты (настоятельная рекомендация, фактические данные низкого качества).

184

Основные отобранные существующие рекомендации Сроки назначения АРТ для взрослых и детей с диагнозом ТБ К урс АРТ следует назначать всем больным ТБ, в том числе лицам с лекарственноустойчивой формой ТБ, независимо от количества клеток CD4 (настоятельная рекомендация, фактические данные низкого качества) (4). первую очередь следует начинать с противотуберкулезного лечения, после В которого как можно раньше в течение первых 8 недель от начала лечения следует приступить к АРТ (настоятельная рекомендация, фактические данные среднего качества). ВИЧ-позитивным больным ТБ с выраженным угнетением иммунитета (например, при количестве лимфоцитов CD4 менее 50 клеток/мм3) следует безотлагательно назначать АРТ в течение первых двух недель от начала лечения по поводу ТБ (2). К урс АРТ следует назначать любому ребенку с активной формой заболевания ТБ как можно раньше в течение первых восьми недель от начала противотуберкулезной терапии независимо от количества клеток CD4 и клинической стадии заболевания (настоятельная рекомендация, фактические данные низкого качества) (5). ациентам, приступающим к АРТ на фоне противотуберкулезного лечения, следует П назначать эфаверенз в качестве предпочтительного препарата класса ННИОТ (настоятельная рекомендация, фактические данные высокого качества) (2).

В Разделе 7.2 представлена более подробная информация и рекомендации относительно одновременного лечения ТБ и ВИЧ. Д етальная информация и рекомендации о лекарственных взаимодействиях при одновременном приеме АРВ-препаратов и ПТП приведена в веб-приложении (www. who.int/hiv/pub/guidelines/arv2013/annexes).

ТБ с множественной лекарственной устойчивостью и ВИЧ Общая информация Под ТБ с множественной лекарственной устойчивостью (МЛУ-ТБ) подразумевается такая форма туберкулеза, при которой имеет место устойчивость одновременно к изониазиду и рифампицину. Больные с диагнозом как ВИЧ, так и МЛУ-ТБ, сталкиваются с проблемой сложного клинического ведения, ограниченного выбора вариантов лечения и более неблагоприятных исходов лечения. На популяционном уровне накоплен ограниченный объем информации о взаимосвязях между ВИЧ и МЛУ-ТБ, особенно в связи с тем, что только 40% лиц с активной формой ТБ проходят обследования на ВИЧ (6). Вспышки МЛУ-ТБ среди ВИЧ-инфицированных были документально подтверждены в больницах и других лечебных учреждениях, в частности в странах Восточной Европы и странах Южной Африки с высоким уровнем распространенности ВИЧ (7). По мере возможности ВИЧ-инфицированные лица с подозрением на лекарственноустойчивый ТБ должны быть обследованы с помощью диагностического теста Xpert MTB/RIF, поскольку этот тест является более чувствительным при выявлении ТБ у людей, живущих с ВИЧ, и позволяет быстро обнаружить устойчивость к рифампицину, значительно сокращая, тем самым, время для постановки диагноза и лечения МЛУ-ТБ.

185

Следует добиваться уменьшения бремени МЛУ-ТБ путем укрепления служб профилактики ВИЧ, совершенствования мер инфекционного контроля и улучшения сотрудничества в деле борьбы с ТБ и ВИЧ, уделяя особое внимание группам, подвергающимся наибольшему риску инфицирования МЛУ-ТБ и ВИЧ, например потребителям инъекционных наркотиков и лицам с высоким риском воздействия заразного начала в местах массового скопления людей.

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Первоисточник для подготовки рекомендаций Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501583_ eng.pdf) (4)

Дополнительные методические материалы Быстрое внедрение диагностического теста Xpert MTB/RIF: технические и операционные рекомендации. Вопросы практического применения. Женева, Всемирная организация здравоохранения (http://whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf).

Основная отобранная существующая рекомендация (4) ВОЗ рекомендует как можно раньше назначать АРТ всем пациентам с ВИЧ и лекарственно-устойчивым заболеванием ТБ, требующим назначения противотуберкулезных препаратов второго ряда независимо от количества клеток CD4 (в течение первых восьми недель от начала курса противотуберкулезной терапии) (настоятельная рекомендация, фактические данные очень низкого качества).

8.1.3 Криптококковая инфекция Общая информация Криптококковый менингит является одной из важнейших оппортунистических инфекций и вносит основной вклад в статистику высокой смертности как до, так и после начала АРТ. В публикации ВОЗ от 2011 г. из серии «Быстрый совет» рассмотрены вопросы, касающиеся диагностики, скрининга и профилактики криптококковой инфекции, режимов индукционной, консолидирующей и поддерживающей терапии, мониторинга и ведения пациентов при проявлениях токсичности, сроков назначения АРТ и отмены режимов поддерживающей терапии. Полный текст руководства будет опубликован в конце 2013 года.

Первоисточник для подготовки рекомендаций Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva, World Health Organization, 2011 (www.who.int/ hiv/pub/cryptococcal_disease2011) (8).

186

Основные отобранные существующие рекомендации Скрининг и профилактика (8) Р утинный скрининг образцов сыворотки или плазмы кровы на определение антигена Cryptococcus neoformans (CrAg) у ранее не получавших АРТ взрослых, наряду с последующей упреждающей противогрибковой терапией при положительном результате анализа на CrAg и отсутствии симптомов, в целях снижения вероятности развития криптококкоза может рассматриваться в качестве возможной тактики лечения до начала АРТ у пациентов с количеством лимфоцитов CD4 менее 100 клеток/мм3, а также тогда, когда эта популяция больных находится в местах с высокой распространенностью криптококковой антигенемии (условная рекомендация, фактические данные низкого качества). Р утинное использование противогрибковой первичной профилактики криптококкоза у людей, живущих с ВИЧ, с количеством лимфоцитов CD4 менее 100 клеток/мм3 и при отрицательном результате анализа на CrAg или при неизвестном CrAg-статусе не рекомендуется до начала проведения АРТ (настоятельная рекомендация, фактические данные высокого качества). Р утинный скрининг на CrAg и упреждающее противогрибковое лечение у ранее не получавших АРТ подростков и детей с количеством лимфоцитов CD4 менее 100 клеток/мм3 до начала АРТ не рекомендуются (условная рекомендация, фактические данные низкого качества).

Сроки назначения АРТ (8) Б езотлагательное начало АРТ не рекомендовано для пациентов с криптококковым менингитом ввиду высокого риска возникновения воспалительного синдрома восстановления иммунитета (ВСВИ) при заболевании центральной нервной системы, которое может оказаться жизнеугрожающим (условная рекомендация, фактические данные низкого качества). П рименительно к людям, живущим с ВИЧ и свежим диагнозом криптококкового менингита, начало проведения АРТ следует отложить на более поздний срок до получения фактических данных в пользу устойчивого клинического ответа на противогрибковую терапию и • по истечении двух-четырех недель от начала индукционного и консолидирующего лечения по комбинированной схеме, включающей в себя амфотерицин в сочетании с флукотозином или флуконазолом; или • по истечении четырех-шести недель от начала индукционного и консолидирующего перорального лечения высокодозным флуконазолом (условная рекомендация, фактические данные низкого качества). См. выше первоисточник с рекомендациями об отмене курса вторичной профилактики.

187

8.1.4 Вирусные гепатиты B и C Общая информация От хронической инфекции вируса гепатита B страдает 5%-20% лиц от 33-миллионного населения мира с ВИЧ-инфекцией, а гепатитом C поражено 5%-15% людей, хотя эта статистика может доходить до 90% среди потребителей инъекционных наркотиков (9,10). Бремя сочетанной инфекции с гепатитом В является наибольшим в странах с низким и средним уровнями дохода, особенно в Юго-Восточной Азии и в странах Африки, расположенных к югу от Сахары. Вирусные гепатиты все чаще становятся причиной заболеваемости и смертности среди людей, живущих с ВИЧ, в том числе среди получающих АРТ. Комплексный подход к этой проблеме включает в себя профилактику, скрининг на гепатиты B и C, вакцинацию против гепатита B, а также организацию лечения и ухода за людьми с ВИЧ и сочетанной инфекцией гепатита B и/или гепатита C.

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Дополнительные методические материалы Guidance on prevention of viral hepatitis B and C among people who inject drugs. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/guidelines/hepatitis/en/index.html).

Методические рекомендации в отношении сроков назначения АРТ при гепатитах B и C Гепатит B: когда и с чего начинать. См. Разделы 7.1.1 и 7.21 Гепатит C: когда и с чего начинать. Начало проведения АРТ у людей с ВИЧ и гепатитом C должно соответствовать тем же общим принципам, которые распространяются в целом на популяцию людей, живущих с ВИЧ (Раздел 7.1). Издание Руководства ВОЗ по ведению гепатита C запланировано на 2014 год. В нем будут даны детальные методические рекомендации по скринингу на гепатит C, конкретному лечению гепатита C и оказанию общей помощи при гепатите C.

8.1.5 Малярия Общая информация Люди с ВИЧ и угнетением функции иммунной системы, проживающие в эндемичных по малярии районах, подвержены высокому риску развития осложнений на фоне малярии, причем в зоне особого риска заболеть тяжелой формой малярии, включая ее осложнения, оказываются все дети грудного возраста, дети моложе пяти лет и беременные женщины. Ключевые меры вмешательства по борьбе с малярией предусматривают своевременное и эффективное лечение по схемам артемизинин-комбинированной терапии, а также использование надкроватных сеток, пропитанных инсектицидами, и внутридомовой обработки инсектицидами остаточного действия для контроля численности комаров – переносчиков малярии. Дополнительной мерой вмешательства в территориях с высокой вероятностью передачи инфекции среди определенных групп высокого риска является интермиттирующий курс профилактического лечения в период беременности и химиопрофилактика при подъеме сезонной заболеваемости малярией.

188

Люди, живущие с ВИЧ и заболевающие малярией, должны получать своевременное, эффективное лечение противомалярийными препаратами. Все случаи с подозрением на малярию должны подтверждаться паразитологически с использованием либо микроскопии, либо метода экспресс-диагностики. Лекарственные средства для лечения малярии и АРВ-препараты могут обладать общей токсичностью (особенно сульфаниламидные препараты) и иметь клинически значимые фармакокинетические взаимовлияния (особенно препараты артемизининового ряда, люмефантрин, ННИОТы и ИПы). По этой причине люди, проходящие курс лечения по поводу как ВИЧ, так и малярии, подлежат тщательному мониторингу на предмет побочного действия лекарственных средств, а ВИЧ-инфицированные люди, получающие AZT или EFV, должны, по мере возможности, избегать амодиахин-содержащих артемизинин-комбинированных схем лечения из-за повышенного риска развития нейтропении при сочетании с AZT, а также гепатотоксичности при сочетании с EFV.

Первоисточник для подготовки рекомендаций Essential prevention and care interventions for adults and adolescents living with HIV in resourcelimited settings. Geneva, World Health Organization, 2008 (www.who.int/hiv/pub/prev_care/ OMS_EPP_AFF_en.pdf) (11).

Дополнительные методические материалы Guidelines for the treatment of malaria. 2nd ed. Geneva, World Health Organization, 2010 (www. who.int/malaria/publications/atoz/9789241547925/en/index.html). WHO policy recommendation: seasonal malaria chemoprevention (SMC) for Plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa. Geneva, World Health Organization, 2012 (www.who.int/malaria/publications/atoz/who_smc_policy_recommendation/en/index.html). Technical Expert Group meeting on intermittent preventive treatment in pregnancy (IPTp). Geneva, World Health Organization, 2007 (www.who.int/malaria/publications/9789241596640/en). Intermittent preventive treatment for infants using sulfadoxine-pyrimethamine (SP-IPTi) for malaria control in Africa: implementation field guide. Geneva, World Health Organization, 2011 (www.who.int/malaria/publications/atoz/whoivb11_07/en/index.html). Test, treat and track. Scaling up diagnostic testing, treatment and surveillance for malaria. Geneva, World Health Organization, 2012 (www.who.int/malaria/publications/atoz/test_treat_track_ brochure.pdf). Additional information: malaria [web site]. Geneva, World Health Organization, 2013 (www.who.int/topics/malaria/en).

189

8.1 Профилактика, скрининг и ведение наиболее распространенных коинфекций

Основные выборочные существующие рекомендации (11)a В районах со стабильной динамикой передачи малярии людям, живущим с ВИЧ (как и в случае населения в целом), следует регулярно пользоваться надкроватными сетками, пропитанными инсектицидами, или же у них должен быть доступ к услугам по внутридомовой обработке инсектицидами остаточного действия в целях снижения степени воздействия малярийной инфекции. (A-I) Лечение или интермиттирующую профилактическую терапию сульфадоксином/ пириметамином не следует назначать пациентам с ВИЧ, проходящим профилактический курс лечения котримоксазолом. (A-III)

м. веб-приложение (www.who.int/hiv/pub/guidelines/arv2013/annexes) с описанием методологии, используемой при С ранжировании качества фактических данных.

8.1.6 И нфекции, передающиеся половым путем, и рак шейки матки Общая информация ВИЧ, другие инфекции, передающиеся половым путем, равно как и инфекции репродуктивной системы, не связанные с половым путем передачи, нередко сосуществуют друг с другом. Основная доля этих инфекций протекает бессимптомно, особенно у женщин. Тем не менее, даже бессимптомные инфекции, передающиеся половым путем, могут вызывать осложнения, передаваться половым партнерам и повышать шансы инфицирования ВИЧ. Более того, ВИЧ-инфекция меняет характер естественного течения инфекций, передающихся половым путем. Задачи диагностики и ведения инфекций, передающихся половым путем, предусматривают выявление инфекции и предоставление соответствующего лечения, а также предупреждение дальнейшей передачи заразного начала. Скрининг, диагностика и лечение инфекций, передающихся половым путем, должны обеспечиваться в рутинной практике в качестве составной части комплексных мероприятий по уходу за ВИЧинфицированными среди взрослых и подростков. Обновление Руководства ВОЗ по лечению и ведению инфекций, передающихся половым путем, запланировано на 2014 год. В других вышедших за последнее время руководствах содержатся рекомендации по периодическому скринингу и периодическому пробному лечению бессимптомных передающихся половым путем инфекций у секс-работников, а также по периодическому обследованию на бессимптомно протекающие уретральные и ректальные инфекции Neisseria gonorrhoeae и Chlamydia trachomatis и бессимптомную инфекцию сифилиса среди работниц коммерческого секса, мужчин, имеющих половые контакты с мужчинами, и трансгендерных лиц. Рак шейки матки является предотвращаемым заболеванием, и его можно излечить при условии раннего диагностирования и лечения. Женщины, живущие с ВИЧ, в большей степени подвержены риску развития предракового заболевания и инвазивного рака шейки матки. Риск и персистирование инфекции вируса папилломы человека (ВПЧ) повышается с понижением количества клеток CD4 и подъемом вирусной нагрузки на фоне ВИЧ-инфекции. Инвазивный рак шейки матки по классификации ВОЗ относится к клинической стадии 4 развития ВИЧ-инфекции. Женщин, живущих с ВИЧ, следует тщательным образом наблюдать на наличие

190

признаков предраковых изменений на шейке матки независимо от статуса АРТ или количества лимфоцитов CD4 и вирусной нагрузки. Скрининг на рак шейки матки позволяет выявлять на ранней стадии предраковые и раковые поражения, благодаря чему можно предотвращать серьезную заболеваемость и смертность. Таким образом, все женщины с ВИЧ независимо от возраста подлежат скринингу на рак шейки матки. Следует обеспечивать безотлагательное лечение предраковых и раковых поражений. В руководстве ВОЗ освещены вопросы профилактики и вакцинации от ВПЧ, скрининга и лечения, а также оказания паллиативной помощи при раке шейки матки. На сегодняшний день опасения по поводу безопасности или пониженной эффективности среди женщин, у которых не исключается ВИЧ-инфекция, не должны служить поводом для отсрочки проведения крупномасштабных прививочных кампаний против ВПЧ. Тестирование на ВИЧ не должно рассматриваться как предварительное условие для начала плановой иммунизации против ВПЧ.

Дополнительные методические материалы Инфекции, передающиеся половым путем E ssential prevention and care interventions for adults and adolescents living with HIV in resourcelimited settings. Geneva, World Health Organization, 2008 (www.who.int/hiv/pub/prev_care/ OMS_EPP_AFF_en.pdf). G uidelines for the management of sexually transmitted infections. Geneva, World Health Organization, 2004 (www.who.int/hiv/pub/sti/pub6/en). G lobal strategy for the prevention and control of sexually transmitted infections: 2006–2015. Breaking the chain of transmission. Geneva, World Health Organization, 2007. (www.who.int/reproductivehealth/publications/rtis/9789241563475/en/index.html). W HO meeting report. Report of the Expert Consultation and review of the latest evidence to update guidelines for the management of sexually transmitted infections. Geneva, World Health Organization, 2011 (www.who.int/reproductivehealth/publications/rtis/ rhr_11_37/en). П ересмотр руководства ВОЗ по синдромному подходу к ведению лиц с симптомами инфекций, передающихся половым путем, и лечению специфических инфекций, передающихся половым путем, намечен на 2014 год. P revention and treatment of HIV and other sexually transmitted infections for sex workers in lowand middle-income countries. Geneva, World Health Organization, 2012 (www.who.int/hiv/ pub/guidelines/sex_worker/en). P revention and treatment of HIV and other sexually transmitted infections among men who have sex with men and transgender people. Recommendations for a public health approach. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/guidelines/msm_guidelines2011/en).

Рак шейки матки Human papillomavirus vaccines: WHO position paper. Weekly Epidemiological Record, 2009, 84:118–131 (www.who.int/wer/2009/wer8415.pdf). Comprehensive cervical cancer prevention and control: a healthier future for girls and women. Geneva, World Health Organization, 2013 (www.who.int/reproductivehealth/topics/cancers/ en/index.html). WHO guidelines on use of cryotherapy for cervical intraepithelial neoplasia. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502856_eng.pdf).

191

8.1.7 Вакцины для людей, живущих с ВИЧ Общая информация Люди, живущие с ВИЧ, подлежат освидетельствованию на предмет соответствия критериям вакцинации на всех этапах оказания медицинской помощи. Подвергшиеся риску воздействия ВИЧ младенцы и дети и молодые взрослые с ВИЧ должны получать все вакцины, предусмотренные рутинной вакцинацией в соответствии с рекомендованными национальными календарями профилактических прививок. Лица с более тяжелой формой иммунодефицита могут подвергаться повышенному риску развития осложнений при введении живых вакцин. Инактивированные вакцины обладают большей эффективностью у лиц, получающих АРТ и не страдающих от иммуносупрессии, но они вполне безопасны и могут использоваться с некоторой степенью эффективности для всех контингентов населения.

8.2 Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ

Дополнительные методические материалы И счерпывающая информация о календарях прививок и детальном руководстве приведена на сайте: WHO recommendations for routine immunization – summary tables [web site]. Geneva, World Health Organization, 2012 (www.who.int/immunization/ policy/immunization_tables/en/index.html). Д оклады с изложением официальной позиции по каждой вакцине, а также заявление об их применении у людей, живущих с ВИЧ, вывешены на сайте: (www. who.int/immunization/documents/positionpapers/en/index.html).

8.2 П рофилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ 8.2.1 С крининг на неинфекционные заболевания и уход за больными Общая информация Люди, живущие с ВИЧ, подвержены повышенному риску развития целого ряда неинфекционных заболеваний (НИЗ), включая сердечно-сосудистые болезни, диабет, хроническую болезнь легких и некоторые виды рака (12,13). Благодаря эффективной АРТ продолжительность жизни у людей, живущих с ВИЧ, также увеличивается наряду с возникновением НИЗ, связанных со старением. Ведение как ВИЧ, так и НИЗ требует наличия таких систем здравоохранения, которые способны оказывать эффективную помощь при острых и хронических состояниях, а также помогать больным в соблюдении режима лечения. Постоянство оказываемой при ВИЧ помощи позволяет заниматься скринингом, мониторингом и ведением НИЗ, особенно на уровне первичного звена. Интеграция таких вмешательств, как оценка состояния питания, консультирование и помощь в подборе режима питания, отказ от курения, поощрение занятий физическими упражнениями, контроль кровяного давления и, если возможно, уровня холестерина в рамках набора услуг, предоставляемых при ВИЧ, создает предпосылки для снижения связанных с НИЗ

192

рисков среди людей, живущих с ВИЧ. Специалистами ВОЗ был определен пакет основных вмешательств в отношении НИЗ (WHO PEN) наряду с рекомендациями по проведению скрининга и лечения НИЗ. Дополнительное руководство по диагностике и ведению НИЗ у людей, живущих с ВИЧ, планируется выпустить в 2014 году.

Дополнительные методические материалы Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva, World Health Organization, 2010 (www.who.int/cardiovascular_ diseases/publications/pen2010/en). Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/76173/1/9789241548397_eng.pdf).

8.2.2 Охрана психического здоровья Общая информация Люди, живущие с ВИЧ, и ухаживающие за ними лица могут иметь весьма широкий диапазон потребностей в охране психического здоровья. Наиболее распространенными сопутствующими психическими расстройствами среди живущих с ВИЧ людей могут быть такие, как депрессия, тревожные состояния, деменция и другие когнитивные расстройства и аддиктивные расстройства. На базе центров ухода за ВИЧ-инфицированными обеспечивается выявление и ведение психических расстройств у людей, живущих с ВИЧ. Пролечивание этих состояний или отсутствие такой возможности может сказываться на приверженности терапии АРВ-препаратами, удержании пациентов в системе ухода за ними и может быть связано с потенциальными побочными эффектами и взаимодействием лекарственных средств. ВОЗ не занималась подготовкой отдельных рекомендаций по скринингу и лечению психических расстройств у людей, живущих с ВИЧ. По линии Программы действий по заполнению пробелов в области охраны психического здоровья (mhGAP) в рамках методического пособия по организации ухода за людьми с психическими, неврологическими и вызванными токсикоманией расстройствами в условиях неспециализированных лечебных учреждений разрабатываются рекомендации, связанные с общим состоянием психического здоровья, которые могут иметь прямое отношение к людям, живущим с ВИЧ. Дополнительное руководство по ведению психических нарушений у живущих с ВИЧ людей планируется издать в 2014 году.

Дополнительные методические материалы mhGAP Intervention Guide for mental, neurological and substance use disorders in nonspecialized health settings. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241548069_eng.pdf).

8.2.3 У потребление наркотиков и расстройства, связанные с этим Общая информация Люди, живущие с ВИЧ и употребляющие наркотики, могут страдать от целого ряда расстройств, связанных с их пристрастием к наркотикам, включая лекарственную зависимость, интоксикацию, синдром отмены и передозировку.

193

Потребление инъекционных наркотиков ассоциируется, помимо ВИЧ, со многими гемотрансмиссивными и локальными инфекциями, в том числе с вирусными гепатитами, сепсисом и бактериальным эндокардитом. ВОЗ разработала руководство по лечению опиоидной зависимости и профилактике гепатитов B и C среди людей, потребляющих наркотики инъекционным путем. Специалисты ВОЗ, ЮНОДК и ЮНЭЙДС рекомендуют руководствоваться всеобъемлющим пакетом из девяти вмешательств по профилактике, лечению и уходу за ВИЧинфицированными лицами – потребителями инъекционных наркотиков, включая программы обмена игл и шприцев, опиоидную заместительную терапию, консультирование и тестирование на ВИЧ, АРТ, профилактику и лечение инфекций, передающихся половым путем, программы в поддержку использования презервативов, адресные информационнопросветительские мероприятия по поощрению поведенческих изменений, профилактику и лечение вирусных гепатитов, а также профилактику и лечение ТБ.

8.2 Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ

Дополнительные методические материалы WHO, UNODC and UNAIDS. Technical guide for countries to set targets for universal access to HIV prevention, treatment and care for injecting drug users. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/idu/targets_universal_access/en/index.html). Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/ publications/2009/9789241547543_eng.pdf). Guidance on prevention of viral hepatitis B and C among people who inject drugs. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/guidelines/hepatitis/en/index.html).

8.2.4 Оказание нутритивной помощи и поддержки 8.2.4.1 Среди подростков и взрослых, живущих с ВИЧ Общая информация Низкокалорийный рацион питания в сочетании с повышенными потребностями в энергии вследствие ВИЧ-инфекции (14–17) и связанные с этим инфекции могут обусловить индуцированную ВИЧ потерю в весе и истощение организма. Кроме того, нарушение метаболизма, снижение аппетита и рост частоты диареи могут снижать уровни поступления нутриентов и их усвоение, а также стать причиной потерь питательных веществ. Все эти последствия могут усугубляться низким уровнем достатка и отсутствием уверенности в обеспеченности продуктами питания. Низкая масса тела у взрослых (при индексе массы телаvi менее 18,5 кг/м2), потеря в весе и состояние истощения у детей – все это представляет собой независимые факторы риска по прогрессированию заболевания, вызванного ВИЧ, и смертности (18,19). Оценка состояния питания (антропометрические данные, клинические обследования и оценка режима питания), консультирование и поддержка должны быть составной частью мероприятий по оказанию помощи при ВИЧ, и этим следует заниматься не только при формировании групп для организации ухода за больными, но и в процессе наблюдения за предоставлением услуг по уходу и лечению ВИЧ-инфицированных на

Индекс массы тела говорит о степени соответствия веса тела и роста у детей старшей возрастной группы, подростков и взрослых. Этот показатель рассчитывают путем деления веса тела в кг на рост в квадратных метрах. Допустимые значения для взрослых колеблются в диапазоне от 18,5 до 24,9, тогда как для детей они меняются в зависимости от возраста.

194

всех этапах. Страдающим недостаточностью питания ВИЧ-инфицированным лицам, особенно при неуверенности в обеспеченности продуктами питания, наряду с АРТ могут быть показаны пищевые добавки, чтобы обеспечить для человека должный рацион питания в поддержку восстановления полноценного статуса питания. Снижение массы тела или неспособность набрать или поддерживать полезный для здоровья вес на любой стадии развития ВИЧ-инфекции или АРТ должны служить основанием для проведения очередной оценки и соответствующих мер вмешательства. В настоящее время ВОЗ пересматривает действующие рекомендации по оказанию нутритивной помощи и поддержки подросткам и взрослым, живущим с ВИЧ, включая беременных и кормящих грудью женщин.

8.2.4.2 Среди детей, живущих с ВИЧ Общая информация Оценка состояния питания является важнейшей мерой для определения недостаточности питания и задержки роста на раннем этапе. При каждом посещении врача следует проводить как первичную оценку состояния питания у младенцев и детей (оценку статуса и режима питания и соответствующих симптомов), в том числе их взвешивание и измерение роста, так и мониторинг динамики развития с использованием стандартных кривых роста, предложенных ВОЗ или отечественными специалистами. Мониторинг динамики роста также должен быть интегрирован в процедуру оценки ответа на АРТ (20). При выявлении неудовлетворительной динамики роста следует проводить углубленную оценку в целях определения причины и запланировать соответствующие ответные меры. В руководстве от 2009 года по осуществлению интегрированного подхода к оказанию нутритивной помощи детям, живущим с ВИЧ, подробно описаны меры вмешательства, касающиеся состояния питания.

Дополнительные методические материалы Guidance on Nutrition assessment, education, counselling and support for adolescents and adults living with HIV. Geneva, World Food Programme and World Health Organization, 2013. Guidelines on HIV and infant feeding. Geneva, World Health Organization, 2010 (http:// whqlibdoc.who.int/publications/2010/9789241599535_eng.pdf). Guidelines for an integrated approach to the nutritional care of HIV-infected children (6 months – 14 years): handbook. Preliminary version for country introduction. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241597524_eng_ Handbook.pdf). WHO and FAO. Nutritional care and support for people living with HIV/AIDS: a training course. Geneva, World Health Organization, 2009 (www.who.int/nutrition/publications/ hivaids/9789241591898/en/index.html).

195

8.2.5 Паллиативная помощь: симптоматическое лечение и уход за умирающими больными Общая информация На всех этапах прогрессирования вызванного ВИЧ заболевания, а также в процессе лечения у людей, живущих с ВИЧ, могут проявляться боли и другие ощущения дискомфорта в различных формах. Провайдеры помощи должны, по мере возможности, выявлять и устранять первопричину, добиваясь купирования болевых ощущений. Помимо этого, эффективное ведение побочных эффектов имеет большое значение для поощрения приверженности лечению.

8.2 Профилактика и ведение других сопутствующих заболеваний и долговременный уход за людьми, живущими с ВИЧ

Дополнительные методические материалы IMAI district clinician manual: hospital care for adolescents and adults. Guidelines for the management of common illnesses with limited resources. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/imai/imai2011/en).

8.2.6 Другие соответствующие общие принципы организации помощи 8.2.6.1 Планирование семьи, консультирование и контрацепция Дополнительные методические материалы M edical eligibility criteria for contraceptive use. 4th ed. Geneva, World Health Organization, 2009 (www.who.int/reproductivehealth/publications/family_ planning/9789241563888/en/index.html). H ormonal contraception and HIV. Technical statement 16 February 2012. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/hq/2012/WHO_RHR_12.08_eng. pdf) .

8.2.6.2 Обеспечение безопасной водой, средствами санитарии и гигиены Дополнительные методические материалы E ssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, World Health Organization, 2008 (www.who.int/hiv/ pubprev_care/OMS_EPP_AFF_en.pdf). Evaluating household water treatment options: health-based targets and microbiological performance specifications. Geneva, World Health Organization, 2011 (www.who.int/ water_sanitation_health/publications/2011/evaluating_water_treatment.pdf). G uidelines for drinking-water quality. 4th ed. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241548151_eng.pdf).

Рекомендации по

осуществлению деятельности и предоставлению услуг

9.1 Введение 198 9.2 Соблюдение режима АРТ 198 9.2.1 Факторы, препятствующие соблюдению 198 9.2.2 Меры, направленные на оптимизацию соблюдения режима АРТ 201 9.2.3 Мониторинг соблюдения режима АРТ в рамках плановых программ и мест оказания помощи 205 9.3 Удержание пациентов в рамках непрерывного оказания помощи 206 9.3.1 Общие сведения 206 9.3.2 Надлежащая практика удержания пациентов на всех этапах оказания помощи 207 9.4 Предоставление услуг 210 9.4.1 Надлежащая практика предоставления долгосрочной медицинской помощи 210 9.4.2 Интеграция и взаимодействие служб 211 9.4.3 Децентрализация лечения и помощи при ВИЧ 217 9.5 Кадровые ресурсы 219 9.5.1 Наращивание кадрового потенциала 219 9.5.2 Перераспределение обязанностей для лечения и оказания помощи при ВИЧ 219 9.6 Лабораторные и диагностические службы 221 9.6.1 Обзор 221 9.6.2 Вопросы осуществления и передовой опыт 222 9.6.3 Укрепление и расширение лабораторных и диагностических служб 222 9.6.4 Поддержка создания специальной системы направления образцов на исследования 223 9.6.5 Расширение доступа к тестированию на вирусную нагрузку ВИЧ 223 9.6.6 Расширение диагностических служб для проведения тестирования по месту оказания помощи 223 9.6.7 Предоставление рекомендаций по наращиванию кадрового потенциала здравоохранения, включая обучение и сертификацию персонала 225 9.6.8 Внедрение комплексных систем управления качеством 225 9.7 Системы управления закупками и поставками 225 9.7.1 Обзор 225 9.7.2 Обоснование и подтверждающие данные 226 9.7.3 Вопросы осуществления и передовой опыт 226

Цель этой главы Предоставление рекомендаций по основным вопросам осуществления деятельности и оказания услуг, которые должны быть решены для усиления непрерывного процесса оказания помощи при ВИЧ и дальнейшей интеграции применения АРВ-препаратов в деятельность систем здравоохранения.

198

9. РЕКОМЕНДАЦИИ ПО ОСУЩЕСТВЛЕНИЮ ДЕЯТЕЛЬНОСТИ И ПРЕДОСТАВЛЕНИЮ УСЛУГ 9.1 Введение АРВ-препараты и соответствующие услуги должны предоставляться максимально эффективным, справедливым и действенным образом путем оптимизации имеющихся людских и финансовых ресурсов, обеспечения надлежащего взаимодействия между учреждениями и службами оказания помощи, соблюдения режима лечения на протяжении всей жизни и удержания пациентов в рамках непрерывного процесса оказания помощи. Данная глава включает рекомендации по шести основным областям деятельности и предоставления услуг, в которых необходимо принимать меры для обеспечения долгосрочной эффективности и устойчивости программ АРТ. Этими областями являются: Соблюдение АРТ; у держание пациентов в системе непрерывного оказания помощи; п редоставление услуг, включая интеграцию, взаимодействие и децентрализацию служб помощи и лечения при ВИЧ; к адровые ресурсы, включая перераспределение обязанностей; л абораторные и диагностические службы; и с истемы управления закупками и поставками. Новые рекомендации, разработанные с помощью процесса GRADE, содержатся в разделах по соблюдению режима лечения, предоставлению услуг и кадровым ресурсам и включают: текстовые сообщения о необходимости соблюдения режима лечения; интеграцию АРТ и взаимодействие со службами охраны здоровья матери и ребенка, противотуберкулезными службами и службами по предоставлению опиоидной заместительной терапии; децентрализацию АРТ; и перераспределение обязанностей.

9.2 Соблюдение режима АРТ 9.2.1 Факторы, препятствующие соблюдению ВОЗ определяет соблюдение режима лечения как “то, в какой мере поведение человека – прием лекарственных средств, соблюдение режима питания и/или изменение образа жизни – соответствует требованиям согласованных рекомендаций провайдера медицинской помощи” (1). При проведении АРТ длительное соблюдение режима лечения необходимо для того, чтобы (1) подавить репликацию вируса и улучшить иммунологические и клинические результаты; (2) снизить риск развития резистентности к АРВ-препаратам; и (3) уменьшить риск передачи ВИЧ. На соблюдение режима АРТ могут влиять многие факторы, связанные с системами предоставления медицинской помощи; лекарственными средствами и особенностями людей, принимающих АРВ-препараты.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

199

Отдельными факторами могут служить следующие: непринятие лекарств по причине забывчивости; отъезд из дома; изменение ежедневного распорядка дня; депрессия или другое заболевание; отсутствие интереса или желания принимать лекарства; и злоупотребление психоактивными веществами или алкоголем. Факторами, связанными с лекарственными средствами, могут являться: побочные эффекты; сложность схем приема лекарств; большое количество принимаемых единиц дозирования препаратов; и диетические ограничения. Факторы, связанные с системами здравоохранения, могут включать следующие: требование, чтобы люди с ВИЧ часто посещали службы здравоохранения для получения помощи и новых лекарств; поездки на большие расстояния для посещения служб здравоохранения; и необходимость прямого или косвенного участия в покрытии расходов. Отсутствие четкой информации или инструкций в отношении лекарственных средств, ограниченные знания о течении ВИЧинфекции и лечении, а также побочные эффекты могут являться препятствиями для соблюдения режима АРТ. Кроме того, для того, чтобы люди соблюдали режим лечения, необходимы бесперебойные поставки АРВ-препаратов и непрерывность оказания помощи. Необеспечение непрерывности помощи позволяет обоснованно предполагать несоблюдение режима лечения в долгосрочной перспективе. Соблюдение режима АРТ может также быть сложной задачей при отсутствии благоприятных условий для людей, живущих с ВИЧ, а также при проявлениях стигматизации и дискриминации (2,3).

9.2 Соблюдение режима АРТ

Беременные и родившие женщины

Женщины в период беременности и в послеродовой период испытывают значительные биологические, социальные и экономические трудности, которые могут неблагоприятно влиять на соблюдение лечения. Другими факторами в этот период могут являться: решение проблем в связи с диагнозом ВИЧ-инфекции (многие женщины узнают о том, что они инфицированы ВИЧ во время планового обследования в период беременности); беспокойство о том, как АРТ влияет на здоровье плода; большое число посещений клиники во время беременности; страх раскрытия информации о ВИЧ-статусе партнерам; длительное время ожидания в клинике; и отсутствие последующего наблюдения и перевод в другие клиники после родов (4,5).

Подростки

Факторы, затрудняющие соблюдение лечения подростками, включают: большое количество принимаемых таблеток, если они уже имеют опыт лечения; стигматизация и страх раскрытия информации; беспокойство в отношении безопасности лекарственных средств; неблагоприятные эффекты; давление со стороны сверстников и воспринимаемая необходимость подчиняться ему; невнимательное отношение к приему лекарств; и нестабильный распорядок дня. Переход от педиатрической помощи к службам помощи подросткам связан с определенными трудностями, которые могут неблагоприятно влиять на соблюдение режима лечения подростками. К ним относятся: принятие на себя повышенного уровня ответственности за собственное лечение (что может приводить к прерыванию лечения в результате забывчивости); неспособность ориентироваться в системе здравоохранения; отсутствие взаимосвязи между службами помощи для взрослых и детей; отсутствие медицинской страховки; и недостаточная квалификация провайдеров медицинской помощи (6,7). Депрессия и токсикомания также создают проблемы для подростков.

новое

200

Дети грудного и более старшего возраста

Соблюдение режима лечения детьми является особой проблемой. На соблюдение лечения могут влиять ограниченный выбор лекарственных форм для детей; большое количество таблеток и большой объем жидкости; большой размер таблеток; частый прием лекарств; диетические ограничения; потеря основного лица, осуществляющего уход; трудности при проглатывании таблеток; и неблагоприятные эффекты (3, 8, 9). Для успешного лечения ребенка требуется поддержка и участие ответственного лица, осуществляющего уход. Родители и другие члены семьи детей, живущих с ВИЧ, сами могут жить с ВИЧ; ненадлежащий уход и лечение при ВИЧ членов семьи может приводить к ненадлежащему уходу и лечению ребенка.

Нарушения психического здоровья Соблюдение режима лечения, как известно, осложняется наличием сопутствующего нарушения психического здоровья, что приводит к забывчивости, неорганизованности и непониманию планов лечения. Результаты исследований указывают на взаимосвязь между неконтролируемыми депрессивными синдромами и низкими показателями соблюдения АРТ и плохими результатами лечения. В связи с этим некоторые стратегии лечения – от консультирования одновременно по вопросам ВИЧ и депрессии до соответствующего медикаментозного лечения лиц с психическими расстройствами – направлены на борьбу с депрессией и психологическим стрессом для усиления соблюдения АРТ (10–13).

Нарушения, связанные с токсикоманией Лица, страдающие токсикоманией, могут не соблюдать режима АРТ. Употребление алкоголя и токсикомания могут быть связаны с забывчивостью, неорганизованностью и смещением денежных и временных приоритетов (10,14–16).

Группы повышенного риска (включая работников секс индустрии, мужчин, практикующих секс с мужчинами, трансгендерных лиц и потребителей инъекционных наркотиков) В некоторых местах группы повышенного риска сталкиваются с множественными проблемами в отношении доступа к службам здравоохранения. Во многих условиях сохраняются серьезные пробелы в области предоставления услуг для улучшения длительного ухода и обеспечения соблюдения режима лечения в большинстве групп повышенного риска. Опыт указывает на получение обнадеживающих результатов при использовании мер с участием самих членов групп того же уровня, включая оказание сильной социальной поддержки выездными бригадами, группами взаимного просвещения и работниками здравоохранения, которые предоставляют многопрофильную, толерантную и уважительную помощь и поддержку.

Лишение свободы Лишение свободы может отрицательно повлиять на непрерывность лечения, снизить уровень доверия и послужить предрасполагающим фактором к снижению финансовой и социальной поддержки отдельных лиц в период лишения свободы и в дальнейшем. Дополнительной проблемой для этой группы населения являются нарушения, связанные с токсикоманией. У этих лиц в местах лишения свободы возникает дополнительный риск заболевания ТБ, что при отсутствии эффективного лечения ВИЧ и ТБ приводит к высоким показателям заболеваемости и смертности (17). Однако при наличии адекватных программ поддержки и структурированного лечения в местах лишения свободы могут быть достигнуты отличные результаты.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

201

9.2.2 Меры, направленные на оптимизацию соблюдения режима АРТ Не существует единственной меры или комплекса мер по обеспечению соблюдения режима лечения, которая была бы эффективной во всех группах населения и при всех обстоятельствах. Потребности и обстоятельства жизни людей могут также меняться с течением времени, в связи с чем программы и лица, осуществляющие уход, должны целенаправленно использовать сочетание практически осуществимых мер для максимизации соблюдения режима АРТ с учетом индивидуальных препятствующих и способствующих факторов. К мерам программного уровня для улучшения соблюдения режима АРТ относятся: (1) недопущение навязывания платежей из собственных средств в местах получения помощи, (2) использование схем комбинированных препаратов с фиксированными дозами для АРТ и (3) укрепление системы управления поставками лекарственных средств в целях надежного планирования, закупок и поставок АРВ-препаратов, не допуская израсходования запасов. Содержащиеся в настоящем разделе рекомендации в отношении мер соблюдения лечения индивидуального характера касаются получения текстовых сообщений на мобильные телефоны. Проводились простые и надежные исследования, которые продемонстрировали важное значение таких мер в числе множества других. Такие меры обеспечения соблюдения режима лечения, как текстовые сообщения, должны предоставляться в рамках общего пакета комплексных мер. Многие меры обеспечения соблюдения требований на индивидуальном уровне рекомендуются по другим причинам, помимо усиления соблюдения режима АРТ. Например, важнейшими компонентами повседневных мер охраны здоровья и помощи при ВИЧ являются нутритивная поддержка, поддержка сверстников, борьба с депрессией и нарушениями, вызванными токсикоманией, а также просвещение пациентов. Усилия, направленные на поддержку и максимизацию соблюдения требований, должны предприниматься до начала АРТ. Важными первыми шагами являются разработка плана обеспечения соблюдения требований и просветительная работа. Первоначальное просвещение пациента должно охватывать основные сведения о ВИЧ, самих АРВпрепаратах, ожидаемых неблагоприятных явлениях, подготовке к лечению и соблюдении требований АРТ. Такие подготовительные меры не должны приводить к задержке начала лечения в тех случаях, когда необходимы незамедлительные действия.

9.2 Соблюдение режима АРТ

Просвещение и консультирование пациентов и взаимная поддержка Просвещение и консультирование пациентов имеют важное значение как при назначении АРТ, так и в ходе лечения. Информирование и поддержка лиц, получающих АРТ, а также их семей и сверстников являются важными компонентами длительного ухода при ВИЧ. Исследования показывают, что консультирование способствует лучшему соблюдению режима АРТ, а в некоторых случаях имеется связь между поддержкой сверстников и высокими показателями соблюдения требований и удержания в рамках помощи (18–23).

202

Токсикомания и меры психического воздействия Данные исследований указывают на то, что укрепление благополучия путем лечения депрессии и расстройств, вызванных употреблением психоактивных веществ, улучшает результаты лечения ВИЧ-инфекции. В ходе систематического обзора были выявлены фактические данные очень низкого качества по результатам одного обсервационного исследования, в котором оценивалась возможность улучшения соблюдения режима лечения с помощью опиоидной заместительной терапии. Через 12 месяцев показатели несупрессированной вирусной нагрузки были сопоставимыми у потребителей инъекционных наркотиков, получавших опиоидную заместительную терапию, и потребителей инъекционных наркотиков, не получавших опиоидной заместительной терапии (24). Систематический обзор также выявил фактические данные очень низкого качества по результатам одного рандомизированного исследования, в котором оценивалась возможность улучшения соблюдения предписанного режима терапии путем лечения депрессии. Через 12 месяцев риск несоблюдения режима был одинаковым у лиц, которые получали лечение от депрессии, и у тех, кто не получал такого лечения (25). ВОЗ рекомендует проводить одновременно лечение депрессии и расстройств, вызванных употреблением психоактивных веществ, и изучать влияние сочетанного лечения на соблюдение режима АРТ. Другие пути оказания помощи людям, живущим с ВИЧ, которые употребляют наркотики, например программы обмена игл и шприцев, лечение наркотической зависимости и информационно-разъяснительная работа с участием сверстников, также способствуют улучшению соблюдения режима лечения.

Нутритивная поддержка Оценка питания, нутритивная помощь и поддержка являются важнейшими компонентами помощи при ВИЧ. Программы борьбы с ВИЧ должны обеспечивать выполнение существующих национальных стратегий по нутритивной поддержке в тех случаях, когда необходимо и практически возможно добиться максимального соблюдения режима АРТ и достичь оптимальных результатов в отношении здоровья в условиях продовольственной нестабильности. Нутритивная поддержка может включать консультирование по вопросам питания, перевод денежных средств и субсидирование стоимости питания и/или выдачу продовольственных карточек. АРТ в сочетании с нутритивной поддержкой могут способствовать более скорому восстановлению здоровья. Систематический обзор выявил одно исследование, проведенное в странах с низким и средним уровнями дохода, в ходе которого были получены фактические данные низкого качества о том, что нутритивная поддержка лиц, получающих АРТ, со стороны участковых работников здравоохранения снижает риск несоблюдения режима лечения после одного года среди лиц, испытывающих недостаток продуктов питания, по сравнению со стандартным оказанием помощи (26).

Финансовая поддержка Финансовая поддержка может включать возмещение затрат, связанных с получением помощи при ВИЧ (включая лекарственные средства, диагностику, клинические процедуры и талоны на транспорт), что дает возможность снизить бремя ВИЧ среди малоимущих групп населения. Систематический обзор выявил фактические данные очень низкого качества о том, что финансовая поддержка снижает риск несоблюдения режима лечения через год после принятия таких мер по сравнению со стандартным оказанием помощи (27).

9. Рекомендации по осуществлению деятельности и предоставлению услуг

203

Программы и провайдеры медицинской помощи должны рассмотреть возможность использования более широкого программного подхода для снижения затрат на получение помощи для людей, живущих с ВИЧ, включая недопущение платежей из собственных средств в месте получения помощи, децентрализацию и координацию предоставления помощи и использование возможностей для сведения к минимуму числа посещений учреждений здравоохранения. Программы должны принимать во внимание этические аспекты и соблюдение принципа справедливости при предоставлении пищевых продуктов и финансовой поддержки или использовании аналогичных мер в отношении людей, живущих с ВИЧ, в отличие от остальных. Может возникнуть необходимость разработки стандартизированных критериев для оказания поддержки лицам, получающим АРТ, на основании национальных уровней бедности.

9.2 Соблюдение режима АРТ

Средства напоминания и взаимодействия Новая рекомендация Следует рассмотреть возможность направления сообщений на мобильные телефоны в качестве средства напоминания о необходимости соблюдения АРТ в рамках комплекса мер по обеспечению соблюдения требований (настоятельная рекомендация, фактические данные среднего качества). новое

Общие сведения В большинстве случаев в качестве основной причины несоблюдения режима АРТ указываются забывчивость и изменение распорядка дня, хотя конкретные причины того, почему люди забывают принимать лекарства, могут быть разными. Средства напоминания и связи, обеспечивающие взаимодействие с людьми, принимающими АРВ-препараты, являются важной мерой улучшения соблюдения режима лечения путем изменения поведения. Текстовые сообщения по мобильной связи для обеспечения соблюдения режима лечения и при предоставлении услуг здравоохранения в целом используются все чаще по мере расширения доступа к телефонным технологиям (28). Однако их использование требует наличия соответствующих национальных нормативных положений, обеспечивающих конфиденциальность личной жизни людей, получающих текстовые сообщения (29,30). В рамках программ можно рассмотреть возможность привлечения частногосударственных партнерств для ускоренного расширения масштабов использования мобильных телефонов.

новое

Обоснование и подтверждающие данные Мобильная телефонная связь может являться удобным механизмом напоминания для людей, живущих с ВИЧ. Кроме того, поскольку мобильные телефоны широко распространены во всем мире, их использование может не требовать серьезных изменений в обычном распорядке дня. Передача текстовых сообщений на мобильные телефоны также не требует больших затрат, позволяет передавать краткую информацию, не требуя голосовой связи, и дает возможность вести учет переданных сообщений.

204

В рамках систематического обзора было выявлено пять рандомизированных и два обсервационных исследования на тему передачи текстовых сообщений на мобильные телефоны для улучшения соблюдения режима АРТ. Фактические данные высокого качества по результатам двух рандомизированных исследований показывают, что текстовые сообщения способствуют снижению несупрессированной вирусной нагрузки через один год (31,32). Это соответствует фактическим данным высокого качества трех рандомизированных исследований, которые указывают на снижение числа случаев несоблюдения режима лечения через один год (31,33,34). Использование текстовых сообщений в течение периода менее одного года оценивалось в рамках четырех обсервационных исследований. Фактические данные очень низкого качества одного обсервационного исследования указывают на снижение несупрессированной вирусной нагрузки через девять месяцев (35). Хотя фактические данные среднего качества двух рандомизированных исследований указывают на аналогичные уровни несоблюдения лечения через 4–6 месяцев (36,37), фактические данные очень низкого качества двух обсервационных исследований указывают на снижение уровней несоблюдения лечения через 6–9 месяцев (35,38). В целом, систематический обзор свидетельствует в пользу использования текстовых сообщений в качестве напоминаний, хотя качество данных было разным, а продолжительность дальнейшего наблюдения была небольшой (до одного года).

Другие формы напоминания пациентам К другим средствам напоминания пациентам относятся предупредительные сигналы, телефонные звонки, электронные дневники и календари. Они используются для направления кратких напоминаний о времени приема АРВ-препаратов, их дозировке и визитах к врачу. Фактические данные не подтверждают, что эти меры способствуют соблюдению схем лечения в большей степени, чем стандартное оказание помощи. Систематический обзор выявил четыре рандомизированных исследования. Фактические данные среднего качества показывают, что риск несупрессированной вирусной нагрузки через 18 месяцев при использовании предупредительных сигналов был таким же, как и при стандартном оказании помощи (19). Фактические данные низкого качества одного рандомизированного исследования также продемонстрировали, что показатели несоблюдения лечения и несупрессированной вирусной нагрузки через три месяца были одинаковыми при использовании телефонных звонков и при стандартном оказании помощи (39). Фактические данные очень низкого качества одного рандомизированного исследования также показывают, что риск несупрессированной вирусной нагрузки через 15 месяцев был схожим при использовании дневников и при стандартном оказании помощи (40). Наконец, фактические данные низкого качества одного рандомизированного исследования указывают на то, что показатели несоблюдения лечения были схожими при использовании календарей и при стандартном оказании помощи через год последующего наблюдения (41). Использование этих мер требует дальнейшего изучения в различных группах населения и при разных условиях.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

205

9.2.3 М ониторинг соблюдения режима АРТ в рамках плановых программ и мест оказания помощи Объективный мониторинг соблюдения режима приема АРВ-препаратов необходим для эффективного и результативного планирования лечения и постоянной помощи. При каждом посещении учреждения имеется возможность оценить ситуацию и оказать содействие в соблюдении схемы лечения. Эффективный мониторинг показателей соблюдения требует сочетания подходов, исходя из наличия людских и финансовых ресурсов, приемлемости для людей, живущих с ВИЧ и для работников здравоохранения, а также местных условий.

9.2 Соблюдение режима АРТ

Мониторинг вирусной нагрузки В настоящем руководстве рекомендуется определять вирусную нагрузку для диагностики и подтверждения эффективности или неудачи лечения. Хотя неэффективность лечения часто бывает вызвана несоблюдением режима АРТ, она может быть связана с другими факторами (такими, как израсходование запасов лекарств, взаимодействие лекарственных средств или плохая усвояемость). Однако мониторинг вирусной нагрузки не позволяет контролировать соблюдение режима в реальном времени и предупреждать ухудшение ситуации, приводящей к неудаче лечения. Таким образом, мониторинг вирусной нагрузки должен сочетаться с другими методами контроля за соблюдением режима лечения.

Учет повторного отпуска лекарственных средств аптеками Учет повторного отпуска лекарственных средств аптеками предоставляет информацию о том, когда люди, живущие с ВИЧ, получают свои АРВ-препараты (42,43). Если люди получают лекарства в аптеках нерегулярно, это может указывать на несоблюдение режима АРТ; однако во многих местах оказания помощи люди могут принимать свои лекарства при получении помощи, независимо от того, насколько они соблюдают режим. В результате такого поведения провайдеры медицинской помощи могут давать завышенную оценку уровня соблюдения требований, если они используют только данные учета повторного отпуска лекарственных средств аптеками. В ходе недавно проведенного исследования по оценке эффективности различных методов мониторинга соблюдения режима лечения было установлено, что данные аптечного учета более надежны, чем самоотчеты (44). Во многих местах данные учета повторного отпуска лекарственных средств аптеками уже являются частью национальных систем мониторинга и оценки и могут также предоставлять дополнительную информацию о соблюдении режима АРТ в сочетании с другими механизмами.

новое

Самоотчет Обращение к людям, живущим с ВИЧ, и лицам, осуществляющим за ними уход, с просьбой сообщать, сколько раз они пропускали прием лекарств с момента последнего посещения (или в течение определенного количества дней в прошлом), может помочь оценить уровень соблюдения режима лечения. Однако, хотя этот метод широко используется, люди могут и не помнить точного числа пропущенных доз или не сообщать об этом, чтобы их считали соблюдающими режим и чтобы избежать критических замечаний. Важнейшими компонентами мониторинга соблюдения режима АРТ в местах планового получения помощи является информирование о том, насколько важно запоминать и/или документировать число принятых АРВ-препаратов, а также наличие условий, обеспечивающих возможность откровенно говорить о несоблюдении режима (45).

206

Подсчет количества таблеток Подсчет остающегося количества таблеток во флаконе может помочь оценить уровень соблюдения режима лечения. Такой подсчет обычно производится при плановых посещениях медицинского учреждения. Однако некоторые люди могут выбрасывать таблетки перед посещением клиники, что приводит к завышенным оценкам уровня соблюдения режима лечения (45,46). Хотя неожиданные посещения людей на дому могут давать более точные оценки, такой подход связан с финансовыми, логистическими и этическими проблемами. Подсчет количества таблеток требует также значительных затрат времени со стороны медицинского персонала и может быть практически неосуществим в местах планового оказания медицинской помощи.

9.3 Удержание пациентов в рамках непрерывного оказания помощи 9.3.1 Общие сведения Удержание людей, живущих с ВИЧ, в рамках непрерывного процесса оказания помощи, имеет важное значение для получения оптимальных результатов лечения. В отношении тех лиц, у которых не имеется непосредственных показаний для АРТ, посещения мест оказания помощи дают возможность проводить скрининг, профилактику и лечение других состояний и сопутствующих заболеваний, включая профилактический прием котримоксазола, ППМР, профилактическое лечение изониазидом и регулярный скрининг на ТБ, а также клинический и лабораторный мониторинг, что позволит своевременно начать АРТ в случае возникновения показаний к ее назначению. Для людей, которые отвечают критериям получения АРТ в момент выявления положительного результата теста на ВИЧ, важное значение имеет незамедлительное установление контактов со службами оказания помощи; задержка на несколько дней или недель для лиц, которые уже страдают ТБ или другими оппортунистическими инфекциями, повышает риск смертности (47,48). Для людей, живущих с ВИЧ, и получающих лечение, непрерывная АРТ и постоянный мониторинг необходимы для достижения устойчивой вирусной супрессии и оптимальных результатов лечения. Удержание лиц, живущих с ВИЧ, в системе оказания помощи – особенно тех, кто еще не отвечает критериям для АРТ, а также тех, кто отвечает критериям, но не начал лечение – является сложной задачей. Изучение имеющихся в литературе данных по странам Африки к югу от Сахары показало, что 54% лиц, которые еще не отвечают критериям для АРТ, выбыли из наблюдения до того, как они стали отвечать этим критериям, в то время как 32% людей, живущих с ВИЧ, отвечающих критериям АРТ, выбыли из наблюдения до начала лечения (49,50). Результаты в отношении лиц, выбывших из наблюдения, могут варьироваться, поскольку в число лиц, выбывших из наблюдения на уровне учреждения здравоохранения, могут входить люди, которые перешли под наблюдение в другое учреждение, неподтвержденные случаи смерти и лица, действительно выбывшие из наблюдения. Люди, которые прекратили обращаться за помощью, особенно не отвечающие критериям АРТ при первоначальном обследовании, часто возвращаются в систему оказания помощи только на поздней стадии заболевания, вызванного ВИЧ. В этих случаях показатели ранней смертности после начала АРТ являются значительными (51,52). Данные о доле людей, продолжающих получать АРТ, в динамике по времени показывают, что в большинстве случаев прекращение получения помощи происходит в первый год после начала лечения. В некоторых местах многие люди, живущие с ВИЧ, которые выбывают из наблюдения в первые месяцы после начала АРТ, погибают (53).

9. Рекомендации по осуществлению деятельности и предоставлению услуг

207

В 2011 г. средний показатель удержания пациентов составлял 81% (данные по 92 странам) через 12 месяцев после начала АРТ, 75% через 24 месяца (данные по 73 странам) и 67% через 60 месяцев (данные по 46 странам) (53). Существует множество факторов, связанных с системами предоставления медицинской помощи и самими пациентами, которые могут способствовать или препятствовать удержанию в рамках оказания помощи при ВИЧ. Меры, направленные на улучшение взаимосвязи и удержание в рамках оказания помощи при ВИЧ – от постановки диагноза и на всех последующих этапах – должны затрагивать вопросы, на которые обращают внимание люди, получающие помощь, касающиеся системы здравоохранения и требующие более целенаправленной оценки в разных условиях и группах населения (54–57).

9.3 Удержание пациентов в рамках непрерывного оказания помощи

9.3.2 Н адлежащая практика удержания пациентов на всех этапах оказания помощи

новое

Оптимальная практика удержания пациентов в системе оказания помощи при ВИЧ требует принятия мер на многих уровнях системы здравоохранения, а также проведения внедренческих исследований. Принимая во внимание широкий круг проблем и различный характер препятствующих факторов в разных местах оказания помощи, не представляется вероятным, что существует единый подход, который будет давать эффективные результаты во всех случаях. Улучшение понимания препятствующих факторов и инновационные стратегии по их устранению являются важнейшими задачами при проведении внедренческих исследований и в работе систем здравоохранения. Результаты исследований показывают, что на возможность удержания людей, живущих с ВИЧ, в рамках оказания помощи влияют прямые и косвенные расходы. По имеющимся данным, препятствием для удержания пациентов в разных местах и на всех этапах оказания помощи при ВИЧ является далекое месторасположение учреждений здравоохранения. Если учреждения здравоохранения расположены далеко от дома, сдерживающим фактором являются транспортные расходы и потеря доходов за время обращения за помощью. Размещение служб ближе к месту жительства в тех случаях, когда это возможно, снижает размер косвенных расходов на получение помощи для людей, живущих с ВИЧ, и их семей и способствует удержанию пациентов. Получение консультации в учреждении здравоохранения нередко требует много времени, особенно в местах с высоким бременем ВИЧ-инфекции (58,59). Реорганизация работы служб, например изменение системы записи на прием и очередности оказания помощи, разделение клинических консультаций и посещений в целях получения лекарств, интеграция и взаимодействие различных служб и оказание помощи, ориентированной на семью – может снизить время ожидания в учреждении здравоохранения (59,60). Многие люди, живущие с ВИЧ, которые еще не отвечают критериям получения АРТ, могут не посещать клинику и не обращаться за помощью, пока у них не появятся симптомы заболевания. Регулярное наблюдение за этими людьми имеет важное значение для обеспечения постоянного контроля и своевременного начала АРТ. В странах применялись различные подходы и были получены положительные результаты, включая бесплатное проведение профилактического лечения котримоксазолом, тестирование на CD4 на местах с получением результатов в тот же день и взаимную поддержку, для улучшения показателей удержания пациентов в системе оказания помощи (22,61,62).

новое

208

Ключевые группы населения обычно сталкиваются с большими препятствиями в доступе к службам здравоохранения. Перспективными мерами борьбы с факторами структурного, экономического и психосоциального характера, препятствующими предоставлению услуг и неблагоприятно влияющими на удержание в системе оказания помощи, является обеспечение общественной поддержки. В Таблице 9.1 кратко представлены факторы, связанные с системой здравоохранения и людьми, получающими АРТ, которые влияют на удержание пациентов и соблюдение режима лечения, а также возможные меры.

Таблица 9.1 Факторы, связанные с системой здравоохранения и людьми, получающими АРТ, которые влияют на удержание пациентов и соблюдение режима лечения, а также возможные меры Факторы, связанные с системой здравоохранения Высокие прямые и косвенные затраты на получение помощи Возможные меры

Бесплатное проведение АРТ, а также диагностики и оказание услуг по месту предоставления помощи Децентрализация АРТ, при наличии возможности П лановые посещения клиники Сокращение времени ожидания в клинике: • Система записи на прием • Разделение клинических консультаций и посещений для получения лекарств • В заимосвязанное, интегрированное и скоординированное оказание помощи • П омощь, ориентированная на семью (организация работы служб с учетом потребностей семьи), в соответствующих случаях

Израсходование запасов АРВ-препаратов

Оптимизация систем управления поставками фармацевтических препаратов для прогнозирования, закупок и предоставления АРВ-препаратов. Использование комбинированных лекарственных средств с фиксированными дозами для упрощения систем прогнозирования и управления закупками Внедрение систем контроля за пациентами на всех этапах оказания помощи, включая когортный анализ и системы слежения за пациентами Взаимосвязанная система контроля за пациентами служб помощи при ВИЧ, ТБ, охраны здоровья матери и ребенка и ППМР; система для перехода от служб педиатрической помощи к службам для подростков и взрослых, а также от служб охраны здоровья матери и ребенка и противотуберкулезных служб к службам долгосрочной помощи при ВИЧ

Отсутствие системы мониторинга удержания пациентов Отсутствие системы перевода пациентов в другие места оказания помощи

9. Рекомендации по осуществлению деятельности и предоставлению услуг

209

Таблица 9.1 (продолжение) Факторы, связанные с системой здравоохранения Большое количество таблеток и сложные схемы приема АРВ-препаратов Отсутствие точной информации для пациентов и их семей и взаимной поддержки Возможные меры

9.3 Удержание пациентов в рамках непрерывного оказания помощи

Использование комбинированных лекарственных средств с фиксированными дозами для уменьшения количества таблеток и упрощения схем лечения Участие и интеграция деятельности участковых работников здравоохранения, добровольцев и людей, живущих с ВИЧ, в программах взаимной поддержки, просвещения и консультирования пациентов, а также поддержки на местном уровне Перераспределение обязанностей для вовлечения участковых работников здравоохранения Взаимосвязь с мерами на уровне местного сообщества и ресурсами, такими как взаимная поддержка соблюдения режима лечения Использование методов напоминания с известным эффектом (например, текстовых сообщений) Взаимная поддержка также для личных напоминаний

Поддержка соблюдения режима лечения

Плохие взаимоотношения между пациентом и провайдером помощи

Обучение работников здравоохранения в следующих областях: борьба со стигматизацией; улучшение показателей обеспечения готовности, соблюдения режима и удержания в системе помощи; предоставление поддержки для соблюдения режима лечения и помощи для ключевых групп населения; и использование упрощенных подходов для просвещения пациентов и их семей Перераспределение и разделение обязанностей между членами клинической группы Люди, живущие с ВИЧ, как пациенты-эксперты и лица, оказывающие взаимную поддержку Коллективный подход к оказанию помощи

Отсутствие времени для просвещения людей в вопросах помощи при ВИЧ

новое

Неблагоприятные эффекты лекарственных средств

Готовность и знание того, как и когда применять самопомощь в отношении неблагоприятных эффектов и когда возвращаться в клинику Использование текстовых сообщений для взаимодействия с пациентами Поддержка окружающих и семьи Связь с группами общественной поддержки

Забывчивость, жизненный стресс, стигматизация и дискриминация

210

Таблица 9.1 (продолжение) Факторы, касающиеся людей, получающих помощь при ВИЧ Сопутствующие заболевания, нарушения, связанные с употреблением психоактивных веществ и алкоголя, и нарушения психического здоровья Знания пациентов и представления, касающиеся ВИЧ-инфекции, ее течения и лечения Возможные меры

Ведение людей с ВИЧ, страдающих нарушениями психического здоровья, нарушениями, связанными с употреблением алкоголя и психоактивных веществ, и связь с мерами коллективной и общественной поддержки

Интеграция мер просвещения и консультирования пациентов и их семей, повышение грамотности и образования местного сообщества и участие местного населения

9.4 Предоставление услуг 9.4.1 Н адлежащая практика предоставления долгосрочной медицинской помощи (63) Во многих странах службы здравоохранения организованы преимущественно для оказания эпизодической помощи при острых состояниях. По мере того как ВИЧ-инфекция становится управляемым хроническим заболеванием, руководители программ и провайдеры помощи должны рассмотреть возможности реорганизации существующих систем здравоохранения таким образом, чтобы они могли предоставлять долгосрочную помощь. После постановки диагноза и включения пациентов в число лиц, получающих долгосрочную помощь, необходимо составить график и план дальнейших посещений клиники. Выжидание до тех пор, пока у людей появятся симптомы или разовьются предупреждаемые осложнения, увеличивает затраты и неэффективно. Людям, живущим с ВИЧ, требуется помощь, которая опережает их потребности на разных этапах непрерывного оказания помощи. По сравнению с моделью оказания помощи при острых состояниях, модели планируемой долгосрочной помощи обеспечивают возможность профилактики, раннего выявлений проблем и своевременного вмешательства. Долгосрочная помощь требует широкой поддержки людей, живущих с ВИЧ, со стороны местного сообщества и работников здравоохранения для того, чтобы они оставались в системе оказания помощи, соблюдали режим лечения и преодолевали проблемы, связанные со стигматизацией. Людей, живущих с ВИЧ, и их семьи необходимо информировать о ВИЧ-инфекции и возможных побочных эффектах лекарственных средств и помогать им соблюдать режим лечения. Работники здравоохранения играют важную роль в обеспечении взаимосвязи людей, живущих с ВИЧ, с местными службами, предоставляющими помощь, ресурсы и поддержку. Для обеспечения непрерывности предоставления помощи важное значение имеет наличие системы хранения информации о людях, получающих помощь в учреждениях здравоохранения. Регистр пациентов служит целям напоминания для служб

9. Рекомендации по осуществлению деятельности и предоставлению услуг

211

последующего наблюдения. Работники здравоохранения могут использовать его для выявления людей, нуждающихся в помощи, и для оценки результатов лечения как отдельных лиц, так и всех пациентов. Информационные системы могут использовать как бумажные картотеки, так и электронные регистры, в зависимости от условий на местах. В рамках программ следует разработать систематизированную стратегию сбора и обобщения основной информации для более эффективного ведения пациентов и обеспечения высокого качества помощи. Надежная информационная система учета пациентов имеет также важнейшее значение для высококачественного мониторинга и оценки программ, а также для систем управления поставками. Если эффективные практические решения, такие как успешные модели предоставления услуг и процессы оказания помощи, выявляются в рамках существующих систем, программам необходимо рассмотреть возможность расширения использования таких моделей оказания помощи.

9.4 Предоставление услуг

9.4.2 Интеграция и взаимодействие служб Долгосрочная помощь требует интеграции и взаимодействия соответствующих служб для обеспечения всестороннего и последовательного ведения пациентов с течением времени, включая предоставление соответствующих услуг в одном месте, наличие систем обмена информацией и эффективного направления для получения специализированной помощи в других местах и у других провайдеров. Интеграция и взаимодействие могут снизить вероятность неиспользования возможностей для проведения АРТ, способствовать длительному соблюдению режима лечения и оптимальному удержанию пациентов в системе оказания помощи. Программы, касающиеся ВИЧ, сексуального и репродуктивного здоровья, охраны здоровья матери и ребенка, ТБ и наркозависимости, должны взаимодействовать для успешного проведения АРТ и предоставления соответствующих услуг на различных уровнях системы здравоохранения. При этом следует принимать во внимание такие вопросы, как мобилизация и распределение ресурсов; обучение, наставничество и курирование работников здравоохранения; закупки и управление поставками лекарственных средств и других медицинских материалов; а также мониторинг и оценка.

9.4.2.1 Предоставление АРТ службами дородовой помощи и охраны здоровья матери и ребенка Новая рекомендация новое

новое

В условиях генерализованной эпидемии службам охраны здоровья матери и ребенка следует начинать и продолжать проведение АРТ беременным и родившим женщинам и грудным детям, отвечающим соответствующим критериям, обеспечивая направление на лечение и взаимодействие, при необходимости, со службами оказания длительной помощи при ВИЧ и проведения АРТ (настоятельная рекомендация, фактические данные очень низкого качества).

212

Общие сведения В 2011 году уровень охвата эффективными схемами приема АРВ-препаратов для ППМР достиг 57% в странах с низким и средним уровнями дохода. Однако в том же году лишь 30% беременных женщин, которые нуждались в АРТ, получали такое лечение, в то время как 54% всех взрослых людей, отвечавших соответствующим критериям, в странах с низким и средним уровнями дохода были охвачены АРТ (53). Обеспечение доступа к АРТ беременным женщинам с ВИЧ, которые отвечают критериям получения лечения, остается серьезной проблемой, так же как и предоставление АРВ-препаратов для ППМР беременным девушкам-подросткам, живущим с ВИЧ, работницам коммерческого секса и женщинам, употребляющим инъекционные наркотики. Поскольку многие женщины, живущие с ВИЧ, имеют доступ к службам здравоохранения только в период беременности, службы охраны здоровья матери и ребенка предоставляют важную возможность расширить доступ к АРТ для тех, кто нуждается в лечении (56,57). В большинстве мест, где эпидемия носит генерализованный характер, услуги в области охраны здоровья матери и ребенка предоставляются на первичном уровне оказания помощи, где большинство беременных женщин и детей получают доступ к услугам здравоохранения. Существующее руководство ВОЗ рекомендует проводить ВИЧ-тестирование и консультирование по инициативе медицинских работников в рамках всех служб дородовой помощи и охраны здоровья матери и ребенка при генерализованной эпидемии, а также рассматривать возможность его проведения среди ключевых групп населения в рамках служб дородовой помощи и охраны здоровья матери и ребенка при концентрированной эпидемии и эпидемии низкого уровня (64). В настоящем руководстве 2013 года рекомендуется назначать трехкомпонентные схемы АРТ или профилактический прием АРВ-препаратов всем беременным и кормящим грудью женщинам, живущим с ВИЧ, при любом количестве клеток CD4 и предлагается странам принимать решение о том, продолжать ли такое лечение всем беременным и кормящим грудью женщинам или только тем, кто отвечает критериям для получения лечения по состоянию здоровья. Таким образом, следует обеспечить возможность проведения АРТ в рамках служб охраны здоровья матери и ребенка или связанных с ними клинических служб. Страны с генерализованной эпидемией могут рассмотреть возможность использования поэтапного подхода к предоставлению АРТ службами охраны здоровья матери и ребенка и эффективной трансформации таких служб в пункты проведения АРТ, отдавая приоритет местам с наиболее высокими показателями распространения ВИЧ и создавая системы здравоохранения, обеспечивающие непрерывное проведение АРТ, соблюдение режима лечения и удержание пациентов. Задачей является продолжение АРТ по завершении периода, когда существует риск передачи ВИЧ от матери ребенку. Не все службы охраны здоровья матери и ребенка располагают возможностями для предоставления долгосрочной помощи и лечения при ВИЧ женщинам, их партнерам и грудным детям. Этим службам следует определить оптимальные сроки направления матерей и их детей на лечение и обеспечить взаимодействие со службами оказания длительной помощи при ВИЧ. Это может включать оценку достигнутого прогресса в лечении этих женщин, потенциальных возможностей и качества помощи при ВИЧ в рамках служб охраны здоровья матери и ребенка, а также приемлемости и близости расположения альтернативных служб помощи при ВИЧ.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

213

Обоснование и подтверждающие данные В рамках систематического обзора была проведена оценка влияния предоставления помощи и лечения при ВИЧ службами дородовой помощи и охраны здоровья матери и ребенка на показатели доступа к АРТ, смертности, заболеваемости и удержания пациентов для продолжения АРТ в условиях генерализованной эпидемии. В одном кластерном рандомизированном исследовании и трех обсервационных исследованиях оценивались результаты предоставления АРТ службами дородовой помощи и охраны здоровья матери и ребенка по сравнению с результатами направления людей в клиники оказания помощи при ВИЧ для получения АРТ. Это оказало положительное влияние на показатели соблюдения режима АРТ во время беременности, обращения за помощью и получения АРТ женщинами, живущими с ВИЧ. Были получены сопоставимые результаты в отношении материнской смертности, заболеваемости, иммунного ответа, тестирования грудных детей на ВИЧ, передачи ВИЧ от матери ребенку и удовлетворенности полученной помощью. Качество некоторых этих исследований было переведено в более низкую категорию ввиду относительно небольшого числа событий (65–70). Альтернативой предоставлению АРТ службами дородовой помощи и охраны здоровья матери и ребенка является направление отвечающих критериям женщин и грудных детей в учреждения помощи при ВИЧ для получения соответствующего лечения. Система направлений на получение помощи может являться причиной низкого охвата АРТ беременных и кормящих грудью женщин и грудных детей (57). Модель, основанная на системе направлений, может потребовать, чтобы женщины и дети получали помощь в разных службах, в результате чего беременные женщины должны будут совершать поездки и ждать в очередях для получения помощи и лечения в связи с ВИЧ. Исследования, проведенные в Малави (55), Уганде (56) и Зимбабве (57), показали, что длинные очереди в клиниках оказания помощи при ВИЧ и стоимость проезда от дома до этих клиник являются основными причинами выбытия беременных и кормящих грудью женщин из наблюдения. Хотя программы борьбы с ВИЧ могут инвестировать средства в расширение доступа и сокращение сроков ожидания в учреждении здравоохранения, предоставление АРТ в местах, где беременные и кормящие грудью женщины уже получают помощь, может улучшить доступ и обеспечить возможности для непрерывного получения помощи от тестирования на ВИЧ до проведения АРТ в одном месте, где предоставляется также дородовая и послеродовая помощь. В недавно проведенном исследовании был продемонстрирован положительный опыт получения женщинами АРТ в клиниках дородовой помощи. Они сообщали, что персонал «обращался с ними» хорошо, они «получали полезные советы», а их детям была оказана «хорошая помощь», в результате чего у них не было ВИЧ-инфекции. В другом исследовании изучалась практическая возможность предоставления АРТ службами охраны здоровья матери и ребенка, а также приемлемость этого для медицинского персонала клиник дородовой помощи. Провайдеры полагали, что интеграция способствует повышению эффективности, снижению времени, проводимого людьми в клиниках, улучшению взаимоотношений с провайдерами и соблюдению режима АРТ в результате снижения стигматизации и соблюдения большей конфиденциальности. Все эти факторы усиливают удовлетворенность людей полученной помощью и могут способствовать повышению качества помощи (66,71).

новое

9.4 Предоставление услуг

214

9.4.2.2 Проведение АРТ в противотуберкулезных учреждениях и противотуберкулезное лечение в учреждениях по оказанию помощи при ВИЧ Новые рекомендации новое

При высоком уровне распространенности ВИЧ и ТБ следует начинать проведение АРТ среди людей, живущих с ВИЧ, в противотуберкулезных учреждениях, обеспечивая взаимодействие со службами оказания длительной помощи при ВИЧ и проведения АРТ (настоятельная рекомендация, фактические данные очень низкого качества). При высоком уровне распространенности ВИЧ и ТБ противотуберкулезное лечение может предоставляться людям, живущим с ВИЧ, в учреждениях по оказанию помощи при ВИЧ, где был поставлен также диагноз ТБ (настоятельная рекомендация, фактические данные очень низкого качества).

Общие сведения В 2011 году 79% и 48% людей, страдающих ТБ, с установленной ВИЧ-инфекцией получали, соответственно, профилактическое лечение котримоксазолом и АРТ (72). Процент людей, страдающих ТБ, с документированными положительными результатами теста на ВИЧ, которые получали АРТ, превышал 75% только в 6 из 41 стран мира с наивысшими показателями бремени ВИЧ и ТБ. С 2010 года ВОЗ рекомендовала проведение АРТ всем больным ТБ, живущим с ВИЧ, независимо от количества CD4. Следует начинать с противотуберкулезного лечения, после чего приступать к проведению АРТ в кратчайшие возможные сроки в течение восьми недель после начала противотуберкулезного лечения. Всем больным ТБ с ВИЧ-инфекцией также рекомендуется проводить профилактическое лечение котримоксазолом. Эти рекомендации по предоставлению услуг призваны способствовать расширению охвата АРТ людей с ВИЧ и ТБ, а также ранней диагностике и лечению ТБ среди людей, живущих с ВИЧ. Хотя противотуберкулезная помощь была децентрализована до уровня местного сообщества в большинстве случаев, во многих местах доступ к лечению ВИЧ остается сложной задачей. Данные исследования, проведенного ВОЗ, показывают, что соотношение числа учреждений здравоохранения, предоставляющих противотуберкулезное лечение, к числу учреждений, предоставляющих АРТ, колеблется от 1,3 до 30,2 (72). Кроме того, несмотря на высокое бремя коинфекции ВИЧ и ТБ, услуги по лечению ВИЧ и ТБ могут представляться в географически разных местах. Хотя программы борьбы с ВИЧ и ТБ могут инвестировать финансовые и людские ресурсы в улучшение доступа и сокращение времени, связанного с получением помощи, предоставление АРТ и противотуберкулезного лечения в одном месте может улучшать доступ и соблюдение режимов лечения ВИЧ и ТБ, обеспечивая непрерывность оказания помощи от тестирования на ВИЧ до одновременного лечения ВИЧ и ТБ в одном месте. Внедрение мер инфекционного контроля в отношении ТБ имеет важнейшее значение в местах оказания помощи при ВИЧ для минимизации риска нозокомиальной (происходящей в учреждении здравоохранения) передачи ТБ. Рекомендации ВОЗ в отношении инфекционного контроля ТБ в учреждениях здравоохранения приводятся в Разделе 8.1.2.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

215

Обоснование и подтверждающие данные Поскольку у людей с ВИЧ и ТБ, не получающих АРТ и профилактическое лечение котримоксазолом, наблюдаются высокие показатели смертности, а комбинированный прием АРТ и котримоксазола улучшает показатели выживаемости (73–75), расширение охвата АРТ и котримоксазолом имеет важнейшее значение для сокращения числа людей, погибающих от ВИЧ и ТБ во всем мире. В систематическом обзоре по изучению эффективности предоставления АРТ в противотуберкулезных учреждениях были выявлены 19 обсервационных исследований, многие из которых указывали на рост числа случаев проведения АРТ и своевременного начала АРТ. Однако данные о смертности и успешных результатах лечения ТБ были непоследовательными. Систематический обзор по оценке эффективности предоставления противотуберкулезного лечения в местах оказания помощи при ВИЧ выявил пять обсервационных исследований: в двух исследованиях сообщалось о снижении смертности, а в одном приводились сопоставимые показатели смертности. Показатели успешности лечения ТБ и проведения АРТ в разных исследованиях были сопоставимыми. Качество фактических данных оценивалось с учетом программных рисков и преимуществ; приемлемости; ценностей; предпочтений; финансовых последствий; практической осуществимости; основных ограничивающих факторов контекстуального характера; и контекстуальной значимости. Было достигнуто общее согласие в том, что хотя качество фактических данных не было высоким по классификации GRADE, имелись достаточные основания для того, чтобы рекомендации носили настоятельный характер (76–96).

9.4 Предоставление услуг

9.4.2.3 АРТ в местах проведения опиоидной заместительной терапии Новая рекомендация Проведение АРТ следует начинать и продолжать среди лиц, живущих с ВИЧ, отвечающих соответствующим критериям, в местах проведения опиоидной заместительной терапии (ОЗТ) (настоятельная рекомендация, фактические данные очень низкого качества). новое новое

Общие сведения Данные из 49 стран показывают, что употребление инъекционных наркотиков увеличивает риск ВИЧ-инфицирования в 22 раза по сравнению с общепопуляционным риском, а в странах Восточной Европы до 40% ВИЧинфицированных лиц составляют потребители инъекционных наркотиков и их половые партнеры (97). В существующем руководстве ВОЗ сказано, что следует рекомендовать проведение тестирования на ВИЧ и консультирования для всех людей, посещающих наркологические службы в условиях генерализованных, концентрированных эпидемий и эпидемий низкого уровня, если это социально приемлемо и целесообразно с эпидемиологической точки зрения. В планах проведения тестирования и консультирования в таких местах по инициативе провайдера следует уделять особое внимание созданию благоприятных механизмов социальной, стратегической и правовой поддержки (64).

216

В этом руководстве рекомендуются одинаковые критерии предоставления АРТ для всех взрослых лиц, независимо от употребления наркотиков. Глобальные данные об охвате АРТ ключевых групп населения носят ограниченный характер; однако среди имеющихся данных часто наблюдаются различия в показателях охвата между потребителями инъекционных наркотиков и населением в целом. Согласно опубликованному в 2010 году докладу, в 19 странах Европы и Центральной Азии с низким и средним уровнями дохода лишь 22% людей, живущих с ВИЧ, которые употребляли инъекционные наркотики и отвечали критериям проведения АРТ, получали такое лечение (53). Для лечения опиоидной зависимости ВОЗ рекомендует проведение опиоидной заместительной терапии (с применением метадона или бупренорфина) в сочетании с психосоциальной помощью (98). Если число людей, живущих с ВИЧ и имеющих опиоидную зависимость, велико, лечение опиоидной зависимости следует интегрировать и проводить в сочетании с лечением ВИЧ. Хотя результаты АРТ улучшаются у людей, живущих с ВИЧ и употребляющих инъекционные наркотики, которые имеют также доступ к опиоидной заместительной терапии, посещение ими служб, проводящих опиоидную заместительную терапию, не должно являться обязательным условием начала или продолжения АРТ для лиц, употребляющие опиоидные наркотики. Тем не менее, предоставление АРТ в местах, где проводится опиоидная заместительная терапия, может способствовать расширению доступа к АРТ для потребителей инъекционных наркотиков. В рамках комплексных мер, направленных на снижение вреда, следует также проводить работу в отношении сопутствующих заболеваний, вызванных употреблением алкоголя, нарушений психического здоровья, ТБ и вирусного гепатита, что требует наличия квалифицированных кадров широкого профиля и тесного сотрудничества в рамках сектора здравоохранения. Принимая во внимание, что потребители инъекционных наркотиков часто попадают в места лишения свободы, следует стремиться к тому, чтобы обеспечить наличие АРТ в рамках тюремных служб здравоохранения для непрерывности оказания помощи при ВИЧ и проведения АРТ после выхода этих людей на свободу.

Обоснование и подтверждающие данные Во многих странах потребители инъекционных наркотиков являются маргинализованными группами населения, имеющими ограниченный доступ к службам здравоохранения и их использованию. Основными причинами смерти в этой группе населения являются передозировка наркотиков и СПИД (99). Рандомизированные исследования показали, что опиоидная заместительная терапия снижает незаконное употребление наркотиков и повышает показатели удержания в системе оказания помощи по сравнению с плацебо (98). Обсервационные исследования указывают на то, что опиоидная заместительная терапия снижает уровень смертности по сравнению с теми, кто не получает лечения (100). Результаты АРТ также улучшаются у людей с ВИЧ, употребляющих инъекционные наркотики, которые получают опиоидную заместительную терапию (16). В рамках систематического обзора было выявлено одно рандомизированное исследование и три обсервационных исследования по изучению эффективности проведения АРТ в местах, где предоставляется опиоидная заместительная терапия. В большинстве этих исследований размер выборки был небольшим, что ограничивает их статистическую значимость. В некоторых исследованиях наблюдались тенденции к улучшению вирусной супрессии и снижению смертности, в то время как в других отмечались сопоставимые показатели вирусной супрессии и смертности (101–103).

9. Рекомендации по осуществлению деятельности и предоставлению услуг

217

В данной рекомендации основное внимание уделяется расширению доступа к АРТ путем ее проведения в местах, где предоставляется опиоидная заместительная терапия. Уровень охвата опиоидной заместительной терапией во многих местах также остается низким, и лица, формирующие политику, должны определить, является ли предоставление опиоидной заместительной терапии в местах оказания помощи и лечения при ВИЧ практически осуществимым. Если органы или сектор здравоохранения не руководит деятельностью наркологических служб, программы борьбы с ВИЧ должны тесно сотрудничать с отделами социального обеспечения, а также общественными и неправительственными организациями, которые оказывают такие услуги.

9.4 Предоставление услуг

9.4.3 Децентрализация лечения и помощи при ВИЧ Новые рекомендации

новое

Необходимо рассмотреть следующие возможности в отношении децентрализации инициирования и проведения АРТ. Инициирование АРТ в больницах при дальнейшем проведении АРТ в периферийных медицинских учреждениях (настоятельная рекомендация, фактические данные низкого качества). Инициирование и проведение АРТ в периферийных медицинских учреждениях (настоятельная рекомендация, фактические данные низкого качества). Инициирование АРТ в периферийных медицинских учреждениях при дальнейшем проведении терапии по месту жительства (то есть вне учреждений здравоохранения, таких как выездные бригады, медицинские пункты, службы помощи на дому или местные общественные организации) в период между регулярными посещениями клиники (настоятельная рекомендация, фактические данные среднего качества).

Общие сведения Хотя быстрое расширение масштабов программы борьбы с ВИЧ значительно улучшило доступ к АРТ и способствовало улучшению состояния здоровья и продлению жизни людей, живущих с ВИЧ, это ставит также серьезные задачи перед системами здравоохранения. Децентрализация АРТ на уровне первичной медикосанитарной помощи может уменьшить бремя повседневного руководства в других частях системы здравоохранения и способствовать усилению соблюдения принципа справедливости путем обеспечения доступа к АРТ в сельской местности. В некоторых местах транспортные расходы являются серьезным препятствием для доступа к оказанию помощи и удержания пациентов в ее рамках. Во многих местах с высокими показателями распространенности ВИЧ-инфекции время ожидания в больницах велико в связи с большим количеством пациентов, нуждающихся в помощи. Децентрализация помощи и лечения при ВИЧ может снизить нагрузку на работников здравоохранения, что сократит время ожидания для людей с ВИЧ и лиц, получающих помощь в больницах в отношении других заболеваний и приблизит службы помощи при ВИЧ к месту проживания этих людей. В некоторых местах службы, связанные с проблемой ВИЧ, такие как службы противотуберкулезной помощи и охраны

новое

218

здоровья матери и ребенка, децентрализованы на уровне первичной медикосанитарной помощи. Люди, живущие с ВИЧ, затронутые этой проблемой сообщества и меры вмешательства по месту жительства играют решающую роль в проведении тестирования на ВИЧ, предоставлении помощи и лечения, а также социальной поддержки. Децентрализация помощи и лечения при ВИЧ может способствовать более активному участию местного сообщества, обеспечивая взаимосвязь мер, осуществляемых на уровне местного сообщества, с учреждениями здравоохранения, а также может оптимизировать доступ к службам, обращаемость за медицинской помощью и показатели удержания в рамках помощи.

Обоснование и подтверждающие данные Систематический обзор выявил два обсервационных исследования для изучения того, как децентрализация инициирования и проведения АРТ в периферийных медицинских учреждениях влияет на отток пациентов (в результате смерти и выбытия из наблюдения). Величина оттока снижается через 12 месяцев, что объясняется, в основном, значительным сокращением случаев выбытия из наблюдения. Систематический обзор выявил четыре обсервационных исследования для изучения того, как проведение АРТ в периферийных медицинских учреждениях влияет на отток пациентов. По данным этого обзора величина оттока снижается через 12 месяцев, что объясняется сокращением случаев как выбытия из наблюдения, так и смерти пациентов. Систематический обзор также выявил два кластерных рандомизированных исследования для изучения влияния на отток пациентов проведения АРТ по месту жительства. Уровни оттока пациентов через 12 месяцев были сопоставимыми (104–115). При принятии решения о том, какой вариант децентрализации следует принять, руководители программ могут принимать во внимание следующие факторы: (1) вероятное количество людей, живущих с ВИЧ, которые будут посещать децентрализованные службы; (2) обеспечит ли децентрализация приближение служб к месту жительства людей, которым иначе приходится ездить на большие расстояния для получения АРТ; и (3) снижает ли децентрализация АРТ нагрузку, которую испытывают централизованные учреждения здравоохранения. Эта рекомендация призывает к обеспечению взаимосвязи с поставками диагностических и лекарственных средств, предоставлением услуг, обучением и контролем за деятельностью работников здравоохранения для поддержания качества помощи. Кроме того, в некоторых местах децентрализация АРТ приведет к перераспределению обязанностей для обеспечения требуемой структуры кадров здравоохранения в периферийных учреждениях. Дополнительные рекомендации приводятся в практическом руководстве ВОЗ по предоставлению помощи и лечения при ВИЧ в центрах первичной медико-санитарной помощи в условиях высокой распространенности ВИЧ и ограниченности ресурсов (116).

Практические аспекты проведения децентрализации АРТ Практические аспекты, касающиеся руководителей программ, приводятся во Вставке 10.5.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

219

9.5 Кадровые ресурсы 9.5.1 Наращивание кадрового потенциала За последнее десятилетие, в условиях быстрого расширения масштабов помощи и лечения при ВИЧ, обучение без отрыва от производства стало играть важную роль для скорейшего повышения квалификации работников здравоохранения. Все работники здравоохранения, в том числе участковые, нуждаются в регулярном обучении, наставничестве и контроле за их деятельностью для обеспечения высокого качества помощи и выполнения обновленных национальных рекомендаций. Принимая во внимание быстрые темпы роста знаний о помощи и лечении при ВИЧ, странам следует рассмотреть возможность создания системы постоянного повышения квалификации работников здравоохранения, включая клиническое наставничество и регулярный поддерживающий контроль. Использование новых технологий, таких как компьютерное самообучение, дистанционное обучение, онлайновые курсы и консультации по телефону, могут дополнить учебные занятия в классе без отрыва от производства и способствовать эффективному использованию рабочего времени и других ресурсов (116,117). Однако столь же важно охватывать все аспекты и усиливать помощь и лечение при ВИЧ в рамках существующих учебных курсов до поступления на работу, чтобы обеспечить подготовку и сертификацию работников здравоохранения по различным дисциплинам. Работникам здравоохранения также следует обладать навыками ведения ВИЧ как хронического заболевания, а также уметь работать в команде и знать национальные нормативные положения и протоколы оказания помощи. В некоторых странах люди, живущие с ВИЧ, другие участковые работники и добровольцы уже участвуют в проведении тестирования на ВИЧ, консультировании, оказании помощи, лечении и социальном обеспечении. Кроме того, люди, живущие с ВИЧ, участвуют в обучении работников здравоохранения в качестве инструкторов-экспертов. Участие людей, живущих с ВИЧ, как в обучении работников здравоохранения, так и в работе служб помощи при ВИЧ, может также способствовать преодолению стигматизации, связанной с ВИЧ. Странам следует рассмотреть возможность проведения долгосрочной реформы, которая

9.5 Кадровые ресурсы

9.5.2 П ерераспределение обязанностей для лечения и оказания помощи при ВИЧ Новые рекомендации Квалифицированный неврачебный клинический персонал, акушерки и медсестры могут инициировать проведение АРТ первого ряда (настоятельная рекомендация, фактические данные среднего качества). Квалифицированный неврачебный клинический персонал, акушерки и медсестры могут продолжать проведение АРТ (настоятельная рекомендация, фактические данные среднего качества). Квалифицированные и работающие под контролем участковые медицинские работники могут отпускать препараты для АРТ в период между регулярными посещениями клиники (настоятельная рекомендация, фактические данные среднего качества). новое

новое

220

может способствовать выполнению стратегий в области кадровых ресурсов, связанных с перераспределением обязанностей и подготовкой работников здравоохранения нового типа (например, для тестирования на ВИЧ или проведения взаимных коллегиальных консультаций) на устойчивой основе в рамках всесторонней национальной нормативноправовой базы (законы и нормативные акты, правила и предписания, меры политики и руководящие принципы). Хотя добровольцы могут вносить важный вклад на краткосрочной и временной основе, все квалифицированные работники здравоохранения, которые предоставляют основные медико-санитарные услуги, включая участковых работников здравоохранения, должны получать адекватную заработную плату и/или другие надлежащие и соответствующие меры поощрения (116).

Общие сведения Реорганизация, интеграция и децентрализация служб лечения и помощи при ВИЧ потребуют пересмотра функций и обязанностей групп работников здравоохранения, участвующих в оказании длительной помощи при ВИЧ. Перераспределение обязанностей предусматривает рациональное перераспределение функций в группе работников здравоохранения. При таком подходе конкретные функции передаются, при необходимости, от высококвалифицированных работников здравоохранения работникам с более низким уровнем подготовки и меньшей квалификацией для более эффективного и результативного использования имеющихся кадровых ресурсов. Перераспределение обязанностей следует осуществлять одновременно с выполнением других стратегий, предназначенных для увеличения численности и потенциала работников здравоохранения всех типов. Во многих местах с высоким бременем ВИЧ численность медицинского персонала остается недостаточной. Хотя усиление потенциала стран по подготовке бóльшего числа работников здравоохранения имеет решающее значение, клинические обязанности должны разделяться и распределяться, чтобы обеспечить достаточную численность медицинских работников для оказания помощи людям с ВИЧ. Перераспределение обязанностей способствует улучшению доступа к АРТ в местах, где отсутствует врачебный персонал (например, в сельских медпунктах, службах противотуберкулезной помощи и охраны здоровья матери и ребенка). Перераспределение обязанностей также позволяет врачам уделять больше времени для ведения более сложных клинических случаев, таких как случаи коинфекции и других сопутствующих заболеваний, токсичность АРТ или неэффективное лечение. Согласно рекомендациям, содержащимся в руководстве ВОЗ 2008 года (118), медсестры и неврачебный клинический персонал могут инициировать и проводить АРТ первого ряда, а участковые работники здравоохранения в общине везде: могут осуществлять мониторинг лиц, получающих АРТ, в ходе длительного последующего наблюдения. Поскольку эти рекомендации основывались преимущественно на анализе программ и передового опыта, при разработке этого сводного руководства были рассмотрены фактические данные, касающиеся перераспределения обязанностей при проведении АРТ. В этом руководстве инициирование АРТ включает оценку соответствия требованиям АРТ (на основе клинических и/или иммунологических критериев); оценку наличия оппортунистических инфекций; консультирование по вопросам соблюдения режима лечения; и назначение АРТ первого ряда. Проведение АРТ включает текущую оценку клинического состояния; мониторинг токсичности; неудовлетворительные результаты лечения (клинические, иммунологические и вирусологические), а также наличие оппортунистических и других сопутствующих инфекций; консультирование по вопросам соблюдения режима лечения; и дальнейшее назначение препаратов для АРТ. Отпуск препаратов для АРТ включает оценку новых признаков и симптомов, контроль за соблюдением режима лечения, а также оказание поддержки и выдачу лекарственных препаратов пациентам, уже получающим АРТ, в период между регулярными посещениями клиники.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

221

Обоснование и подтверждающие данные В ходе систематического обзора были выявлены три рандомизированных исследования и шесть обсервационных исследований по вопросам перераспределения обязанностей. В целом, данные указывают на отсутствие различий в показателях смертности и выбытия из системы помощи, когда медсестры или неврачебный клинический персонал инициируют или проводят АРТ или участковые работники здравоохранения проводят АРТ по сравнению с оказанием этих услуг врачами. Качество оказываемой помощи в этих исследованиях обеспечивалось путем (1) обучения, наставничества, контроля и поддержки медсестер, неврачебного клинического персонала и участковых работников здравоохранения; (2) четких показаний для направления пациентов в другие учреждения; (3) внедрения системы направлений; и (4) внедрения систем мониторинга и оценки. Просветительная работа среди пациентов может помочь им и их семьям понять, что качество помощи, оказываемой медсестрами и участковыми работниками здравоохранения, не ниже, чем врачебным персоналом (106–108,111,113,114,119–121). Передача функций инициирования и проведения АРТ медсестрам и участковым работникам здравоохранения должной квалификации под соответствующим контролем может обеспечить значительную экономию средств за счет (1) децентрализации оказания помощи на уровне первичных служб здравоохранения; (2) снижения накладных расходов при предоставлении высококачественной помощи (при сопоставимых или лучших результатах) медсестрами, неврачебным клиническим персоналом и участковыми работниками здравоохранения по сравнению с врачами; и (3) снижения расходов на содержание помещений и коммунальное обслуживание (если помощь предоставляется в учреждениях здравоохранения в сочетании со службами на уровне местного сообщества).

9.6 Лабораторные и диагностические службы

9.6 Лабораторные и диагностические службы 9.6.1 Обзор Рекомендации, содержащиеся в данном руководстве, направлены на расширение доступа к службам помощи и лечения при ВИЧ, что требует, в свою очередь, расширения доступа к лабораторным и диагностическим службам. Для обеспечения точности и надежности тестирования необходимо разработать и укрепить соответствующие системы обеспечения качества. Тестирование в стране может проводиться в разных условиях, например в лабораториях, клиниках охраны здоровья матери и ребенка, пунктах тестирования на ВИЧ и консультирования, в связи с чем следует разработать и использовать многосторонний и коллективный подход к выбору средств диагностики и лабораторных систем. Поскольку число новых диагностических тестов и систем оказания помощи на местах возрастает, необходимо обеспечить использование только высококачественных средств диагностики и оборудования. Для их надлежащего использования и экономической эффективности следует осуществлять стратегическое планирование для правильного размещения и гармонизации платформ тестирования.

новое

222

9.6.2 Вопросы осуществления и передовой опыт В рекомендациях по усилению лабораторных и диагностических служб подчеркивается важное значение лидерства и стратегического руководства, высококачественных лабораторных служб, расширения служб тестирования и подготовки кадров здравоохранения для достижения следующих целей: у крепление и расширение лабораторных и диагностических служб; п оддержка создания специальной системы направления образцов на исследования; р асширение доступа к тестированию на вирусную нагрузку ВИЧ; п оддержка расширения диагностических служб, включая тестирование по месту оказания помощи; о бучение и сертификация работников здравоохранения, проводящих тестирование; и о беспечение высококачественной диагностики и планов ее осуществления, включая гарантию качества.

9.6.3 У крепление и расширение лабораторных и диагностических служб Следующие области имеют важное значение для усиления сети лабораторных и диагностических служб для выполнения рекомендаций, содержащихся в руководстве: тандартизация методов тестирования для рационализации закупок, обеспечения с качества и обучения; ведение новых подходов и систем тестирования в национальные стратегические планы в и меры политики; ценка эффективности и операционных характеристик диагностических средств для о подтверждения алгоритмов тестирования (с возможностью дублирования результатов) до их введения; роведение стратегического планирования для правильного размещения и п гармонизации платформ тестирования для обеспечения надлежащего использования и экономической эффективности; асширение существующих лабораторных сетей для поддержки и мониторинга р децентрализации и интеграции служб тестирования или для обеспечения доступа к тестированию, когда службы диагностики по месту предоставления помощи отсутствуют; и аспределение соответствующих ресурсов для обеспечения наличия служб р тестирования, включая людские и финансовые ресурсы.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

223

9.6.4 Поддержка создания специальной системы направления образцов на исследования Система направления в лаборатории и процедуры сбора и обработки образцов должны быть усилены для расширения доступа к тестированию вирусной нагрузки, а также для проведения других тестов (например, CD4 и ранняя диагностика у грудных детей). Для создания и укрепления специальной эффективной, безопасной и экономически эффективной системы направления образцов требуется надежная транспортировка образцов с соблюдением адекватных условий для цельной крови, плазмы и сухих капель капиллярной крови (СККК), а также оперативное и ответственное представление результатов тестов направившему образцы учреждению, обеспечивая взаимосвязь со службами помощи. Оперативное представление результатов имеет важное значение для своевременного оказания помощи.

9.6 Лабораторные и диагностические службы

9.6.5 Расширение доступа к тестированию на вирусную нагрузку ВИЧ В данном руководстве предлагается проводить мониторинг эффективности лечения и диагностики и подтверждать случаи неэффективности лечения с помощью определения вирусной нагрузки. Это потребует усиления существующих лабораторных служб и постепенного расширения служб для проведения мониторинга в периферийных учреждениях, включая: у крепление и усиление существующих сетей тестирования на CD4 и ранней диагностики у грудных детей; беспечение наличия у лабораторий адекватной инфраструктуры, технических знаний о и опыта в области тестирования, а также программ обеспечения качества и повышения качества; беспечение надлежащего сочетания программ массового централизованного о лабораторного тестирования и тестирования по месту оказания помощи для далеко расположенных учреждений; и и спользование сухих капель крови в качестве средства расширения доступа к определению вирусной нагрузки.

9.6.6 Р асширение диагностических служб для проведения тестирования по месту оказания помощи Для децентрализации лабораторных и диагностических служб требуется, чтобы до введения таких служб в действие имелись все аспекты, необходимые для проведения лабораторных тестов, включая: и спользование только высококачественных, аттестованных и надежных диагностических тестов; беспечение контроля и мониторинга качества и надежности тестов, проводимых о по месту оказания помощи; существление стратегии по управлению цепочкой поставок и обслуживания о оборудования; и оздание систем управления данными для своевременного выявления проблем с в отношении качества и представления региональных и национальных данных.

новое

224

В Таблице 9.2 приводятся рекомендации по организации служб тестирования на разных уровнях системы предоставления медицинской помощи.

Таблица 9.2 Многоступенчатая лабораторная сеть на разных уровнях системы предоставления медицинской помощи Уровень предоставления медицинской помощи Национальный Лабораторные исследования Кадровые ресурсы

Иммуноферментные анализы для диагностики Высокое число CD4 Молекулярные технологии изучения ВИЧ, включая определение вирусной нагрузки ВИЧ, а также количественную и качественную раннюю диагностику у грудных детей Определение лекарственной устойчивости ВИЧ

Старшие специалисты по лабораторным исследованиям

Региональный или территориальный

Специалисты по лабораторным исследованиям и старшие лаборанты

Районный

Иммуноферментные анализы для диагностики Низкое число CD4 Химия, гематология и микробиология

Лаборанты и помощники

Первичная помощь

Диагностические экспресс-тесты на ВИЧ и другие тесты по месту оказания помощи Сбор СККК

Квалифицированные работники здравоохранения первого уровня, такие как медсестры и старшие сестры Участковые работники здравоохранения

Местное сообщество

Диагностические экспресс-тесты на ВИЧ

Источник: адаптировано по: WHO expert meeting report on short, medium, and longer term product development priorities in HIV-related diagnostics, 6–7 June 2012, Geneva, Switzerland (122).

9. Рекомендации по осуществлению деятельности и предоставлению услуг

225

9.6.7 П редоставление рекомендаций по наращиванию кадрового потенциала здравоохранения, включая обучение и сертификацию персонала Страны нуждаются в руководстве по повышению квалификации персонала, выполняющего лабораторные тесты. Это руководство должно включать требования к обучению для выполнения конкретных тестов и процесса сертификации и повторной сертификации. Все работники здравоохранения, назначенные для проведения тестов по месту оказания помощи, должны иметь квалификацию и опыт работы по выполнению процедур тестирования, сбора образцов и обеспечения качества до оказания таких услуг.

9.7 Системы управления закупками и поставками

9.6.8 Внедрение комплексных систем управления качеством Разработка комплексной системы управления качеством, включая внешнюю оценку качества и контроля качества, имеет важное значение. Система управления качеством должна: б ыть введена в действие в рамках лабораторной сети и во всех отдаленных пунктах тестирования; быть включена в стандартные процедуры тестирования и подвергаться мониторингу; беспечивать проведение контроля качества в пунктах тестирования, о в соответствующих случаях; беспечивать участие пунктов тестирования в программе внешней оценки качества о (программе квалификационных испытаний); беспечивать использование стандартных операционных процедур для всех процессов, о включая сбор и обработку образцов, методы тестирования, интерпретацию результатов и отчетность; беспечивать использование стандартизированных регистрационных журналов о или электронных систем управления данными и составления отчетности, включая выявление ошибок и возможной неправильной классификации; и беспечивать техническое обслуживание оборудования и помещений как с о профилактической целью, так и для устранения неисправностей.

9.7 Системы управления закупками и поставками 9.7.1 Обзор Обеспечение постоянного наличия в достаточном объеме качественных и доступных по цене основных лекарственных и диагностических средств, а также других расходных материалов в местах предоставления услуг является основной функцией систем управления закупками и поставками. Возрастающее число лиц, которым требуется длительная помощь при ВИЧ, особенно в условиях высокой распространенности ВИЧинфекции, требует бесперебойных поставок медицинской продукции, связанной с ВИЧ. Это может быть достигнуто только путем укрепления системы управления закупками и поставками на всех уровнях системы здравоохранения. Кроме того, рекомендации в отношении лекарственных форм и режима приема АРВ-препаратов, а также лечения при ВИЧ должны регулярно обновляться в результате изменения ситуации и появления новых фактических данных. Это требует наличия более эффективной и динамичной системы управления поставками, что позволит избежать расточительного использования средств и дефицита средств.

новое

226

9.7.2 Обоснование и подтверждающие данные Успешное выполнение программ борьбы с ВИЧ возможно только в том случае, если все службы, предоставляющие АРТ, располагают системой бесперебойных и постоянных поставок высококачественных АРВ-препаратов, желательно прошедших преквалификацию ВОЗ. Другими фармакологическими средствами, необходимыми для предоставления АРТ, являются средства для профилактики или лечения оппортунистических инфекций, а также лабораторные реагенты, материалы и оборудование для диагностики ВИЧ и оппортунистических инфекций, контроля за прогрессированием ВИЧ-инфекции и эффективности лечения, а также выявления неблагоприятных лекарственных реакций. Поскольку выдача всех необходимых фармацевтических препаратов в одном учреждении здравоохранения может не представляться возможной, в некоторых местах может возникнуть необходимость направления пациентов в другие службы для их получения.

9.7.3 Вопросы осуществления и передовой опыт Управленческая поддержка является неотъемлемой частью каждого компонента цикла управления закупками и поставками: отбор, закупки, хранение и распределение, использование и контроль. Это включает целый ряд мер на всех уровнях системы предоставления медицинской помощи: от уровня национальной программы до уровня распределения лекарственных средств и проведения диагностики. Основными направлениями деятельности являются управление информационной системой, обеспечение своевременного обмена информацией между участниками на разных уровнях и обеспечение наличия финансовых и других ресурсов, включая лекарственные и диагностические средства, необходимые для программы. Ниже приводится общее описание основных действий на каждом этапе в рамках цикла управления поставками.

9.7.3.1 Отбор фармацевтических и диагностических средств Странам, адаптирующим это руководство к своим условиям, может потребоваться обновить национальный список лекарственных средств, чтобы включить в него новые рекомендованные схемы и формы АРВ-препаратов. Преимущество использования списка основных средств заключается в том, что он позволяет ограничить закупки других более дорогих или исключенных из списка ВОЗ лекарственных и диагностических средств, а также ускорить регистрацию преквалифицированных ВОЗ продуктов в целях содействия закупкам гарантированного качества (123). Если какиелибо комбинированные препараты с фиксированными дозами или другие схемы приема АРВ-препаратов не входят в национальный список или не зарегистрированы в стране, руководители программ борьбы с ВИЧ должны связаться с национальным органом регулирования в области лекарственных средств и предложить включить эти средства в список и зарегистрировать их. Детальное национальное руководство, которое, например, содержит рекомендации в отношении лечения токсичности или неэффективности лечения, а также рекомендуемые лекарственные формы с учетом веса и возраста, может помочь стандартизировать процедуры назначения и выдачи лекарственных средств, а также прогнозировать наличие АРВ-препаратов. Принятие новых рекомендаций, одновременно с прогнозированием, закупками и планированием распределения, при введении новых и при отказе от старых АРВпрепаратов будет сводить к минимуму нерациональное использование продуктов, которые выводятся из употребления, и дефицит новых рекомендованных средств.

9. Рекомендации по осуществлению деятельности и предоставлению услуг

227

В ряде мест наблюдается нехватка лекарственных форм для детей. Национальный список лекарственных средств следует оптимизировать в отношении форм АРВ-препаратов для детей, чтобы он включал комбинированные препараты с фиксированными дозами, делимые или диспергируемые таблетки, что облегчает соблюдение режима лечения и управление поставками. Страны могут рассмотреть возможность исключения менее предпочтительных продуктов и, по возможности, обеспечить соответствие между лекарственными формами для детей и для взрослых. Работники здравоохранения на различных уровнях должны проходить обучение по вопросам регулирования фармацевтических и диагностических средств, включая прогнозирование, поставки и распределение, и обеспечивать надлежащий надзор в рамках всей системы поставок.

9.7 Системы управления закупками и поставками

9.7.3.2 Закупки Для эффективных закупок приемлемых по цене АРВ-препаратов и диагностических средств гарантированного качества требуется единая и согласованная национальная система закупок (124, 125). Закупки должны проводиться на основе правильного отбора продуктов и прогнозирования на основе потребностей, принимая во внимание потребление, расширение служб, введение новых и выведение старых лекарственных форм, а также выполнение новых рекомендаций. Для того чтобы закупки носили оптимальный характер, следует использовать транспарентные процедуры и ввести в действие систему обеспечения качества для закупок, хранения и распределения высококачественных фармацевтических и диагностических средств и других медицинских продуктов (124,126). Системы закупок должны: беспечивать закупку наиболее эффективных, термостабильных форм АРВ о препаратов с фиксированными дозами и гарантированного качества в нужных объемах по наименьшей возможной стоимости и своевременно; редусматривать, чтобы партнеры, поддерживающие национальную программу п борьбы с ВИЧ, укрепляли и гармонизировали системы управления закупками и поставками АРВ-препаратов и диагностических средств и объединяли в общий пул заказы на АРВ-препараты и диагностические средства, изучая возможности создания таких пулов в рамках единой системы тендеров; спользовать открыто доступные базы данных для обеспечения доступа к и информации о ценах и поддержания конкуренции (127–130); и ледовать принципам, описанным в межучрежденческом руководстве Организации с Объединенных Наций по лекарственным средствам, передаваемым в дар (131).

новое

228

9.7.3.3 Хранение и распределение Надлежащее хранение и распределение лекарственных и диагностических средств и других материалов, используемых в отношении ВИЧ, являются важными компонентами системы управления поставками (Таблица 9.3). При хранении и распределении следует обеспечить сохранность продуктов и их качества (125,132), при этом следует сводить к минимуму потери продуктов в результате их порчи и истечения срока годности. При планировании децентрализации следует развивать комплексные системы поставок на основе существующих систем и, при необходимости, укреплять потенциал. Например, существующую инфраструктуру программ иммунизации, включая холодовую цепь, для расширения поставок форм для детей, таких как жидкая форма LPV/r. Медицинские учреждения должны иметь достаточную площадь для хранения, обученный персонал и возможности эффективного управления поставками. Число уровней хранения следует рационализировать, чтобы сократить цепочку поставок. Следует вести правильный учет запасов и создать систему отслеживания продукции, поступающей в систему поставок и покидающей ее. Следует обеспечить наличие стандартной системы повторных заказов на основе потребления в местах предоставления услуг. Система поставок должна быть гибкой, например, путем использования процедур отчетности и перераспределения избыточных запасов АРВпрепаратов, более частых и нестандартных заказов для минимизации случаев истечения срока годности и израсходования запасов. Фармацевтические и диагностические средства должны храниться надлежащим образом, особенно если поставки препаратов для АРТ децентрализованы и они выдаются в большом числе периферийных учреждений здравоохранения. При транспортировке и хранении следует принимать меры, чтобы не допускать хищений и злоупотреблений, такие как системы отслеживания транспортных средств, охраняемые зоны хранения, проверки и нанесение на АРВ-препараты, полученные программами борьбы с ВИЧ, соответствующей маркировки.

9.7.3.4 Использование и мониторинг Надежные информационные системы обеспечивают наличие точных и оперативных данных о потреблении АРВ-препаратов и другой информации, требуемой для эффективного мониторинга деятельности всей системы снабжения и для прогнозирования потребностей в АРВ-препаратах и диагностических средствах. Мониторинг системы управления закупками и поставками путем использования индикаторов раннего оповещения позволяет избежать дефицита или избытка запасов, который может приводить к истечению сроков годности (126).

Таблица 9.3 Контрольный перечень вопросов управления поставками фармацевтических средств Стадия Планирование Действия Отбор продукции Определение Обновленные национальные рекомендации по ВИЧ Обновленные национальные списки, включающие новые рекомендованные схемы приема и формы АРВ‑препаратов и диагностические средства Анализ и количественная оценка потребностей в АРВ‑препаратах

9. Рекомендации по осуществлению деятельности и предоставлению услуг

229

9.7 Системы управления закупками и поставками

Стадия Закупки

Действия Выбор и нахождение поставщиков

Определение Открытые и прозрачные контакты с представителями промышленности Предварительный квалификационный отбор поставщиков Введение механизмов рассмотрения

Обеспечение качества продукции и источников

Критерии для предварительного квалификационного отбора производителей Введение системы предварительной квалификации Использование схемы сертификации ВОЗ, инспектирования и определения качества образцов Физический контроль перед поставкой с выборочным лабораторным тестированием Системы ведения учета и мониторинга поставок

Организация закупок

Постоянная оценка опционов покупателя Необходимость специальной маркировки и упаковки Необходимость создания резервных или буферных запасов Управление организацией закупок

Распределение, рациональное использование и мониторинг

Получение поставок в стране

Вывоз прибывших грузов, включая наличие средств для уплаты пошлин и налогов Обеспечение надлежащего хранения на всех необходимых уровнях Физический контроль по прибытии каждой партии с выборочным лабораторным тестированием

Распределение в стране Рациональное использование и мониторинг фармацевтических средств

Система логистики для своевременной передачи конечным пользователям Адекватная квалификация провайдеров Системы мониторинга и отчетности, включая мониторинг неблагоприятных эффектов для проведения отбора; рациональное назначение лекарств; и прогнозирование На центральном уровне любые проблемы, такие как хищение, отмена поставок поставщиком, плохое качество и неблагоприятные лекарственные реакции, должны регистрироваться и доводиться до сведения соответствующих органов на разных уровнях. Это включает разработку форм уведомления о проблемах с указанием, кому они должны быть посланы и какие действия следует предпринять

новое

Рекомендации для

руководителей программ

10.1 Введение 232 10.2 Процесс принятия решений 233 10.3 Данные в поддержку принятия решений 233 10.3.1 Обзор 233 10.3.2 Эпидемиология ВИЧ на национальном и местном уровнях 234 10.3.3 Анализ эффективности программ и ответных мер 234 10.3.4 Социально-экономическая, политическая и правовая ситуация 234 10.4 Основные параметры для принятия решений 238 10.4.1 Вопросы этики, справедливости и прав человека 238 10.4.2 Воздействие и экономическая эффективность 238 10.4.3 Благоприятные возможности и риски 240 10.5 Вопросы реализации в рамках системы здравоохранения 240 10.6 Вопросы реализации в отношении основных рекомендаций 244 10.7 Выполнение рекомендаций в разных условиях 250 10.7.1 Обзор 250 10.7.2 Выполнение рекомендаций в разных эпидемиологических ситуациях 250 10.8 Полезные инструменты для калькуляции затрат и планирования 252

Цель этой главы Предоставление рекомендаций по принятию решений и планированию программ на национальном уровне, касающихся введения в действие и выполнения клинических и операционных рекомендаций, содержащихся в данном руководстве.

232

10. РЕКОМЕНДАЦИИ ДЛЯ РУКОВОДИТЕЛЕЙ ПРОГРАММ 10.1 Введение Рекомендации, содержащиеся в данном руководстве, расширяют число людей, отвечающих критериям АРТ, способствуют принятию новых схем первого и второго ряда и предлагают внести изменения в подходы и стратегии лабораторного мониторинга для обеспечения максимальной эффективности лечения. Заинтересованные стороны на национальном уровне сталкиваются с необходимостью важного выбора путей оптимального осуществления этих рекомендаций на практике в стране. Хотя, например, фактические данные о клинической эффективности свидетельствуют в пользу принятия определенных мер, необходимо принимать во внимание также такие вопросы, как затраты и экономическая эффективность, этические аспекты и права человека, восприятие различными участниками, а также нормативно-правовая база (1). Руководители национальных программ борьбы с ВИЧ играют особую роль в управлении процессом адаптации и выполнения рекомендаций по ведению ВИЧ в своих странах. Во-первых, проведение широкого, всестороннего и транспарентного консультативного процесса может помочь определить, какие изменения в программе являются актуальными и необходимыми, например в отношении пересмотра национальных протоколов, руководств и правил. Во-вторых, необходимо также обеспечить финансовые ресурсы и политическую поддержку, которые требуются для осуществления предлагаемых изменений. В-третьих, необходимы системы обеспечения общей ответственности за осуществление со стороны всех партнеров на всех уровнях и адекватное документирование эффективности деятельности для обоснованного принятия решений и сохранения политической поддержки. Наконец, следует поддерживать проведение внедренческих и операционных исследований для оценки инновационных подходов и введение их в действие. Пересмотр национальной политики в отношении лечения следует проводить с учетом прав человека и этических принципов, чтобы обеспечить соблюдение справедливости и удовлетворение конкретных потребностей всех сторон. Новые рекомендации должны приниматься во внимание при формировании концептуальной основы, целей и задач программы борьбы с ВИЧ, и существующие стратегические планы должны соответствующим образом адаптироваться для обеспечения последовательности, недопущения дублирования усилий и использования возможной экономии средств за счет широких масштабов деятельности (2). По мере становления программ борьбы с ВИЧ и усиления их ориентации на решение задач долгосрочной профилактики, лечения, помощи и поддержки, следует рассматривать возможность ответных действий на национальном уровне в рамках более широкой деятельности в области охраны здоровья и развития. Устойчивость и эффективность программ борьбы с ВИЧ можно значительно усилить путем обеспечения и укрепления взаимосвязи с другими программами в области здравоохранения и других областях (3).

10. Рекомендации для руководителей программ

233

10.2 Процесс принятия решений Решения в отношении выполнения глобальных рекомендаций следует принимать в рамках транспарентного, открытого и научно обоснованного процесса с учетом многосекторального характера мер борьбы с ВИЧ. Национальные программы борьбы с ВИЧ должны предусматривать возможность создания многопрофильной рабочей группы, если такая группа уже не создана, для предоставления рекомендаций в отношении вариантов выбора и решений, необходимых для обновления и выполнения национальных рекомендаций. Группа по подготовке рекомендаций может выполнять следующие функции: (1) изучение текущего положения дел в развитии эпидемии ВИЧ и ТБ на национальном уровне, включая меры сектора здравоохранения и общую политическую ситуацию; (2) оценка глобальных и местных фактических данных, касающихся новых рекомендаций и предоставление рекомендаций в отношении того, как их правильно интерпретировать с учетом местных условий; и (3) выявление проблем, связанных с реализацией, таких как примерный уровень затрат, людские ресурсы и необходимая инфраструктура, а также путей их решения (4). Эти вопросы рассматриваются более подробно в Разделах 10.3 и 10.5. Хотя руководители национальных программ должны осуществлять общий контроль за процессом принятия решений, следует обеспечить его широкую репрезентативность. Широкое участие заинтересованных сторон в разработке политики, реализации, мониторинге и оценке будет способствовать тому, что в результате принятия глобальных рекомендаций в стране будут приняты программы борьбы с ВИЧ, являющиеся легитимными, приемлемыми, эффективными, справедливыми и учитывающими потребности населения на местах (1,5). Состав рабочей группы может меняться со временем в зависимости от конкретных обсуждаемых рекомендаций. Например, при рассмотрении путей улучшения программ ППМР их следует планировать совместно с лицами, отвечающими за охрану здоровья матери и ребенка. Контрольный перечень вопросов 10.1 включает основные элементы, которые следует принимать во внимание при реализации транспарентного и всестороннего процесса принятия решений.

10.3 Данные в поддержку принятия решений

10.3 Данные в поддержку принятия решений (5) 10.3.1 Обзор Решения о том, как адаптировать и выполнять эти рекомендации, должны приниматься на основе тщательной оценки эпидемиологической динамики и результатов выполнения программы для выявления сильных и слабых сторон программы и определения необходимых изменений политики в соответствии с принципами «знать свою эпидемию, знать свои ответные меры» (Контрольный перечень 10.1) (6,7). В некоторых странах эти данные могут быть получены путем регулярного мониторинга и оценки или изучения недавних результатов выполнения программ. В других странах может быть целесообразно проведение новых анализов, например исследований путей передачи ВИЧ для изучения основных аспектов эпидемиологии или ответных мер. Количественные и качественные данные следует, по возможности, дезагрегировать по полу, возрасту, единицам административного деления (например, по районам и областям) и по другим стратификационным критериям, включая ключевые группы населения, для обеспечения того, чтобы новые меры политики устраняли нарушения принципа справедливости в обеспечении доступа и расширяли уровень охвата мерами вмешательства. Укрепление информационных систем здравоохранения, включая регистры учета пациентов, путем создания электронных баз данных имеет важнейшее значение, способствуя управлению возрастающим объемом данных и повышению их надежности и доступности для принятия решений в рамках программ (см. Раздел 11.5).

234

10.3.2 Эпидемиология ВИЧ на национальном и местном уровнях Эпидемиологический анализ должен показывать уровни распространенности среди населения в целом и в конкретных группах, в также частоту ВИЧ-инфицирования среди разных категорий населения, включая грудных детей, детей младшего возраста, беременных женщин и серодискордантные пары. Оценки распространенности и частоты случаев должны быть направлены на выявление групп населения повышенного риска ВИЧ-инфицирования, в том числе в условиях генерализованных эпидемийix, при этом для правильной интерпретации результатов требуется, чтобы численность групп, в которых проводится оценка, была достаточной (9). Для принятия решений требуются также данные о распространенности и частоте случаев основных сопутствующих инфекций (таких, как ТБ и гепатит B и C) и других сопутствующих заболеваний.

10.3.3 Анализ эффективности программ и ответных мер Для определения того, являются ли текущие программы АРТ адекватными для удовлетворения выявленных потребностей, необходимо знание того, кто обращается за помощью в эти службы. В рамках программ следует оценивать существующий уровень охвата АРТ населения в целом и ключевых групп, на какой стадии заболевания люди обращаются за помощью, каковы показатели их удержания в рамках предоставления помощи и лечения, какие схемы АРТ применяются, а также какое влияние оказывает АРТ на снижение вирусной нагрузки, заболеваемость и смертность. Программы, в которых рассматривается возможность повышения порогового уровня клеток CD4 как критерия для назначения АРТ, в идеале должны располагать данными о среднем числе клеток CD4 и стадии ВИЧ-инфицирования у людей в момент обнаружения у них ВИЧ и в момент начала лечения. Дезагрегированные данные по различным группам позволяют проводить оценку потребностей в АРТ и определять приоритеты для предоставления услуг. Данные о соблюдении режима лечения, удержании в рамках лечения и супрессии вирусной нагрузки имеют важнейшее значение для оценки качества предоставляемых услуг. Эпиднадзор за наследуемой и приобретенной лекарственной устойчивостью ВИЧ также может способствовать принятию обоснованных решений в отношении выбора оптимальных схем (Вставка 11.1). При наличии возможности, следует также изучать показатели воздействия, такие как изменение связанных с ВИЧ показателей частоты случаев, распространенности, заболеваемости и смертности.

10.3.4 Социально-экономическая, политическая и правовая ситуация Анализ эпидемиологических и программных данных будет неполным без более глубокого понимания причин уязвимости к ВИЧ и того, как различные политические, социальные, экономические и правовые факторы влияют на возможности и готовность различных групп – мужчин, женщин, подростков, работников сексиндустрии, мужчин, практикующих секс с мужчинами, трансгендерных лиц и потребителей инъекционных наркотиков – обращаться в службы здравоохранения и иметь к ним доступ. Основными элементами, которые следует принимать во внимание при разработке эффективных программ борьбы с ВИЧ, являются стигматизация, дискриминация, бедность, гендерное неравенство, образование и миграционный статус. Правовая ситуация также может оказывать влияние на доступ к мерам вмешательства, например законы, касающиеся прав интеллектуальной собственности, а также объявляющие противозаконными гомосексуализм, воздействие и/или передачу ВИЧ, употребление наркотиков и коммерческий секс. Такие законы должны быть пересмотрены и реформированы, чтобы исключить дискриминационную практику, уменьшить уязвимость в отношении ВИЧ, расширить доступ к услугам здравоохранения и обеспечить соблюдение прав человека. ix

ценки частоты случаев с разбивкой по путям передачи инфекции уже были проведены в некоторых странах О и имеются на веб-сайте ЮНЭЙДС (8).

10. Рекомендации для руководителей программ

235

10.3 Данные в поддержку принятия решений

Контрольный перечень 10.1 Процесс и фактические данные для принятия решений Процесс принятия решений (10,11) 1. Обеспечивает ли процесс соблюдение принципов для обоснованного и надлежащего принятия решений? ласность: Является ли процесс прозрачным и открытым? Доступны ли широкой Г общественности данные и обоснования для решений? А ктуальность: Согласны ли стороны, которых затрагивают эти решения, с обоснованностью причин, принципов и фактических данных? Возможность пересмотра и опротестования: Могут ли решения быть пересмотрены и/или опротестованы в свете новых данных и аргументов? Обеспечение соблюдения: Все ли стороны знают, как обеспечить соблюдение этих условий (гласности, актуальности и возможности пересмотра)? 2. Участвуют ли представители всех соответствующих сторон? ксперты и руководители программ, включая экспертов и представителей служб Э охраны сексуального и репродуктивного здоровья, здоровья матери и ребенка, программ помощи при ТБ, ВИЧ (АРТ, ВИЧ-тестирование и консультирование и ППМР), наркологических служб и служб по снижению вреда Провайдеры медицинской помощи, включая врачей, медсестер и консультантов из клиник помощи при ВИЧ для детей и взрослых, программ охраны здоровья в тюрьмах, охраны здоровья матери и ребенка, противотуберкулезных клиник и служб по снижению вреда и наркологических служб в государственном и частном секторах Гражданское общество, включая людей, живущих с ВИЧ, женщин и молодых людей, религиозных лидеров, инвалидов и представителей ключевых групп, включая мужчин, практикующих секс с мужчинами, трансгендерных лиц, работников сексиндустрии и потребителей инъекционных наркотиков Технические специалисты, включая экспертов в конкретных областях, таких как лабораторные службы, фармацевтика, лекарственная устойчивость, ведение случаев токсичности, цепочка поставок и общественное здоровье Государственные партнеры, включая представителей других министерств (например, финансов и планирования) и децентрализованных (например, областных) органов власти, международные агентства, религиозные организации, другие местные неправительственные и общественные организации и частногосударственные провайдеры услуг Эксперты по финансово-бюджетным вопросам, такие как сотрудники программ по бюджетным вопросам и экономисты здравоохранения А кадемические учреждения, включая экспертов по операционным и внедренческим исследованиям, по вопросам обучения и контроля Профессиональные ассоциации работников здравоохранения разного уровня (врачей, медсестер и участковых работников здравоохранения)

236

Контрольный перечень 10.1 (продолжение) 3. Могут ли все стороны активно участвовать, вносить свой вклад и влиять на принятие решений оступна ли информация для всех основных сторон в письменном виде, и понятна Д ли она? Предусмотрены ли процедуры для обеспечения полноценного участия всех сторон? Выявлены ли возможные социальные, культуральные и юридические барьеры, мешающие полноценному участию групп, традиционно являющихся маргинализованными, и устраняются ли они? 4. Транспарентность в отношении оснований для решений Являются ли критерии принятия решений транспарентными, и ясно ли сформулированы основания для решений следующего характера: Н аучные данные, включая эффективность и риск? В мененные издержки при использовании мер, включая экономическую эффективность? О беспечение справедливости (распределение положительных эффектов для здоровья и затрат для разных групп)? Фактические данные для принятия решений 1. Частота случаев и распространенность ВИЧ каких группах населения частота случаев и распространенность ВИЧ В являются самыми высокими? К соответствующим критериям относятся пол, местонахождение (сельская местность или город), возраст, население в целом и беременные женщины, а также ключевые группы (такие, как мужчины, практикующие секс с мужчинами, потребители инъекционных наркотиков, работники секс-индустрии и заключенные) акова серопревалентность ВИЧ среди партнеров при индексных К случаях заболевания? Какова частота случаев ВИЧ-инфицирования в серодискордантных парах? 2. Анализ программ и ответных мер Принимались ли во внимание в процессе принятия решений следующие аспекты: с уществующий уровень охвата ВИЧ-тестированием и консультированием с разбивкой по соответствующим факторам стратификации? уществующий уровень охвата АРТ с разбивкой по соответствующим факторам с стратификации? уществующий уровень охвата АРВ-препаратами для ППМР и АРТ среди с беременных женщин, живущих с ВИЧ? с реднее количество клеток CD4 и стадия ВИЧ у лиц, начинающих получать АРТ? оля людей, начинающих получать АРТ, которые остаются в живых и д продолжают получать АРТ через 12, 24 и 60 месяцев? аспространенность вирусной супрессии (и % случаев неэффективности р лечения) среди лиц, получающих АРТ, через 12 месяцев? аспространенность лекарственной устойчивости ВИЧ среди лиц, начинающих р АРТ первого ряда, и среди тех, кто уже получает лечение?

10. Рекомендации для руководителей программ

237

Контрольный перечень 10.1 (продолжение) 3. Справедливость в отношении доступа о данным изучения эпидемиологических данных и результатов программ, П обеспечивают ли рекомендации расширение доступа к АРВ-препаратам и другим службам для людей, имеющих наименьший доступ или наиболее нуждающихся в нем, включая ключевые группы населения? 4. Согласованность между фактическими данными и рекомендациями вляются ли рекомендации обоснованными для эпидемиологической ситуации, Я при которой они будут выполняться? огласованы ли рекомендации с общим видением, целями и задачами С программы и способствуют ли они их достижению? спользовались ли при разработке рекомендаций местные и национальные И фактические данные? 5. Контекстуальные аспекты ринималось ли во внимание при принятии решений то, как бедность, гендерное П неравенство, образование, стигматизация, дискриминация и миграционный статус влияют на уязвимость к ВИЧ и доступ к услугам? меются ли какие-либо законодательные акты и правила на любом уровне, И предусматривающие наказание в связи с передачей ВИЧ, коммерческим сексом, употреблением наркотиков или гомосексуализмом? ыло ли определено, как устранять такие препятствия и как принятые меры Б повлияют на планирование программ? меются ли юридические или регуляторные препятствия для того, чтобы И подростки имели независимый доступ к ВИЧ-тестированию, консультированию, лечению и помощи?

10.3 Данные в поддержку принятия решений

238

10.4 Основные параметры для принятия решений 10.4.1 Вопросы этики, справедливости и прав человека Обилие препятствий юридического, социального и нормативного характера приводит к нарушению принципа справедливости в отношении доступа к службам лечения и помощи при ВИЧ. Например, данные из 19 стран Европы и Центральной Азии показывают, что хотя на долю потребителей инъекционных наркотиков приходилось 62% всех регистрируемых случаев ВИЧ с известным путем передачи в 2010 году, они составляли лишь 22% всех получавших АРТ в странах, где проводились исследования (12,13). Выполнение обязательств, принятых на глобальном и национальном уровнях, требует предоставления лечения и профилактики ВИЧ всем, кто в этом нуждается, соблюдая такие принципы прав человека, как отсутствие дискриминации, подотчетность и участие (14–16). Национальные стратегии борьбы с ВИЧ следует планировать и осуществлять, ставя с самого начала конечной целью предоставление полного пакета услуг и мер, рекомендуемых в настоящем руководстве, в кратчайшие возможные сроки. В процессе пересмотра и адаптации данного руководства также следует соблюдать основные этические принципы равноправия, справедливости и актуальности. Разработка эффективных и справедливых мер политики предусматривает, чтобы стратегии обеспечивали всестороннее решение проблем, препятствующих доступу к службам тестирования, профилактики и лечения, особенно для ключевых групп населения. Для понимания того, насколько службы являются доступными и адаптированными к конкретным потребностям ключевых групп населения, может быть целесообразно проведение обзорных исследований на уровне учреждения и местного сообщества.

10.4.2 Воздействие и экономическая эффективность Важной целью программ и мер общественного здравоохранения является оказание положительного воздействия на определенную группу населения. Примерами воздействия программы борьбы с ВИЧ являются снижение частоты случаев, распространенности, заболеваемости и смертности, а также улучшение качества жизни при ВИЧ (17). Воздействие часто является результатом влияния сложного комплекса факторов и сочетания различных действий или процессов, и оно нередко не может быть связано с какой-либо одной мерой вмешательства или программой (5). Анализ экономической эффективности является одним из нескольких инструментов экономической оценки, применяемой для определения ценностной значимости предоставления определенных услуг. Экономическая оценка позволяет измерить величину затрат и последствий выполнения альтернативных программ, которые затем сравнивают друг с другом, чтобы оценить возможность получения максимального положительного эффекта для здоровья. При анализе экономической эффективности воздействие часто измеряется с помощью показателей, связанных с изменением состояния здоровья, таких как добавленные годы жизни, скорректированные на нетрудоспособность (DALYs), включая примерное число случаев смерти и инфицирования, которых удалось избежать. Как показывает опыт расширения масштабов АРТ в странах с низким и средним уровнями дохода, экономическая эффективность мер охраны здоровья также меняется со временем в результате снижения расходов за счет эффекта масштаба, совершенствования технологии или разработки более эффективных систем предоставления услуг. В период подготовки этого руководства консорциум исследовательских групп независимым образом разработал и затем сопоставил математические модели для

10. Рекомендации для руководителей программ

239

оценки эпидемиологического и клинического воздействия, а также коэффициенты эффективности затрат для различных мер вмешательства, в частности в связи с началом АРТ в более ранние сроки (Вставка 10.1). Хотя оценка экономической эффективности и воздействия на состояние здоровья может быть полезна при систематическом сопоставлении различных мер, принимаемых в рамках программ, их следует рассматривать с учетом аспектов этического характера, обеспечения справедливости и соблюдения прав человека при различном характере действий, особенно в условиях, когда не все отвечающие критериям лица в настоящее время имеют доступ к АРТ. Инвестиции в важнейшие программы содействия (например, программы комплексного лечения и повышения грамотности в вопросах прав человека, программы юридической помощи и борьбы со стигматизацией и дискриминацией, обучения работников здравоохранения и обеспечения соблюдения законов) могут играть определенную роль в преодолении препятствий в доступе к службам лечения ВИЧ и другим службам, а также в обеспечении связи со службами оказания помощи. Эти программы могут способствовать общей экономической эффективности, помимо достижения других важных задач, таких как снижение дискриминации (18). Вставка 10.1 Оценка воздействия и экономической эффективности некоторых рекомендаций с помощью математической модели: результаты независимого Консорциума по моделированию эпидемии ВИЧ

10.4 Основные параметры для принятия решений

В ходе работы по выполнению этих рекомендаций руководители программ борьбы с ВИЧ могут сталкиваться с необходимостью сложного выбора вариантов оптимального распределения ресурсов для лечения ВИЧ: например определение относительного распределения ресурсов для расширения масштабов тестирования на ВИЧ и обеспечения взаимосвязи со службами помощи, а также для усиления доступа к АРТ на основе расширения круга лиц, отвечающих критериям. Консорциум по моделированию эпидемии ВИЧ, являющийся независимой группой научно-исследовательских учреждений (www.hivmodelling.org), использовал многие независимые математические модели, основанные на наборах данных из четырех стран с эпидемиями разного типа и разными уровнями охвата АРТ – Индии, Южной Африки, Вьетнама и Замбии – для изучения положительного воздействия на здоровье, стоимости и экономической эффективности различных стратегий расширения круга лиц, отвечающих критериям АРТ, а также тестирования и доступа к помощи при ВИЧ (19). (Веб-приложение www.who.int /hiv / pub /guidelines /arv2013 /annexes). В каждом случае изучались различные возможные варианты, включая различные пороговые уровни в качестве критерия для проведения АРТ (количество клеток CD4 ≤500 клеток/мм3, все люди с ВИЧ и конкретные ключевые группы населения), принимая во внимание существующие, а также расширенные схемы ВИЧ-тестирования и обеспечения взаимосвязи со службами помощи. Определялась стоимость достижения как индивидуальных, так и профилактических положительных эффектов для здоровья, связанных с каждой мерой вмешательства, включая изменение частоты случаев ВИЧ, сокращение числа утраченных лет здоровой жизни и долговременные затраты. В этих моделях также рассматривается относительная экономическая эффективность стратегий, подчеркивая при этом, от какой из них в рамках существующего бюджета можно ожидать получения максимального положительного эффекта.

240

Вставка 10.1 (продолжение)

Было установлено, что принятие в качества критерия отбора для АРТ количества клеток CD4 ≤500 клеток/мм3 высокоэффективно с точки зрения затрат в странах с низким и средним уровнями дохода. Однако сочетание расширения критериев со значительным расширением ВИЧ-тестирования и взаимосвязи со службами помощи обеспечивает получение максимального положительного эффекта, особенно в условиях низкого охвата АРТ. Расширение круга лиц, отвечающих критериям АРТ, включая в него всех взрослых с ВИЧ (независимо от количества CD4) было экономически менее эффективно, чем расширение критерия до ≤500 клеток/мм3, в связи с тем, что повышение порогового уровня CD4 для начала АРТ приводило к не столь быстрому улучшению состояния здоровья. Результаты моделирования следует интерпретировать с учетом ряда важных ограничений. Многие выводы могут значительно измениться в зависимости от предполагаемых издержек, особенно связанные с тестированием и консультированием, а также удержанием людей в рамках помощи до начала АРТ. Кроме того, в моделях не рассматривается, как изменятся оценки воздействия и экономической эффективности различных мер вмешательства, если они будут сочетаться друг с другом или выполняться лишь частично. Модели также не учитывают возможные преимущества и недостатки в сравнении с иными мерами, кроме антиретровирусной терапии. Не были затронуты некоторые важные вопросы, такие как лечение детей.

10.4.3 Благоприятные возможности и риски Рекомендации, содержащиеся в этом руководстве, могут способствовать дальнейшему снижению связанной с ВИЧ смертности, улучшить качество жизни, сократить число ВИЧинфицируемых людей и повысить эффективность лечения. Получаемый положительный эффект при этом может значительно перевесить необходимые начальные инвестиции и способен коренным образом изменить ход развития эпидемии. Тем не менее, внутренние факторы (такие, как сокращение бюджета, хищение АРВ-препаратов, утечка квалифицированных кадров здравоохранения и развитие лекарственной устойчивости) и внешние непредвиденные обстоятельства (такие, как прекращение внешней финансовой помощи, политическая нестабильность и стихийные бедствия) могут отрицательно повлиять на их выполнение. Необходимо разработать стратегии противодействия таким факторам, чтобы обеспечить непрерывное предоставление услуг, особенно наиболее нуждающимся в них (20).

10.5 Вопросы реализации в рамках системы здравоохранения Для нахождения оптимальных путей выполнения этих рекомендаций странам следует проанализировать бюджетные и кадровые потребности, а также другие аспекты систем здравоохранения, чтобы выявить имеющиеся в настоящее время ресурсы и системы и определить, в каких областях требуются дополнительные инвестиции. Важной аналитической основой являются шесть структурных элементов систем здравоохранения, которые были определены ВОЗ (21). Контрольный перечень 10.2 включает основные важнейшие вопросы в этих областях. Эти вопросы не предназначены для того, чтобы определять, следует ли включать или исключать какую-либо конкретную рекомендацию в

10. Рекомендации для руководителей программ

241

национальное руководство, но могут способствовать пониманию того, какое воздействие может оказать данная рекомендация и как наилучшим образом ее адаптировать и мобилизовать ресурсы для ее выполнения. При рассмотрении относительной бюджетной значимости конкретных рекомендаций важно также принимать во внимание стоимостные последствия бездействия с точки зрения роста показателей смертности, заболеваемости и случаев передачи ВИЧ. План реализации должен ясно определять, какие действия должны быть предприняты в течение определенного периода времени для достижения намеченных результатов, при четком разделении труда между всеми сторонами, принимающими участие в реализации программ. Необходимы надежные системы закупок и поставок для обеспечения постоянного наличия всех необходимых лекарственных и диагностических средств, а также других материалов на разных уровнях системы здравоохранения. Для снижения стоимости за счет эффекта масштаба можно использовать механизмы объединенных или совместных закупок, а для сведения к минимуму потерь следует тщательно прогнозировать спрос. По возможности следует использовать комбинированные препараты с фиксированными дозами и схемы их приема один раз в день, что будет способствовать соблюдению режима лечения и сделает его более удобным для людей, получающих лечение, и ухаживающих за ними лиц. Следует также изучить лабораторный потенциал и укрепить соответствующие службы для удовлетворения повышенного спроса. Повсеместно следует использовать национальные стандартизированные информационные системы здравоохранения и механизмы мониторинга пациентов. Требуются также более эффективные меры для обеспечения максимального соблюдения режима лечения и удержания пациентов для непрерывного оказания помощи. В некоторых местах могут потребоваться особые меры, например послеродовое наблюдение за матерью и ребенком. Качество медицинской помощи имеет важнейшее значение в процессе планирования и адаптации. Быстрое расширение масштабов помощи за последнее десятилетие иногда приводило к снижению качества предоставляемых услуг, что отрицательно повлияло, например, на показатели соблюдения схем лечения, своевременного начала или удержания пациентов в рамках АРТ. Выполнение новых рекомендаций дает возможность всесторонне изучить и устранить такие недостатки. Важным условием для этого является наличие эффективных систем мониторинга и оценки (см. Главу 11). Одним из основных компонентов эффективных механизмов обеспечения качества является четкое разделение ролей и обязанностей для выполнении отдельных функций и действий (таких, как руководство, финансирование, управление цепочкой поставок, кадровые ресурсы, мониторинг и оценка, необходимые для эффективного предоставления услуг на национальном, областном, районном, местном и индивидуальном клиническом уровнях). Механизм обеспечения и повышения качества, разработанный для целей ВИЧ-тестирования и консультирования, может лежать в основе более широких мер обеспечения и повышения качества на всех этапах непрерывного оказания помощи (22). Эффективное выполнение программ борьбы с ВИЧ по своей природе требует участия многих секторов и выходит за рамки мер биомедицинского характера. Важно оценить, как меры борьбы с ВИЧ могут оптимально взаимодействовать с другими программами здравоохранения и немедицинскими услугами для расширения охвата и оптимизации использования ресурсов. При планировании следует также принимать во внимание широкий круг сторон, участвующих в предоставлении услуг здравоохранения, включая государственные, частные и некоммерческие организации. Важное значение для улучшения структуры программ, обеспечения устойчивости их результатов и максимального охвата имеют участие населения и стратегии взаимной помощи на местах.

10.5 Вопросы реализации в рамках системы здравоохранения

242

Контрольный перечень 10.2 Основные важнейшие вопросы реализации Успешное выполнение новых рекомендаций зависит от ряда важных решений в основных областях программы. 1. Коммуникация, лидерство и информационно-пропагандистская деятельность Б ыло ли решено, кто будет отвечать за обновление существующих в настоящее время материалов, включая рекомендации по предоставлению услуг, протоколы, клинические и лабораторные стандартные операционные процедуры, механизмы мониторинга и оценки, механизмы или системы мониторинга пациентов, справочные руководства, учебные материалы для работников здравоохранения, инструкции, контрольные перечни вопросов, а также материалы для информирования общественности, обучения и коммуникации? Б ыло ли решено, как новые рекомендации будут доведены до сведения (1) руководителей программ на местах, включая государственные, некоммерческие и частные организации; (2) работников здравоохранения; и (3) других соответствующих сторон, например людей, живущих с ВИЧ? Б ыло ли решено, кто будет нести общую ответственность за информационнопропагандистскую работу с такими заинтересованными сторонами, как политические лидеры, работники здравоохранения и СМИ? 2. Кадровое обеспечение и людские ресурсы Б ыло ли определено, сколько дополнительных работников требуется для выполнения новых рекомендаций? Какие категории работников здравоохранения (врачи, санитарные инспекторы, медсестры, акушерки, участковые работники здравоохранения и лаборанты) требуются, и как они могут быть приняты на работу? М ожно ли использовать перераспределение и разделение обязанностей для оптимизации имеющихся людских ресурсов и расширения предоставляемых услуг? (см. Раздел 9.5.2) 3. Лекарственные средства и материалы И меются ли какие-либо новые лекарственные средства (такие, как АРВ-препараты), необходимые для выполнения новых рекомендаций? В каких количествах? Б ыло ли определено, какие системы требуются для прогнозирования потребностей и закупок лекарственных средств и других материалов по наилучшей возможной цене? Б ыл ли разработан переходный план для прекращения использования старых препаратов (например, d4T) и введения новых? С ледует ли укрепить системы управления поставками – особенно на периферийном уровне – для удовлетворения возросшего спроса? И меется ли регуляторный процесс для своевременного разрешения и регистрации новых лекарственных и диагностических средств? И меются ли системы лабораторного контроля качества и внешнего обеспечения качества и полностью ли они функционируют? П озволяют ли национальные законы закупать и импортировать все необходимые материалы? Существуют ли проблемы патентования и можно ли использовать возможности Соглашения по торговым аспектам прав интеллектуальной собственности (ТРИПС) для расширения доступа? 4. Организация системы Я вляются ли связи и системы направлений адекватными? Н еобходима ли децентрализация и/или интеграция служб для реализации политики? П роводились ли при разработке политики консультации с руководителями других связанных программ (например, по борьбе с ТБ, охране здоровья матери и ребенка и наркологических служб)?

10. Рекомендации для руководителей программ

243

10.5 Вопросы реализации в рамках системы здравоохранения

Контрольный перечень 10.2 (продолжение) 5. Инфраструктура Б ыла ли определена физическая инфраструктура (например, склады, помещения для совещаний и консультаций, лаборатории, аптеки, административные зоны и оборудование) и транспортная инфраструктура (например, средства передвижения), необходимые для реализации? Имеются ли они в рамках системы здравоохранения или требуются дополнительные инвестиции со стороны программ АРТ? Т ребуется ли дополнительная инфраструктура для коммуникаций, в том числе между учреждениями здравоохранения, работниками здравоохранения, лабораториями и клиентами? 6. Затраты Б ыла ли проведена оценка общих годовых затрат на выполнение новых рекомендаций, включая вспомогательные и другие службы? Были ли определены удельные затраты на следующие компоненты программы? АРТ; ППМР (для женщин только в период беременности и кормления грудью или пожизненная АРТ?); Тестирование и консультирование; Общая помощь уход при ВИЧ; К линический мониторинг; Наставничество, обеспечение качества и мониторинг; и Услуги, предоставляемые на местном уровне. 7. Финансирование Б ыли ли определены источники финансирования, такие как государственный бюджет, социальное обеспечение или медицинское страхование, Глобальный фонд, Чрезвычайный план Президента США для оказания помощи в связи со СПИДом, ЮНИТЭЙД и частные фонды? (Важно принимать во внимание, что расходы за счет собственных средств могут ограничивать доступ к мерам вмешательства и их проведение) Н еобходимы ли новые стратегии для изыскания средств, необходимых для удовлетворения ожидаемых потребностей в инвестициях? М ожно ли обеспечить снижение расходов за счет экономии от эффекта масштаба или синергизма от взаимодействия с другими мерами и программами? 8. Мониторинг и оценка Я сно ли в плане мониторинга и оценки определены показатели на уровне учреждений и программ, необходимые для адекватного мониторинга уровня охвата мерами и воздействия новых рекомендаций? Были ли определены требования в отношении людских ресурсов, оборудования и инфраструктуры? О беспечивают ли системы мониторинга и оценки взаимодействие (между местным и центральным уровнями и между различными донорами), чтобы избежать дублирования усилий и обеспечить последовательность? Б ыли ли определены и введены в действие необходимые системы контроля и обеспечения качества для оптимизации предоставления услуг? 9. План реализации П редусматривает ли план ограниченные по времени задачи или цели? П редусматривает ли план конкретные конечные результаты? Я сно ли в плане определены роли и обязанности различных заинтересованных сторон (таких, как центральные, территориальные и местные органы власти, неправительственные организации, технические партнеры, местные сообщества и люди, живущие с ВИЧ или затронутые ВИЧ), участвующих в процессе реализации?

244

10.6 В опросы реализации в отношении основных рекомендаций Во Вставках 10.2–10.7 для руководителей программ приводятся вопросы реализации, касающиеся шести основных рекомендаций в данном руководстве: (1) изменение порогового уровня количества клеток CD4 для начала АРТ у взрослых и подростков с 350 до 500 клеток/мм3; (2) расширение масштабов тестирования на вирусную нагрузку; (3) переход к пожизненной АРТ для всех беременных и кормящих грудью женщин; (4) децентрализация служб АРВ-терапии; (5) расширение масштабов лечения для детей; и (6) прекращение использования d4T. Вставка 10.2 Основные вопросы реализации для руководителей программ: повышение порогового уровня CD4 для начала АРТ у взрослых и подростков с 350 до 500 клеток/мм3 (Раздел 7.1.1) 1. Л ечение наиболее больных людей в первую очередь. Уровень смертности среди лиц с количеством CD4 ниже 350 клеток/мм3 отличается от лиц с большим количеством клеток CD4. Какие системы будут обеспечивать уделение приоритетного внимания более больным людям, особенно при низком уровне охвата АРТ? 2. Прекращение использования d4T. Принимая во внимание долгосрочную токсичность и подобные эффекты d4T, программы, в которых пороговый уровень начала АРТ повышается до 500 клеток CD4/мм3, должны добиваться значительного прогресса в прекращении использования d4T в схемах лечения взрослых и подростков для оптимизации результатов лечения. 3. Рассмотрение возможности перераспределения обязанностей и децентрализации. Следует разработать или скорректировать планы в отношении кадровых ресурсов в поддержку стратегического решения повышения порогового уровня CD4, в том числе путем перераспределения обязанностей и подготовки новых кадров работников здравоохранения (см. Раздел 9.5.2). 4. У силение поддержки в соблюдении режима лечения. Повышение порогового уровня для начала АРТ означает, что больше людей, которые чувствуют себя здоровыми, будут отвечать критериям проведения лечения. Какие меры обеспечения и усиления соблюдения режима лечения будут использоваться для этих людей? 5. Проведение мониторинга лечения. Поскольку большее число людей будут начинать АРТ раньше и продолжать это лечение дольше, мониторинг вирусной супрессии приобретает все большее значение, так как неудачное лечение может привести к увеличению лекарственной устойчивости, что может снизить эффективность лечения, особенно ННИОТ. Как будет обеспечено расширение доступа к мониторингу вирусной нагрузки?

10. Рекомендации для руководителей программ

245

10.6 В опросы реализации в отношении основных рекомендаций

Вставка 10.3 Основные вопросы реализации для руководителей программ: расширение масштабов тестирования на вирусную нагрузку (Раздел 7.3.2) 1. Р ассмотрение различных вариантов диагностики. Существует несколько стратегий расширения доступа к тестированию на вирусную нагрузку, включая использование сухих капель капиллярной крови (СККК) и, в ближайшее время, технологии тестирования по месту оказания помощи. Руководители программы должны рассмотреть возможности оптимального выбора с учетом множества факторов, таких как наличие существующей инфраструктуры и число людей, получающих услуги на разных уровнях помощи (например, центральные или периферийные учреждения). 2. Рассмотрение использования мониторинга вирусной нагрузки в рамках альтернативных стратегий мониторинга пациентов. Может возникнуть необходимость пересмотра относительных преимуществ мониторинга CD4 при наличии более широких возможностей тестирования на вирусную нагрузку, принимая во внимание разную специфичность этих технологий в качестве индикаторов неэффективного лечения, их стоимости и технических требований для реализации. Например, в рамках программ можно рассмотреть возможность сокращения числа тестов на CD4 для людей, которым проводится регулярное определение вирусной нагрузки. Тестирование на CD4 все же требуется в качестве критерия для проведения АРТ. 3. О казание поддержки в соблюдении режима лечения. У значительной доли лиц, получающих АРВ-препараты, развивается определяемая вирусная нагрузка вследствие недостаточного соблюдения режима лечения. Ее уровень может вновь стать неопределяемым при проведении адекватного консультирования, что позволяет избежать ненужного перехода на схемы второго ряда. 4. П овышение уровня грамотности в вопросах лечения с использованием вирусной нагрузки. Поскольку большинство программ в странах с низким и средним уровнями дохода традиционного используют мониторинг CD4, люди, получающие АРВ-препараты, и работники здравоохранения могут быть не знакомы с концепцией и значимостью определения вирусной нагрузки. Следует проводить консультирование, чтобы люди, получающие АРВ-препараты, и работники здравоохранения понимали значение и последствия наличия определяемой или неопределяемой вирусной нагрузки и ее связь с соблюдением режима лечения. 5. Обеспечение наличия адекватного запаса АРВ-препаратов второго ряда. У людей, уровень вирусной нагрузки которых остается определяемым после оказания поддержки в соблюдении режима лечения, могла развиться лекарственная устойчивость и может возникнуть необходимость изменения схемы лечения. Руководители программ в таких ситуациях должны быть готовы предложить альтернативные схемы, включая комбинации АРВ-препаратов. 6. Осуществление стратегий обеспечения качества. При расширении масштабов тестирования на вирусную нагрузку необходимо обеспечить его качество. Централизованные системы должны быть охвачены программами обеспечения качества, в то время как для децентрализованных служб и служб по месту оказания помощи могут потребоваться новые подходы к обеспечению качества.

246

Вставка 10.4 Основные вопросы реализации для руководителей программ: переход к пожизненной АРТ для всех беременных и кормящих грудью женщин (Вариант B+) (Раздел 7.1.2 и Приложение 6) 1. Изучение возможностей надлежащего подхода к расширению масштабов лечения. Следует тщательно изучить инфраструктурные и операционные последствия проведения пожизненной АРТ всем беременным и кормящим грудью женщинам, живущим с ВИЧ. Страны могут рассмотреть возможность принятия поэтапного подхода с проведением просветительной работы на раннем этапе до полного расширения масштабов лечения. 2. Обеспечение связи со службами помощи и перевод пациентов. До реализации программы следует изучить ситуацию и принять решение в отношении места, где беременным и кормящим грудью женщинам предоставляются АРВ-препараты, а также возможности проведения пожизненной АРТ. Будут ли женщины продолжать получать АРТ в месте предоставления АРВ-препаратов для ППМР, или они будут переведены в одну из имеющихся служб проведения АРТ? Какие стратегии будут использоваться для сведения к минимуму риска выбытия женщины из системы оказания помощи при переходе в другое место получения АРТ? 3. Рассмотрение потребностей в людских ресурсах. Многие сотрудники в местах ППМР имеют ограниченный уровень подготовки и опыт в области АРТ, особенно в местах, где для ППМР используется Вариант А. Для того чтобы в местах ППМР имелась возможность брать на себя дополнительные обязанности по проведению пожизненной АРТ, может потребоваться наращивание потенциала, перераспределение обязанностей и, возможно, увеличение численности медицинского персонала. 4. Обеспечение соблюдения режима лечения и удержания пациентов. Соблюдение режима лечения и удержание в системе оказания помощи матери и ребенка может быть особенно сложной задачей в послеродовой период грудного вскармливания. Какие стратегии следует использовать для мониторинга и обеспечения соблюдения режима лечения и удержания пациентов, а также возвращения выбывших из наблюдения, включая матерей и детей, подвергающихся риску ВИЧ-инфицирования? 5. Рассмотрение этических вопросов. Инициирование проведения пожизненной АРТ для всех беременных и кормящих грудью женщин, независимо от количества CD4, может приводить к возникновению временных различий в доступе к лечению. Например, беременная женщина с высоким количеством CD4 может продолжать получать АРТ после родов, в то время как ее муж, другие члены семьи, соседи или другие женщины, желающие забеременеть, с более низким уровнем CD4 могут еще не отвечать критериям для проведения АРТ. Какой процесс и стратегии должны использоваться на уровне проведения политики и предоставления услуг для устранения таких возможных различий? Как можно обеспечить охват пожизненным лечением всех беременных и кормящих грудью женщин для усиления семейного подхода, включая тестирование на ВИЧ и лечение партнеров и других членов семьи? 6. Обеспечение качества тестирования на ВИЧ. Для обеспечения оптимальной реализации мер во всей стране важное значение имеет разработка программ обеспечения качества, включая проведение экспресс-тестов на ВИЧ (которые в некоторых местах могут являться единственными тестами для определения необходимости АРТ) и соответствующее использование алгоритмов тестирования.

10. Рекомендации для руководителей программ

247

10.6 В опросы реализации в отношении основных рекомендаций

Вставка 10.4 (продолжение) 7. Оценка потребностей в лабораторном мониторинге. Хотя тестирование на CD4 может не требоваться для инициирования проведения АРТ у беременных женщин, должны иметься возможности мониторинга токсичности и эффективности АРТ, включая вирусную нагрузку (что имеет важнейшее значение для оценки вирусной супрессии), как и для всех людей, получающих АРТ. Важное значение имеет также проведение диагностики среди грудных детей для выявления случаев ВИЧ-инфицирования и направления их для получения соответствующего лечения и помощи. Следует создать системы эпиднадзора (которые могут являться дозорными участками) для оценки влияния АРТ в отношении врожденных пороков, исходов беременности, обеспечения безопасности грудных детей и детей младшего возраста, подвергающихся риску через грудное вскармливание, а также результатов передачи вируса и переносимости АРТ первого ряда. 8. Создание адекватных механизмов мониторинга и оценки. Необходимы новые стратегии для получения высококачественных данных продольных когортных исследований в отношении матерей и их детей, подвергающихся риску ВИЧинфицирования, во всех пунктах обращения и на всех этапах непрерывного оказания помощи. Для кормящих грудью женщин и грудных детей истинная эффективность программы ППМР зависит от инфекционного статуса грудного ребенка и выживания без ВИЧ в конце периода грудного вскармливания, а не от раннего инфекционного статуса в возрасте шести недель. 9. Предоставление профилактической помощи грудным детям. Профилактическая помощь грудным детям имеет особенно важное значение для ППМР при поздней постановке диагноза ВИЧ матери, ограниченном проведении или отсутствии АРТ у матери в дородовой период, а также при прерывании АРТ у матери в связи с токсичностью, непереносимостью или несоблюдением режима лечения. 10. О беспечение непрерывных поставок лекарственных средств. Бесперебойное проведение АРТ матерям в период беременности и грудного вскармливания имеет важное значение для ППМР и охраны здоровья матери. Необходимо правильное прогнозирование и наличие адекватной цепочки поставок лекарственных средств. Контекстные факторы при рассмотрении вариантов ППМР Хотя программы в странах будут определять выбор между (1) проведением АРТ у беременных и кормящих грудью женщин, живущих с ВИЧ, в течение периода риска передачи от матери ребенку или (2) пожизненной АРТ при любом количестве клеток CD4 в зависимости от местных обстоятельств, предпочтений и ценностей, некоторые контекстные факторы имеют особенно важное значение для принятия решений. 1. Пожизненное проведение АРТ (“Вариант B+”) всем беременным и кормящим грудью женщинам особенно важно при наличии следующих характеристик: • г енерализованная эпидемия; • в ысокая частота случаев повторной беременности vii и низкий уровень охвата службами планирования семьи; • н изкие показатели тестирования партнеров; • о граниченный доступ к тестированию на CD4; • н изкий существующий уровень охвата АРТ беременных женщин, отвечающих критериям проведения лечения для небеременных лиц; и • д лительный период грудного вскармливания у женщин, живущих с ВИЧ.

vii

местах с высоким коэффициентом фертильности приоритетной задачей должно являться создание В программ планирования семьи, что даст возможность женщинам избегать незапланированной беременности

248

Вставка 10.4 (продолжение) 2. П роведение АРТ только в период риска передачи от матери ребенку (Вариант B) при продолжении пожизненной АРТ только женщинам, отвечающим стандартным критериям для проведения лечения небеременным взрослым людям, особенно важно при наличии следующих характеристик: • к онцентрированная эпидемия; • н изкая частота случаев повторной беременности и высокий уровень охвата службами планирования семьи; • в ысокие показатели доступа к тестированию на CD4; • в ысокий существующий уровень охвата АРТ беременных женщин, отвечающих критериям проведения лечения для небеременных лиц; и • и скусственное вскармливание рекомендуется, искусственные питательные смеси имеются и являются безопасными.

Вставка 10.5 Основные вопросы реализации для руководителей программ: децентрализация служб АРТ (Раздел 9.4.3) 1. И зучение моделей и вариантов. Программы должны определить, какие клинические и лабораторные службы имеются и на каком уровне системы предоставления услуг здравоохранения. Оптимальная модель децентрализации АРТ (частичной или полной) зависит от местных условий. 2. Р ассмотрение политики в области кадровых ресурсов и перераспределение обязанностей. Следует регулярно проводить обучение, наставничество и контроль деятельности работников здравоохранения, включая участковых работников здравоохранения, для обеспечения высококачественной помощи и выполнения обновленных национальных рекомендаций. Во многих местах децентрализация АРТ требует перераспределения обязанностей для обеспечения нужной кадровой структуры работников здравоохранения в периферийных учреждениях. Для выполнения соответствующих функций разными категориями работников здравоохранения необходима соответствующая нормативноправовая база (законы, правила, положения и руководящие принципы), помимо национальной стандартизированной системы обучения, наставничества и контроля для всех работников здравоохранения, участвующих в оказании помощи при ВИЧ. 3. О существление стратегий для удержания персонала. Руководители программ должны оказывать содействие в разработке и осуществлении стратегий для создания благоприятных условий для набора, удержания и мотивации сотрудников в сельских и отдаленных районах, где текучесть и убыль работников здравоохранения может быть выше, чем в городской местности. 4. У крепление связей и систем направлений. Хотя программы лечения по месту жительства предоставляют хорошие возможности для децентрализации АРТ, они всегда должны быть связаны с оказанием обычной медицинской помощи в учреждениях здравоохранения, а также соответствующими лабораторными и диагностическими службами и системами мониторинга, оценки и управления поставками лекарственных средств и материалов. 5. Согласованное разделение труда. Эффективное разделение обязанностей на разных уровнях системы здравоохранения (национальном, областном или территориальном и районном) имеет важнейшее значение для сведения к минимуму дублирования усилий и оптимального использования ресурсов. Роль каждого уровня должна соответствовать его потенциальным возможностям, а порядок подчиненности и подотчетности должен быть ясен и хорошо пониматься всеми. 6. С оздание партнерств. Национальные органы регулирования, профессиональные ассоциации и другие стороны должны принимать участие в определении сферы деятельности, ролей и обязанностей работников здравоохранения.

10. Рекомендации для руководителей программ

249

10.6 В опросы реализации в отношении основных рекомендаций

Вставка 10.6 Основные вопросы реализации для руководителей программ: расширение масштабов лечения для детей – лечение детей в возрасте до 5 лет и повышение порогового уровня CD4 у детей более старшего возраста с 350 до 500 клеток/мм³ (Разделы 7.1.4 и 7.2.3) 1. Р асширение охвата АРТ должно быть главным приоритетом. Поскольку все схемы лечения способствуют снижению заболеваемости и смертности, использование менее предпочтительных вариантов лучше, чем оставление детей без лечения. 2. У детей младшего возраста выше риск неудовлетворительных результатов. У детей в возрасте до двух лет, живущих с ВИЧ, выше показатели смертности и быстрого прогрессирования заболевания, чем у детей более старшего возраста. Ранняя диагностика и быстрое начало АРТ имеют особенно важное значение для грудных детей и детей младшего возраста. 3. Укрепление связей между диагнозом и лечением. Диагностика и лечение детей часто выполняются в разных учреждениях, что повышает риск их выбытия из наблюдения. Укрепление связей между ранней диагностикой у грудных детей и службами проведения АРТ имеет важное значение для сведения к минимуму случаев выбытия и улучшения показателей проведения АРТ у детей. Важными подходами к диагностике и лечению ВИЧ у детей является тестирование на ВИЧ в семье, а также тестирование и консультирование по инициативе провайдера. 4. О птимизация и улучшение выбора имеющихся форм АРВ-препаратов. Важное значение имеет сокращение сроков утверждения предпочтительных форм регулирующими органами. Расширению масштабов АРТ для детей в отдаленных районах могут способствовать делимые и диспергируемые комбинированные препараты с фиксированными дозами для детей, рассчитанные по их весу. 5. Использование существующей инфраструктуры и каналов. Обеспечение доступности АРТ для детей в рамках программ АРТ для взрослых и ППМР имеет важное значение для расширения доступа и проведения лечения, особенно в условиях децентрализации предоставления услуг в учреждениях здравоохранения на более низком уровне. 6. Обеспечение удержания и соблюдения режима лечения. Лечение детей зависит от взрослых. Важно разработать и осуществлять стратегии оказания помощи в семье, что может способствовать удержанию и соблюдению режима лечения среди детей. При этом следует принимать во внимание также особые проблемы соблюдения режима лечения детьми при смене места жительства. Вставка 10.7 Основные вопросы реализации для руководителей программ: прекращение использования d4T (Раздел 7.2) 1. В ыбор подходящей альтернативы. В качестве предпочтительной альтернативы d4T в схемах лечения первого ряда ВОЗ рекомендует TDF. TDF также обычно более эффективен, чем AZT среди лиц, у которых развилась лекарственная устойчивость при приеме d4T. 2. Разработка плана прекращения использования d4T с калькуляцией затрат. Общий операционный план прекращения использования d4T должен сопровождаться калькуляцией всех затрат и включать дополнительные инвестиции в усиление и наращивание потенциала лабораторий, которые могут потребоваться для его реализации. 3. Установление приоритетов для реализации. В связи с программными ограничениями, не все страны имеют возможность оперативно перевести всех пациентов, получающих d4T, на новые схемы лечения. Приоритеты должны быть четко определены и согласованы со всеми заинтересованными сторонами.

250

Вставка 10.7 (продолжение) 4. Н едопущение прерывания лечения. Хотя новые закупки d4T следует прекратить, адекватное и своевременное прогнозирование и закупки предпочтительного альтернативного препарата имеют важнейшее значение для того, чтобы не допустить исчерпывания запасов и прерывания лечения. 5. Изучение и сравнение цен. В последние годы наблюдается значительное снижение цен как на TDF, так и на предпочтительный сопутствующий препарат EFV. Странам предлагается обеспечить закупки этих препаратов по наилучшей возможной цене. Ценным источником информации о цене может служить разработанный ВОЗ Глобальный механизм информирования о цене (23). 6. У правление запасами. Возможными вариантами является резервирование запасов для непредвиденных ситуаций для лиц, которым может потребоваться d4T при отсутствии альтернативного выбора. 7. Обучение и просвещение клинического персонала и лиц, получающих АРТ. Клинический персонал должен быть обучен и готов к осуществлению перехода и просвещения пациентов, получающих АРТ, в отношении новых схем лечения. 8. Прекращение использования d4T у детей при наличии альтернативных препаратов. Рекомендация ВОЗ о прекращении использования d4T касается как взрослых, так и детей. Однако принимая во внимание ограниченное наличие форм НИОТ, соответствующих определенному возрасту, d4T может использоваться при особых обстоятельствах, особенно там, где формы ABC для детей отсутствуют (см. Разделы 7.2.3. и 7.2.4).

10.7 В ыполнение рекомендаций в разных условиях 10.7.1 Обзор Хотя все страны выразили согласие обеспечить всеобщий доступ к службам профилактики, лечения, помощи и поддержки при ВИЧ к 2015 году, ход работы по достижению этой цели будет определяться местными условиями, включая эпидемиологию и текущий уровень охвата. В данном разделе приводится общее описание возможных последовательных подходов к поэтапному выполнению основных рекомендаций, принимая во внимание имеющиеся научные данные, результаты математического моделирования (Вставка 10.2), а также вопросы этики и соблюдения прав человека. Они основываются на взглядах, высказанных группой по подготовке рекомендаций в области программных вопросов, в связи с чем не являются официальными рекомендациями. Ответственность за процесс пересмотра и адаптации настоящего руководства несут заинтересованные стороны на национальном уровне, при этом могут быть необходимы разные подходы, имеющие равную силу.

10.7.2 Выполнение рекомендаций в разных эпидемических ситуациях В руководстве рекомендуется, чтобы при всех условиях все лица (взрослые, подростки и дети), у которых количество клеток CD4 ниже 500 клеток/мм3, получали АРТ в приоритетном порядке. Эта мера является высокоэффективной с точки зрения затрат, и помимо частоты случаев ВИЧ, с ее помощью можно значительно снизить показатели смертности и заболеваемости в связи с ВИЧ. АРТ следует также проводить всем беременным и кормящим грудью женщинам, независимо от количества клеток CD4, и всем людям с активной формой ТБ и коинфекцией ВГВ с тяжелым заболеванием печени, а также ВИЧ-положительным партнерам в серодискордантных парах, независимо от

10. Рекомендации для руководителей программ

251

количества CD4. Уровень охвата АРТ среди детей также часто является низким, в связи с чем необходимы целенаправленные инвестиции для того, чтобы все отвечающие критериям дети, в том числе в возрасте менее пяти лет, своевременно получали доступ к лечению. Кроме того, в руководстве рекомендуется прекращать прием d4T и расширять использование комбинированных АРВ-препаратов с фиксированными дозами. В условиях концентрированной эпидемии при низком уровне охвата АРТ важное значение имеет выявление возможностей для расширения доступа к лечению и помощи при ВИЧ, включая тестирование и консультирование, групп населения повышенного риска, таких как мужчины, практикующие секс с мужчинами, трансгендерные лица, работники секс-индустрии, потребители инъекционных наркотиков и заключенные. Это требует устранения любых структурных барьеров, которые могут препятствовать обращению этих людей за помощью и доступу к ней. Интеграция служб помощи при ВИЧ со службами лечения наркозависимости и снижения вреда, а также противотуберкулезной помощи может быть высокоэффективным подходом к обеспечению охвата этих групп населения (см. Раздел 9.4.2). В этих условиях, принимая во внимание относительно ограниченное число беременных женщин, живущих с ВИЧ, высокоэффективными и относительно низкозатратными стратегиями являются постепенное прекращение использования Варианта А для ППМР и проведение АРТ в период беременности и кормления грудью для снижения риска передачи ВИЧ от матери ребенку (Вариант В). В условиях генерализованной эпидемии при низком уровне охвата АРТ одной из первоочередных задач является выявление и предоставление помощи и лечения всем людям с количеством клеток CD4 менее 350 клеток/мм3, что требует значительно расширенного проведения тестирования на ВИЧ и консультирования среди всего населения. Это может быть достигнуто путем расширения масштабов комплексного использования соответствующих подходов к тестированию на ВИЧ и консультированию, включая проводимые по инициативе провайдера ВИЧ-тестирование и консультирование всех лиц, обращающихся за помощью, а также всех беременных и кормящих грудью женщин, при наличии эффективных систем направлений и связей со службами помощи и лечения (Раздел 5.1). Выявление лиц с количеством клеток CD4 от 350 до 500 клеток/ мм3 обеспечивает важную возможность установления их связи со службами помощи для проведения АРТ на ранней стадии. К другим стратегиям повышения общих уровней доступа и проведения АРТ относятся децентрализация служб ВИЧ на уровне первичной медико-санитарной помощи и интеграция служб ВИЧ с противотуберкулезными службами, службами дородовой помощи и охраны здоровья матери и ребенка (см. Раздел 9.4.2), а также предоставление беременным и кормящим грудью женщинам, живущим с ВИЧ, возможности пожизненного получения АРТ на основе решений национальных программ. Кроме того, при концентрированной эпидемии важно выявлять и обеспечивать охват ключевых групп населения и лиц, имеющих недостаточный доступ к клиническим службам и службам по месту жительства. К ним могут относиться работники секс-индустрии, потребители инъекционных наркотиков, мужчины, практикующие секс с мужчинами, трансгендерные лица и другие группы, такие как девочки-подростки, мигранты и другие мобильные группы населения, пожилые женщины и некоторые профессиональные группы повышенного риска. As coverage of ART increases and programmes mature, expanding access to second-line regimens increasingly becomes a programmatic priority. Scaling up viral load monitoring will be important to adequately identify treatment failure and to avoid switching unnecessarily to second-line regimens. Viral load monitoring is also likely to play a central monitoring role in places in which ART is being broadly expanded to reduce HIV incidence. As people initiate treatment earlier and stay on it for longer, monitoring the quality of service delivery and strengthening service linkages to improve retention throughout the cascade of care are essential to optimize treatment outcomes and long-term programme performance.

10.7 Выполнение рекомендаций в разных условиях

252

10.8 П олезные инструменты для калькуляции затрат и планирования Оценка размеров затрат, связанных с выполнением новых рекомендаций, является одним из важных этапов процесса реализации. Имеется несколько инструментов для калькуляции затрат и ресурсов, которые могут помочь странам в проведении оценки затрат и составлении сметы расходов на проведение мероприятий и оказание услуг, связанных с ВИЧ. Система Spectrum включает целый ряд моделей и аналитических средств, используемых при принятии решений. К ним относятся несколько программных приложений, включая AIM (Модель воздействия СПИДа) и Goals (Затраты и воздействие мер борьбы с ВИЧ). Модули AIM и Resource Needs (Потребности в ресурсах) могут использоваться для оценки воздействия основных новых рекомендаций в отношении числа случаев смерти, предотвращенных благодаря АРТ, числа случаев инфицирования грудных детей, предотвращенных благодаря ППМР, а также потребностей в лечении детей и соответствующих затрат. Основными данными, необходимыми для получения таких оценок, являются демографические прогнозы, тенденции в отношении частоты случаев ВИЧ, хронологические данные о количестве людей, получающих АРТ, количество беременных женщин, охваченных мерами ППМР, а также удельные затраты на АРТ для взрослых и на ППМР. Все страны уже подготовили данные AIM в рамках своих национальных эпидемиологических оценок, в связи с чем оба модуля могут быть использованы оперативным образом. Модуль Goals может быть использован для оценки числа случаев ВИЧ-инфекции среди взрослых людей, предотвращенных благодаря АРТ, при различных критериях и масштабах проведения лечения. Основными необходимыми данными являются: распределение взрослого населения по группам риска (таким, как серодискордантные стабильные пары; лица со случайными связями; работницы секс-индустрии; мужчины-клиенты работников секс-индустрии; мужчины, практикующие секс с мужчинами; трансгендерные лица; и потребители инъекционных наркотиков); сексуальное поведение в группах риска (количество партнеров в год, количество половых актов из расчета на одного партнера и использование презервативов) и совместное использование игл потребителями инъекционных наркотиков. Модели Goals уже имеются примерно в 25 странах, другие страны получают такие данные в рамках исследований путей передачи инфекции. OneHealth является программным средством, предназначенным для усиления анализа и калькуляции затрат систем здравоохранения, а также разработки сценариев финансирования на страновом уровне. Оно специально предназначено для оценки потребностей инвестиций в здравоохранение в странах с низким и средним уровнями дохода и предоставляет разработчикам единую платформу для планирования, калькуляции затрат, анализа воздействия, бюджетирования и финансирования стратегий, касающихся всех основных заболеваний и компонентов системы здравоохранения. Программу OneHealth можно загрузить бесплатно (24). ВОЗ и сотрудничающие организации недавно разработали целый ряд инструментов, помогающих в проведении количественной оценки лекарственных средств и управлении поставками. Некоторые из них могут быть загружены и сопровождаются описанием основного назначения и областей применения в программах (25). Было также разработано руководство по калькуляции затрат для различных вариантов ППМР (26). Разработан и также может быть бесплатно загружен вместе с руководством пользователя гибкий инструмент для калькуляции инвестиций в важнейшие факторы, способствующие реализации (такие, как комплексные программы просвещения в вопросах лечения и прав, юридические службы, программы борьбы со стигматизацией и дискриминацией, обучение работников здравоохранения и обеспечение соблюдения законов) (27,28).

МОНИТОРИНГ И ОЦЕНКА

11.1 Введение 254 11.2 Значение новых рекомендаций для мониторинга 255 11.3 Мониторинг промежуточных и конечных результатов расширения доступа к АРВ-препаратам 256 11.4 Другие аспекты мониторинга 259 11.4.1 Лекарственная устойчивость ВИЧ 259 11.4.2 Дозорный эпиднадзор для мониторинга токсичности АРВ-терапии 260 11.4.3 О ценка, включая воздействие и результаты деятельности программ, а также внедренческие исследования 260 11.5 Изучение и укрепление систем мониторинга и оценки 262

Цель данной главы Предоставление рекомендаций по программам для лиц, принимающих решения и осуществляющих планирование на национальном уровне, в отношении контроля за выполнением этих рекомендаций и мониторинга их воздействия на программы по ВИЧ и людей, получающих АРТ.

254

11. МОНИТОРИНГ И ОЦЕНКА 11.1 Введение При адаптации и выполнении этих рекомендаций в странах необходимо адаптировать механизмы и системы мониторинга и оценки для сбора и анализа информации, позволяющей контролировать выполнение новых рекомендаций и их воздействие. Мониторинг и оценка будут помогать руководителям программ определять эффективность мер вмешательства и установления связей между службами на всех последовательных этапах лечения и помощи при ВИЧ и сопутствующих заболеваниях (Рис. 11). Такая информация имеет важное значение для выявления и устранения недостатков или пробелов в деятельности программ, а также для адекватной оценки проблемы отсева пациентов и принятия ответных мер. В ходе выполнения программы важное значение для оценки ее воздействия имеет также мониторинг результатов на индивидуальном и популяционном уровне, включая токсичность и неблагоприятные эффекты, лекарственную устойчивость, вирусную супрессию, смертность, выживаемость и частоту случаев.

Рис. 11.1 Последовательность этапов лечения и помощи при ВИЧ Люди, живущие с ВИЧ Диагноз ВИЧ Взаимосвязь и получение помощи Антиретровирусная терапия Вирусная супрессия Воздействие на популяционном уровне

Сбор данных можно осуществлять разным образом, включая плановое предоставление данных всеми учреждениями или дозорными участками; популяционные обследования; данные эпиднадзора; наблюдение за когортами людей, живущих с ВИЧ; и периодическая оценка. Мониторинг результатов выполнения программы и процессов можно осуществлять также с помощью обзорных исследований учреждений или обновленных списков имеющихся услуг; документирования наличия и уровня подготовки кадров; и мониторинга наличия лекарственных и диагностических средств на разных географических и учрежденческих уровнях. Можно рассмотреть возможность проведения специальных исследований, если плановый мониторинг является нецелесообразным. При рассмотрении наилучших путей сбора важнейших данных следует также стремиться к пересмотру систем мониторинга, например для обеспечения большей взаимосвязи между мониторингом служб ППМР, ТБ м АРТ, а также интеграции мониторинга лекарственной устойчивости ВИЧ с существующими информационными системами здравоохранения. Участие гражданского общества в мониторинге и оценке также имеет важное значение для понимания причин успехов и неудач, особенно при оценке представлений, ценностей и предпочтений людей, живущих с ВИЧ, ключевых групп и всего населения в отношении доступа к службам и их использования. Общество может также играть основную роль в разработке и использовании инструментов для сбора данных, а также в проведении анализа и интерпретации результатов. В настоящее время ВОЗ разрабатывает сводное руководство по мониторингу и оценке ВИЧ в секторе здравоохранения, которое объединяет различные элементы систем мониторинга и оценки для программ ВИЧ. В руководстве существующие подходы к мониторингу и оценке в соответствующих программных областях (таких, как тестирование на ВИЧ и консультирование, АРТ, ППМР и лекарственная устойчивость ВИЧ) будут обобщены и согласованы с рекомендациями, содержащимися в данном руководстве. Оно будет включать также новые

11. мониторинг и оценка

255

рекомендации в отношении мониторинга и оценки в новых областях, касающихся ВИЧ. Публикация, в которой описаны три взаимосвязанные системы мониторинга пациентов (1), также будет обновлена с учетом этого нового руководства по мониторингу и оценке.

11.2 значение новых рекомендаций для мониторинга

11.2 Значение новых рекомендаций для мониторинга Стратегия мониторинга и оценки должна обеспечивать мониторинг предоставления услуг, включая вводимые ресурсы и процессы, а также промежуточные и конечные результаты, такие как количество людей, получающих помощь, и воздействие на индивидуальном и популяционном уровнях (см. Раздел 11.3). План мониторинга и оценки должен включать механизм слежения за ходом работ по выполнению рекомендаций, чтобы определить, действительно ли реализуются новые стратегии в отношении критериев для АРТ, а также рекомендации и планы по проведению лечения или предоставлению услуг. Это позволит национальным программам документировать влияние изменений в рекомендациях и может способствовать проведению оценки их воздействия. В Таблице 11.1 перечислены основные аспекты, требующие рассмотрения при выполнении основных новых рекомендаций, содержащихся в данном руководстве. По каждой из основных областей приводятся возможные вопросы для мониторинга и их значение для пересмотра систем мониторинга. Не вся информация должна собираться в плановом порядке; потребности в данных и сроки сбора данных зависят от условий на местах.

Таблица 11.1 Значение основных рекомендаций, содержащихся в данном руководстве, для мониторинга Новые области рекомендаций Тестирование на ВИЧ и консультирование Когда начинать АРВ-терапия Значение для мониторинга

Мониторинг осуществления стратегий тестирования на ВИЧ по месту жительства и работы служб тестирования для подростков, включая системы для обеспечения связи со службами помощи Мониторинг численности и доли разных групп населения (например, взрослых, подростков, детей, беременных и кормящих грудью женщин), которые начали получать АРТ на основе новых критериев Рассмотрение системы мониторинга для определения, какие дезагрегированные данные требуются и для какой цели (например, количество CD4 ≤200 клеток/мм3 для планового мониторинга случаев поздней диагностики или количества CD4 ≤350 клеток/мм3 и 350–500 клеток/мм3 для периодической оценки распределения CD4 в начале проведения АРТ) и как лучше всего собирать соответствующие данные, а также разбивка данных по детям (например, в возрасте до двух лет и до 5 лет)

С каких схем АРВтерапии следует начинать

Мониторинг схем АРВ-терапии первого и второго ряда, получаемых людьми Мониторинг прекращения использования и/или введения конкретных препаратов (например, d4T и TDF) Может потребоваться изменение средств мониторинга в связи с введением новых схем Мониторинг доли людей, получающих АРТ, у которых определялась вирусная нагрузка и были получены результаты Мониторинг причин изменения схемы АРВ-терапии

Эффективность АРТ и выявление неудачи лечения

256

Таблица 11.1 (продолжение) Новые области рекомендаций Предоставление услуг Значение для мониторинга

Мониторинг удержания пациентов и соблюдения режима лечения в различных группах населения Мониторинг интеграции АРТ в работу служб охраны здоровья матери и ребенка, противотуберкулезных и наркологических служб, если это планировалось, путем документирования учреждений, предоставляющих АРТ Мониторинг децентрализации назначения и проведения АРТ, если это планировалось, в различных учреждениях путем документирования расширения числа служб АРТ Мониторинг функционирования связей служб охраны здоровья матери и ребенка, противотуберкулезных и наркологических служб со службами помощи при ВИЧ и АРТ, а также связей между местными сообществами, периферийными учреждениями и больницами путем документирования перевода пациентов

Перераспределение обязанностей

Мониторинг численности неврачебного клинического персонала, акушерок и медсестер, прошедших обучение в области АРТ Мониторинг численности неврачебного клинического персонала, акушерок и медсестер, инициирующих АРТ первого ряда и продолжающих проводить АРТ, а также числа людей, которым они инициировали или продолжили проведение АРТ Мониторинг численности участковых работников здравоохранения ОБЩИНЫ, которые прошли обучение и отпускают препараты для АРТ в период между посещениями клиники, а также числа людей, которым они отпускают препараты для АРТ

11.3 М ониторинг промежуточных и конечных результатов расширения доступа к АРВ-препаратам Помимо мониторинга выполнения новых рекомендаций, необходимо пересмотреть и адаптировать информационные системы здравоохранения для надлежащего мониторинга промежуточных и конечных результатов, связанных с новыми рекомендациями. В Таблице 11.2 перечислены области для сбора данных в целях оценки того, приводит ли расширение программ к получению ожидаемых промежуточных и конечных результатов на различных этапах лечения и помощи при ВИЧ. Большинство этих областей располагают соответствующими показателями, указанными в существующем руководстве ВОЗ (более подробная информация о показателях и ссылки приводятся в веб-приложении www.who.int /hiv /pub /guidelines /arv2013 /annexes) и/или являются частью международных согласованных основных показателей, которые должны отслеживаться странами в рамках процесса представления отчетности о достигнутом прогрессе в осуществлении глобальных мер в ответ на СПИД (2). В некоторых новых областях (таких, как связь между диагнозом ВИЧ и АРТ, удержание беременных женщин в программах приема АРВ-препаратов и мониторинг вирусной нагрузки) показатели в настоящее время изучаются и оцениваются. Более детальные рекомендации будут приведены в готовящемся к выпуску сводном руководстве по ВИЧ в секторе здравоохранения.

11. мониторинг и оценка

257

Таблица 11.2 Обзор областей данных для мониторинга и оценки последовательности этапов лечения Этап Люди, живущие с ВИЧ Показатель Расчетное число людей, живущих с ВИЧ в различных категориях Значимость Показывает распределение людей, живущих с ВИЧ, среди населения Указывает на численность соответствующих групп населения и необходимость помощи в отношении ВИЧ для целенаправленного планирования Уровень охвата тестированием соответствующих групп населения указывает на величину усилий по расширению масштабов тестирования на ВИЧ и консультирования, в том числе инициированных провайдером Оценка доли людей, знающих о своем ВИЧ-статусе, среди групп населения показывает, где могут потребоваться дополнительные усилия Количество людей, живущих с ВИЧ, у которых впервые установлен диагноз ВИЧ-инфекции в течение определенного периода времени, показывает общую численность людей, которые должны установить контакт со службами оказания помощи Показатель эффективности взаимосвязи между установлением диагноза и охватом медицинской помощью Указывает на доступность и эффективность помощи при ВИЧ после положительного теста на ВИЧ-инфекцию Показывает, кто охвачен медицинской помощью и установлена ли связь между службами помощи и ключевыми и приоритетными группами населения Служит косвенным показателем поддержания связи со службами оказания помощи взрослым и детям, которые могут начать получать АРТ в будущем

11.3 Мониторинг промежуточных и конечных результатов расширения доступа к АРВ-препаратам

Диагноз ВИЧ

Доля людей с известным ВИЧ-статусом среди всего населения, а также отдельных групп населения

Число людей с впервые установленным диагнозом ВИЧинфекции

Взаимосвязь и получение помощи при ВИЧ

Доля людей с впервые установленным диагнозом ВИЧ-инфекции, охваченных службами помощи при ВИЧ

Профиль людей, живущих с ВИЧ и начинающих получать помощь в отношении ВИЧ Удержание в системе помощи людей, живущих с ВИЧ, но еще не получающих АРТ, включая грудных детей с риском ВИЧинфицирования

258

Таблица 11.2 (продолжение) Этап Показатель Число людей, получающих АРТ (и охват) Значимость Охват АРТ людей, живущих с ВИЧ, отвечающих критериям по интересующим группам населения и схемам лечения П оказывает тенденции в отношении числа людей, получающих АРТ, для изучения результатов расширения программы и планирования поставок препаратов П омогает оценить неудовлетворенные потребности в АРТ и обеспечение справедливости в доступе к АРТ Охват АРВ-препаратами для ППМР среди беременных женщин с ВИЧ П озволяет оценить неудовлетворенные потребности в АРВ-препаратах для ППМР Д анные для моделирования воздействия служб ППМР Антиретровирусные препараты: поставки препаратов Доля служб АРТ, где были израсходованы запасы АРВ-препаратов в течение определенного периода времени Соблюдение режима лечения Указывает на израсходование запасов, что может непосредственно повлиять на соблюдение режима лечения и клинические результаты и может приводить к лекарственной устойчивости ВИЧ Указывает на качество помощи и вероятность вирусной супрессии Соблюдение режима лечения служит показателем для раннего предупреждения о возможности развития лекарственной устойчивости Доля пациентов, остающихся в программах АРТ и ППМР Служит показателем удержания пациентов с течением времени и успеха программ АРТ Помогает контролировать выбытия и определять, где следует усилить охват помощью Низкий уровень удержания пациентов служит показателем для раннего предупреждения о возможности развития лекарственной устойчивости Вирусная супрессия Процент вирусной супрессии Эффективность программ АРТ в достижении вирусной супрессии

Антиретровирусные препараты: охват Число людей, получающих АРВ-препараты для ППМР (и охват)

Антиретровирусные препараты: соблюдение режима лечения и удержание пациентов

11. мониторинг и оценка

259

Таблица 11.2 (продолжение) Этап Показатель Смертность Значимость Снижение числа случаев смерти, связанных с ВИЧ, и даже общей смертности в странах с высоким бременем ВИЧ указывает на успех программ оказания помощи при ВИЧ Снижение частоты случаев показывает, насколько эффективны программы профилактики и лечения ВИЧ для сокращения числа людей, инфицируемых ВИЧ Определение круга лиц, инфицируемых ВИЧ, и мест, где происходит инфицирование, способствует целенаправленному планированию Воздействие Недопущение новых случаев ВИЧинфицирования среди детей является показателем успеха программ ППМР Распространенность случаев передачи ВИЧ от матери ребенку Распространенность случаев передачи ВИЧ от матери ребенку указывает, насколько часто происходит вертикальная передача вируса Увеличение выживаемости и лет жизни людей, живущих с ВИЧ и получающих АРТ, является показателем воздействия АРТ Выживаемость, включая детей с риском ВИЧ-инфицирования и детей, живущих с ВИЧ, указывает на уровни доступности и качества медицинской помощи

11.4 Д ругие аспекты мониторинга

Частота случаев и число взрослых и детей, инфицируемых ВИЧ

Выживаемость

11.4 Другие аспекты мониторинга Программы все чаще выходят за рамки показателей охвата, уделяя основное внимание наиболее важным конечным результатам, таким как супрессия вирусной нагрузки и восстановление иммунитета, включая связанную с ВИЧ смертность и частоту случаев ВИЧ. Однако в рамках программ необходимо также оценивать возможные непредвиденные результаты, такие как лекарственная устойчивость ВИЧ и связанная с АРТ токсичность. При пересмотре программ важное значение имеет также проведение периодических оценок и внедренческих исследований.

11.4.1 Лекарственная устойчивость ВИЧ ВОЗ рекомендует использовать показатели раннего предупреждения для выявления недостатков в работе программы, способствующих развитию лекарственной устойчивости ВИЧ (Вставка 11.1). ВОЗ также рекомендует странам проводить эпиднадзор за лекарственной устойчивостью ВИЧ и предоставляет специальное руководство о том, как следует проводить требуемые исследования.

260

11.4.2 Дозорный эпиднадзор для мониторинга токсичности АРВ-терапии Эпиднадзор в целях мониторинга токсичности АРВ-препаратов имеет важное значение для выявления и устранения предупреждаемых побочных эффектов. Для мониторинга токсичности АРВ-препаратов были разработаны различные подходы, включая целенаправленное и систематическое представление данных эпиднадзора о конкретных видах токсичности и серьезных побочных эффектах, вызываемых определенным препаратом в ключевых группах населения, а также регистры учета воздействия препарата при беременности после проведения АРТ у группы беременных женщин, включая надзор за врожденными пороками. Техническое руководство ВОЗ по проведению мониторинга токсичности на дозорных участках будет выпущено в 2013 году.

11.4.3 Оценка, включая воздействие и результаты деятельности программ, а также внедренческие исследования Плановый мониторинг должен дополняться систематическим изучением и анализом программ для оценки результатов деятельности и эффективности программ борьбы с ВИЧ как в целом, так и в отношении конкретных приоритетных областей. Социальные и внедренческие исследования имеют важное значение для оценки представлений и ценностей получателей услуг и местных сообществ, а также препятствий, благоприятных факторов и практического опыта в отношении предоставления и получения услуг. Показатели воздействия, такие как частота случаев, заболеваемость и смертность, часто с трудом поддаются измерению. Недавно было разработано руководство по использованию анализов на недавнюю инфекцию для оценки частоты случаев ВИЧ на популяционном уровне (3). В 2013 году будет выпущено руководство по мониторингу показателей смертности, включая причины смерти. Имеется также краткое руководство с описанием пяти методов оценки воздействия программ ППМР (4), а подробное руководство, которое может быть адаптировано к использованию каждого из этих методов, будет выпущено в 2013 году. Для прогнозирования различных сценариев при планировании программ и оценке воздействия часто используется математическое моделирование. Обеспечение наличия надежных данных особенно важно при оценке профилактического воздействия АРВпрепаратов на популяционном уровне, так как имеется множество источников информации и факторов неопределенности. Более точные результаты оценки могут быть получены путем сбора конкретных данных и использования моделей для конкретных ситуаций. Вставка 11.1 Мониторинг лекарственной устойчивости ВИЧ Лекарственная устойчивость ВИЧ представляет собой значительную угрозу для успешного выполнения национальных программ по ВИЧ. Лекарственная устойчивость приводит к вирусологической неэффективности лечения в более короткие сроки среди лиц, получающих лечение первого ряда, и усиливает необходимость применения схем второго ряда, что может сопровождаться большей токсичностью, побочными эффектами, более низкими показателями соблюдения лечения и более высокими затратами. Лекарственная устойчивость может также отрицательно влиять на возможности предупреждения передачи ВИЧ с помощью профилактики до или после контакта с вирусом на основе АРВ-препаратов или бактерицидных препаратов местного применения. Эпиднадзор за лекарственной устойчивостью должен быть неотъемлемой частью национальных программ борьбы с ВИЧ. Данные эпиднадзора должны приниматься во внимание при выборе схем АРТ первого и второго ряда, а также АРВ-препаратов для ППМР в целях оптимизации результатов лечения в рамках подхода общественного здравоохранения. ВОЗ и ее партнеры разработали стандартизированную и вспомогательную стратегию оценки для внедрения в странах в отношении как взрослого, так и детского населения со следующими компонентами.

11. мониторинг и оценка

261

11.4 Д ругие аспекты мониторинга

Вставка 11.1 (продолжение) Мониторинг показателей раннего предупреждения о лекарственной устойчивости ВИЧ. Показатели раннего предупреждения основываются на существующей учетной документации клиник и аптек для оценки факторов, касающихся возникновения лекарственной устойчивости ВИЧ на уровне программ АРТ и клиник. К этим факторам относятся: практика назначения АРТ; бесперебойность поставок препаратов; соблюдение режима приема АРВ-препаратов, оцениваемое на основе своевременного получения АРВпрепаратов; удержание пациентов в системе помощи; и, при наличии, супрессия вирусной нагрузки. Мониторинг показателей раннего предупреждения должен быть интегрирован в национальную систему мониторинга и оценки и обеспечивать получение информации, необходимой для устранения факторов, способных приводить к неудовлетворительным результатам лечения и к лекарственной устойчивости ВИЧ. Обследования для мониторинга приобретенной лекарственной устойчивости ВИЧ и сопутствующих факторов в группах населения, получающих АРТ. В типовом протоколе ВОЗ для мониторинга случаев приобретенной лекарственной устойчивости ВИЧ используется стандартизированная методика проведения обследования для оценки вирусологической супрессии на национальном уровне и возникновения лекарственной устойчивости ВИЧ среди групп населения, получающих лечение. При регулярном проведении на репрезентативных участках эти обследования предоставляют фактические данные для осуществления действий на уровне программ и клиник в целях сведения лекарственной устойчивости ВИЧ к минимуму. Они также предоставляют данные для оптимизации выбора схем АРВ-терапии первого и второго ряда. Обследования для мониторинга лекарственной устойчивости ВИЧ до начала лечения. Типовой протокол ВОЗ для эпиднадзора за лекарственной устойчивостью ВИЧ до начала лечения обеспечивает получение репрезентативной национальной оценки лекарственной устойчивости ВИЧ в группах населения, приступающих к лечению. При регулярном проведении в репрезентативных клиниках АРТ эти обследования способствуют принятию решений на национальном, региональном и глобальном уровнях в отношении выбора схем лечения первого ряда. Эпиднадзор за наследуемой лекарственной устойчивостью ВИЧ среди лиц, недавно инфицированных ВИЧ. Типовой протокол ВОЗ для эпиднадзора за наследуемой лекарственной устойчивостью ВИЧ обеспечивает получение оценки наследуемой лекарственной устойчивости ВИЧ в недавно инфицированных группах населения, и ее результаты должны способствовать принятию стратегических решений в области АРТ, включая рекомендации по схемам АРВ-терапии и профилактики ВИЧ. Эпиднадзор за лекарственной устойчивостью ВИЧ среди детей в возрасте до 18 месяцев. Типовой протокол ВОЗ для эпиднадзора за лекарственной устойчивостью ВИЧ среди детей в возрасте до 18 месяцев может обеспечивать получение оценок распространенности лекарственной устойчивости ВИЧ на национальном уровне среди грудных детей с диагнозом ВИЧ-инфекции, поставленным с помощью раннего диагностического тестирования. Результаты позволяют оценивать различия в распространенности лекарственной устойчивости ВИЧ между группами населения, получающими АРВ-препараты для ППМР, и лицами с неизвестным риском воздействия, что будет способствовать выбору оптимальной схемы АРТ первого ряда для этой группы населения. Национальные стратегии оценки лекарственной устойчивости ВИЧ должны разрабатываться и вводиться в действие на регулярной основе в рамках всесторонних программ лечения ВИЧ.

262

11.5 И зучение и укрепление систем мониторинга и оценки Рекомендации, содержащиеся в данном руководстве, могут потребовать внесения некоторых изменений в систему мониторинга и оценки. Имеется руководство в отношении 12 компонентов системы мониторинга и оценки, а также средств изучения и укрепления национальных систем мониторинга и оценки в области ВИЧ (5). В Таблице 11.3 приводятся некоторые конкретные вопросы для рассмотрения в целях обеспечения соответствия систем мониторинга и оценки новым рекомендациями по АРВ-терапии.

Таблица 11.3 Основные аспекты систем мониторинга и оценки и значение новых рекомендаций Некоторые элементы систем мониторинга и оценки Система мониторинга пациентов Основные вопросы для рассмотрения в связи с новыми рекомендациями

У лучшение мониторинга охвата и удержания пациентов в системе помощи при ВИЧ Т очный учет случаев перевода и выбытия пациентов Д ля мониторинга пациентов в соответствии с новыми рекомендациями требуется обновление элементов данных, таких как изменения в схеме лечения, включая вирусную нагрузку (при наличии) П ересмотр категорий дезагрегации, а также связей и синергетических эффектов для систем мониторинга приема АРВ-препаратов в отношении ППМР, ТБ и АРТ П ереход на электронные системы, если это осуществимо

Поток данных и интеграция

Е диная стандартизированная система мониторинга и оценки, согласованная всеми партнерами и заинтересованными сторонами, включая необходимые обновления на основании новых стратегий и практики в отношении АРВ-препаратов Е диные национальные стандарты и поток данных на основе любых изменений в предоставлении услуг П рояснение вопросов интеграции программ для ППМР, противотуберкулезных программ с программами АРТ и переход на программы АРТ Р ассмотрение возможности введения индивидуального идентификационного номера пациента И спользование мобильных телефонов при наличии подтвержденных возможностей Ф ункциональные связи между информационными системами по вопросам ВИЧ и управления здравоохранением

11. мониторинг и оценка

263

Таблица 11.3 (продолжение) Некоторые элементы систем мониторинга и оценки Получение данных и обеспечение качества Основные вопросы для рассмотрения в связи с новыми рекомендациями

11.5 И зучение и укрепление систем мониторинга и оценки

Я сные протоколы для получения данных, стандартные операционные процедуры для агрегации данных, если они отсутствуют, в отношении любых новых показателей и новых сценариев предоставления услуг Р ассмотрение имеющихся лабораторных данных как источника основной информации Р егулярная оценка качества данных в учреждениях и на субнациональном уровне П оддерживающий контроль, включая новые элементы стратегии и планов реализации в отношении АРВ-препаратов О бновление национальных форм отчетности для включения любых новых данных национального уровня, в том числе определение частоты сбора данных, необходимых для различных показателей

Использование данных на различных уровнях и изучение программ

Р егулярное изучение стандартизированных данных на учрежденческом, региональном и национальном уровнях для выявления проблем и усовершенствования программ, включая изучение показателей раннего оповещения о лекарственной устойчивости ВИЧ И зучение и обновление стратегии использования данных на основе новых стратегий приема АРВ-препаратов и соответствующего механизма и плана мониторинга и оценки

Периодическая отчетность и доступность данных

В едение национальных и субнациональных баз данных, включая новые элементы данных Р егулярное распространение данных и открытая доступность данных, связанных с развитием программы ВИЧ П ериодическое представление (суб-) национальных и международных данных, отражающих и документирующих осуществление и воздействие новых стратегий, касающихся АРВ-препаратов

Потенциальные возможности системы мониторинга и оценки

К адровый и институциональный потенциал для получения и анализа данных на учрежденческом, субнациональном и национальном уровнях для мониторинга и оценки, касающийся обновленных рекомендаций и стратегий в отношении АРВ-препаратов С оответствующие инвестиции в мониторинг и оценку и отражение в грантах (в том числе предоставляемых Глобальным фондом для борьбы со СПИДом, туберкулезом и малярией) корректирующих изменений в системе мониторинга и оценки, требуемых для усиления существующего потенциала с учетом новых рекомендаций в отношении АРВ-препаратов

264

Таблица 11.3 (продолжение) Некоторые элементы систем мониторинга и оценки План мониторинга и оценки Основные вопросы для рассмотрения в связи с новыми рекомендациями

Н ациональный план с калькуляцией затрат, содержащий список основных показателей и планируемых оценок, уделяющий особое внимание результатам и подотчетности, пересмотренный в свете новых рекомендаций в отношении АРВ-препаратов Р егулярная оценка осуществления плана мониторинга и оценки на основании обновленного плана

Оценка и операционные и внедренческие исследования

П лан и стратегия для оценки воздействия, принимая во внимание осуществление новых рекомендаций в отношении АРВ-препаратов П рограмма и план действий для внедренческих исследований, принимая во внимание осуществление новых рекомендаций в отношении АРВ-препаратов О бзор результатов исследований для усовершенствования программ

Мониторинг и оценка: партнерства и координация

К оординация деятельности в области мониторинга и отчетности по программам среди основных заинтересованных сторон и партнеров С огласованность с национальной стратегией здравоохранения, связь с другими программными стратегиями (службы охраны здоровья матери и ребенка, ТБ и ключевые группы населения) и международными инициативами (Комиссия по информации и подотчетности в отношении здоровья женщин и детей, прекращение передачи ВИЧ от матери ребенку (eMTCT) и отчетность о достигнутом прогрессе в осуществлении глобальных мер в ответ на СПИД (2))

12. Приложения

ПРИЛОЖЕНИЯ

Приложение 1. Клинические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей 266 Приложение 2. Алгоритм для рекомендаций 2013 года в отношении взрослых и подростков 268 Приложение 3. Алгоритмы для рекомендаций 2013 года в отношении беременных и кормящих грудью женщин 270 Приложение 4. Алгоритм для рекомендаций 2013 года в отношении детей 272 Приложение 5. Алгоритм для ранней диагностики у грудных детей 273 Приложение 6. К онтрольный перечень вопросов для оценки готовности: переход к АРТ для беременных и кормящих грудью женщин 274 Приложение 7. Дозировки рекомендованных антиретровирусных препаратов 279

266

12. ПРИЛОЖЕНИЯ Приложение 1. К линические стадии ВИЧ-инфекции по классификации ВОЗ у взрослых, подростков и детей Источник: Адаптировано по WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. Geneva, World Health Organization, 2007 (www.who.int/hiv/pub/guidelines/HIVstaging150307.pdf). Взрослые и подростки a Клиническая стадия 1 Бессимптомное течение Персистирующая генерализованная лимфаденопатия Клиническая стадия 2 Необъяснимая умеренная потеря веса (<10% предполагаемой или измеренной массы тела) Рецидивирующие инфекции дыхательных путей (синусит, ангина, средний отит, фарингит) Опоясывающий лишай Ангулярный хейлит Рецидивирующие язвы во рту Папулезная зудящая сыпь Онихомикозы Себорейный дерматит Необъяснимая персистирующая гепатоспленомегалия Рецидивирующие или хронические инфекции верхнего дыхательного тракта (средний отит, оторея, синусит, тонзиллит) Опоясывающий лишай Линейная эритема десен Рецидивирующие язвы во рту Папулезная зудящая сыпь Онихомикозы Распространенная инфекция, вызванная вирусом папилломы человека Распространенный контагиозный моллюск Необъяснимое персистирующее увеличение околоушных слюнных желез Необъяснимые нарушения питания средней тяжестиb, плохо поддающиеся стандартному лечению Необъяснимая хроническая диарея (14 дней и дольше) Необъяснимая упорная лихорадка (выше 37,5°C, постоянная или перемежающаяся, дольше месяца) Постоянный кандидозный стоматит (у детей старше 6 недель) Волосатая лейкоплакия полости рта Туберкулезный лимфаденит Туберкулез легких Тяжелая рецидивирующая бактериальная пневмония Острый язвенно-некротический гингивит или периодонтит Необъяснимые анемия (8 г/дл), нейтропения (<0,5 х 109 л) или постоянная тромбоцитопения (<50 х 109 л) Клинически выраженная лимфоидная интерстициальная пневмония Хроническое поражение легких, связанное с ВИЧинфекцией, включая бронхоэктазы Дети Бессимптомное течение Персистирующая генерализованная лимфаденопатия

Клиническая стадия 3 Необъяснимая сильная потеря веса (>10% предполагаемой или измеренной массы тела) Необъяснимая хроническая диарея длительностью более месяца Необъяснимая персистирующая лихорадка (перемежающаяся или постоянная, длительностью более месяца) Персистирующий кандидозный стоматит Волосатая лейкоплакия полости рта Туберкулез легких Тяжелые бактериальные инфекции (например, пневмония, эмпиема плевры, гнойный миозит, инфекции костей и суставов, менингит, бактериемия) Острый язвенно-некротический стоматит, гингивит или пародонтит Необъяснимая анемия (<8 г/дл), нейтропения (<0.5 x 109/л) и/или хроническая тромбоцитопения (<50 x 109/л)

12. Приложения

267

Приложение 1. К линические стадии ВИЧ-инфекции по классификации ВОЗ

Взрослые и подростки a Клиническая стадия 4 c Синдром кахексии, обусловленный ВИЧ Пневмония, вызванная Pneumocystis (jiroveci) Рецидивирующая тяжелая бактериальная пневмония Хронический герпес (оролабиальный, генитальный или аноректальный длительностью более месяца или висцеральный любой локализации) Кандидозный эзофагит (или кандидоз трахеи, бронхов или легких) Внелегочный туберкулез Саркома Капоши Цитомегаловирусная инфекция (ретинит или инфекция других органов) Токсоплазмоз центральной нервной системы Энцефалопатия, обусловленная ВИЧ Внелегочный криптококкоз, включая менингит Диссеминированные инфекции, вызванные атипичными микобактериями Прогрессирующая мультифокальная лейкоэнцефалопатия Хронический криптоспоридиоз Хронический изоспориаз Диссеминированные грибковые инфекции (внелегочный гистоплазмоз, кокцидиоидоз) Лимфома (головного мозга или B-клеточная неходжкинская лимфома Нефропатия и кардиомиопатия, обусловленные ВИЧ, с клинической симптоматикой Рецидивирующий сепсис (включая сальмонеллезный) Инвазивный рак шейки матки Атипичный диссеминированный лейшманиоз

Дети Необъяснимые тяжелые истощение, задержка роста или выраженные нарушения питания d, не поддающиеся стандартному лечению Пневмония, вызванная Pneumocystis (jiroveci) Рецидивирующие тяжелые бактериальные инфекции, за исключением пневмонии (например, эмпиема плевры, пиомиозит, инфекции костей и суставов, менингит) Хронический герпес (лица и полости рта или кожи длительностью более месяца, либо висцеральный любой локализации) Кандидозный эзофагит (или кандидоз трахеи, бронхов, легких) Внелегочный туберкулез Саркома Капоши Цитомегаловирусная инфекция (ретинит или поражение других органов), развившаяся у ребенка старше 1 месяца Токсоплазмозный энцефалит (кроме новорожденных) ВИЧ-энцефалопатия Внелегочный криптококкоз, в том числе криптококковый менингит Диссеминированная инфекция, вызванная нетуберкулезными микобактериями Прогрессирующая многоочаговая лейкоэнцефалопатия Хронический криптоспоридиоз (с диарейным синдромом) Хронический изоспороз Диссеминированный глубокий микоз (например, внелегочный гистоплазмоз, кокцидиоидомикоз, пенициллиоз) Лимфома головного мозга или B-клеточная неходжкинская лимфома ВИЧ-кардиомиопатия или ВИЧ-нефропатия

При подготовке этой таблицы подростками считались лица в возрасте 15 лет и старше. Для лиц младше 15 лет следует использовать клинические стадии для детей. b Для детей в возрасте до 5 лет нарушение питания средней тяжести определяется как соотношение веса и роста <–2 Z-шкала или окружность середины плеча от ≥115 мм до <125 мм. c В региональных классификациях могут включаться некоторые дополнительные специфические заболевания, такие как пенициллиоз в Азии, ВИЧ-ассоциированный ректовагинальный свищ в южной части Африки и реактивация трипаносомоза в Латинской Америке. d Для детей в возрасте до 5 лет выраженное нарушение питания определяется как соотношение веса и роста <–3 Z-шкала; задержка роста определяется как соотношение длины тела/роста и возраста <–2 Z-шкала; а тяжелое острое нарушение питания определяется либо как соотношение веса и роста <–3 Z-шкала или окружность середины плеча <115 мм или как наличие отечности. a

268

Приложение 2. А лгоритм для рекомендаций 2013 года в отношении взрослых и подростков Взрослые и подростки, ранее не получавшие АРТ Клиническая оценка

КОГДА НАЧИНАТЬ АРТ

Симптоматическая ВИЧ-инфекция или наличие состояний, не зависящих от CD4? Клиническая стадия ВОЗ 3 или 4?a b Активная форма ТБ?c Тяжелая хроническая болезнь печени, вызванная ВГВ?d Беременность или кормление грудью? HIV+ у серодискордантных пар?f e

Бессимптомная ВИЧ-инфекция?a

Клиническая стадия ВОЗ 1 или 2?a Количество клеток CD4 CD4 ≤ 500 клеток/мм³?b

Да

Нет

Да

Нет

Начинать АРТ

Не начинать АРТ

Начинать АРТ

Не начинать АРТ

С КАКОЙ СХЕМЫ АРТ ПЕРВОГО РЯДА НАЧИНАТЬ

Начинать с одной из следующих схем АРВ-терапииg: Предпочтительный вариант: • TDF + 3TC (или FTC) + EFV Альтернативные варианты: • TDF + 3TC (или FTC) + NVP • AZT + 3TC + EFV • AZT + 3TC + NVP

Клинические стадии ВИЧ-инфекции по классификации ВОЗ приводятся в Приложении 1. АРТ следует назначать в приоритетном порядке лицам с тяжелым течением или на поздней стадии симптоматического заболевания (клиническая стадия ВОЗ 3 или 4), независимо от количества клеток CD4, или при CD4 ≤350 клеток/мм3, независимо от клинических симптомов. c Активной формой ТБ является период, когда латентная инфекция активизируется и вызывает заболевание. Латентная инфекция ТБ имеет место, когда иммунная система успешно сдерживает Mycobacterium tuberculosis и не допускает развития заболевания. d Тяжелая хроническая болезнь печени включает цирроз и болезнь печени в конечной стадии и подразделяется на компенсированную и декомпенсированную. Декомпенсированный цирроз определяется развитием клинически выраженных осложнений портальной гипертензии (асцит, варикозное кровотечение и гепатическая энцефалопатия) или печеночной недостаточности (желтуха). e Подробное описание АРВ-терапии для беременных и кормящих грудью женщин с ВИЧ (Вариант B и Вариант B+) приводится в Приложении 3 и Разделах 7.1.2, 7.1.3 и 7.2.2. f ВИЧ-серодискордантной парой является такая пара, в которой один из сексуальных партнеров является ВИЧ-положительным, а второй ВИЧ-отрицательным. Хотя один партнер является в данный момент ВИЧ-отрицательным, это не означает, что этот партнер обладает иммунитетом или защитой от ВИЧ-инфицирования в будущем. g Для подростков весом менее 35 кг применяется алгоритм для детей, указанный в Приложении 4,где приводятся соответствующие варианты схем АРВ-терапии первого ряда. a b

12. Приложения

269

Приложение 2. А лгоритм для рекомендаций 2013 года в отношении взрослых и подростков

270

Приложение 3. А лгоритмы для рекомендаций 2013 года в отношении беременных и кормящих грудью женщин Пожизненная АРТ для всех беременных и кормящих грудью женщин с ВИЧ (Вариант B+)

ЖЕНЩИНЫ С ВИЧ ДЕТИ, ПОДВЕРГАЮЩИЕСЯ РИСКУ ВИЧ

ДЕТИ, ПОДВЕРГАЮЩИЕСЯ РИСКУ ВИЧ

Кормление грудью ПЕРИОД РИСКА ППМР Один раз в сутки NVP 6 недель

Замещающее питание 4-6 недель NVP один раз в сутки или AZT два раза в сутки

Начинать пожизненную АРТ: TDF + 3TC (или FTC) + EFV (предпочтительная схема) (по возможности, оценка исходного уровня CD4) Ранний диагноз у грудных детейa

ОКОНЧАНИЕ ПЕРИОДА РИСКА ППМР

Окончательный диагноз у грудных детей

СВЯЗЬ СО СЛУЖБАМИ ЛЕЧЕНИЯ И ПОМОЩИ ДЛЯ МАТЕРИ И РЕБЕНКА

См. Приложение 5. Алгоритм для ранней диагностики у грудных детей

12. Приложения

271

Приложение 3. А лгоритмы для рекомендаций 2013 года в отношении беременных и кормящих грудью женщин

АРТ для беременных и кормящих грудью женщин с ВИЧ (Вариант B)

БЕРЕМЕННЫЕ И КОРМЯЩИЕ ГРУДЬЮ ЖЕНЩИНЫ С ВИЧ

ДЕТИ, ПОДВЕРГАЮЩИЕСЯ РИСКУ ВИЧ

Начинать следующую рекомендованную схему АРТ: TDF + 3TC (или FTC) + EFV ПЕРИОД РИСКА ППМР (оценка соответствия критериям (клиническая стадия ВОЗ 3 или 4 или CD4 ≤500 клеток/мм3) для лечения по состоянию здоровья)

Кормление грудью Один раз в сутки NVP 6 недель

Замещающее питание 4-6 недели NVP один раз в сутки или AZT два раза в сутки

Соответствие критериям для лечения по состоянию здоровья при исходной оценке

Ранний диагноз у грудных детейa ОКОНЧАНИЕ ПЕРИОДА РИСКА ППМР

Да

Нет

Продолжать АРТ

Прекратить АРТ через 1 неделю после окончания кормления грудью и направить на повторную оценку

Окончательный диагноз у грудных детей

СВЯЗЬ СО СЛУЖБАМИ ЛЕЧЕНИЯ И ПОМОЩИ ДЛЯ МАТЕРИ И РЕБЕНКА

См. Приложение 5. Алгоритм для ранней диагностики у грудных детей

272

Приложение 4. А лгоритм для рекомендаций 2013 года в отношении детей Дети грудного и более старшего возраста, инфицированные ВИЧ

Возраст <5 лет

Возраст ≥5 лет

КОГДА НАЧИНАТЬ АРТ У ДЕТЕЙ

Клиническая стадия ВОЗ 3 или 4 или CD4 ≤500 клеток /мм³?

Да

Нет

Начинать АРТa

Начинать ARTb

Контроль клинической стадии и CD4

Возраст <3 лет?

Возраст <10 лет или вес <35kg

С КАКОЙ СХЕМЫ ПЕРВОГО РЯДА НАЧИНАТЬ АРТ У ДЕТЕЙ

Да Начать одну из следующих схем:c Предпочтительный вариант: ABC или AZT + 3TC + LPV/r Альтернативный вариант: ABC или AZT + 3TC + NVP

Нет

Да

Нет Начать одну из следующих схем: Предпочтительный вариант: TDF + 3TC (или FTC) + EFV Альтернативный вариант: AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + NVP

Начать одну из следующих схем:c Предпочтительный вариант: ABC + 3TC + EFV Альтернативный вариант: ABC + 3TC + NVP AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (или FTC) + EFV TDF + 3TC (или FTC) + NVP

случае непринятия этой рекомендации для лечения всех детей в возрасте от одного до пяти лет: начинать АРТ при В клинической стадии ВОЗ 3 или 4 или CD4 ≤750 клеток /мм 3 или <25%, в зависимости от того, что будет ниже, независимо от клинической стадии ВОЗ (105). b В случае непринятия этой рекомендации, АРТ следует начинать при клинической стадии ВОЗ 3 и 4 или CD4 ≤350 клеток / мм 3, независимо от клинической стадии ВОЗ (105, Глава 7). c С ледует особо отметить, что использование d4T должно быть ограничено ситуациями подозреваемой или подтвержденной токсичности AZT и отсутствия доступа к ABC или TDF. Продолжительность лечения этим препаратом должна быть, по возможности, максимально короткой. a

12. Приложения

273

Приложение 5. Алгоритм для ранней диагностики у грудных детей Выявление ВИЧ-инфекции у младенцев и детей в возрасте до 18 месяцев, подвергающихся риску инфицирования ВИЧ, в местах с ограниченными ресурсами. Источник: Адаптировано по Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. 2010 revision. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf). Младенец или ребенок <18 месяцев с риском ВИЧ Проведение теста на вирусa Тест на вирус имеется Положительный Отрицательный

Приложение 5. Алгоритм для ранней диагностики у грудных детей

Тест на вирус отсутствует

Инфицирование вероятно <24 месяцев: немедленно начать АРТb И повторить тест на вирус для подтверждения инфекции

Грудного вскармливания не получал Ребенок не инфицирован

Грудное вскармливание получал или получает Регулярный и периодический контроль

Риск ВИЧ-инфицирования сохраняется до окончания кормления грудьюc

У ребенка развиваются признаки или симптомы, указывающие на ВИЧ

Ребенок остается здоров и достигает возраста 9 месяцев Провести тест на антитела к ВИЧ в возрасте примерно 9 месяцев

Тест на вирус отсутствует

Тест на вирус имеется

Положительный

Отрицательный

Положительный

Ребенок инфицирован

Тест на вирус отсутствует: предполагать инфицирование, если болен; предполагать отсутствие инфекции, если здоров болен здоров

Начать АРТb и повторить тест на вирус для подтверждения инфекции

ВИЧ-инфекция маловероятна, если не продолжается кормление грудьюc

Повторить тест на антитела в 18 месяцев и/или через 6 недель после прекращения кормления грудью FДля новорожденных при рождении или вскоре после рождения или при первом визите к врачу (примерно 4-6 недель). См. также Таблицу 5.1 в отношении диагностики у грудных детей. b Начать АРТ, при наличии показаний, без промедления. Одновременно провести повторный тест для подтверждения инфекции. c Риск передачи ВИЧ сохраняется, если продолжается грудное вскармливание. a

274

Приложение 6. К онтрольный перечень вопросов для оценки готовности: переход к АРТ для беременных и кормящих грудью женщин В сводном руководстве 2013 года рекомендуется начинать проведение АРТ у всех беременных и кормящих грудью женщин с ВИЧ, исходя из решений, принимаемых в рамках национальных программ, о том, что либо все женщины продолжают АРТ в качестве пожизненного лечения, либо женщины, не отвечающие критериям получения АРТ по состоянию здоровья, прекращают лечение по истечению периода, когда существует риск передачи вируса от матери ребенку. Страны, планирующие переход к такой схеме, и работающие над расширением и укреплением своей программы, могут пожелать воспользоваться настоящим контрольным перечнем вопросов для оценки готовности, который охватывает широкий круг вопросов – от национальной политики до готовности учреждения. Этот контрольный перечень (приводится ниже), а также руководство по проведению дискуссии были разработаны в рамках Чрезвычайного плана президента США по оказанию помощи в связи со СПИДом. Они являются частью более широкого инструментария Межучрежденческой рабочей группы по ликвидации случаев передачи от матери ребенку: Расширение и упрощение схемы лечения для беременных женщин, живущих с ВИЧ: Руководство переходом к Варианту B/B+: Ссылка на контрольный перечень: www.emtct-iatt.org/wp-content/uploads/2013/03/ Toolkit-Section-2.pdf; Ссылка на полный инструментарий: www.emtct-iatt.org/toolkit Рекомендуемые сроки: До реализации В начале реализации Во время реализации

ПОЛИТИЧЕСКИЕ ОБЯЗАТЕЛЬСТВА И УТВЕРЖДЕНИЕ ПОЛИТИКИ Поддержка целей Глобального плана (на национальном и субнациональном уровнях) Штатный сотрудник МЗ отвечает за ППМР (национальный и, возможно, субнациональный) Функциональные технические рабочие группы с участием представителей служб охраны здоровья матерей, новорожденных и детей, ППМР и лечения ВИЧ, включая работников здравоохранения и людей, живущих с ВИЧ Утверждение схемы АРТ для всех беременных и кормящих грудью женщин на национальном и субнациональном уровнях (Вариант B или B+) Руководство предусматривает предлагать проведение АРТ всем беременным и кормящим грудью женщинам

Завершено

В процессе

Еще не начато

12. Приложения

275

Приложение 6. К онтрольный перечень вопросов для оценки готовности: переход к АРТ для беременных и кормящих грудью женщин

ФИНАНСОВЫЕ АСПЕКТЫ Калькуляция затрат на выполнение текущей стратегии ППМР Калькуляция затрат на АРТ для всех беременных и кормящих грудью женщин, как краткосрочную, так и долговременную Проведение анализа дефицита ресурсов Увеличение финансирования программы должно быть отражено в бюджете Демонстрация финансовой поддержки на национальном уровне МОДЕЛЬ ПРЕДОСТАВЛЕНИЯ УСЛУГ Определение минимального набора услуг для предоставления АРТ всем беременным и кормящим грудью женщинам Оценка потенциала системы (инфраструктура, кадровые ресурсы и материалы) для децентрализации АРТ до уровня служб ППМР, включая охват женщин с ВИЧ и их семей МОДЕЛЬ ПРЕДОСТАВЛЕНИЯ УСЛУГ Сроки и место проведения переходных процедур между службами ППМР и долговременного лечения было определено (включая рассмотрение возможности проведения пожизненной АРТ службами ППМР) Систематическое выявление клиентов АРТ, которые забеременели, и установление связей с ППМР Тестирование и лечение партнеров и членов семьи службами охраны здоровья матери, новорожденных и детей Направление постоянных клиентов существующих служб АРТ в новые децентрализованные пункты проведения АРТ КАДРОВЫЙ ПОТЕНЦИАЛ Утверждение схем перераспределения/разделения обязанностей по назначению и проведению АРТ на национальном уровне Оценка кадрового потенциала (медсестры, акушерки, фармацевты, лаборанты) для расширения масштабов АРТ Основные возможности в области ведения ВИЧ для всех категорий работников здравоохранения Стратегия обучения методам предоставления АРТ для ускорения темпов расширения масштабов Обновление национальных учебных программ обучения по месту работы и до поступления на работу Стратегия для удержания, переобучения и повышения профессиональной квалификации работников здравоохранения, особенно в области ППМР/АРТ

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

276

ВЫБОР СХЕМЫ АРВ-ТЕРАПИИ Упрощение и гармонизация ППМР и схем лечения взрослых План применения альтернативной схемы для беременных женщин, не переносящих АРТ первого ряда Оптимизация схемы первого уровня для детей Создание системы фармакологического надзора, при возможности (см. Руководство по проведению дискуссии) УПРАВЛЕНИЕ ЦЕПОЧКОЙ ПОСТАВОК Оценка недостатков цепочки поставок, включая количественную оценку, распределение и управление запасами Составление прогноза на 18 месяцев, количественная оценка и разработка плана поставок Управление запасами АРТ в службах ППМР (обучение, потенциал и безопасность) УПРАВЛЕНИЕ ЦЕПОЧКОЙ ПОСТАВОК При изменении схемы первого ряда планирование использования уже заказанных АРВ-препаратов Пересмотр системы управления цепочкой поставок (потребление, прогноз и распределение) МОНИТОРИНГ, ОЦЕНКА И ИСПОЛЬЗОВАНИЕ ДАННЫХ Регистр учета дородовой помощи и ППМР позволяет документировать начало или продолжение проведения АРТ Регистр АРТ позволяет документировать статус при беременности и кормлении грудью Инструменты и регистры ППМР позволяют проводить когортный мониторинг удержания матерей в службах АРТ и подвергающихся риску детей в службах помощи Беременные и кормящие грудью женщины, получающие АРТ в службах охраны здоровья матерей, новорожденных и детей, включаются в системы мониторинга и оценки на местном и национальном уровнях Система для отслеживания и оценки взаимодействия и процедур перехода между службами охраны здоровья матерей, новорожденных и детей и службами долговременной помощи и лечения при ВИЧ для матери и ребенка (например, регистр длительного наблюдения матери и ребенка, уникальный идентификационный номер Программа оценки, предназначенная для выявления успехов и проблем на ранней стадии и для оценки долгосрочных результатов у матери и ребенка, включая передачу от матери ребенку Стандартная система обеспечения качества данных Гармонизация систем мониторинга и оценки ППМР и АРТ и анализ данных Стандартизированное досье или карточка учета для беременных и кормящих грудью женщин с ВИЧ и подвергающихся риску детей

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

12. Приложения

277

НАДЗОР И УПРАВЛЕНИЕ КАЧЕСТВОМ НА МЕСТАХ Плановый надзор и клиническое наставничество по качеству помощи на местах Процесс постоянного контроля качества для программы ППМР ТЕСТИРОВАНИЕ НА ВИЧ И КОНСУЛЬТИРОВАНИЕ В СЛУЖБАХ ППМР Меры обеспечения качества для экспресс-тестирования на ВИЧ во всех службах ППМР Стратегические решения о лечении дискордантных пар Тестирование на ВИЧ и консультирование, а также последующее наблюдение дискордантных пар, включенных в ППМР Стратегия включения или регистрации партнеров-мужчин с ВИЧ в программы АРТ КОНСУЛЬТИРОВАНИЕ ПО ПРОВЕДЕНИЮ АРТ И УДЕРЖАНИЮ ПАЦИЕНТОВ Специальные услуги рассылки сообщений и поддержки для беременных и кормящих грудью женщин, начинающих АРТ Структуры, ускоряющие подготовку к АРТ Альтернативные протоколы, разработанные для женщин, не нуждающихся в АРТ по состоянию здоровья, которые отказываются от пожизненного лечения ЛАБОРАТОРНЫЙ И КЛИНИЧЕСКИЙ МОНИТОРИНГ Возможности мониторинга токсичности лечения Наличие исходного уровня CD4 (в месте оказания помощи или надежная транспортировка образцов) Алгоритм для мониторинга CD4 и/или вирусной нагрузки ДИАГНОСТИКА У ГРУДНЫХ ДЕТЕЙ И ПЕДИАТРИЧЕСКОЕ ЛЕЧЕНИЕ Возможности ранней диагностики у грудных детей параллельно с расширением программы ППМР Усиление последовательных процедур ранней диагностики у грудных детей – ранний диагноз, быстрое получение результатов, активное выявление случаев ВИЧ-инфицирования детей и начало лечения Удержание грудных детей, подвергающихся риску ВИЧ, после окончания грудного вскармливания, включая подтверждение окончательного диагноза Расширение доступа к педиатрическому лечению

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

278

УДЕРЖАНИЕ ПАЦИЕНТОВ В СИСТЕМЕ ПОМОЩИ И ЛЕЧЕНИЯ Система, обеспечивающая охват ВСЕХ беременных и родивших женщин с ВИЧ службами помощи и/или лечения при ВИЧ Модели предоставления услуг, предусматривающие гармонизированное наблюдение за парами матерей и детей Услуги на уровне учреждений или по месту жительства, обеспечивающие соблюдение режима лечения и отслеживание нарушителей Инновационные решения для улучшения доступности АРТ ПЛАНИРОВАНИЕ СЕМЬИ Оценка наличия служб и средств планирования семьи Оценка добровольного использования служб планирования семьи в местах проведения АРТ УЧАСТИЕ ОБЩЕСТВА Женщины, живущие с ВИЧ, участвуют в планировании, реализации и мониторинге на национальном, субнациональном и местном уровнях Меры и услуги, способствующие расширению использования и удержанию в программе ППМР по месту жительства Общественные структуры в поддержку сирот и уязвимых детей СТРАТЕГИЯ РЕАЛИЗАЦИИ Имеется план проведения стратегии реализации Оценка хода реализации в режиме реального времени для дальнейшего расширения масштабов деятельности Использованные сокращения: МЗ (Министерство здравоохранения).

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

Завершено

В процессе

Еще не начато

12. Приложения

279

Приложение 7. Д озировки рекомендованных антиретровирусных препаратов Дозировки антиретровирусных препаратов для взрослых и детейa Международное непатентованное наименование Доза

Приложение 7. Дозировки рекомендованных антиретровирусных препаратов

Нуклеозидные ингибиторы обратной транскриптазы (НИОТ) Абакавир (ABC) Диданозин (ddI) Эмтрицитабин (FTC) Ламивудин (3TC) Ставудин (d4T) Зидовудин (AZT) 300 мг два раза в сутки или 600 мг один раз в сутки 400 мг один раз в сутки (>60 кг) 250 мг один раз в сутки (≤60 кг) 200 мг один раз в сутки 150 мг два раза в сутки или 300 мг один раз в сутки 30 мг два раза в сутки 250−300 мг два раза в сутки

Нуклеотидные ингибиторы обратной транскриптазы (НтИОТ) Тенофовир (TDF) 300 мг один в раз в сутки

Ненуклеозидные ингибиторы обратной транскриптазы (ННИОТ) Эфавиренз (EFV) Этравирин (ETV) Невирапин (NVP) Ингибиторы протеазы (ИП) Атазанавир + ритонавир (ATV/r) Дарунавир + ритонавир (DRV/r) Лопинавир/ритонавир (LPV/r) 300 мг + 100 мг один раз в сутки 800 мг + 100 мг один раз в сутки или 600мг + 100 мг два раза в сутки 400 мг/100 мг два раза в сутки Для лиц, получающих противотуберкулезное лечение В присутствии рифабутина корректировка дозы не требуется. В присутствии рифампицина применяют скорректированную дозу LPV/r (LPV 800 мг + RTV 200 мг два раза в сутки или LPV 400 мг + RTV 400 мг два раза в сутки) или SQV/r (SQV 400 мг + RTV 400 мг два раза в сутки), при тщательном контроле. Ингибитор интегразы (ИИ) Ралтегравир (RAL) 400 мг два раза в день 600 мг один раз в сутки 200 мг два раза в сутки 200 мг один раз в сутки в течение 14 суток, затем 200 мг два раза в сутки

a Для подростков весом менее 35 кг, см. дозировку лекарственных форм АРВ-препаратов для детей, рассчитанную по весу на следующей странице.

280

Дозировка лекарственных форм АРВ-препаратов для детей, рассчитанная по весу Информация по назначению препаратов и рассчитанная по весу дозировка имеющихся лекарственных форм АРВ-препаратов для детей грудного и более старшего возраста В этом приложении содержится информация о антиретровирусных препаратах, имеющих показания к применению у детей, лекарственные формы для детей или о которых имеется достаточная информация и фактические данные для предоставления рекомендаций в отношении их назначения и дозировки. Разработка и обновление упрощенного руководства по антиретровирусным препаратам, применяемых для детей, проводились ВОЗ в рамках Рабочей группы по антиретровирусным препаратам для детей.ix Для простоты и удобства пользования дозы приводятся по диапазонам веса, а не из расчета на килограмм или квадратный метр площади поверхности тела. При разработке этой упрощенной схемы дозировки особое внимание обращалось на обычные показатели площади поверхности тела детей из стран с низким и средним уровнями дохода в рамках этого диапазона веса. Основным источником информации для представленных рекомендаций являлся вкладыш в упаковке с информацией изготовителя о лекарственном средстве. Эта информация дополнялась данными других клинических исследований, а также результатами консультаций с экспертами по педиатрической фармакологии. В отношении комбинированных препаратов с фиксированными дозами использовался метод моделирования дозы (www.who.int/hiv/paediatric/generictool/en/index.html) для прогнозирования принимаемой дозы для каждого компонента препарата относительно рекомендованного режима дозирования. В некоторых случаях доза какого-либо компонента в определенном весовом диапазоне может быть несколько выше или ниже целевой дозы, рекомендуемой изготовителем. Это является неизбежным, принимая во внимание ограничения, связанные с использованием комбинированного препарата с фиксированными дозами, однако внимание обращалось на то, чтобы не допускать случаев приема ребенком дозы, которая более чем на 25% выше максимальной целевой дозы или более чем на 5% ниже минимальной целевой дозы. Для упрощения схем антиретровирусные препараты, которые более не считаются предпочтительными или альтернативными вариантами для детей, такие как диданозин и саквинавир, не включены в рекомендации по дозировкам. Кроме того, дозировки для проведения послеродовой профилактики грудных детей, подвергающихся риску ВИЧ-инфицирования, здесь не приводятся, но они содержатся в Таблице 7.7 Главы 7. В период завершения подготовки этого руководства Управление по контролю качества пищевых продуктов и лекарственных препаратов США выдало разрешение на использование EFV у детей в возрасте от 3 месяцев до 3 лет, масса тела которых составляет не менее 3,5 кг. Признавая наличие возможности предоставить дополнительный вариант лечения детям и обеспечить дальнейшую гармонизацию схем в разных возрастных группах, Группа по разработке рекомендаций подчеркнула необходимость получения дополнительных данных, прежде чем рекомендовать EFV в качестве одного из вариантов лечения для детей в возрасте до трех лет. Данное приложение с рекомендуемыми дозировками и упрощенными режимами дозирования будет регулярно пересматриваться и обновляться по мере появления новых данных или новых лекарственных форм, однако национальным программам рекомендуется принимать во внимание новейшие маркировки на продукции для ix

Текущий членский состав приводится в приложении к докладу последнего совещания Рабочей группы по антиретровирусным препаратам для детей: Developing dosing guidance for new and upcoming formulations of paediatric antiretrovirals in line with Treatment 2.0 priorities. Meeting report, Paediatric Antiretroviral Working Group, Geneva, Switzerland, 25 –26 October 2011. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75159/1/WHO_ HIV_2012.8_eng.pdf, по состоянию на 15 мая 2013 г.).

12. Приложения

281

получения самой современной информации. Дополнительная информация также приводится в информационных листках по конкретным препаратам, которые содержатся в веб-приложении www.who.int/hiv/pub/guidelines/antiretroviral2013/annexes. Имеющиеся антиретровирусные препараты и их лекарственные формы изготавливаются несколькими компаниями, и содержание действующих веществ в таблетках, капсулах и жидких формах может отличаться от представленной здесь информации. Кроме того, внесение в список какой-либо лекарственной формы в настоящем приложении не означает гарантии качества этой лекарственной формы. Руководители национальных программ должны обеспечивать, чтобы любой продукт, приобретенный для использования, был разрешен и отвечал требованиям качества и стабильности. Указания в отношении гарантии качества лекарственных средств приводятся на веб-сайте ВОЗ по лекарственным средствам (www.who.int/medicines/areas/quality_safety/quality_assurance/about/en/ index.html) и в материалах о доступе к лекарственным и диагностическим средствам при ВИЧ/СПИДе, которые доступны и обновляются на веб-сайте www.who.int/hiv/amds/ selection/en/index.html. Текущий перечень преквалифицированных ВОЗ лекарственных средств имеется на веб-сайте: http://apps.who.int/prequal/query/ProductRegistry.aspx. С текущим списком антиретровирусных препаратов, разрешенных и предварительно разрешенных Управлением по контролю качества пищевых продуктов и лекарственных препаратов США, можно ознакомиться на веб-сайте: www.fda.gov/internationalprograms/ FDAbeyondourbordersforeignoffices/AsiaandAfrica/ ucm119231.htm. Политика Глобального фонда для борьбы со СПИДом, туберкулезом и малярией, приводится на веб-сайте www. theglobalfund.org/en/procurement/quality/pharmaceutical.

Приложение 7. Дозировки рекомендованных антиретровирусных препаратов

Общие принципы При подготовке упрощенных таблиц ВОЗ использовались следующие принципы; елательно использовать комбинированный препарат с фиксированными дозами, Ж соответствующий определенному возрасту, для любой схемы, если такая форма имеется. о возможности, следует избегать форм для перорального приема в виде П жидкости или сиропа, особенно при больших объемах – например, более 10 мл. редпочтительными твердыми пероральными лекарственными формами являются П диспергируемые таблетки (или таблетки для приготовления пероральных растворов), поскольку каждую диспергируемую таблетку можно растворять в жидкости непосредственно перед приемом. целом, детей младшего возраста следует переводить на имеющиеся твердые В пероральные формы препаратов, как только они становятся переносимыми. сли дети должны использовать лекарственные формы для взрослых, следует Е не допускать занижения дозы. Таблетки для взрослых с насечками легче делить. Если таблетку сложно разделить, ВОЗ рекомендует делать это в аптеке, отпускающей лекарства, используя устройство для деления таблеток. екоторые таблетки, такие как термостабильные таблетки LPV/r, изготовлены в Н специальной матричной форме (с помощью запатентованной технологии экструзии из расплава, которая обеспечивает стабилизацию молекул препарата, обычно являющихся термолабильными). Их не следует разрезать, делить или дробить, так как они при этом теряют биологическую доступность. П о возможности, следует избегать использования разных доз утром и вечером. етей следует взвешивать при каждом посещении клиники. По мере роста детей и/ Д или увеличении их веса следует изменять дозировки.

282

Таблица 1. Упрощенные режимы дозирования твердых лекарственных препаратов в формах для детей с фиксированными дозами для приема два раза в сутки Кол-во таблеток в зависимости от веса утром и вечером Содержание действующего вещества в таблетке для взрослых (мг) утро 300/150 1 1,5 1,5 2 2 2,5 2,5 3 3 300/150/200 1 1,5 1,5 2 2 2,5 2,5 3 3 300/300/150 1 1,5 1,5 2 2 2,5 2,5 3 3 600/300 1 1,5 1,5 2 2 2,5 2,5 3 3 30/150 1 1,5 1,5 2 2 2,5 2,5 3 3 – 1 1,5 1,5 2 2 2,5 2,5 3 3 4 4 1 1 0.5 0.5 1 1 1 1 1 Кол-во таблеток в зависимости от веса 25–34,9 кг вечер 1

Препарат

Содержание действующего вещества в таблетке (мг) 6–9,9 кг утро вечер утро вечер утро вечер утро вечер 10–13,9 кг 14–19,9 кг 20–24,9 кг

3–5,9 кг вечер

утро

AZT/3TC

Таблетка (диспергируемая) 60 мг /30 мг

AZT/3TC/ NVP

Таблетка (диспергируемая) 60 мг /30 мг /50 мг

ABC/ AZT/3TC

Таблетка (диспергируемая) 60 мг /60 мг /30 мг

ABC/3TC

Таблетка (диспергируемая) 60 мг /30 мг

d4T/3TC

Таблетка (диспергируемая) 6 мг /30 мг

d4T/3TC/ NVP

Таблетка (диспергируемая) 6 мг /30 мг /50 мг

Таблица 2. Упрощенные режимы дозирования твердых лекарственных препаратов в формах для детей для приема один раз в сутки Содержание действующего вещества в таблетке (мг) 25–34,9 кг 200 600 2 2/3 Кол-во таблеток или капсул в зависимости от веса для приема один раз в сутки

Препарат

Содержание действующего вещества в таблетке (мг) 6–9,9 кг – – одна треть половина две трети 1 1.5 1.5 10–13,9 кг 14–19,9 кг 20–24,9 кг

Кол-во таблеток или капсул в зависимости от веса для приема один раз в сутки

3–5,9 кг

EFV

Таблетка (делимая) 200 мг

–

Таблетка (с двойным делением)b 600 мг 3 4 5 6

–

ABC/3TC

Таблетка (диспергируемая) 60/30 мг

600 + 300

EFV не рекомендуется для детей в возрасте до 3 лет и весом менее 10 кг. В период завершения подготовки этого руководства Управление по контролю качества пищевых продуктов и лекарственных препаратов США выдало разрешение на использование EFV у детей в возрасте до 3 лет, масса тела которых составляет более 3,5 кг (3,5-5 кг – две капсулы по 50 мг; 5-7,5 кг – три капсулы по 50 мг; 7,515 кг – одна капсула по 200 мг), однако для разработки рекомендации об использовании EFV в этой возрастной группе срочно необходимы дополнительные данные. b Таблетка с двойным делением имеет две насечки на одной стороне и одну насечку на другой стороне, что позволяет, при необходимости, делить таблетку на три и две части.

12. Приложения

283

Приложение 7. Дозировки рекомендованных антиретровирусных препаратов

284

Таблица 3. Упрощенные режимы дозирования твердых и жидких лекарственных препаратов в формах для детей для приема два раза в сутки Кол-во таблеток в зависимости от веса утром и вечером Кол-во таблеток в зависимости от веса 25–34,9 кг утро вечер

Препарат

Содержание действующего вещества в таблетке (мг) или пероральном растворе (мг/мл) 6–9,9 кг утро Твердые формы 1,5 1,5 1,5 1,5 – Жидкие формы 9 мл 4 мл 4 мл 8 мл 1,5 мл 1,5 мл 2 мл 8 мл 10 мл 10 мл 2 мл 4 мл 6 мл 6 мл 4 мл 6 мл 6 мл – – – 2,5 мл 9 мл 12 мл 12 мл – – – – – 2,5 мл – – – – 3 мл – – – – 3 мл – – – – – – – – – – 2 1 2 2 2 1,5 2 2 2,5 2,5 3 1,5 2 2 2,5 2,5 3 3 3 2 1,5 2 2 2,5 2,5 3 3 1,5 2 2 2,5 2,5 3 3 150 300 300 200 100/25 1 1 1 1 3 вечер утро вечер утро вечер утро вечер 10–13,9 кг 14–19,9 кг 20–24,9 кг

3–5,9 кг

Содержание действующего вещества в таблетке для взрослых (мг)

утро

вечер

3TC

Таблетка (диспергируемая) 30 мг

1 1 1 1 3

AZT

Таблетка (диспергируемая) 60 мг

ABC

Таблетка (диспергируемая) 60 мг

NVPa

Таблетка (диспергируемая) 50 мг

LPV/rb

Таблетка (термостабильная)

–

AZT

10 мг/мл

6 мл

– –

ABC

20 мг/мл

3 мл

3TC

10 мг/мл

3 мл

NVP

10 мг/мл

5 мл

– –

LPV/r

80/20 мг/мл

1 мл

Рекомендуется в начале АРТ увеличивать дозу NVP на полдозы за 2 недели, чтобы избегать токсичности в результате приема NVP сразу в высоких дозах. Однако вторичный анализ результатов недавно проведенного исследования (CHAPAS-1) показал, что у детей младшего возраста риск токсичности ниже, в связи с чем можно рассмотреть возможность начинать лечение с полной дозы (Fillekes Q et al. Is nevirapine dose escalation appropriate in young, african, HIV-infected children? AIDS, 2013, в печати (http://www.ncbi.nlm.nih.gov/pubmed/23595153, по состоянию на 17 июля 2013 г.). doi: 10.1097/QAD.0b013e3283620811). Более определенные фактические данные ожидаются по результатам проводимого в настоящее время исследования. b LPV/r в жидкой форме требует наличия холодовой цепи во время транспортировки и хранения. LPV/r в виде термостабильной таблетки следует проглатывать целиком, не делить и не дробить.

Таблица 4. Упрощенные гармонизированные режимы дозирования существующих форм TDF для детей Кол-во ложек или таблеток в зависимости от веса для приема один раз в сутки 6–9,9 кг – – – 1 (150 мг) 1 (200 мг) 3 – – 300 мг 10–13,9 кг 14–19,9 кг

Препарат

Размер дозирующей ложки порошка (мг) или содержание действующего вещества в таблетке (мг) – –

3–5,9 кг

Содержание Кол-во таблеток действующего в зависимости от веса вещества в таблетке 20–24,9 кг для взрослых (мг) 25–34,9 кг 1 (200 мг)b или 1 (300 мг)

TDFa

Порошок для перорального приема 40 мг/ложка

Таблетки 150 мг или 200 мг

Целевая доза: 8 мг /кг или 200 мг /м 2 (максимум 300 мг). Рабочая группа по антиретровирусным препаратам для детей разработала эти рекомендации, чтобы гармонизировать дозировку TDF с диапазонами веса ВОЗ и для снижения числа доз. Была использована методика ВОЗ, основанная на размере целевой дозы, указанной изготовителем на вкладыше в упаковке. В соответствии со стандартным подходом Рабочей группы по антиретровирусным препаратам для детей при установлении дозировки принималось во внимание, чтобы ребенок не получал дозу, которая более чем на 25% выше максимальной целевой дозы или более чем на 5% ниже минимальной целевой дозы. b 200-мг таблетки следует использовать при весе 25 –29,9 кг и 300-мг таблетки при весе 30–34,9 кг.

Таблица 5. Упрощенные режимы дозирования изониазида (INH) и котримоксазола (CTX) в профилактических целях Кол-во ложек или таблеток в зависимости от веса для приема один раз в сутки Содержание Кол-во таблеток действующего в зависимости от веса вещества в таблетке для взрослых (мг) 20–24,9 кг 2.5 10 мг 4 1 – – половина половина 10 мг 4 1 половина половина 300 мг – – 400/80 мг 800/160 мг 960 мг/300 мг/25 мг 25–34,9 кг 1 – – 2 1 1

Препарат

Содержание действующего вещества в таблетке или пероральном жидком растворе (мг или мг/5 мл) 6–9,9 кг 1 5 мг 2 половина – – 2 половина 5 мг 1.5 2 10–13,9 кг 14–19,9 кг

3–5,9 кг 0.5 2.5 мг 1 – – –

INH

100 мг

CTX

Суспензия 200/40 мг на 5 мл

Таблетки (диспергируемые) 100/20 мг

Таблетки (делимые) 400/80 мг

Таблетки (делимые) 800/160 мг

INH/CTX/ Таблетки (делимые) 960 мг/ 300 мг/25 мг B6a

12. Приложения

Эта форма в настоящее время ожидает разрешения регулирующих органов. Разрабатывается также делимая таблетка для юношеского возраста (480 мг /150 мг /12,5 мг).

285

Приложение 7. Дозировки рекомендованных антиретровирусных препаратов

286

Потребность в новых лекарственных формах Результаты деятельности Рабочей группы по антиретровирусным препаратам для детей подчеркивают настоятельную необходимость в разработке лекарственных форм, особенно комбинированных препаратов с фиксированными дозами, содержащих LPV/r в твердом виде, пригодных для лечения детей младшего возраста, делимых таблеток TDF и основанных на TDF форм с фиксированными дозами для детей. Кроме того, для обеспечения последовательности лечения все более важное значение приобретает наличие ATV/r и DRV/r в виде термоустойчивых комбинированных препаратов с фиксированными дозами. Доступ к термоустойчивым формам, содержащим 30 мг RTV также имеет важное значение для «сверхусиления» действия LPV при проведении противотуберкулезного лечения на основе рифампицина. В приводимой ниже таблице содержатся некоторые примеры дублирования форм. Например, делимая комбинированная форма препарата для взрослых с фиксированными дозами TDF + 3TC + EFV не потребуется при наличии лекарственной формы для детей. Однако Рабочая группа по антиретровирусным препаратам для детей признает, что хотя специальные формы для детей могут быть идеальным решением в качестве первого шага может быть легче разработать делимую форму для взрослых. Недавнее разрешение на использование EFV у детей в возрасте от 3 месяцев до 3 лет открывает дополнительные возможности для детей младшего возраста и дальнейшей гармонизации. По мере получения новых данных, позволяющих определить наилучшие пути использования этого препарата для детей младшего возраста, следует обеспечить наличие его лекарственной формы в виде капсул с покрытыми частицами в условиях ограниченности ресурсов. В ходе осуществления совместной инициативы ЮНЭЙДС/ВОЗ «Лечение 2.0» ВОЗ будет продолжать работу по упрощению руководств по вопросам назначения, отпуска и дозирования препаратов, а также будет сотрудничать с фармацевтической промышленностью (производителями оригинальных и генерических лекарственных средств) и другими партнерами для разработки более практических рекомендаций в отношении целого ряда лекарственных форм, необходимых для безопасного ускорения темпов расширения масштабов проведения АРТ для детей.

12. Приложения

287

Таблица 6. Упрощенные режимы дозирования срочно необходимых АРВ-препаратов для детей, рекомендованных Рабочей группой по антиретровирусным препаратам для детей Препарат Содержание действующего вещества в таблетке или пакете или капсуле с покрытыми частицами (мг) 60мг/30мг/50мг 40мг/10мг 30мг/15мг/ 40мг/10мг 30мг/15мг/ 40мг/10мг 240/40мг 100/33мг 120/60мг 75мг/75мг 75мг/75мг/ 150мг 300мг/ 300мг Кол-во таблеток или капсул/пакетов в зависимости от веса 3–5,9 кг 6–9,9 кг 10–13,9 кг 14–19,9 кг 20–24,9 кг 25–34,9 кг

Приложение 7. Дозировки рекомендованных антиретровирусных препаратов

утро вечер утро вечер утро вечер утро вечер утро вечер утро вечер

ABC/3TC/NVP LPV/r sprinkles ABC/3TC/ LPV/r AZT/3 TC/ LPV/r DRV/r ATV/r ABC/3TC TDF/3TC TDF/3TC/ EFV TDF/3TC с двойным делением для взрослыхb TDF/3TC/EFV с двойным делением для взрослыхb a b

1 2 2 2 – – 1 – –

1 2 2 2 –

1,5 3 3 3 – –

1,5 3 3 3 –

2 4 4 4 1 1 2 1,5 1,5

2 4 4 4 1

2,5 5 5 5 1 1

2,5 5 5 5 1

3 6 6 6 2 2 3 2,5 2,5

3 6 6 6 1

4 – – – – – –

1,5 – –

2,5 2 2 половина

3–3,5a 3–3,5a 1

–

одна треть

две трети

300мг/300мг/ 600мг

–

одна треть

половина

две трети

3 таблетки при весе 25–29,9 кг и 3,5 таблетки при весе 30–34,9 кг. Таблетка с двойным делением имеет две насечки на одной стороне и одну насечку на другой стороне, что позволяет, при необходимости, делить таблетку на три или две части.

БИБЛИОГРАФИЯ

290

13. Библиография Глава 1 1. S caling up antiretroviral therapy in resource-limited settings. Guidelines for a public health approach. Geneva, World Health Organization, 2002 (www.who.int/hiv/pub/prev_care/ScalingUp_E.pdf, accessed 15 May 2013). 2. A ntiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines on care, treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. Geneva, World Health Organization, 2004 (www.who.int/hiv/pub/mtct/en/arvdrugswomenguidelinesfinal.pdf, accessed 15 May 2013). 3. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2006 revision. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf, accessed 15 May 2013). 4. A ntiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access: recommendations for a public health approach. 2006 revision. Geneva, World Health Organization, 2006 (http://www.who.int/ hiv/pub/mtct/antiretroviral/en/index.html, accessed 15 May 2013). 5. A ntiretroviral therapy of HIV infection in infants and children: towards universal access. Recommendations for a public health approach. 2006 revision. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/guidelines/paediatric020907. pdf, accessed 15 May 2013). 6. Gilks C et al. WHO public health approach to ART against HIV in resource-limited settings. Lancet, 2006, 368:505–510. 7. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2010 revision. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf, accessed 15 May 2013). 8. A ntiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access: recommendations for a public health approach. 2010 revision. Geneva, World Health Organization, 2010 http://whqlibdoc.who. int/publications/2010/9789241599818_eng.pdf, accessed 15 May 2013). 9. A ntiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. 2010 revision. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599801_eng.pdf, accessed 15 May 2013). 10. T he strategic use of antiretrovirals for treatment and prevention of HIV infection. Report of a WHO technical consultation, 14–16 November 2011, Geneva, Switzerland. Geneva, World Health Organization, 2011 (https://extranet.who.int/iris/restricted/ bitstream/10665/70912/5/9789241503808_eng.pdf, accessed 15 May 2013).

Глава 2 1. United Nations General Assembly. 2006 Political Declaration on HIV/AIDS. New York, United Nations, 2006. 2. United Nations General Assembly. 2011 Political Declaration on HIV and AIDS: Intensifying Our Efforts to Eliminate HIV and AIDS. New York, United Nations, 2011. 3. G lobal health sector strategy on HIV/AIDS 2011–2015. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/hiv_ strategy/en, accessed 15 May 2013). 4. G lobal Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva, UNAIDS, 2011 (http://www.unaids.org/believeitdoit/the-global-plan.html, accessed 15 May 2013).

Глава 3 1. W HO handbook for guideline development. Geneva, World Health Organization, 2012 (www.who.int/kms/guidelines_review_ committee/en, accessed 15 May 2013). 2. Guyatt GH et al. GRADE guidelines. 1. Introduction – GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology, 2011, 64:383–394. 3. Guyatt GH et al. GRADE guidelines. 2. Framing the question and deciding on the importance of outcomes. Journal of Clinical Epidemiology, 2011, 64:395–400. 4. Balshem H et al. GRADE guidelines. 3. Rating the quality of evidence introduction. Journal of Clinical Epidemiology, 2011, 64:401–406. 5. Guyatt GH et al. GRADE guidelines. 4. Rating the quality of evidence – study limitations (risk of bias). Journal of Clinical Epidemiology, 2011, 64:407–415. 6. Guyatt GH et al. GRADE guidelines. 5. Rating the quality of evidenced publication bias. Journal of Clinical Epidemiology, 2011, 64:1277–1282. 7. Guyatt GH et al. GRADE guidelines. 6. Rating the quality of evidenced imprecision (random error). Journal of Clinical Epidemiology, 2011, 64:1283–1293. 8. Guyatt GH et al. GRADE guidelines. 7. Rating the quality of evidenced inconsistency. Journal of Clinical Epidemiology, 2011, 64:1294–1302. 9. Guyatt GH et al. GRADE guidelines. 8. Rating the quality of evidenced indirectness. Journal of Clinical Epidemiology, 2011, 64:1303–1310. 10. Guyatt GH et al. GRADE guidelines. 9. Rating up the quality of evidence. Journal of Clinical Epidemiology, 2011, 64:1311–1316. 11. Andrews J et al. GRADE guidelines. 15. Going from evidence to recommendations: the significance and presentation of recommendations. Journal of Clinical Epidemiology, in press. doi: 10.1016/j.jclinepi.2012.03.013.

13. Библиография

291

Глава 5 S ervice delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75206/1/9789241593877_eng.pdf, accessed 15 May 2013). 2. G uidance on provider-initiated HIV testing and counselling in health facilities. Geneva, World Health Organization, 2007 (http:// whqlibdoc.who.int/publications/2007/9789241595568_eng.pdf, accessed 15 May 2013). 3. Sweat M et al. Community-based intervention to increase HIV testing and case detection in people aged 16-32 years in Tanzania, Zimbabwe, and Thailand (NIMH Project Accept, HPTN 043): a randomised study. Lancet Infectious Diseases, 2011, 11:525–532. 4. Corbett EL et al. Uptake of workplace HIV counselling and testing: a cluster-randomised trial in Zimbabwe. PLoS Medicine, 2006, 3:e238. 5. Grabbe KL et al. Increasing access to HIV counseling and testing through mobile services in Kenya: strategies, utilization, and cost-effectiveness. Journal of Acquired Immune Deficiency Syndromes, 2010, 54:317–323. 6. Granich R et al. Achieving universal access for human immunodeficiency virus and tuberculosis: potential prevention impact of an integrated multi-disease prevention campaign in Kenya. AIDS Research and Treatment, 2012, 412643. 7. Lugada E et al. Comparison of home and clinic-based HIV testing among household members of persons taking antiretroviral therapy in Uganda: results from a randomized trial. Journal of Acquired Immune Deficiency Syndromes, 2010, 55:245–252. 8. Menzies N et al. The costs and effectiveness of four HIV counseling and testing strategies in Uganda. AIDS, 2009, 23:395–401. 9. van Schaik N et al. Earlier HIV diagnosis – are mobile services the answer? South African Medical Journal, 2010, 100:671–674. 10. Wolff B et al. Evaluation of a home-based voluntary counselling and testing intervention in rural Uganda. Health Policy and Planning, 2005, 20:109–116. 11. Bingham TA et al. HIV risk factors reported by two samples of male bathhouse attendees in Los Angeles, California, 2001–2002. Sexually Transmitted Diseases, 2008, 35:631–636. 12. Lahuerta M et al. Comparison of users of an HIV/syphilis screening community-based mobile van and traditional voluntary counselling and testing sites in Guatemala. Sexually Transmitted Infections, 2011, 87:136–140. 13. Nhurod P et al. Access to HIV testing for sex workers in Bangkok, Thailand: a high prevalence of HIV among street-based sex workers. Southeast Asian Journal of Tropical Medicine and Public Health, 2010, 41:153–162. 14. Kranzer K et al. Individual, household and community factors associated with HIV test refusal in rural Malawi. Tropical Medicine and International Health, 2008, 13:1341–1350. 15. Negin J et al. Feasibility, acceptability and cost of home-based HIV testing in rural Kenya. Tropical Medicine and International Health, 2009, 14:849–855. 16. Chirawu P et al. Acceptability and challenges of implementing voluntary counselling and testing (VCT) in rural Zimbabwe: evidence from the Regai Dzive Shiri Project. AIDS Care, 2010, 22:81–88. 17. Ostermann J et al. Who tests, who doesn’t, and why? Uptake of mobile HIV counseling and testing in the Kilimanjaro Region of Tanzania. PLoS One, 2011, 6:e16488. 18. Choko AT et al. The uptake and accuracy of oral kits for HIV self-testing in high HIV prevalence setting: a cross-sectional feasibility study in Blantyre, Malawi. PLoS Medicine, 2011, 8:e1001102. 19. Frank AP et al. Anonymous HIV testing using home collection and telemedicine counseling. A multicenter evaluation. Archives of Internal Medicine, 1997, 157:309–314. 20. Spielberg F et al. Home collection for frequent HIV testing: acceptability of oral fluids, dried blood spots and telephone results. HIV Early Detection Study Group. AIDS, 2000, 14:1819–1828. 21. Feeley FG et al. A successful workplace program for voluntary counseling and testing and treatment of HIV/AIDS at Heineken, Rwanda. International Journal of Occupational and Environmental Health, 2007, 13:99–106. 22. Outlaw AY et al. Using motivational interviewing in HIV field outreach with young African American men who have sex with men: a randomized clinical trial. American Journal of Public Health, 2010, 100(Suppl. 1):S146–S151. 23. Bell DN et al. Case finding for HIV-positive youth: a special type of hidden population. Journal of Adolescent Health, 2003, 33:10–22. 24. Champenois K et al. ANRSCOM’TEST: description of a community-based HIV testing intervention in nonmedical settings for men who have sex with men. BMJ Open, 2012, 2:e000693. 25. Morin SF et al. Removing barriers to knowing HIV status: same-day mobile HIV testing in Zimbabwe. Journal of Acquired Immune Deficiency Syndromes, 2006, 41:218–224. 26. Couples HIV testing and counselling including antiretroviral therapy for treatment and prevention in serodiscordant couples. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/publications/2012/9789241501972_eng.pdf, accessed 15 May 2013). 27. W HO recommendations on the diagnosis of HIV infection in infants and children. Geneva, World Health Organization, 2010 (http:// whqlibdoc.who.int/publications/2010/9789241599085_eng.pdf, accessed 15 May 2013). 28. G uideline on HIV disclosure counselling for children up to 12 years of age. Geneva, World Health Organization, 2011 (http:// whqlibdoc.who.int/publications/2011/9789241502863_eng.pdf, accessed 15 May 2013). 29. G uidance on HIV testing and counselling for adolescents and care for adolescents living with HIV. Geneva, World Health Organization, 2013. 30. P revention and treatment of HIV and other sexually transmitted infections for sex workers in low- and middle-income countries: recommendations for a public health approach. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/77745/1/9789241504744_eng.pdf, accessed 15 May 2013). 1.

13. Библиография

292

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 31. P revention and treatment of HIV and other sexually transmitted infections among men who have sex with men and transgender people: recommendations for a public health approach. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501750_eng.pdf, accessed 15 May 2013). 32. D elivering HIV test results and messages for re-testing and counselling in adults. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599115_eng.pdf, accessed 15 May 2013). 33. P lanning, implementing and monitoring home-based HIV testing. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75366/1/9789241504317_eng.pdf, accessed 15 May 2013). 34. Baeten JM, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. New England Journal of Medicine, 2012, 367 (5):399-410 35. Grant R et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. New England Journal of Medicine, 2010, 363 (27):2587-2599. 36. Thigpen MC, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. New England Journal of Medicine, 2012, 367(5):423-434 37. Choopanya K, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet, 2013, 381 (9883): 2083-2090 38. G uidance on oral pre-exposure prophylaxis (PrEP) for serodiscordant couples, men and transgender women who have sex with men at high risk of HIV: recommendations for use in the context of demonstration projects. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75188/1/9789241503884_eng.pdf, accessed 15 May 2013). 39. R esponding to intimate partner violence and sexual violence against women: clinical and policy guidelines. Geneva, World Health Organization, in press. 40. Weller SC, Davis-Beaty K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database of Systematic Reviews, 2009, (1):CD003255. 41. French PP et al. Use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women. Sexually Transmitted Diseases, 2003, 30:433–439. 42. Effectiveness of sterile needle and syringe programming in reducing HIV/AIDS among IDUs. Geneva, World Health Organization, 2004 (www.who.int/hiv/pub/idu/e4a-needle/en/index.html, accessed 15 May 2013). 43. Effectiveness of drug dependence treatment in preventing HIV among injecting drug users. Geneva, World Health Organization, 2003 (www.who.int/entity/hiv/pub/idu/drugdependencefinaldraft.pdf, accessed 15 May 2013). 44. G uidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241547543_eng.pdf, accessed 15 May 2013). 45. Siegfried N et al. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database of Systematic Reviews, 2009, (2):CD003362.

Глава 6 1. S ervice delivery approaches to HIV testing and counselling (HTC): a strategic HTC programme framework . Geneva, World Health Organization, 2012 (http://apps.who.int/iris/bitstream/10665/75206/1/9789241593877_eng.pdf, accessed 15 May 2013). 2. Kranzer K et al. Quantifying and addressing losses along the continuum of care for people living with HIV infection in subSaharan Africa: a systematic review. Journal of the International AIDS Society, 2012, 15:173–183. 3. Faal M et al. Providing immediate CD4 count results at HIV testing improves ART initation. Journal of Acquired Immune Deficiency Syndromes, 2011, 58:e54–e59. 4. Jani IV et al. Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study. Lancet, 2011, 378:1572–1579. 5. E ssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, World Health Organization, 2008 (www.who.int/hiv/pub/prev_care/OMS_EPP_AFF_en.pdf, accessed 15 May 2013). 6. P riority interventions. HIV/AIDS prevention, treatment and care in the health sector. Geneva, World Health Organization, 2010 (http://www.who.int/hiv/pub/guidelines/9789241500234_eng.pdf, accessed 15 May 2013). 7. I MAI district clinician manual: hospital care for adolescents and adults. Geneva, World Health Organization, 2011 (http://www. who.int/hiv/pub/imai/imai2011/en, accessed 15 May 2013). 8. Gupta A et al. Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis. PLoS One, 2011, 6:e28691. 9. Brinkhof MW et al. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality. PLoS Medicine, 2009, 6:e1000066. 10. Mocroft A et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet, 2007, 370:407–413. 11. Haddow LJ et al. Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa. PLoS One, 2012, 7:e40623. 12. Huis in ‘t Veld D et al. The immune reconstitution inflammatory syndrome related to HIV co-infections: a review. European Journal of Clinical Microbiology and Infectious Diseases, 2012, 31:919–927.

13. Библиография

293

Глава 7 1. Vitoria M, Vella S, Ford N. Scaling up antiretroviral therapy in resource-limited settings: adapting guidance and meet the challenges. Current Opinion in HIV and AIDS, 2013, 8:12–18. 2. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf, accessed 15 May 2013. 3. Emery S et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. Journal of Infectious Diseases, 2008, 197:1133–1144. 4. Severe P et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. New England Journal of Medicine, 2010, 363:257–265. 5. Badri M et al. Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines. AIDS, 2004, 18:1159–1168. 6. Moha R et al. Incidence and determinants of mortality and morbidity following early antiretroviral therapy initiation in HIVinfected adults in West Africa. AIDS, 2007, 21:2483–2491. 7. Wong KH et al. Establishing CD4 thresholds for highly active antiretroviral therapy initiation in a cohort of HIV-infected adult Chinese in Hong Kong. AIDS Patient Care and STDs, 2007, 21:106–115. 8. Sterne JA et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet, 2009, 373:1352–1363. 9. Granich RM et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet, 2009, 373:48–57. 10. G lobal HIV/AIDS response: epidemic update and health sector progress towards universal access: progress report 2011. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502986_eng.pdf, accessed 15 May 2013). 11. U NAIDS report on the global AIDS epidemic 2012. Geneva, UNAIDS, 2012 (http://www.unaids.org/en/media/unaids/ contentassets/documents/epidemiology/2012/gr2012/20121120_UNAIDS_Global_Report_2012_en.pdf). 12. Mugglin C et al. Immunodeficiency at the start of ART: global view. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 27 February – 2 March 2012 (http://retroconference.org/2012b/Abstracts/43569.htm, accessed 15 May 2013). 13. Egger M et al. Immunodeficiency at start of combination antiretroviral therapy in low, middle and high income countries. Journal of Acquired Immune Deficiency Syndromes, in press. 14. Lessells RJ et al. Reduction in early mortality on antiretroviral therapy for adults in rural South Africa since change in CD4+ cell count eligibility criteria. Journal of Acquired Immune Deficiency Syndromes, in press. 15. Kowalska JD et al. A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: results from the EuroSIDA study. HIV Clinical Trials, 2011, 12:109–117. 16. Moore RD et al. Rate of comorbidities not related to HIV infection or AIDS among HIV-infected patients, by CD4 cell count and HAART use status. Clinical Infectious Diseases, 2008, 47:1102–1104. 17. Baker JV et al. CD4R count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS, 2008, 22:841–848. 18. Cohen MS et al. Prevention of HIV-1 infection with early antiretroviral therapy. New England Journal of Medicine, 2011, 365:493– 505. 19. Ahdieh-Grant L et al. When to initiate highly active antiretroviral therapy: a cohort approach. American Journal of Epidemiolog y, 2003, 157:738–746. 20. Althoff K et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS, 2010, 24:2469–2479. 21. Antiretroviral Therapy (ART) Cohort Collaboration. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet, 2003, 362:679–686. 22. Antiretroviral Therapy (ART) Cohort Collaboration. Effect of baseline CD4 cell counts on the clinical significance of short-term immunologic response to antiretroviral therapy in individuals with virologic suppression. Journal of Acquired Immune Deficiency Syndromes, 2009, 52:357–363. 23. CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Archives of Internal Medicine, 2011, 171:1560–1569. 24. CASCADE Collaboration. Short-term CD4 cell response after highly active antiretroviral therapy initiated at different times from seroconversion in 1500 seroconverters. Journal of Acquired Immune Deficiency Syndromes, 2003, 32:303–310. 25. Cozzi Lepri A et al. When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from ICONA study. AIDS, 2001, 15:983–990. 26. Egger M et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet, 2002, 360:119–129. 27. Garcia F et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. Journal of Acquired Immune Deficiency Syndromes, 2004, 36:702–713. 28. Gras L et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. Journal of Acquired Immune Deficiency Syndromes, 2007, 45:183–192. 29. HIV-CAUSAL Collaboration. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS, 2010, 24:123–137. 30. HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries. Annals of Internal Medicine, 2011, 154:509–515. 31. Kitahata M et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. New England Journal of Medicine, 2009, 360:1815–1826.

13. Библиография

294

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 32. Krishnan S et al. Incidence of non-AIDS-defining cancer in antiretroviral treatment-naïve subjects after antiretroviral treatment initiation: an ACTG longitudinal linked randomized trials analysis. Oncology, 2011, 80:42–49. 33. Merito M, Pezzotti P. Comparing costs and effectiveness of different starting points for highly active antiretroviral therapy in HIV-positive patients. European Journal of Health Economics, 2006, 7:30–36. 34. Opravil M et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count >350 106/l. AIDS, 2002, 16:1371–1381. 35. Palella F et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Annals of Internal Medicine, 2003, 138:620–626. 36. Phillips A et al. HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load. JAMA , 2001, 286:2560–2567. 37. Plettenberg A et al. Impact of earlier HAART initiation on the immune status and clinical course of treated patients on the basis of cohort data of the German Competence Network for HIV/AIDS. Infection, 2011, 39:3–12. 38. Gallant JE et al. Health outcomes associated with the timing of antiretroviral therapy initiation. 6th IAS Conference on HIV Pathogenesis and Treatment, 17–20 July 2011, Rome, Italy (Abstract CDB320; www.iasociety.org/Abstracts/A200742892.aspx, accessed 15 May 2013). 39. When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet, 2009, 373:1352–1362. 40. Grant P et al. Association of baseline viral load, CD4 count, and week 4 virologic response (VR) with virologic failure (VF) in ACTG Study A5202. 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 5–8 March 2011 (http:// retroconference.org/2011/PDFs/535.pdf, accessed 15 May 2013). 41. Suthar AB et al. Antiretroviral therapy for prevention of tuberculosis in adults with HIV: a systematic review and meta-analysis. PLoS Medicine, 2012, 9:e1001270. 42. Golub JE et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007, 11;21:1441–1448. 43. Badri M et al. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet, 2002, 359:2059–2064. 44. Golub JE et al. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2008, 22:2527–2533. 45. Williams BG et al. Antiretroviral therapy for tuberculosis control in nine African countries. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107:19485–19489. 46. Donnell D et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. Lancet, 2011, 375:2092–2098. 47. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989 through 31 July 2012. Wilmington, NC, Registry Coordinating Center, 2012 (www.APRegistry.com, accessed 15 May 2013). 48. Akinbami A et al. CD4 count pattern and demographic distribution of treatment-naive HIV patients in Lagos, Nigeria. AIDS Research and Treatment, 2012, 2012:352753. 49. G uidance on couples HIV testing and counseling including antiretroviral therapy for treatment and prevention in serodiscordant couples: recommendations for a public health approach. Geneva, World Health Organization, 2012 (http://whqlibdoc.who.int/ publications/2012/9789241501972_eng.pdf, accessed 15 May 2013). 50. Abdool Karim SS et al. Integration of antiretroviral therapy with tuberculosis treatment. New England Journal of Medicine, 2011, 365:1492–1501. 51. Havlir DV et al. Timing of antiretroviral therapy for HIV 1 infection and tuberculosis. New England Journal of Medicine, 2011, 365:1482–1491. 52. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine, 2011, 365:1471–1481. 53. Hoffmann CJ et al. Hepatitis B and long-term HIV outcomes in coinfected HAART recipients. AIDS, 2009, 23:1881–1889. 54. Thio CL et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet, 2002, 360:1921–1926. 55. Konopnicki D et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS, 2005, 19:593–601. 56. Puoti M et al. Mortality for liver disease in patients with HIV infection: a cohort study. Journal of Acquired Immune Deficiency Syndromes, 2000, 2:211–217. 57. Weber R et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D: A:D study. Archives of Internal Medicine, 2006, 166:1632–1641. 58. Salmon-Ceron D et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. Journal of Hepatology, 2005, 42:799–805. 59. Nikolopoulos GK et al. Impact of hepatitis B virus infection on the progression of AIDS and mortality in HIV-infected individuals: a cohort study and meta-analysis. Clinical Infectious Diseases, 2009, 48:1763–1771. 60. Martin-Carbonero L et al. Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues. AIDS, 2011, 25:73–79. 61. Matthews GV et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology, 2008, 48:1062–1069. 62. Matthews G et al. Combination HBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HIV/HBV coinfected individuals. AIDS, 2009, 23:1707–1715. 63. Benhamou Y et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology, 1999, 30:1054–1058. 64. Deng LP et al. Impact of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. World Journal of Gastroenterology, 2009, 15:996–1003.

13. Библиография 65. Pineda JA et al. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis. Hepatology, 2005, 41:779–789. 66. Thein HH et al. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS, 2008, 22:1979–1991. 67. Castel AD et al. Use of the community viral load as a population-based biomarker of HIV burden. AIDS, 2012, 26:345–353. 68. Cowan SA et al. Stable incidence of HIV diagnoses among Danish MSM despite increased engagement in unsafe sex. Journal of Acquired Immune Deficiency Syndromes. 2012, 61:106–111. 69. Das M et al. Decreases in community viral load are accompanied by reductions in new HIV infections in San Francisco. PLoS ONE, 2010, 5:e11068. 70. Fang C-T et al. Decreased HIV transmission after a policy of providing free access to highly active antiretroviral therapy in Taiwan. Journal of Infectious Diseases, 2004, 190:879–885. 71. Hogg RS et al. HAART-related decrease in the rate of new HIV diagnoses – a unique trend. 19th Annual Conference on Retroviruses and Opportunistic Infections. Seattle, WA, USA, 5–8 March 2012 (http://retroconference.org/2012b/Abstracts/42768. htm, accessed 15 May 2013). 72. Geng EH et al. The effect of a “universal antiretroviral therapy” recommendation on HIV RNA levels among HIV-infected patients entering care with a CD4 count greater than 500/μL in a public health setting. Clinical Infectious Diseases, 2012, 55:1690–1697. 73. Katz MH et al. Impact of highly active antiretroviral treatment on HIV seroincidence among men who have sex with men: San Francisco. American Journal of Public Health, 2002, 92:388–394. 74. Law MG et al. Trends in detectable viral load by calendar year in the Australian HIV observational database. Journal of the International AIDS Society, 2011, 14:10. 75. Manavi K et al. Community viral load counts and new HIV-positive patients in Birmingham, United Kingdom, between 2006 and 2011. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract TUPE213; www.iasociety.org/Abstracts/ A200747416.aspx, accessed 15 May 2013). 76. Montaner JS et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet, 2010, 376:532–539. 77. Montaner J et al. Expanded HAART coverage is associated with decreased HIV/AIDS morbidity and new HIV diagnoses: an update on the ‘treatment as prevention’ experience in British Columbia, Canada. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract THPE103; www.iasociety.org/Abstracts/A200745196.aspx, accessed 15 May 2013). 78. Porco TC et al. Decline in HIV infectivity following the introduction of highly active antiretroviral therapy. AIDS, 2004, 18:81–88. 79. Wood E et al. Longitudinal community plasma HIV-1 RNA concentrations and incidence of HIV-1 among injecting drug users: prospective cohort study. British Medical Journal, 2009, 338:b1649. 80. S trategic timing of antiretroviral treatment (START). Minneaolis, Clinical and Translational Science Institute, University of Minnesota, 2012 (http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2008-006439-12-FI, accessed 15 May 2013). 81. E arly antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in HIV-infected adults (ANRS 12136 TEMPRANO). Paris, French National Agency for Research on AIDS and Viral Hepatitis, 2012 (http://apps.who.int/trialsearch/ Trial.aspx?TrialID=NCT00495651, accessed 15 May 2013). 82. A ntiretroviral drugs for treating pregnant women and preventing HIV infections in infants: recommendations for a public health approach. 2010 version. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599818_eng.pdf, accessed 15 May 2013). 83. Countdown to zero: global plan for the elimination of new HIV infections among children by 2015 and keeping their mothers alive, 2011–2015. Geneva, UNAIDS, 2011 (http://www.unaids.org/en/media/unaids/contentassets/documents/ unaidspublication/2011/20110609_JC2137_Global-Plan-Elimination-HIV-Children_en.pdf, accessed 15 May 2013). 84. Schouten EJ et al. Prevention of mother-to-child transmission of HIV and the health-related Millennnium Development Goals: time for a public health approach. Lancet, 2011, 378:282–284. 85. I ntegrated HIV program report July–September 2012. Lilongwe, Ministry of Public Health, Government of Malawi (http://www. hivunitmohmw.org/uploads/Main/Quarterly_HIV_Programme_Report_2012_Q3.pdf, accessed 15 May 2013). 86. United States Centers for Disease Control and Prevention. Impact of an innovative approach to prevent mother-to-child transmission of HIV – Malawi, July 2011 –September 2012. MMWR Morbidity and Mortality Weekly Report, 2013, 62:148–151. 87. U se of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: programmatic update. Geneva, World Health Organization, 2012 (http://www.who.int/hiv/pub/mtct/programmatic_update2012/en/index.html, accessed 15 May 2013). 88. Taha TE et al. Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial. Journal of Acquired Immune Deficiency Syndromes, 2011, 57:319–325. 89. The Kesho Bora Study Group. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infectious Diseases, 2011, 11:171–180. 90. Coovadia HM et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomized, double-blind, placebo-controlled trial. Lancet, 2012, 379:221–228. 91. Jamieson DJ et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission (the BAN Study Group). New England Journal of Medicine, 2010, 362:2271–2281. 92. Jamieson DJ et al. Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial. Lancet, 2012, 379:2449–2458.

295

13. Библиография

296

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 93. The Kesho Bora Study Group. Maternal HIV-1 disease progression 18–24 months post delivery according to antiretroviral prophylaxis regimen (triple-antiretroviral prophylaxis during pregnancy and breastfeeding vs zidovudine/single-dose nevirapine prophylaxis): the Kesho Bora randomized controlled trial. Clinical Infectious Diseases, 2012, 55:449–460. 94. Ciaranello AL et al. Cost-effectiveness of World Health Organization 2010 guidelines for prevention of mother-to-child HIV transmission in Zimbabwe. Clinical Infectious Diseases, 2013, 56:430–446. 95. Olufunke Fasawe O et al. Cost-effectiveness analysis of option B+ for HIV prevention and treatment of mothers and children in Malawi. PLoS ONE, 8:e57778. 96. Nachega JB et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and highincome countries: a systematic review and meta-analysis. AIDS, 2012, 26:2039–2052. 97. Ekouevi D et al. Maternal CD4+ cell count decline after interruption of antiretroviral prophylaxis for the prevention of motherto-child transmission of HIV. PLoS ONE, 2012, 7:e43750. 98. Toolkit – expanding and simplifying treatment for pregnant women living with HIV: managing the transition to option B/B+. New York, Interagency Task Team on the Prevention and treatment of HIV Infection in Pregnant Women, Mothers and Children, 2013 (www.emtct-iatt.org/toolkit, accessed 15 May 2013). 99. G uidelines on HIV and infant feeding: principles and recommendations for infant feeding in the context of HIV. 2010 version. Geneva, World Health Organization, 2010 (www.who.int/child_adolescent_health/documents/en, accessed 15 May 2013). 100. S chneider S et al. Efavirenz in human breast milk, mothers’, and newborns’ plasma. Journal of Acquired Immune Deficiency Syndromes, 2008, 48:450–454. 101. G ibb DM et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Med, 2012, 9):e1001217. 102. B enaboud S et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d’Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrobial Agents and Chemotherapy, 2011, 55:1315. 103. C outsoudis A et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. Journal of Infectious Diseases, 2004, 189:2154–2166. 104. K uhn L et al. Potential impact of new WHO criteria for antiretroviral treatment for prevention of mother-to- child HIV transmission. AIDS, 2010, 24:1374–1377. 105. A ntiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach: 2010 revision. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241599801_eng.pdf, accessed 15 May 2013). 106. N ewell ML et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet, 2004, 364:1236–1243. 107. D unn D et al. Current CD4 cell count and the short-term risk of AIDS and death before the availability of effective antiretroviral therapy in HIV-infected children and adults. Journal of Infectious Diseases, 2008, 197:398–404. 108. C ross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee. Markers for predicting mortality in untreated HIV-infected children in resource-limited settings: a meta-analysis. AIDS, 2008, 22:97–105. 109. R aguenaud M et al. Excellent outcomes among HIV+ children on ART, but unacceptably high pre-ART mortality and losses to follow-up: a cohort study from Cambodia. BMC Pediatrics, 2009, 9:54. 110. T he South African antiretroviral treatment guidelines. Pretoria, Republic of South Africa National Department of Health 2013 (http://www.sahivsoc.org/upload/documents/2013%20ART%20Treatment%20Guidelines%20Final%2025%20March%20 2013%20corrected.pdf, accessed 15 May 2013). 111. National guidelines on management of HIV in Rwanda. 4th ed. Kigali, Ministry of Health, 2011. 112. S iegfried N et al. Optimal time for initiating antiretroviral therapy (ART) in HIV-positive, treatment-naive children aged 24 to 59 months (2 to 5 years old). Cochrane Database of Systematic Reviews, in press. 113. P uthanakit T et al. Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial. Lancet Infectious Diseases, 2012, 12:933–941. 114. Davies MA et al. When to start ART in children aged 2-5 years? Causal modeling analysis of IeDEA Southern Africa. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia. 115. Penazzato M et al. Programmatic impact of the evolution of WHO pediatric antiretroviral treatment guidelines for resource-limited countries 2012. Tukula Fenna Project, Uganda). Journal of Acquired Immune Deficiency Syndromes, 2012, 61:522–525. 116. P enazzato M et al. Paediatric antiretroviral treatment (ART): health care worker perspectives contributing to the WHO 2013 consolidated guidelines development. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia. 117. B arker PM, Mate K. Eliminating mother-to-child HIV transmission will require major improvements in maternal and child health services. Health Affairs, 2012, 31:1489–1497. 118. H ealy SA, Gupta S, Melvin AJ. HIV/HBV coinfection in children and antiviral therapy. Expert Review of Anti-infective Therapy, 2013, 11:251–263. 119. T he Treatment 2.0 framework for action: catalysing the next phase of treatment, care and support. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241501934_eng.pdf, accessed 15 May 2013). 120. D uncombe C et al. Treatment 2.0: catalyzing the next phase of treatment, care and support Current Opinion in HIV and AIDS, 2013, 8:4–11. 121. S hubber Z et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS, 2013, 27:1403-1412. 122. F ord N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and metaanalysis. AIDS, 2011, 25:2301–2304. 123. Technical update on treatment optimization: pharmacological equivalence and clinical interchangeability between lamivudine and emtricitabine, a review of current literature. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/70936/1/9789241503815_eng.pdf, accessed 15 May 2013).

13. Библиография 124. P hanuphak N et al. Nevirapine-associated toxicity in HIV-infected Thai men and women, including pregnant women. HIV Medicine, 2007, 8:357–366. 125. J amisse L et al. Antiretroviral-associated toxicity among HIV-1-seropositive pregnant women in Mozambique receiving nevirapine-based regimens. Journal of Acquired Immune Deficiency Syndromes, 2007, 44:371–376. 126. A aron E et al. Adverse events in a cohort of HIV infected pregnant and non-pregnant women treated with nevirapine versus non-nevirapine antiretroviral medication. PLoS One, 2010, 5:e12617. 127. F ord N et al. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS, 2010, 27:1135–1143. 128. A ntiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva, World Health Organization, 2006 (www.who.int/hiv/pub/guidelines/artadultguidelines.pdf, accessed 15 May 2013). 129. Zerit – CHMP renewal assessment report, March 2011 (EMA/CHMP/103159/2011). London, European Medicines Agency (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000110/ WC500106749.pdf, accessed 15 May 2013). 130. Fernandez-Fernandez B et al. Tenofovir nephrotoxicity: 2011 update. AIDS Research and Treatment, 2011, 2011:354908. 131. Young J et al. Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or atazanavir. AIDS, 2012, 26:567–575. 132. Sturt AS, Dokubo EK, Sint TT. Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women. Cochrane Database of Systematic Reviews, 2010, (3):CD008440. 133. B era E, Mia R. Safety of nevirapine in HIV-infected pregnant women initiating antiretroviral therapy at higher CD4 counts: a systematic review and meta-analysis. South African Medical Journal, 2012, 102:855–859. 134. F ord N et al. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS, 2013, [Epub ahead of print]. 135. L alllemant M et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. New England Journal of Medicine, 2000, 343:982–991. 136. S ix Week Extended-Dose Nevirapine Study Team et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet, 2008, 372:300–313. 137. T aha TE et al. Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi trial. Journal of Acquired Immune Deficiency Syndromes, 2011, 57:319–325. 138. R ecommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Washington, DC, United States Department of Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012 (http://aidsinfo.nih.gov/ contentfiles/lvguidelines/PerinatalGL.pdf, accessed 15 May 2013). 139. E kouevi DK et al. Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS Databases, Abidjan, Côte d’Ivoire. Journal of Acquired Immune Deficiency Syndromes, 2011, 56:183–187. 140. U se of efavirenz during pregnancy: a public health perspective. Technical update on treatment optimization. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/treatment2/efavirenz/en, accessed 15 May 2013). 141. Nightingale SL. From the Food and Drug Administration. JAMA , 1998, 280:1472. 142. D e Santis M et al. Periconceptional exposure to efavirenz and neural tube defects. Archives of Internal Medicine, 2002, 162:355. 143. B ritish HIV Association. Guidelines for the management of HIV infection in pregnant women 2012. HIV Medicine, 2012, 13(Suppl. 2):87–157. 144. V igano A et al. In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antiviral Therapy, 2011, 16:1259–1266. 145. S iberry GK et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS, 2012, 26:1151–1159. 146. K ilewo C et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. Journal of Acquired Immune Deficiency Syndromes, 2008, 48:315·323. 147. N agot N et al. Lopinavir/ritonavir versus lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174. BMC Infectious Diseases, 2012, 6:246. 148. C oovadia A et al. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA , 2010, 304:1082–1090. 149. K uhn L et al. Pre-treatment drug resistance mutations among HIV+ children <2 years of age who failed or missed PMTCT: Johannesburg, South Africa. 20th Annual Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, USA, 3–6 March 2013 (http://retroconference.org/2013b/Abstracts/46091.htm, accessed 15 May 2013). 150. A rrivé E et al. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis. International Journal of Epidemiology, 2007, 36:1009–1021. 151. M usiime V et al. Response to nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-infected children with perinatal exposure to single-dose nevirapine. AIDS Research and Human Retroviruses, 2009, 25:989–996. 152. L ockman S et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. New England Journal of Medicine, 2007, 356:135–147. 153. Palumbo P et al. Antiretroviral treatment for children with peripartum nevirapine exposure. New England Journal of Medicine, 2010, 363:1510–1520. 154. V iolari A et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. New England Journal of Medicine, 2012, 366:2380–2389. 155. A pollo T et al. World Health Organization HIV drug resistance surveillance in children less than 18 months newly diagnosed with HIV in Zimbabwe. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia.

297

13. Библиография

298

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 156. V iolari A. CHER Trial: virological responses achieved in infants with early ART. Eleventh International Congress on Drug Therapy in HIV Infection, Glasgow, United Kingdom, 11–15 November 2012. 157. D onegan KL et al. The prevalence of darunavir-associated mutations in HIV-1-infected children in the UK. Antiviral Therapy, 2012, 17:599–603. 158. P ENPACT-1 (PENTA 9/PACTG 390) Study Team et al. First-line antiretroviral therapy with a protease inhibitor versus nonnucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infectious Diseases, 2011, 11:273–283. 159. F itzgerald F, Penazzato M, Gibb D. Development of antiretroviral resistance in children with HIV in low and middle-income countries. Journal of Infectious Diseases, in press. 160. A chan J et al. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children. New England Journal of Medicine, 2012, 367:2110–2118. 161. K uhn L et al. Switching children previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial. Lancet Infectious Diseases, 2012, 12:521–530. 162. N EVEREST 3 trial. Treatment options for protease inhibitor-exposed children (NEVEREST-III). Washington, DC, ClinicalTrials.gov, 2013 (Identifier: NCT01146873; www.clinicaltrials.gov/ct2/show/NCT01146873?term=NEVEREST&rank=1, accessed 15 May 2013). 163. A RROW trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet, 2013, doi:pii: S0140-6736(12)621989. 10.1016/S0140-6736(12)62198-9 [Epub ahead of print]. 164. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet, 2002, 359:733–740. 165. P illay D et al. Implications of HIV drug resistance on first and second line therapies in resource-limited settings: recommendations from the Collaborative HIV and Anti-HIV Drug Resistance Network. Antiviral Therapy, in press. 166. C hildren with HIV in Africa – pharmacokinetics and adherence/acceptability of simple antiretroviral regimens (CHAPAS-3). Kampala, CHAPAS 3 trial, 2013 (www.chapas3trial.org, accessed 15 May 2013). 167. K aletra (lopinavir/ritonavir): label change – serious health problems in premature babies. Washington, DC, United States Food and Drug Administration, 2013 (www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm246167.htm). 168. Tolle M et al. Reverse transcriptase genotypes in pediatric patients failing initial antiretroviral therapy in Gaborone, Botswana. Journal of the International Association of Physicians AIDS Care, 2012, 11:260–268. 169. U se of tenofovir in HIV-infected children and adolescents: a public health perspective – technical update on treatment optimization. Geneva, World Health Organization, 2012 (http://www.who.int/hiv/pub/treatment2/tenofovir/en, accessed 15 May 2013). 170. H azra R et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics, 2005, 116:e846. 171. P urdy J et al. Decreased bone mineral density with off-label use of tenofovir in HIV-infected children and adolescents. Journal of Pediatrics, 2008, 152:582–584. 172. V iread. Washington, DC, United States Food and Drug Administration, 2013 (www.accessdata.fda.gov/scripts/cder/drugsatfda/ index.cfm?fuseaction=Search.Overview&DrugName=VIREAD, accessed 15 May 2013). 173. V iread. London, European Medicines Agency, 2013 (http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/ EMEA-000533-PIP01-08-M04/pip_000375.jsp&mid=WC0b01ac058001d129, accessed 15 May 2013). 174. L yseng-Williamson KA, Reynolds NA, Plosker GL. Tenofovir disoproxil fumarate: a review of its use in the management of HIV infection. Drugs, 2005, 65:413–432. 175. M artin A et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96week trial. Clinical Infectious Diseases, 2009, 49:1591–1601. 176. F itzgerald F, Penazzato M, Gibb D. Development of antiretroviral resistance in children with HIV in low- and middle-income countries. Journal of Infectious Diseases, in press. 177. P uthanakit T et al. Prevalence of human leukocyte antigen-B*5701 among HIV-infected children in Thailand and Cambodia: implications for abacavir use. Pediatric Infectious Diseases, 2013, 32:252–253. 178. T ang MW, Kanki PJ, Shafer RW. A review of the virological efficacy of the 4 World Health Organization–recommended tenofovircontaining regimens for initial HIV therapy. Clinical Infectious Diseases, 2012, 54:862–875. 179. v an Dijk JH et al. Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings. PLoS One, 2013, 8:e55111. 180. M eya D et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cells count <100 cells/μl who start HIV therapy in resource-limited settings. Clinical Infectious Diseases, 2010, 51:448–455. 181. L outfy MR et al. Systematic review of HIV transmission between heterosexual serodiscordant couples where the HIV-positive partner is fully suppressed on antiretroviral therapy. PLoS One, 2013, 8:e55747. 182. R utherford GW et al. Predicting treatment failure (TF) in patients on antiretroviral therapy (ART): a systematic review of the performance characteristics of the 2010 World Health Organization (WHO) immunologic and clinical criteria for virologic failure. 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, 30 June – 3 July 2013, Kuala Lumpur, Malaysia. 183. O rrell C et al. Conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. Antiviral Therapy, 2007, 12:83–88. 184. M ermin J et al. Utility of routine viral load, CD4 cell count, and clinical monitoring among adults with HIV receiving antiretroviral therapy in Uganda: randomised trial. BMJ, 2011, 343:d6792. 185. J ourdain G et al. PHPT-3: a randomized clinical trial comparing CD4 vs viral load ART monitoring/switching strategies in Thailand. 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA, 5–8 March 2011 (http://retroconference. org/2011/Abstracts/41399.htm, accessed 15 May 2013).

13. Библиография 186. S aag MS et al. A cluster randomized trial of routine vs discretionary viral load monitoring among adults starting ART: Zambia. 19th Annual Conference on Retroviruses and Opportunistic Infections. Seattle, WA, USA, 5–8 March 2012 (http://retroconference. org/2012b/Abstracts/44483.htm, accessed 15 May 2013). 187. K eiser O et al. Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy. Tropical Medicine and International Health, 2009, 14:1220–1225. 188. A bouyannis M et al. Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa. AIDS, 2011, 25:1627–1635. 189. C haiwarith R et al. Sensitivity and specificity of using CD4+ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. International Journal of Infectious Diseases, 2007, 11:413–416. 190. H osseinipour M et al. Validating clinical and immunological definitions of antiretroviral treatment failure in Malawi. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22–25 July 2007 (Abstract WEAB101; www. iasociety.org/Abstracts/A200701701.aspx, accessed 15 May 2013 191. K antor R et al. Misclassification of first-line antiretroviral treatment failure based on immunological monitoring of HIV infection in resource-limited settings. Clinical Infectious Diseases, 2009, 49:454–462. 192. L abhardt ND et al. A clinical prediction score in addition to WHO criteria for anti-retroviral treatment failure in resource-limited settings - expeirence from Lesotho. PLoS ONE, 2012, 7:e47937. 193. M ee P et al. Evaluation of World Health Organization criteria for antiretroviral treatment failure in resource-limited settings. XVI International AIDS Conference, Toronto, Canada, 13–18 August 2006 (Abstract WEPE065; www.iasociety.org/Abstracts/A2191232. aspx, accessed 15 May 2013). 194. M ee P et al. Evaluation of WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS, 2008, 22:1971– 1977. 195. M eya D et al. Development and evaluation of a clinical algorithm to monitor patients on antiretrovirals in resource-limited settings using adherence, clinical and CD4 cell count criteria. Journal of the International AIDS Society, 2009, 12:3. 196. M oore DM et al. CD4+ T-cell count monitoring does not accurately identify HIV-infected adults with virologic failure receiving antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 2008, 49:477–484. 197. R awizza H et al. Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings. Clinical Infectious Diseases, 2011, 53:1283–1290. 198. R ewari BB. Evaluating patients for second-line antiretroviral therapy in India: the role of targeted viral load testing. Journal of Acquired Immune Deficiency Syndromes, 2010, 55:610–614. 199. R eynolds SJ et al. Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda. AIDS, 2009, 23:697–700. 200. v an Oosterhout JJ et al. Diagnosis of antiretroviral therapy failure in Malawi: poor performance of clinical and immunological WHO criteria. Tropical Medicine and International Health, 2009, 14:856–861. 201. B arlow-Mosha L et al. Validation of WHO 2010 immunologic criteria in predicting pediatric first-line antiretroviral treatment (ART) failure in ART-experienced children in Uganda: CD4 is a poor surrogate for virologic monitoring of pediatric ART failure. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract THPE062; http://www.iasociety.org/ Abstracts/A200744978.aspx, accessed 15 May 2013). 202. Davies M-A, Boulle A, Eley B, et al. Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy – the IeDEA Southern Africa Collaboration. Tropical Medicine and International Health, 2011, 16:1367– 1371. 203. Davies M-A et al. The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure. Tropical Medicine and International Health, 2012, doi: 10.1111/j.1365-3156.2012.03073.x [Epub ahead of print]. 204. Westley BP et al. Prediction of treatment failures using 2010 World Health Organization guidelines is associated with high misclassification rate and drug resistance among HIV-infected Cambodian children. Clinical Infectious Diseases, 2012, 55:432–440. 205. L aurent C et al. Monitoring of HIV viral loads, CD4 cell counts, and clinical assessments versus clinical monitoring alone for antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER): a randomised non-inferiority trial. Lancet Infectious Diseases, 2011, 11:825–833. 206. M ugyenyi P et al. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial. Lancet, 2010, 375:123–131. 207. H avlir DV et al. Prevalence and predictive value of intermittent viremia with combination HIV therapy. JAMA , 2001, 286:171– 179. 208. M ocroft A et al. Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/µl? Clinical Infectious Diseases, 2010, 51:611–619. 209. G ale HB et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts ≥300 cells/μl and HIV-1 suppression? Clinical Infectious Diseases, in press. 210. J ohannessen A et al. Dried blood spots perform well in viral load monitoring of patients who receive antiretroviral treatment in rural Tanzania. Clinical Infectious Diseases, 2009, 49:976–981. 211. G arrido C et al. Correlation between human immunodeficiency virus type 1 (HIV-1) RNA measurements obtained with dried blood spots and those obtained with plasma by use of Nuclisens EasyQ HIV-1 and real time HIV load tests. Journal of Clinical Microbiology, 2009, 47:1031–1036. 212. M onleau M et al. Evaluation of different RNA extraction methods and storage conditions of dried plasma or blood spots for human immunodeficiency virus type 1 RNA quantification and PCR amplification for drug resistance testing. Journal of Clinical Microbiology, 2009, 47:1107–1118. 213. Steinmetzer K et al. HIV load testing with small samples of whole blood. Journal of Clinical Microbiology, 2010, 48(8): 2786–2792.

299

13. Библиография

300

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 214. V iljoen J et al. Dried blood spot HIV-1 RNA quantification using open real-time systems in South Africa and Burkina Faso. Journal of Acquired Immune Deficiency Syndromes, 2010, 55:290–298. 215. B onjoch A et al. High rate of reversibility of renal damage in a cohort of HIV-infected patients receiving tenofovir-containing antiretroviral therapy. Antiviral Research, 2012, 96:65–69. 216. Treatment of tuberculosis: guidelines for national programmes. 4th ed. Geneva, World Health Organization, 2010 (http:// whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf, accessed 15 May 2013). 217. G uidelines for the treatment of malaria. 2nd ed. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241547925_eng.pdf, accessed 15 May 2013). 218. G uidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241547543_eng.pdf, accessed 15 May 2013). 219. M edical eligibility criteria for contraceptive use. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2010/9789241563888_eng.pdf, accessed 15 May 2013). 220. P ackage of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241598996_eng.pdf, accessed 15 May 2013). 221. J ohnson M et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS, 2006, 20:711–718. 222. A rasteh K et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antiviral Therapy, 2009, 14:859–864. 223. B anhegyi D et al. Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN. Current HIV Research, 2012, 10:171–181. 224. M olina JM et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. Journal of Acquired Immune Deficiency Syndromes, 2010, 53:323–332. 225. J osephson F et al. The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naive HIV-1 infected patients. European Journal of Clinical Pharmacology, 2010, 66:349–357. 226. O rkin C et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1infected treatment-naive patients in the ARTEMIS trial. HIV Medicine, 2012, doi: 10.1111/j.1468-1293.2012.01060.x. 227. A costa EP et al. Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily. Antimicrobial Agents and Chemotherapy, 2007, 51:3104–3110. 228. B urger DM et al. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrobial Agents and Chemotherapy, 2006, 50:3336–3342. 229. J ustesen US et al. Pharmacokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir in HIV-infected patients. Clinical Infectious Diseases, 2004, 38:426–429. 230. L aPorte C et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrobial Agents and Chemotherapy, 2004, 48:1553–1560. 231. D ecloedt EH et al. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavirritonavir tablets. Antimicrobial Agents and Chemotherapy, 2011, 55:3195–3200. 232. A trial of 2 options for second line combination antiretroviral therapy following virological failure of a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)+2N(t)RTI first line regimen SECOND-LINE. Darlinghurst, Kirby Institute, 2012 (http://apps. who.int/trialsearch/Trial.aspx?TrialID=NCT00931463, accessed 15 May 2013). 233. S tudy of Options for Second-Line Effective Combination Therapy (SELECT) SELECT. AIDS Clinical Trials Group, 2013 (http://apps. who.int/trialsearch/Trial.aspx?TrialID=NCT01352715, accessed 15 May 2013). 234. Evaluation of three strategies of second-line antiretroviral treatment in Africa (Dakar – Bobo-Dioulasso – Yaoundé) 2LADY. Paris, French National Agency for Research on AIDS and Viral Hepatitis, 2012 (http://apps.who.int/trialsearch/Trial. aspx?TrialID=NCT00928187, accessed 15 May 2013). 235. A multicentre trial of second-line antiretroviral treatment strategies in African adults using atazanavir or lopinavir/ritonavir ALISA . Paris, French National Agency for Research on AIDS and Viral Hepatitis, 2013 (http://apps.who.int/trialsearch/Trial. aspx?TrialID=NCT01255371, accessed 15 May 2013). 236. Europe–Africa Research Network for Evaluation of Second-line Therapy EARNEST. London, United Kingdom Medical Research Council, 2013 (http://apps.who.int/trialsearch/Trial.aspx?TrialID=ISRCTN37737787, accessed 15 May 2013). 237. T aylor BS et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Research and Human Retroviruses, 2011, 27:945–956. 238. Z anoni B et al. Predictors of poor CD4 and weight recovery in HIV-infected children initiating ART in South Africa. PLOS ONE, 2012, 7:e33611. 239. O rrell C et al. Resistance in pediatric patients experiencing virologic failure with first- and second-line antiretroviral therapy. Pediatric Infectious Diseases Journal, in press [Epub ahead of print]. 240. v an Zyl GU et al. Protease inhibitor resistance in South African children with virologic failure. Pediatric Infectious Diseases Journal, 2009, 28:1125–1127. 241. K ing JR et al. Antiretroviral pharmacokinetics in the paediatric population: a review. Clinical Pharmacokinetics, 2002, 41:1115– 1133. 242. KONCERT A Kaletra ONCE Daily Randomised Trial of the Pharmacokinetics, Safety and Efficacy of Twice-daily Versus Once-daily Lopinavir/Ritonavir Tablets Dosed by Weight as Part of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-1 (HIV1) Infected Children (PENTA 18). Identifier: NCT01196195. Bethesda, MD, www.clinicaltrials.gov, 2012 (http://clinicaltrials.gov/ ct2/show/NCT01196195?term=penta+18&rank=1, accessed 15 May 2013). 243. B akeera-Kitaka S et al. Pharmacokinetics and acceptability of a new generic lopinavir/ritonavir sprinkle formulation in African, HIV+ children 1–4 years: CHAPAS-2. 20th Annual Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, USA, 3–6 March 2013 (http://retroconference.org/2013b/Abstracts/47964.htm, accessed 15 May 2013).

13. Библиография 244. G otte M et al. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. Journal of Virology, 2000, 74:3579–3585. 245. A jose O et al. Treatment outcomes of patients on second-line antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. AIDS, 2012, 26:929–938. 246. G atell JM et al. Long-term efficacy and safety of the HIV integrase inhibitor raltegravir in patients with limited treatment options in a Phase II study. Journal of Acquired Immune Deficiency Syndromes, 2010, 53:456–463. 247. S teigbigel RT et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatmentexperienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clinical Infectious Diseases, 2010, 50:605–612. 248. K atlama C et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET1 and DUET-2 trials. Antiviral Therapy, 2010, 15:1045–1052. 249. I maz A et al. Efficacy and safety of nucleoside reverse transcriptase inhibitor-sparing salvage therapy for multidrug-resistant HIV-1 infection based on new-class and new-generation antiretrovirals. Journal of Antimicrobial Chemotherapy, 2011, 66:358–362. 250. F agard C et al. Long-term efficacy and safety of raltegravir, etravirine, and darunavir/ritonavir in treatment-experienced patients: week 96 results from the ANRS 139 TRIO trial. Journal of Acquired Immune Deficiency Syndromes, 2012, 59:489–493. 251. Etravirine full prescribing information. Titusville, NJ, Janssen Products, 2008 (www.intelence.com/shared/product/intelence/ prescribing-information.pdf, accessed 15 May 2013).

301

13. Библиография

Глава 8 1. G uidelines on co-trimoxazole prophylaxis for HIV-related infection among children, adolescents and adults: recommendations for a public health approach. Geneva, World Health Organization, 2006 (http://www.who.int/hiv/pub/plhiv/ctx/en, accessed 15 May 2013). 2. W HO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders. Geneva, World Health Organization, 2012 (http://www.who.int/tb/publications/2012/tb_hiv_policy_9789241503006/en) 3. W HO policy on TB infection control in health-care facilities, congregate settings and households. Geneva, World Health Organization, 2009 (http://www.who.int/tb/publications/2009/9789241598323/en, accessed 15 May 2013). 4. G uidelines for the programmatic management of drug-resistant tuberculosis. Geneva, World Health Organization, 2011 (http:// whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf, accessed 15 May 2013). 5. Childhood tuberculosis guidelines. Geneva, World Health Organization, forthcoming (expected 2013). 6. G lobal tuberculosis report 2012. Geneva, World Health Organization, 2012 (www.who.int/iris/ bitstream/10665/75938/1/9789241564502_eng.pdf, accessed 15 May 2013). 7. Zignol M, Falzon D, Getahun H. HIV infection and multidrug-resistant tb: 2 overlapping epidemics. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, Georgia, USA, 3–6 March 2013 (www.retroconference.org/2013b/ Abstracts/46973.htm, accessed 15 May 2013). 8. R apid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva, World Health Organization, 2011 (http://www.who.int/hiv/pub/cryptococcal_disease2011, accessed 15 May 2013). 9. Mathers BM et al. Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. Lancet, 2008, 372:1733–1745. 10. Easterbrook P, Sands A, Harmanci H. Challenges and priorities in the management of HIV/HBV and HIV/HCV coinfection in resource-limited settings. Seminars in Liver Disease, 2012, 32:147–157. 11. E ssential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, World Health Organization, 2008 (http://www.who.int/hiv/pub/prev_care/OMS_EPP_AFF_en.pdf) 12. Muronya W et al. Cardiovascular risk factors in adult Malawians on long-term antiretroviral therapy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2011, 105:644–649. 13. N utrient requirements for people living with HIV/AIDS: report of a technical consultation, 13–15 May 2003, Geneva, Switzerland. Geneva, World Health Organization, 2003 (http://www.who.int/nutrition/publications/hivaids/9241591196/en, accessed 15 May 2013). 14. E xecutive summary of a scientific review – Consultation on Nutrition and HIV/AIDS in Africa: evidence, lesson and recommendations for action, Durban, South Africa, 10–13 April 2005. Geneva, World Health Organization, 2005 (www.who.int/nutrition/topics/ Executive_Summary_Durban.pdf, accessed 15 May 2013). 15. E xecutive summary of a scientific review – Consultation on Nutrition and HIV/AIDS in Africa: evidence, lesson and recommendations for action, Durban, South Africa, 10–13 April 2005. Geneva, World Health Organization, 2005 (http://www.who.int/nutrition/topics/ Executive_Summary_Durban.pdf, accessed 15 May 2013). 16. N utrition counselling, care and support for HIV-infected women. Geneva, World Health Organization, 2005 (www.who.int/hiv/pub/ prev_care/en/nutri_eng.pdf, accessed 15 May 2013). 17. P articipants’ Statement – Consultation on Nutrition and HIV/AIDS in Africa: evidence, lesson and recommendations for action, Durban, South Africa, 10–13 April 2005. Geneva, World Health Organization, 2005 (www.who.int/nutrition/topics/Participants_ Statement_EB116.pdf, accessed 15 May 2013). 18. Paton NI et al. The impact of malnutrition on survival and the CD4 count response in HIV-infected patients starting antiretroviral therapy. HIV Medicine, 2006, 7:323–330. 19. van der Sande MA et al. Body mass index at time of HIV diagnosis: a strong and independent predictor of survival. Journal of Acquired Immune Deficiency Syndromes, 2004, 37:1288–1294.

302

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 20. WHO Multicentre Growth Reference Study Group. WHO child growth standards: methods and development. Length/height-forage, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Geneva, World Health Organization, 2006 (www.who.int/childgrowth/standards/technical_report/en, accessed 15 May 2013). 21. Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational “how-to”. Practical considerations. Geneva, World Health Organization, 2011 (whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf, accessed 15 May 2013).

Глава 9 dherence to long-term therapies: evidence for action. Geneva, World Health Organization, 2003 (www.who.int/entity/chp/ A knowledge/publications/adherence_full_report.pdf, accessed 15 May 2013). 2. Mills EJ et al. Adherence to HAART: a systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Medicine, 2006, 3:2039. 3. Martin S et al. Patient, caregiver and regimen characteristics associated with adherence to highly active antiretroviral therapy among HIV-infected children and adolescents. Paediatric Infectious Disease Journal, 2007, 26:61–67. 4. Reddington C et al. Adherence to medication regimens among children with human immunodeficiency virus infection. Paediatric Infectious Disease Journal, 2000, 19:1148–1153. 5. Murphy DA et al. Antiretroviral medication adherence among the REACH HIV-infected adolescent cohort in the USA. AIDS Care, 2001, 13:27–40. 6. Dowshen N, D’Angelo L. Health care transition for youth living with HIV/AIDS. Paediatrics, 2011, 128:762–771. 7. Murphy DA et al. Barriers to HAART adherence among human immunodeficiency virus-infected adolescents. Archives of Paediatrics and Adolescent Medicine, 2003, 157:249–255. 8. Duff P et al. Barriers to accessing highly active antiretroviral therapy by HIV-positive women attending an antenatal clinic in a regional hospital in western Uganda. Journal of the International AIDS Society, 2010, 13:37. 9. Nachega JB et al. Adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and highincome countries: a systematic review and meta-analysis. AIDS, 2012, 26:2039–2052. 10. Nakimuli-Mpungu E et al. Depression, alcohol use and adherence to antiretroviral therapy in sub-saharan Africa: a systematic review. AIDS and Behavior, 2012, 16:2101–2118. 11. Gonzalez JS et al. Depression and HIV/AIDS treatment non-adherence: a review and meta-analysis. Journal of Acquired Immune Deficiency Syndromes, 2011, 58:181–187. 12. Bottonari KA et al. Correlates of antiretroviral and antidepressant adherence among depressed HIV-infected patients. AIDS Patient Care and STDs, 2012, 26:265–273. 13. Springer SA, Dushaj A, Azar MM. The impact of DSM-IV mental disorders on adherence to combination antiretroviral therapy among adult persons living with HIV/AIDS: a systematic review. AIDS and Behavior, 2012, 16:2119–2143. 14. Altice FL et al. HIV treatment outcomes among HIV-infected, opioid-dependent patients receiving buprenorphine/ naloxone treatment within HIV clinical care settings: results from a multisite study. Journal of Acquired Immune Deficiency Syndrome s, 2011, 56(Suppl. 1):S22–S32. 15. Roux P et al. The impact of methadone or buprenorphine treatment and ongoing injection on highly active antiretroviral therapy (HAART) adherence: evidence from the MANIF2000 cohort study. Addiction, 2008;103:1828–1836. 16. Malta M et al. Adherence to antiretroviral therapy among HIV-infected drug users: a meta-analysis. AIDS and Behavior, 2010, 14:731–747. 17. Rich JD et al. HIV-related research in correctional populations: now is the time. Current HIV/AIDS Reports, 2011, 8:288–296. 18. Bärnighausen T et al. Interventions to increase antiretroviral adherence in sub-Saharan Africa: a systematic review of evaluation studies. Lancet Infectious Diseases, 2011, 11:942–951. 19. Chung MH et al. A randomized controlled trial comparing the effects of counselling and alarm device on HAART adherence and virologic outcomes. PLoS Medicine, 2011, 8:e1000422. 20. Rueda S et al. Patient support and education for promoting adherence to highly active antiretroviral therapy for HIV/AIDS. Cochrane Database of Systematic Reviews, 2006, (3):CD001442. 21. Altice FL et al. Trust and the acceptance of and adherence to antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 2001, 28:47–58. 22. Decroo T et al. Distribution of antiretroviral treatment through self-forming groups of patients in Tete Province, Mozambique. Journal of Acquired Immune Deficiency Syndromes, 2011, 56:e39–e44. 23. Bupamba et al. (2010). Ambassadors for adherence: provision of highly effective defaulter tracing and re-engagement by peer educators in Tanzania. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract MOAE0303; www.iasociety. org/Abstracts/A200739059.aspx, accessed 15 May 2015). 24. Lucas GM et al. Directly administered antiretroviral therapy in methadone clinics is associated with improved HIV treatment outcomes, compared with outcomes among concurrent comparison groups. Clinical Infectious Diseases, 2006, 42:1628–1635. 25. Pyne JM et al. Effectiveness of collaborative care for depression in human immunodeficiency virus clinics. Archives of Internal Medicine, 2011, 171:23–31. 26. Cantrell RA et al. A pilot study of food supplementation to improve adherence to antiretroviral therapy among food-insecure adults in Lusaka, Zambia. Journal of Acquired Immune Deficiency Syndromes, 2008, 49:190–195. 27. Muñoz M et al. Community-based DOT-HAART accompaniment in an urban resource-poor setting. AIDS and Behavior, 2010, 14:721–730. 28. m Health: new horizons for health through mobile technologies, based on the findings of the second global survey on eHealth. Geneva, World Health Organization, 2011 (www.who.int/goe/publications/goe_mhealth_web.pdf, accessed 15 May 2013). 29. Haberer JE et al. Challenges in using mobile phones for collection of antiretroviral therapy adherence data in a resource-limited 1.

13. Библиография setting. AIDS and Behavior, 2010, 14:1294–1301. 30. Sidney K et al. Supporting patient adherence to antiretrovirals using mobile phone reminders: patient responses from South India. AIDS Care, 2012, 24:612–617. 31. Lester RT et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet, 2010, 376:1838–1845. 32. Ikeda JM et al. SMS messaging improves treatment outcome among the HIV-positive Mayan population in rural Guatemala. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract TUPE673; www.iasociety.org/Abstracts/ A200745374.aspx, accessed 15 May 2013). 33. Pop-Eleches C et al. Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AIDS, 2011, 25:825–834. 34. Curioso W et al. Evaluation of a computer-based system using cell phones for HIV-infected people in Peru. PhD dissertation. Seattle, University of Washington, 2012. 35. Ammassari A et al. Timed short messaging service improves adherence and virological outcomes in HIV-1-infected patients with suboptimal adherence to antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 2011, 58:e113–e115. 36. da Costa TM et al. Results of a randomized controlled trial to assess the effects of a mobile SMS-based intervention on treatment adherence in HIV/AIDS-infected Brazilian women and impressions and satisfaction with respect to incoming messages. International Journal of Medical Informatics, 2012, 81:257–269. 37. Mbuagbaw L et al. The Cameroon Mobile Phone SMS (CAMPS) trial: a randomized trial of text messaging versus usual care for adherence to antiretroviral therapy. PLoS One, 2012, 7:e46909. 38. Dowshen N et al. Improving adherence to antiretroviral therapy for youth living with HIV/AIDS: a pilot study using personalized, interactive, daily text message reminders. Journal of Medical Internet Research, 2012, 14:e51. 39. Uzma Q et al. Efficacy of interventions for improving antiretroviral therapy adherence in HIV/AIDS cases at PIMS, Islamabad. Journal of the International Association of Physicians in AIDS Care (Chicago), 2011, 10:373–383. 40. Wamalwa DC et al. Medication diaries do not improve outcomes with highly active antiretroviral therapy in Kenyan children: a randomized clinical trial. Journal of the International AIDS Society, 2009, 12:8. 41. Mugusi F et al. Enhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries; the Tanzanian experience. Tropical Medicine and International Health, 2009, 14:1226–1232. 42. Bisson GP et al. Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy. PLoS Medicine, 2008, 5:e109. 43. Ndubuka NO et al. Adult patients’ adherence to anti-retroviral treatment: a survey correlating pharmacy refill records and pill counts with immunological and virological indices. International Journal of Nursing Studies, 2011, 48:1323–1329. 44. McMahon J et al. Pharmacy adherence measures to assess adherence to antiretroviral therapy: review of the literature and implications for treatment monitoring. Clinical Infectious Diseases, 2011, 52:493–506. 45. Minzi OM, Naazneen AS. Validation of self-report and hospital pill count using unannounced home pill count as methods for determination of adherence to antiretroviral therapy. Tanzania Journal of Health Research, 2008, 10:84–88. 46. Kalichman SC et al. Adherence to antiretroviral therapy assessed by unannounced pill counts conducted by telephone. Journal of General Internal Medicine, 2007, 22:1003–1006. 47. Zolopa A et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One, 2009, 4:e5575. 48. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine, 2011, 365:1471–1481. 49. Fox MP, Rosen S Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007–2009: systematic review. Tropical Medicine and International Health, 2010, 15(Suppl. 1):1–16. 50. Mugglin C et al. Loss to programme between HIV diagnosis and initiation of antiretroviral therapy in sub-Saharan Africa: systematic review and meta-analysis. Tropical Medicine and International Health, 2012, doi: 10.1111/j.1365-3156.2012.03089.x. 51. Brinkhof MW et al. Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis. PLoS One, 2009, 4:e5790. 52. Kranzer K et al. Quantifying and addressing losses along the continuum of care for people living with HIV infection in subSaharan Africa: a systematic review. Journal of the International AIDS Society, 2012, 15:173–183. 53. WHO, UNAIDS and UNICEF. Progress report 2011: global HIV/AIDS response. Epidemic uptake and health sector progress towards universal access. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241502986_eng. pdf). 54. Sprague C et al. Health system weaknesses constrain access to PMTCT and maternal HIV services in South Africa: a qualitative enquiry. AIDS Research and Therapy, 2011, 8:10. 55. Bwirire LD et al. Reasons for loss to follow-up among mothers registered in a prevention-of-mother-to-child transmission program in rural Malawi. Transactions of the Royal Soceity of Tropical Medicine and Hygiene, 2008, 102:1195–1200. 56. Duff P et al. Barriers to accessing highly active antiretroviral therapy by HIV-positive women attending an antenatal clinic in a regional hospital in western Uganda. Journal of the International AIDS Society, 2010, 13:37. 57. Muchedzi A et al. Factors associated with access to HIV care and treatment in a prevention of mother to child transmission programme in urban Zimbabwe. Journal of the International AIDS Society, 2010, 13: 38. 58. Wanyenze RK et al. Evaluation of the efficiency of patient flow at three HIV clinics in Uganda. AIDS Patient Care and STDs, 2010, 24:441–446. 59. Were MC et al. Patterns of care in two HIV continuity clinics in Uganda, Africa: a time-motion study. AIDS Care, 2008, 20:677– 682. 60. Mahomed H, Bachmann MO. Block appointments in an overloaded South African health centre: quantitative and qualitative evaluation. International Journal of Health Care Quality Assurance, 1998, 11:123–126.

303

13. Библиография

304

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 61. Kohler P et al. Free co-trimoxazole prophylaxis substantially improves clinic retention among ART-ineligible clients in Kenya. AIDS, 2011, 25:1657–1661. 62. Nwuba et al. A laboratory-based approach to reduce loss to follow-up of HIV-positive clients. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract WEAE0202; www.iasociety.org/Abstracts/A200745121.aspx, accessed 15 May 2015). 63. I nnovative care for chronic conditions: building blocks for action. Geneva, World Health Organization, 2002 (www.who.int/chp/ knowledge/publications/icccreport/en, accessed 15 May 2013). 64. G uidance on provider-initiated HIV testing and counselling in health facilities. Geneva, World Health Organization, 2007 (http:// whqlibdoc.who.int/publications/2007/9789241595568_eng.pdf, accessed 15 May 2013). 65. Killam WP et al. Antiretroviral therapy in antenatal care to increase treatment initiation in HIV-infected pregnant women: a stepped-wedge evaluation. AIDS, 2010, 24:85–91. 66. Ong’ech JO et al. Provision of services and care for HIV-exposed infants: a comparison of maternal and child health (MCH) clinic and HIV comprehensive care clinic (CCC) models. Journal of Acquired Immune Deficiency Syndromes, 2012, 61:83–89. 67. Turan J et al. Effects of antenatal care–HIV service integration on the prevention of mother-to-child transmission cascade: results from a cluster-randomized controlled trial in Kenya. Integration for Impact: Reproductive Health & HIV Services in sub-Saharan Africa, Nairobi, Kenya, 12–14 September 2012 (http://integrationforimpact.org/abstract-presentationsseptember-1-2012, accessed 15 May 2013). 68. Washington S et al. The impact of integration of HIV care and treatment into antenatal care clinics on mother-to-child HIV transmission and maternal outcomes in Nyanza, Kenya: results from a cluster randomized trial. Integration for Impact: Reproductive Health & HIV Services in sub-Saharan Africa, Nairobi, Kenya, 12–14 September 2012 (http://integrationforimpact.org/ abstract-presentations-september-1-2012, accessed 15 May 2013). 69. Vo BN et al. Patient satisfaction with integrated HIV and antenatal care services in rural Kenya. AIDS Care, 2012, 24:1442–1447. 70. Tsague L et al. Comparing two service delivery models for the prevention of mother-to-child transmission (PMTCT) of HIV during transition from single-dose nevirapine to multi-drug antiretroviral regimens. BMC Public Health, 2010, 10:753. 71. Winestone LE et al. Acceptability and feasibility of integration of HIV care services into antenatal clinics in rural Kenya: a qualitative provider interview study. Global Public Health, 2012, 7:149–163. 72. G lobal tuberculosis report 2012. Geneva, World Health Organization, 2012 (www.who.int/iris/ bitstream/10665/75938/1/9789241564502_eng.pdf, accessed 15 May 2013). 73. Havlir DV et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. New England Journal of Medicine, 2011, 365:1482–1491. 74. Blanc FX et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. New England Journal of Medicine, 2011, 365:1471–1481. 75. Suthar AB et al. Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis. Bulletin of the World Health Organization, 2012, 90:128C–138C. 76. Bento C et al. Assessment of the effectiveness of a home-based care program for patients coinfected with tuberculosis and human immunodeficiency virus after discharge from a reference hospital in South-Eastern Brazil. Brazilian Journal of Infectious Diseases, 2010, 14:594–600. 77. Cerda R et al. Health care utilization and costs of a support program for patients living with the human immunodeficiency virus and tuberculosis in Peru. International Journal of Tuberculosis and Lung Diseases, 2011, 15:363–368. 78. Hermans SM et al. Integration of HIV and TB services results in improved TB treatment outcomes and earlier prioritized ART initiation in a large urban HIV clinic in Uganda. Journal of Acquired Immune Deficiency Syndromes, 2012, 60:e29–e35. 79. Howard A et al. PEPFAR support for the scaling up of collaborative TB/HIV activities. Journal of Acquired Immune Deficiency Syndromes, 2012, 60:S136–S144. 80. Huerga H et al. Impact of introducing human immunodeficiency virus testing, treatment and care in a tuberculosis clinic in rural Kenya. International Journal of Tuberculosis and Lung Diseases, 2010, 14:611–615. 81. Kerschberger B et al. The effect of complete integration of HIV and TB services on time to initiation of antiretroviral therapy: a before-after study. PLoS One, 2012, 7:e46988. 82. Lawn SD et al. Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical services in a South African township. BMC Infectious Diseases, 2011, 11:258. 83. Louwagie G et al. Missed opportunities for accessing HIV care among Tshwane tuberculosis patients under different models of care. International Journal of Tuberculosis and Lung Diseases, 2012, 16:1052–1058. 84. Pevzner E et al. Evaluation of the rapid scale-up of collaborative TB/HIV activities in TB facilities in Rwanda, 2005–2009. BMC Public Health, 2011, 11:550. 85. Phiri S et al. Integrated tuberculosis and HIV care in a resource-limited setting: experience from the Martin Preuss centre, Malawi. Tropical Medicine and International Health, 2011, 16:1397–1403. 86. Bygrave H et al. TB/HIV integration: lessons learned from implementation of a TB/HIV “one stop shop” at primary health care clinics in rural Lesotho. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract MOAB0301; www. iasociety.org/Abstracts/A200740348.aspx, accessed 15 May 2015). 87. Chifundo K et al. What is the best model of TB/HIV service delivery? Experience from Malawi. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract MOPE0858; www.iasociety.org/Abstracts/A200740018.aspx, accessed 15 May 2015). 88. Dube C et al. Step forward to health system strengthening: the impact of scaling up of ART services on TB services in rural settings, Zambia. XVIII International AIDS Conference, Vienna Austria, 18–23 July 2010 (Abstract THAE0104; http://www. iasociety.org/Abstracts/A200737901.aspx, accessed 15 May 2015). 89. Howard AA et al. On-site location of TB services is associated with TB screening of HIV-infected patients at enrollment in HIV care programs in 6 sub-Saharan African countries. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 8–11 February 2009 (Abstract 590; http://retroconference.org/2009/Abstracts/36106.htm, accessed 15 May 2013).

13. Библиография 90. Ikeda J et al. HIV and TB and integration reduce mortality among the indigenous population in rural Guatemala. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract MOPE643; www.iasociety.org/Abstracts/ A200744285.aspx, accessed 15 May 2015). 91. Kaplan R et al. Provision of ART in TB facilities in Cape Town South Africa: impact on TB treatment outcomes. 43rd Union World Conference on Lung Health, Kuala Lumpur, Malaysia, 13–17 November 2012 (Abstract OP-147-16). 92. Morse J et al. Integrated TB/ART clinics in Lusaka, Zambia: an evaluation of enrollment into HIV care and early initiation of antiretroviral therapy in TB/HIV co-infected patients. 43rd Union World Conference on Lung Health, Kuala Lumpur, Malaysia, 13–17 November 2012 (Abstract PC-545-17). 93. Mugo P et al. Integrating TB and HIV care services: experience from a rural district hospital in Kenya. 40th Union World Conference on Lung Health, Cancun, Mexico, 3–7 December 2009 (Abstract PS-94524-07). 94. Muvuma S et al. Poor linkages between TB and HIV services affects the quality of care; a retrospective cohort study of TB/HIV patients from HIV testing to ART initiation in a rural setting in Zambia. XIX International AIDS Conference, Washington, DC, USA, 22–27 July 2012 (Abstract MOPE644; www.iasociety.org/Abstracts/A200744841.aspx, accessed 15 May 2013). 95. Odhiambo J et al. Models of TB-HIV integration and accomplishments in Nyanza Province, Kenya. 43rd Union World Conference on Lung Health, Kuala Lumpur, Malaysia, 13–17 November 2012 (Abstract PC-542-17). 96. Schwartz A et al. Outcomes among HIV+ adults with active pulmonary TB treated in clinics with and without on-site HIV clinics – a retrospective cohort study: Botswana. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 5–8 March 2012 (Abstract 928; http://retroconference.org/2012b/Abstracts/43189.htm, accessed 15 May 2013). 97. 2012 World AIDS Day report: results. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/ epidemiology/2012/gr2012/JC2434_WorldAIDSday_results_en.pdf, accessed 15 May 2013). 98. G uidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva, World Health Organization, 2009 (http://whqlibdoc.who.int/publications/2009/9789241547543_eng.pdf, accessed 15 May 2013). 99. Mathers MB et al. Mortality among people who inject drugs: a systematic review and meta-analysis. Bulletin of the World Health Organization, 2013, 91:102–123. 100. Y an Zhao et al. Methadone maintenance treatment and mortality in HIV-positive people who inject opioids in China. Bulletin of the World Health Organization, 2013, 91:93–101 101. A chmad Y et al. Integration of methadone maintenance treatment and HIV care for injecting drug users: a cohort study in Bandung, Indonesia. Acta Medica Indonesiana, 2009, 41(Suppl. 1):23–27. 102. L ucas G et al. Clinic-based treatment for opioid-dependent HIV-infected patients versus referral to an opioid treatment program: a randomized controlled trial. Annals of Internal Medicine, 2010, 152:704–711. 103. Z aller N et al. A model of integrated primary care for HIV-positive patients with underlying substance use and mental illness. AIDS Care, 2007, 19:1128–1133. 104. F atti G et al. Better antiretroviral therapy outcomes at primary healthcare facilities: an evaluation of three tiers of ART services in four South African provinces. PLoS One, 2010, 5:e12888. 105. B ock P et al. Provision of antiretroviral therapy to children within the public sector of South Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2008, 102:905–911. 106. H umphreys CP et al. Nurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland. BMC Health Services Research, 2010, 10:229. 107. A ssefa Y et al. Effectiveness and acceptability of delivery of antiretroviral treatment in health centres by health officers and nurses in Ethiopia. Journal of Health Services Research and Policy, 2012, 1:24–29. 108. B rennan AT et al. Outcomes of stable HIV-positive patients down-referred from a doctor-managed antiretroviral therapy clinic to a nurse-managed primary health clinic for monitoring and treatment. AIDS, 2011, 25:2027–2036. 109. C han AK et al. Outcome assessment of decentralization of antiretroviral therapy provision in a rural district of Malawi using an integrated primary care model. Tropical Medicine and International Health, 2010, 15(Suppl. 1):90–97. 110. B alcha TT, Jeppsson A. Outcomes of antiretroviral treatment: a comparison between hospitals and health centers in Ethiopia. Journal of the International Association of Physicians in AIDS Care, 2010, 9:318–324. 111. B edelu M et al. Implementing antiretroviral therapy in rural communities: the Lusikisiki model of decentralized HIV/AIDS care. Journal of Infectious Diseases, 2007, 196(Suppl. 3):S464–S468. 112. M assaquoi M et al. Patient retention and attrition on antiretroviral treatment at district level in rural Malawi. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2009, 103:594–600. 113. Jaffar S et al. Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial. Lancet, 2009, 374:2080–2089. 114. K ipp W et al. Results of a community-based antiretroviral treatment program for HIV-1 infection in western Uganda. Current HIV Research, 2010, 8:179–185. 115. S elke HM et al. Task-shifting of antiretroviral delivery from health care workers to persons living with HIV/AIDS: clinical outcomes of a community-based program in Kenya. Journal of Acquired Immune Deficiency Syndromes, 2010, 55:483–490. 116. O perations manual for delivery of HIV prevention, care and treatment at primary health centres in high-prevalence, resourceconstrained settings. Geneva, World Health Organization, 2008 (www.who.int/entity/hiv/pub/imai/om.pdf, accessed 15 May 2013). 117. W HO recommendations for clinical mentoring to support scale-up of HIV care, antiretroviral therapy and prevention in resourceconstrained settings. Geneva, World Health Organization, 2006 (www.who.int/hiv/pub/meetingreports/clinicalmentoring/en/ index.html, accessed 15 May 2013). 118. Task shifting: global recommendations and guidelines. Geneva, World Health Organization, 2008 (www.who.int/healthsystems/ TTR-TaskShifting.pdf, accessed 15 May 2013). 119. Fairall L et al. Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial. Lancet, 2012, 380:889–898.

305

13. Библиография

306

Сводное руководство по использованию антиретровирусных препаратов для лечения и профилактики ВИЧ-инфекции: рекомендации с позиций общественного здоровья 120. S herr KH et al. Quality of HIV care provided by non-physician clinicians and physicians in Mozambique: a retrospective cohort study. AIDS, 2010, 24(Suppl. 1):S59–S66. 121. S anne I et al. Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet, 2010, 376:33–40. 122. W HO expert meeting report on short, medium, longer term product development priorities for HIV-related diagnostics, 6–7 June 2012, Geneva, Switzerland. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/75971/1/9789241504522_eng.pdf, accessed 15 May 2013). 123. W HO model list of essential medicines. 17th ed. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/hq/2011/ a95053_eng.pdf, accessed 15 May 2013). 124. A model quality assurance system for procurement agencies. Geneva, World Health Organization, 2007 (http://apps.who.int/ medicinedocs/documents/s14866e/s14866e.pdf, accessed 15 May 2013). 125. O perational principles for good pharmaceutical procurement. Geneva, World Health Organization, 1999 (http://apps.who.int/ medicinedocs/pdf/whozip49e/whozip49e.pdf, accessed 15 May 2013). 126. H armonized monitoring and evaluation indicators for procurement and supply management systems. Geneva, World Health Organization, 2011 (http://whqlibdoc.who.int/publications/2011/9789241500814_eng.pdf, accessed 15 May 2013). 127. T he price and quality reporting (PQR). Geneva, Global Fund to Fight AIDS, Tuberculosis and Malaria, 2012 (www.theglobalfund. org/en/procurement/pqr, accessed 15 May 2013). 128. I nternational drug price indicator guide. Cambridge, MA, Management Sciences for Health, 2012 (http://erc.msh.org/dmpguide/ index.cfm?search_cat=yes&display=yes&module=dmp&language=english&year=2011, accessed 15 May 2013). 129. U ntangling the web of antiretroviral price reductions. Geneva, Médecins Sans Frontières, 2012 (http://utw.msfaccess.org, accessed 15 May 2013). 130. G lobal Price Reporting Mechanism [online database]. Geneva, World Health Organization, 2012 (http://apps.who.int/hiv/amds/ price/hdd, accessed 15 May 2013). 131. G uidelines for medicine donations. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/ publications/2011/9789241501989_eng.pdf, accessed 15 May 2013). 132. G uide to good storage practices for pharmaceuticals. Geneva, World Health Organization, 2003 (http://apps.who.int/ medicinedocs/documents/s18675en/s18675en.pdf, accessed 15 May 2013).

Глава 10 1. HO Consultation: the Strategic Use of Antiretrovirals for Treatment and Prevention of HIV Infection: 2nd Expert Panel Meeting, W 2–4 May 2012, Geneva, Switzerland. Meeting report. Geneva, World Health Organization, 2012 (http://apps.who.int/iris/ bitstream/10665/77946/1/WHO_HIV_2013.1_eng.pdf, accessed 15 May 2013). 2. A framework for national health policies, strategies and plans. Geneva, World Health Organization, 2010 (www.who.int/hiv/ topics/ppm/framework_nhpsp.pdf, accessed 15 May 2013). 3. G lobal health sector strategy on HIV/AIDS 2011–2015. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/hiv_ strategy, accessed 15 May 2013). 4. A dapting WHO normative HIV guidelines for national programmes. Geneva, World Health Organization, 2010 (www.who.int/hiv/ pub/who_normative, accessed 15 May 2013). 5. P lanning guide for the health sector response to HIV/AIDS. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/ guidelines/9789241502535/en/index.html, accessed 15 May 2013). 6. P ractical guidelines for intensifying HIV prevention: towards universal access. Geneva, UNAIDS, 2007 (www.unaids.org/en/ resources/presscentre/featurestories/2007/march/20070306preventionguidelines, accessed 15 May 2013). 7. Schwartländer B et al. Towards an improved investment approach for an effective response to HIV/AIDS. Lancet, 2011, 377:2031–2041. 8. Incidence by modes of transmission [web site]. Geneva, UNAIDS, 2013 (www.unaids.org/en/dataanalysis/datatools/ incidencebymodesoftransmission, accessed 15 May 2013). 9. WHO and UNAIDS. Guidelines on estimating the size of populations most at risk to HIV. Geneva, World Health Organization, 2010 (http://data.unaids.org/pub/Manual/2010/guidelines_popnestimationsize_en.pdf, accessed 15 May 2013). 10. Daniels N. Fair process in patient selection for antiretroviral treatment in WHO’s goal of 3 by 5. Lancet, 2005, 366:169–171. 11. G uidance on ethics and equitable access to HIV treatment and care. Geneva, World Health Organization, 2004 (http://www.who.int/ethics/en/ethics_equity_HIV_e.pdf, accessed 15 May 2013). 12. WHO, UNAIDS and UNICEF. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2011. Geneva, World Health Organization, 2011 (www.who.int/hiv/topics/universalaccess/en, accessed 15 May 2013). 13. WHO, UNODC and UNAIDS. WHO/UNODC/UNAIDS technical guide for countries to set targets for universal access to HIV prevention, treatment and care for injecting drug users. Geneva, World Health Organization, 2009 (www.who.int/hiv/pub/idu/ targets_universal_access/en/index.html, accessed 15 May 2013). 14. United Nations General Assembly. Declaration of Commitment on HIV/AIDS. New York, United Nations, 2001 (www.unaids.org/ en/media/unaids/contentassets/dataimport/publications/irc-pub03/aidsdeclaration_en.pdf, accessed 15 May 2013). 15. United Nations General Assembly. Political Declaration on HIV/AIDS – United Nations General Assembly Resolution 60/262. New York, United Nations, 2006. 16. I nternational Covenant on Economic, Social and Cultural Rights. New York, United Nations, 1966 (www.ohchr.org/EN/ ProfessionalInterest/Pages/CESCR.aspx, accessed 15 May 2013). 17. M onitoring and evaluation toolkit: HIV, tuberculosis, malaria and health and community systems strengthening. 4th ed. Geneva, Global Fund to Fight AIDS, Tuberculosis and Malaria, 2011 (www.theglobalfund.org/en/me/documents/toolkit, accessed 15 May 2013).

13. Библиография 18. K ey programmes to reduce stigma and discrimination and increase access to justice in national HIV responses. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/document/2012/Key_Human_Rights_Programmes_en_ May2012.pdf, accessed 15 May 2013). 19. Eaton JW et al. How should HIV programmes respond to evidence for the benefits of earlier treatment initiation? A combined analysis of 12 mathematical models (http://www.hivmodelling.org). 20. G uidelines for HIV/AIDS interventions in emergency settings. New York, United Nations, 2003 (http://data.unaids.org/ Publications/External-Documents/iasc_guidelines-emergency-settings_en.pdf, accessed 15 May 2013). 21. Everybody’s business: strengthening health systems to improve health outcomes – WHO’s framework for action. Geneva, World Health Organization, 2007 (www.who.int/healthsystems/strategy/everybodys_business.pdf, accessed 15 May 2013). 22. H andbook for improving HIV testing and counselling services. Field-test version. Geneva, World Health Organization, 2010 (www. who.int/hiv/pub/vct/9789241500463/en/index.html, accessed 15 May 2013). 23. Global Price Reporting Mechanism [online database]. Geneva, World Health Organization, 2013 (http://apps.who.int/hiv/amds/ price/hdd, accessed 15 May 2013). 24. Futures Institute [web site]. Glastonbury, CT, Futures Institute, 2013 (www.futuresinstitute.org/onehealth.aspx). 25. PSM Toolbox [web site]. Geneva, PSM Toolbox, 2013 (www.psmtoolbox.org, accessed 15 May 2013). 26. Toolkit – expanding and simplifying treatment for pregnant women living with HIV: managing the transition to option B/B+. New York, Interagency Task Team on the Prevention and treatment of HIV Infection in Pregnant Women, Mothers and Children, 2013 (www.emtct-iatt.org/toolkit, accessed 15 May 2013). 27. T he human rights costing tool (HRCT): a tool to cost programs to reduce stigma and discrimination and increase access to justice. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/data-and-analysis/tools/The_Human_ Rights_Costing_Tool_v_1_5_May-2012.xlsm, accessed 15 May 2013). 28. T he user guide for the human rights costing tool: costing programmes to reduce stigma and discrimination and increase access to justice in the context of HIV. Geneva, UNAIDS, 2012 (www.unaids.org/en/media/unaids/contentassets/documents/document/2012/ The_HRCT_User_Guide_FINAL_ 2012-07-09.pdf, accessed 17 June 2013).

307

13. Библиография

Глава 11 1. WHO, UNAIDS, UNICEF and Global Fund to Fight AIDS, Tuberculosis and Malaria. Three interlinked patient monitoring systems for HIV care/ART, MCH/PMTCT (including malaria prevention and pregnancy), and TB/HIV: standardized minimum data set and illustrative tools. Geneva, World Health Organization, 2013 (www.who.int/hiv/pub/me/patient_monitoring_systems/en/index. html, accessed 15 May 2013). 2. The process of the Global AIDS Response Progress Reporting process now includes indicators from the Universal Access reporting process: UNAIDS, UNICEF and WHO. Global AIDS Response Progress Reporting: construction of core indicators for monitoring the 2011 UN Political Declaration on HIV/AIDS. Includes additional WHO/UNICEF universal access health sector indicators. Geneva, UNAIDS, 2013 (www.unaids.org/en/media/unaids/contentassets/documents/document/2013/GARPR_2013_ guidelines_en.pdf, accessed 17 June 2013). 3. UNAIDS/WHO working group on global HIV/AIDS and STI surveillance. When and how to use assays for recent infection to estimate HIV incidence at a population level. Geneva, World Health Organization, 2011 (www.who.int/hiv/pub/surveillance/ sti_surveillance/en, accessed 15 May 2013). 4. M easuring the impact of national PMTCT programmes: towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva, World Health Organization, 2012 (www.who.int/hiv/pub/mtct/national_pmtct_guide/en/ index.html, accessed 15 May 2013). 5. 12 components monitoring and evaluation system strengthening tool. Geneva, UNAIDS, 2010 (www.unaids.org/en/media/unaids/ contentassets/documents/document/2010/2_MERG_Strengthening_Tool_12_Components_ME_System.pdf, accessed 17 June 2013).

Для получения дополнительной информации обратитесь: Всемирная организация здравоохранения отдел по ВИЧ/СПИД 20, avenue Appia 1211 Женева 27 Швейцария эл. почта: hiv-aids@who.int www.who.int/hiv

ISBN 978 92 4 450572 4

指南

使用抗逆转录病毒药物治疗和预防艾滋病毒感染的综合指南针对公共卫生措施的建议

2013年6月

使用抗逆转录病毒药物治疗和预防艾滋病毒感染的综合指南针对公共卫生措施的建议

2013年6月

WHO Library Cataloguing-in-Publication Data 使用抗病毒药物治疗和预防艾滋病毒感染的综合指南:针对公共卫生措施的建议 2013年６月 1.HIV infections – drug therapy. 2.HIV infections – prevention and control. 3.Anti-Retroviral agents – therapeutic use. 4.Guideline. I.World Health Organization. ISBN 978 92 4 550572 3 © 世界卫生组织， 2014年版权所有。世界卫生组织出版物可从世卫组织网站（www.who.int）获得，或者自WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland （电话： +41 22 791 3264；传真： +41 22 791 4857；电子邮件： bookorders@who.int）购买。要获得复制许可或翻译世界卫生组织出版物的许可 – 无论是为了出售或非商业性分发，应通过世卫组织网站http://www.who.int/about/licensing/copyright_form/en/index.html）向世界卫生组织出版处提出申请。本出版物采用的名称和陈述的材料并不代表世界卫生组织对任何国家、领地、城市或地区或其当局的合法地位，或关于边界或分界线的规定有任何意见。地图上的虚线表示可能尚未完全达成一致的大致边界线。凡提及某些公司或某些制造商的产品时，并不意味着它们已为世界卫生组织所认可或推荐，或比其它未提及的同类公司或产品更好。除差错和疏忽外，凡专利产品名称均冠以大写字母，以示区别。世界卫生组织已采取一切合理的预防措施来核实本出版物中包含的信息。但是，已出版材料的分发无任何明确或含蓄的保证。解释和使用材料的责任取决于读者。世界卫生组织对于因使用这些材料造成的损失不承担责任。 (NLM classification: WC 503.2)

设计编排： ACW, 伦敦

目录缩略语与简称主要术语定义致谢前言执行概要新建议摘要第一章引言 1.1 1.2 1.3 1.4 1.5 背景和环境综合指南的理论依据目标目标人群范围及内容 1.5.1 1.5.2 1.5.3 1.5.4 1.5.5 概述章节临床指南实施和服务提供指南规划管理者指南监控与评估 11 13 16 23 24 26 35 36 36 37 37 38 38 38 38 39 39 41 42 42 42 42 43 43 45 46 46 47 47 47

第二章指导原则 2.1 2.2 2.3 2.4 2.5 2.6 对全球卫生目标的贡献公共卫生措施通过学习和创新加强卫生系统提高规划的效率和效果促进人权和卫生公平因地制宜

第三章指南的编制方法和过程 3.1 3.2 3.3 概述资料来源外部参与 3.3.1 指南制定小组和同行评议过程

3.3.2 利益冲突

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

3.4 3.5 3.6

建议的制定过程其他方法发布

48 50 50 51 52 54 54 54 55 56 58 59 61 62 62 63 64 65 74 74 74 75 75 77 78 78 78 81 82 83 84

第四章指南的结构 4 4.1 4.2 4.3 关怀体系新建议的介绍结构选自现有指南的建议的介绍结构如何将指南应用于特定人群 4.3.1 孕妇和哺乳期妇女

4.3.2 青少年 4.3.3 儿童 4.3.4 重点人群

第五章贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防应用 5.1 HIV检测与咨询 5.1.1 5.1.2 5.1.3 5.1.4 5.2 前言医疗机构开展的HIV检测与咨询社区开展的的HIV检测与咨询特定人群HIV检测与咨询

应用抗病毒药物预防HIV 5.2.1 使用口服药物进行暴露前预防

5.2.2 单阳配偶抗病毒治疗预防HIV传播 5.2.3 职业暴露和非职业暴露的暴露后预防 5.2.4 HIV综合性预防第六章贯穿关怀体系的临床指南：将确诊HIV感染者转介至关怀与治疗服务 6.1 6.2 6.3 6.4 6.5 前言衔接关怀服务的最佳实践措施 HIV感染者的综合关怀服务 HIV感染者的抗病毒治疗准备抗病毒治疗最初几个月的预期效果

第七章贯穿关怀体系的临床指南：抗病毒治疗 7.1 何时启动抗病毒治疗

7.1.1 7.1.2 7.1.3 7.1.4 7.2

成人及青少年的抗病毒治疗何时启动孕妇及哺乳妇女的抗病毒治疗何时启动抗病毒药物与哺乳期

85 92 95 98 102 103 105 110

儿童的抗病毒治疗何时启动

抗病毒治疗起始方案（一线抗病毒治疗） 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 成人的一线抗病毒治疗

怀孕及哺乳妇女的一线抗病毒治疗及其婴儿的抗病毒药物不满3岁儿童的一线抗病毒治疗

岁及以上儿童及青少年的一线抗病毒治疗 HIV与结核合并感染儿童的治疗

114 118 119 119 120 124 124 125 127 128 129 129 132

7.3

抗病毒治疗效果监测及治疗失败判断 7.3.1 7.3.2 启动抗病毒治疗前后进行实验室监测抗病毒治疗效果监测及治疗失败判断

7.4

抗病毒药物毒性监测与药物更换 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5 7.4.6

指导原则抗病毒药物毒性的主要类型替诺福韦（TDF）毒性监测其他抗病毒药物的毒性监测因抗病毒药物毒性更换药物主要抗病毒药物的交互作用

7.5

更换至何种（二线）抗病毒治疗方案 7.5.1 7.5.2 成人与青少年的二线抗病毒治疗儿童及青少年的二线抗病毒治疗

132 136 138 141 142 142 143 150 151 152 153 154

7.6

三线抗病毒治疗

第八章贯穿关怀体系的临床指南：常见合并感染和合并症的管理 8.1 常见合并感染的预防，筛查和管理 8.1.1 8.1.2 8.1.3 8.1.4 8.1.5 8.1.6 8.1.7 复方新诺明预防性治疗结核病隐球菌感染乙型和丙型肝炎疟疾性传播感染和宫颈癌艾滋病毒感染者的疫苗接种

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

8.2

HIV感染者的其他合并症和慢性疾患的预防和管理 8.2.1 非传染性疾病的筛查和护理

154 154 155 155 156 157 157 159 160 160 160 162 164 165 165 165 167 167 168 171 172 172 173 174 174 174 174 175 175 175 176 176 177

8.2.2 心理健康 8.2.3 吸毒及相关疾患 8.2.4 营养关怀和支持 8.2.5 姑息治疗：症状处理和临终关怀 8.2.6 艾滋病关怀的其他相关指南第九章实施和服务提供指南 9.1 9.2

引言抗病毒治疗的依从性 9.2.1 依从性的防碍因素

9.2.2 通过干预提高抗病毒治疗的依从性 9.2.3 通过日常规划和关怀机构监测抗病毒治疗的依从性 9.3 使患者保留在关怀体系中 9.3.1 背景

9.3.2 使患者保留在关怀体系的良好实践 9.4 提供服务 9.4.1 9.4.2 9.4.3 9.5 提供长期关怀服务的良好实践服务整合与衔接艾滋病治疗和关怀服务下沉

人力资源 9.5.1 9.5.2 人力资源能力建设艾滋病毒治疗和关怀的职责调整

9.6

实验室和诊断服务 9.6.1 9.6.2 9.6.3 9.6.4 9.6.5 9.6.6 9.6.7 9.6.8 概述实施考量和良好实践加强和扩大实验室和诊断服务支持专用的标本转移系统提高获得HIV病毒载量检测的机会将诊断服务扩展至关怀服务点为发展卫生工作者的能力,包括员工培训和认证提供的指南实施全面的质量管理系统

9.7

采购和供应管理系统

9.7.1 9.7.2 9.7.3

概述理论和证据支持实施考量和良好实践

177 177 177 181 182 182 183 183 183 183 183 186 186 186 187 187 190 195 195 195 196 197 198 198 200 202 202 202 202 203 205 206

第十章规划管理者指南 10.1 10.2 10.3 引言决策过程支持决策的数据 10.3.1 概述 10.3.2 国家和地方艾滋病流行病学分析 10.3.3 规划运行情况和应对分析 10.3.4 社会经济、政策和法律环境 10.4 决策的重要参数 10.4.1 伦理、公平和人权 10.4.2 影响和成本效益 10.4.3 机会和风险 10.5 10.6 10.7 卫生系统实施新建议的考虑因素主要建议的实施考量不同地区的实施建议 10.7.1 概述 10.7.2 不同的流行地区的实施建议 10.8 用于成本估算和计划制定的实用工具

第十一章监控与评估 11.1 11.2 11.3 11.4 引言新建议对监控工作的暗示监控提高抗病毒药物可及性的结果与产出其他监控考量 11.4.1 HIV耐药 11.4.2 抗病毒药物毒性的哨点监控 11.4.3 规划运行情况及影响评估和实施性研究 11.5 审视和加强监控评估体系

第十二章附录附录1. 世卫组织针对成人、青少年及儿童的HIV感染临床分期体系

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

附录2. 2013年成人及青少年抗病毒治疗流程建议附录3. 2013年孕妇及哺乳期妇女抗病毒治疗流程建议附录4. 2013年儿童抗病毒治疗流程建议附录5. 婴儿早期诊断流程

208 210 212 213 214 218 227

附录6. 准备情况检查评估表：努力为所有孕期和哺乳期妇女提供抗病毒治疗附录7 推荐的抗病毒药物的剂量

第十三章参考文献

缩略语与简称

缩略语与简称 3TC ABC AIDS ART ARV ATV ATV/r AZT BMI CD4 CDC CNS d4T DALYs DBS ddI DNA DRV DRV/r EFV eGFR ELISA ETV FPV FPV/r FTC GNP+ 拉米夫定阿巴卡韦获得性免疫缺陷综合征，艾滋病抗逆转录病毒治疗（在本指南中简称 “抗病毒治疗” ）抗逆转录病毒（药物）（在本指南中简称 “抗病毒药物” ）阿扎那韦阿扎那韦/利托那韦合剂齐多夫定（也称为ZDV）体重指数 CD4+T淋巴细胞（美国）疾病预防控制中心中枢神经系统司他夫定死亡及伤残调整寿命年干血斑去羟肌苷脱氧核糖核酸达芦那韦达芦那韦/利托那韦合剂依非韦仑估计肾小球滤过率酶联免疫吸附试验依曲韦林夫沙那韦夫沙那韦/利托那韦合剂恩曲他滨全球艾滋病毒携带者网络

GRADE 推荐分级的评价、制定及评估 HBsAg 乙型肝炎病毒表面抗原 HBV HCV HIV 乙肝病毒丙肝病毒人类免疫缺陷病毒

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

HPTN HSV INH IPT IRIS LPV LPV/r MDR MTCT NFV NNRTI NRTI NVP OST PCR PI PICO

HIV预防试验网络单纯疱疹病毒异烟肼异烟肼预防性治疗免疫重建炎性综合征洛匹那韦洛匹那韦/利托那韦合剂耐多药结核，至少对异烟肼和利福平耐药艾滋病毒母婴传播奈非那韦非核苷类逆转录酶抑制剂核苷类逆转录酶抑制剂奈韦拉平阿片类药物替代疗法聚合酶链式反应蛋白酶抑制剂人群、干预、对照及结局

PCP/PJP 耶氏肺孢子菌肺炎 PMTCT 预防母婴传播 PrEP RAL RBV RIF RNA RTV 暴露前预防拉替拉韦利巴韦林利福平核糖核酸利托那韦

sd-NVP 单剂量奈韦拉平 TAM TB TDF TPV 胸（腺嘧啶脱氧核）苷类似物突变结核病替诺福韦替拉那韦

UNAIDS 联合国艾滋病规划署 UNICEF 联合国儿童基金会 UNODC 联合国毒品和犯罪问题办公室 WHO 世卫组织

主要术语定义

主要术语定义通用术语艾滋病毒（HIV）：人类免疫缺陷病毒，包含HIV-1和HIV-2两种类型。 HIV-1是引起全世界绝大多数HIV感染的病毒类型。在本指南中，除特别注明， HIV 均指 HIV-1和HIV-2两种类型病毒。

年龄组和人群使用以下对成人、青少年、儿童和婴儿的定义以保证本综合指南和世卫组织其他指南相关定义相互一致。其他机构所使用的相关定义可能有所不同。成人指年龄19岁以上，除非国家法律规定以其他较小年龄作为成人标准。青少年指年龄为10岁至19岁之间。儿童指年龄19岁及以下，除非国家法律规定以其他较小年龄作为成人标准。但是，本指南中年龄10岁～19岁之间归类为青少年（见 “青少年” 定义）。婴儿指不满1岁的儿童。本指南中定义的 “重点人群” 包括脆弱人群和高危人群。这些人群对于特定环境中HIV的传播变化至关重要，同时也是有效应对流行的关键合作伙伴。在各种流行水平下， HIV感染者均为重点人群。本指南中定义的 “高危人群” 指男男性接触人群、注射吸毒人群以及性工作者。高危人群几乎在所有HIV流行水平情况下都会受到不同程度的影响。脆弱人群指在特定环境或情况下特别容易感染HIV的人群，如青少年（特别是青少年女性）、孤儿、街头流浪儿、位于封闭环境（如监狱或羁押场所）中的人员、残疾人以及流动人口。每个国家都应根据本国的HIV流行特征和社会因素状况，确定影响艾滋病流行和应对的脆弱人群和重点人群。单阳配偶指一方为HIV感染者而另一方HIV阴性的配偶。配偶指保持性关系的两个人；这种关系中的每个人均为对方性伴。而配偶个体如何定义他们之间的关系在不同的文化和社会背景下差别较大。

卫生保健服务艾滋病关怀体系指对HIV感染者及其家庭提供的综合服务包，包括预防、诊断、治疗和支持服务，具体服务内容包括：首次HIV诊断及治疗转介；机会性感染和其他并发症诊治；启动、维持并监测抗病毒治疗；必要时转二线和三线抗病毒治疗；临终关怀。公共卫生措施指针对人群而非个体的健康需求或解决该人群公共健康问题的措施。一项公共卫生措施包含卫生系统各部门之间的共同努力，通过包含预防、治疗、保健服务和支持措施等在内的综合措施来保证公众健康。对于HIV，公共卫生措施包括：简化的抗病毒治疗方案；成人和儿童的一线抗病毒治疗方案广泛应用固定剂量复合制剂（FDC）；免费提供关怀服务并使服务下沉；工作职责转变和简化临床及毒性监测在内的整合服务。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

HIV检测与预防自愿咨询检测（也称为以患者为中心的检测和咨询）指有了解自己HIV感染状况意愿的个体主动寻求的检测与咨询服务。目前有多种社区途径提供HIV检测与咨询服务，并且人们寻求检测的动机常常是混合性的（包括由医务人员建议和个人主动），因此世卫组织提出使用 “HIV检测和咨询” 这个术语。所有形式的HIV检测咨询必须是自愿的并坚持 “五个C” 原则，即同意、保密、咨询、检测结果提供和确定以及转介至关怀、治疗和预防服务体系中。保证检测和咨询质量对各种 HIV检测咨询策略至关重要。医务人员主动提供的检测咨询是由临床机构卫生保健人员主动提供的HIV检测与咨询服务。和所有形式的HIV检测咨询一样，医务人员主动提供的检测咨询必须是自愿的并坚持五个C 原则。综合性预防指通过行为学、生物医学和结构性HIV预防措施的相互结合，以取得最大化减少 HIV传播的效应。

ART （抗病毒治疗）抗病毒药物指药物本身而非其应用。 ART指联合应用三种或三种以上抗病毒药物以实现抑制病毒的效果。通常指终身治疗。联合抗病毒治疗和高效抗病毒治疗为同义词。预防性抗病毒治疗（ART）指通过抗病毒治疗实现预防HIV传播的效果。抗病毒治疗入选标准（Eligible for ART）指根据世卫组织治疗指南中临床和免疫学入选标准，如HIV感染者符合此标准则开始抗病毒治疗。该名词经常用 “需要治疗” 来替代。这也意即艾滋病即刻危险性或者必须启动治疗。病毒抑制是即指抗病毒治疗的目的是保持病毒载量始终处于低于目前试验检测方法可检测到的水平，通常低于50拷贝/毫升。目前世卫组织关于治疗失败的病毒载量标准是大于等于1000 拷贝/毫升。艾滋病抗病毒治疗（ART）普遍可及定义：致力于实现最有效干预措施大面积覆盖的策略方向（覆盖80%以上的需要治疗的人群），同时满足公平、可及、可负担、综合以及长期可持续的原则；但这并不意味着必须实现100%覆盖。

卫生工作人员社区卫生工作人员指接受过除护理、产科或医学课程之外的全国性认同的标准化培训的卫生工作人员。助产士指接受过助产培训的人员，包括注册助产士和登记助产士。非医师类临床医生是指具备一名医生各项诊断和临床能力的专业卫生工作者，但并不作为医生进行培训。这种类型卫生工作者通常担任卫生官员、临床官员、医师助理、执业护理师或临床护理工作者。护士包括专业护士、登记护士、辅助护士和其他类型的护士，如牙科或初级卫生保健护士。

主要术语定义

流行病学 HIV集中流行（即HIV中度流行）： HIV在一种或多种亚人群中迅速蔓延，但没有在大众人群中流行。数值指标： HIV感染率在至少一种特定亚人群中持续高于5%，但在城市地区孕妇人群中未超过1%。 HIV普遍流行（即HIV高度流行）： HIV在大众人群中持续流行。数值指标：孕妇人群中HIV 感染率持续超过1%。大多数HIV普遍性流行地区其流行方式往往是复合型的，其特定（重点）亚人群也受到严重影响。复合流行： HIV逐渐波及一种或多种特定亚人群乃至普通人群。因此合并感染是指普遍性流行同时并存一种或多种特定亚人群的集中性流行。低水平流行：全国大众人群的HIV感染率没有持续超过1%，或者任何一种亚人群中HIV感染率没有超过5%。抗病毒治疗低、中、高覆盖面/地区分别指需要抗病毒治疗人群中已经接受抗病毒治疗的人群比率不足50%、达到50%～80%和高于80%的地区。结核病和艾滋病高负担地区指成人HIV感染率≥1%或者结核病人群中HIV感染率≥5%的地区。新发HIV感染是指特定时期特定人群中新获得HIV感染的人数。 HIV患病率指特定时间点HIV感染者的数量，常用人群比例来描述。

主要术语定义

预防艾滋病母婴传播（PMTCT）本指南中，世卫组织逐渐舍弃了以前的 “方案A、 B和B+” 说法，而是推荐了两种方案： (1)感染HIV的孕妇和哺乳妇女提供终身抗病毒治疗，不论其CD4+T淋巴细胞计数或临床分期如何；或者(2)母婴传播危险时期对感染HIV的孕妇和哺乳妇女提供抗病毒治疗（抗病毒药物），进而向符合治疗入选标准的妇女提供终身抗病毒治疗以保证其健康。尚未为所有感染HIV的孕妇和哺乳妇女终身抗病毒治疗的地区，则区分预防（在特定母婴传播危险期提供抗病毒药物以预防母婴传播）和治疗（以母亲的健康为目的，根据当前成人治疗入选标准而提供抗病毒治疗，以及以预防垂直传播为目的）也非常重要。感染HIV孕妇和哺乳妇女的抗病毒药物指孕期和整个哺乳期（当采用母乳喂养时）以预防为主要目的提供给感染HIV的孕妇和哺乳妇女的三联抗病毒药物。此方案即分娩完成或者哺乳结束后，仅感染HIV的母亲CD4+T淋巴细胞计数或临床分期符合抗病毒治疗标准时，则实施终身治疗，保证健康，即世卫组织前指南中的方案B。所有感染HIV的孕妇和哺乳妇女终身抗病毒治疗是指不管CD4+T淋巴细胞计数或临床分期如何，所有感染HIV的孕妇均接受三联药物抗病毒治疗，以同时达到保证其自身健康及预防垂直传播的目的，同时还获得HIV预防所带来的其他好处。世卫组织前指南中将此方案称为方案B+。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

致谢 Anthony Harries (International Union against Tuberculosis and Lung Disease, United Kingdom) 及 Gottfried Hirnschall (Department of HIV, World Health Organization) 共同主持了本指南编写过程。

成人指南制定小组两名组长: Serge Eholie (ANEPA/Treichville Hospital, Abidjan, Côte d’ Ivoire) 及 Stefano Vella (Istituto Superiore di Sanità, Italy)。 GRADE 方法学专家: Elie Akl (American University of Beirut, Lebanon)。 Pedro Cahn (Fundación Huesped, Argentina), Alexandra Calmy (University of Geneva, Switzerland), Frank Chimbwandira (Ministry of Health, Malawi), David Cooper (University of New South Wales and St Vincent’ s Hospital, Australia), Judith Currier (UCLA Clinical AIDS Research & Education Center, USA), François Dabis (School of Public Health (ISPED), University Bordeaux Segalen, France), Charles Flexner (Johns Hopkins University, USA), Beatriz Grinsztejn (Fundação Oswaldo Cruz (FIOCRUZ), Brazil), Diane Havlir (University of California at San Francisco, USA), Charles Holmes (Centre for Infectious Disease Research in Zambia, Zambia), John Idoko (National Agency for the Control of AIDS, Nigeria), Kebba Jobarteh (Centers for Disease Control and Prevention, Mozambique), Nagalingeswaran Kumarasamy (Y.R. Gaitonde Centre for AIDS Research and Education, India), Volodymyr Kurpita (All-Ukrainian Network of People Living with HIV, Ukraine), Karine Lacombe (Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), France), Albert Mwango (Ministry of Health, Zambia), Leonardo Palombi (DREAM Program, Community of Sant’ Egidio, Rome, Italy), Anton Pozniak (Chelsea and Westminster Hospital, United Kingdom), Luis Adrián Quiroz (Derechohabientes Viviendo con VIH del IMSS (DVIMSS), Mexico), Kiat Ruxrungtham (Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thailand), Michael Saag (University of Alabama at Birmingham, USA), Gisela Schneider (German Institute for Medical Mission, Germany), Yanri Subronto (Universitas Gadjah Mada, Indonesia) 及 Francois Venter (University of the Witwatersrand, South Africa)。

妇幼保健指南制定小组两名组长: Elaine Abrams (International Center for AIDS Care and Treatment Programs (ICAP), Columbia University, USA) 及 Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Uganda)。 GRADE方法学专家: Joerg Meerpohl (German Cochrane Centre, University Medical Center, Freiburg, Germany)。 Renaud Becquet (Internationale Institut de Santé Publique d’ Epidémiologie et de Développement, Université Bordeaux Segalen, France), Deborah Birx (United

致谢

States Centers for Disease Control and Prevention, USA), Benjamin Chi (Centre for Infectious Disease Research in Zambia, Zambia), Mark Cotton (Stellenbosch University, South Africa), Nonhlanhla Dlamini (National Department of Health, South Africa), René Ekpini (United Nations Children’ s Fund, USA), Carlo Giaquinto (Paedatric Infectious Disease Unit and Clinical Trials Unit of Azienda Ospedaliera di Padua, Italy), Diana Gibb (Medical Research Council Clinical Trials Unit, United Kingdom), Sabrina Bakeera-Kitaka (Makerere University and Mulago National Referral Hospital, Uganda), Louise Kuhn (Columbia University, USA), Evgenia Maron (Charitable Women’ s Foundation Astra, Russian Federation), Babalwa Mbono (mothers2mothers, South Africa), James McIntyre (University of Cape Town, South Africa), Lynne Mofenson (National Institutes of Health, USA), Angela Mushavi (Ministry of Health and Child Welfare, Zimbabwe), Ryan Phelps (United States Agency for International Development, USA), Jorge Pinto (Federal University of Minas Gerais, Brazil), Andrew Prendergast (Queen Mary University of London, United Kingdom), Thanyawee Puthanakit (Chulalongkorn University, Thailand), Atiene Sagay (Unversity of Jos, Nigeria), Roger Shapiro (Harvard School of Public Health, USA), George Siberry (National Institutes of Health, USA), Landry Tsague (United Nations Children’ s Fund, Zambia), Thorkild Tylleskar (University of Bergen, Norway), Paula Vaz (Fundação Ariel Glaser contra o SIDA Pediátrico, Mozambique), Evgeny Voronin (Russian AIDS Pediatric Center, Russian Federation) 及 Linhong Wang (Chinese Center for Disease Control and Prevention, China)。

致谢

实施和服务提供指南制定小组两名组长: Kevin De Cock (United States Centers for Disease Control and Prevention, USA) 及 Yogan Pillay (National Department of Health, South Africa)。 GRADE方法学专家: Holger Schünemann (Faculty of Health Sciences, McMaster University, Canada)。 Tsitsi Mutasa Apollo (Ministry of Health and Child Welfare, Zimbabwe), Yibletal Assefa (Ministry of Health, Ethiopia), Paula Braitstein (Indiana University School of Medicine, USA), Zengani Chirwa (Ministry of Health, Malawi), Bui Duc Duong (Ministry of Health, Viet Nam), Ade Fakoya (Global Fund to Fight AIDS, Tuberculosis and Malaria, Switzerland), Robert Ferris (United States Agency for International Development, USA), Ronaldo Hallal (Departamento de DST, Aids e Hepatites Virais, Brazil), Eihab Ali Hassan (Federal Ministry of Health, Sudan), David Hoos (International Centre for AIDS Care and Treatment Programs, Columbia University, USA), Barbara Milani (Médecins Sans Frontières (MSF), Switzerland), Christine Nabiryo (The AIDS Support Organization (TASO), Uganda), Natalia Nizova (Ministry of Health, Ukraine), Anupam Pathni (International Planned Parenthood Federation South Asia, India), Elliot Raizes (United States Centers for Disease Control and Prevention, USA), Kenly Sekwese (Treatment Advocacy Literacy Campaign, Zambia), Larissa Stabinski (Office of the United States Global AIDS Coordinator, USA), Miriam Taegtmeyer (Liverpool School of Tropical Medicine, United Kingdom), Wim Van Damme (Institute of Tropical Medicine, Belgium), Eric van Praag (Family Health International (FHI), United Republic of Tanzania), Mean Chhi Vun (Ministry of Health, Cambodia), Larry Westerman (United States Centers for Disease Control

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

and Prevention, USA), Steve Wignall (Clinton Health Access Initiative (CHAI), Indonesia) 及 Anna Zakowicz (Global Network of People Living with HIV (GNP+), Europe)。

规划指南制定小组两名组长: Tsitsi Apollo (Ministry of Health and Child Welfare, Zimbabwe) 及 Adeeba Kamarulzaman (University of Malaya, Malaysia)。 Ihab Abdelrahman (Ministry of Health and Population, Egypt), John AberleGrasse (United States Centers for Disease Control and Prevention, USA), Yibeltal Assefa (Ministry of Health, Ethiopia), Rob Baltussen (Radboud University Nijmegen, Netherlands), Anton Best (Ministry of Health, Barbados), John Blandford (United States Centers for Disease Control and Prevention, USA), Sergiy Filippovych (International HIV/AIDS Alliance in Ukraine, Ukraine), Eric Goemaere (Médecins Sans Frontières (MSF), South Africa), Dirceu Greco (Ministry of Health, Brazil), Timothy Hallett (Imperial College London, United Kingdom), Priscilla Idele (United Nations Children’ s Fund, USA), Ushma Mehta (Independent Consultant, South Africa), Irene Mukui (National AIDS & STI Control Programme, Kenya), Jean Paul Moatti (French National Institute of Health and Medical Research (INSERM), Université de la Méditerranée, France), Natalia Nizova (Ministry of Health, Ukraine), Ole Frithjof Norheim (University of Bergen, Norway), Asia Russell (Health GAP, USA), Kenly Sikwese (Positive Health Outcomes, Zambia), Jerome Singh (Centre for the AIDS Programme of Research in South Africa, South Africa), Petchsri Sirinirund (Ministry of Public Health, Thailand), John Stover (Futures Institute, USA), Aliou Sylla (Ministry of Health, Mali), Wim Van Damme (Institute of Tropical Medicine, Belgium), Stefan Weinmann (Deutsche Gessellschaft für Internationale Zusammenarbeit (GIZ) GmbH, Germany) 及 Annemarie M. J. Wensing (University Medical Centre Utrecht, Netherlands)。参与规划指南制定小组会议的观察员： Bernhard Schwartländer (UNAIDS, Switzerland)。

外部同行评议小组 Michelle Adler (United States Centers for Disease Control and Prevention, USA), Isabelle Andrieux-Meyer (Médecins Sans Frontières, Switzerland), Xavier Anglaret (Programme PACCI du site ANRS de Côte d’ Ivoire, Côte d’ Ivoire), Marcelo Araujo de Freitas (Ministry of Health, Brazil), Pamela Bachanas (United States Centers for Disease Control and Prevention, USA), Shaiful Bahari Ismail (Universiti Sains Malaysia, Malaysia), Pierre Barker (University of North Carolina at Chapel Hill, USA), David Barr (HIV Collaborative Fund at Tides Center, USA), Jose Gerard Belimac (National AIDS and STI Prevention and Control Program, Philippines), Soumia Benchekroun (Centre Hospitalier Universaitaire Ibn Sina de Rabat, Morocco), Mitchell Besser (mothers2mothers, South Africa), Marc Bulterys (Chinese Centers for Disease Control and Prevention, China), Helen Bygrave (Médecins Sans Frontières, South Africa), Carlos F. Cáceres (Universidad Peruana Cayetano Heredia, Peru), Georgina Caswell (Global Network of People

致谢

Living with HIV, South Africa), Alexander Chuykov (AIDS Healthcare Foundation, Russian Federation), Polly Clayden (HIV i-base, United Kingdom), Suzanne Crowe (Burnet Institute, Australia), Margarett Davis (United States Centers for Disease Control and Prevention, USA), Chris Duncombe (Bill & Melinda Gates Foundation, USA), Marhoum El Filali (Ibn Rochd University Hospital, Morocco), Wafaa ElSadr (International Center for AIDS Care and Treatment Programs, USA), Carlos Falistocco (SIDA y ETS del Ministerio de Salud de la Nación, Argentina), Donna Futterman (Children’ s Hospital at Montefiore, USA), Elvin Geng (University of California at San Francisco, USA), Charles Gilks (University of Queensland, Australia), Giovanni Guidotti (DREAM Program, Community of Sant’ Egidio, Italy), Bertrand Kampoer (Health consultant, Cameroon), Jonathan Kaplan (United States Centers for Disease Control and Prevention, USA), Sairankul Kassymbekova (National AIDS Center, Kazakhstan), Tamil Kendall (Trudeau Fondation, Mexico), Karusa Kiragu (UNAIDS, Switzerland), Emily Koumans (United States Centers for Disease Control and Prevention, USA), Richard Lester (University of British Columbia, Canada), Oyun Lkhagvasuren (Geneva Foundation for Medical Education and Research, Switzerland), Rangsima Lolekha (Ministry of Public Health, Thailand), Yolisa Mashologu (Human Sciences Research Council, South Africa), Edward Mills (University of Ottawa, Canada), Thomas Minior (United States Agency for International Development, USA), Julio Montaner (University of British Columbia, Canada), Lydia Mungherera (The AIDS Support Organization, Uganda), Joseph Murungu (Ministry of Health, Zimbabwe), Anthony Mutiti (Kitwe Central Hospital, Zambia), Jean Nachega (Johns Hopkins Bloomberg School of Public Health, USA), Steave Nemande (Alternatives-Cameroun, Cameroon), John Nkengasong (United States Centers for Disease Control and Prevention, USA), Siobhan O’ Connor (United States Centers for Disease Control and Prevention, USA), Sylvia Ojoo (University of Maryland, USA), Nittaya Phanuphak (AIDS Research Centre, Thailand), Christian Pitter (Elizabeth Glaser Pediatric AIDS Foundation, USA), Praphan Pranuphak (Thai Red Cross AIDS Research Centre, Thailand), Helena Rabie (University of Cape Town and Stellenbosch University, South Africa), Gilles Raguin (GIP Esther, France), Peter Saranchuk (Médecins Sans Frontières, South Africa), Erik Schouten (Management Sciences for Health, Malawi), Jason Sigurdson (UNAIDS, Switzerland), Mariângela Simao (UNAIDS, Switzerland), Annette Sohn (TREAT Asia/amfAR – Foundation for AIDS Research, Thailand), Luis Soto-Ramirez (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico), Wendy Stevens (National Health Laboratory Service, South Africa), Omar Sued (Fundacion Huésped, Argentina), Fatiha Terki (World Food Programme, Switzerland), Tengiz Tsertsvadze (Tbilisi State University, Georgia), Emilia Valadas (Clínica Universitária de Doenças Infecciosas e Parasitárias, Portugal), Helena Walkowiak (Management Sciences for Health, USA), Alice Welbourn (Salamander Trust, United Kingdom), Robin Wood (University of Cape Town, South Africa), Zhao Yan (Chinese Center for Disease Control and Prevention, China), Yazdan Yazdanpanah (Université Paris Diderot, France), José M. Zuniga (The International Association of Providers of AIDS Care, USA) and Sheryl Zwerski (National Institutes of Health, USA)。

致谢

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

为GRADE系统综述和支持性证据做出贡献的人员参与GRADE方法和证据审查: Folasade Adeniyi (Stellenbosch University, South Africa), Isabelle Andrieux-Meyer (Médecins Sans Frontières, Switzerland), Andrew Anglemyer (University of California at San Francisco, USA), Hana Azman (University of California at San Francisco, USA), Till Barnighausen (Harvard School of Public Health, USA), Deborah Bain-Brickley (University of California at San Francisco, USA), Hilary Barte (University of California at San Francisco, USA), Moses Bateganya (University of Washington, USA), Heiner Bucher (University Hospital Basel, Switzerland), Krisda Chaiyachati (Yale School of Medicine, USA), Larry Chang (Johns Hopkins University, USA), Andrea De Luca (Azienda Ospedaliera Universitaria Senese, Italy), Jane Drake (University of California at San Francisco, USA), Didier Koumavi Ekouevi (PACCI Programme, France), Paul Garner (Liverpool School of Tropical Medicine, United Kingdom), Elvin Geng (University of California at San Francisco, USA), Tara Horváth (University of California at San Francisco, USA), Andreas Jahn ( Ministry of Health, Malawi), Alexander Kay (Stanford University, USA), Gail Kennedy (University of California at San Francisco, USA), Tamara Kredo (South African Cochrane Centre, South Africa), Erin McCarthy (University of California at San Francisco, USA), Joy Oliver (South African Cochrane Centre, South Africa), Rosanna Peeling (London School of Hygiene and Tropical Medicine, United Kingdom), Martina Penazzato (WHO consultant, Switzerland), Rose Phillips (University of California at San Francisco, USA), Elizabeth Pienaar (South African Cochrane Centre, South Africa), Heike Raatz (University Hospital Basel, Switzerland), Jennifer Read (University of California at San Francisco, USA), Sarah Royce (University of California at San Francisco, USA), George Rutherford (University of California at San Francisco, USA), Nandi Siegfried (University of California at San Francisco, USA), Alicen Spaulding (University of Minnesota, USA), Amitabh Suthar ( WHO Consultant, Switzerland), Joseph Tucker (University of North Carolina School of Medicine, USA), Gavrilah Wells (University of California at San Francisco, USA) 及 Zara Shubber (Imperial College London, United Kingdom)。参与建模工作： Andrea Ciaranello (Massachusetts General Hospital, USA), Anne Cori (Imperial College London, United Kingdom), Mary-Ann Davies (University of Cape Town, South Africa), Jeffrey Eaton (Imperial College London, United Kingdom), Matthias Egger (University of Berne, Switzerland), Christophe Fraser (Imperial College London, United Kingdom), Timothy Hallett (Imperial College London, United Kingdom), Daniel Keebler (South African DST/NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, South Africa), Nicolas Menzies (Harvard School of Public Health, USA), Paul Revill (University of York, United Kingdom), Michael Schomaker (University of Cape Town, South Africa), John Stover (Futures Institute, USA) 及 Peter Vickerman (London School of Hygiene and Tropical Medicine, United Kingdom)。参与社区价值观和偏好相关工作： Alice Kate Armstrong (Children’ s HIV Association, South Africa), Laura Ferguson (Institute for Global Health, University of Southern California, USA), Adam Garner (Global Network of People

致谢

Living with HIV, USA), Carolyn Green (International HIV/AIDS Alliance Associated Consultant, United Kingdom), Amy Hsieh (Global Network of People Living with HIV, USA), Nick Keeble (International HIV/AIDS Alliance, United Kingdom), Gitau Mburu (International HIV/AIDS Alliance, United Kingdom), Florence Ngobeni (Children’ s HIV Association, South Africa), Mala Ram (International HIV/AIDS Alliance, United Kingdom), Anja Teltschik (International HIV/AIDS Alliance, United Kingdom) Robert Worthington (Kwantu, United Kingdom), 及 the WHO Civil Society Reference Group. i Christoforos Mallouris (WHO consultant) 与国际艾滋病联盟和艾滋病毒感染者全球网络一起，为社区咨询工作提供了协作支持。

致谢

世卫组织员工和顾问在CadiIrvine （Consultant, Department of HIV）的支持下， Andrew Ball 和 Philippa （来自艾滋病控制司）负责整个指南编写过程中的协调工作。本指南中的临床和服务提供方面的内容由 MegDoherty （来自艾滋病控制司）负责督促，其他4个指南编写小组的工作流程由EyerusalemKebedeNegussie （(实施及服务提供指南制制定小组的协调员，来自艾滋病控制司）， LuluMuhe， NathanShaffer （妇幼保健指南制定小组协调员，分别来自妇幼卫生和青少年卫生司、艾滋病控制司）， MarcoVitoria （成人指南制定小组协调员，来自艾滋病控制司）及 JosephPerri ë ns （规划指南制定小组协调员，来自艾滋病控制司）进行协调。上述人员组成了世卫组织指南制定领导小组。特别感谢在指南编撰和研究中做出重要贡献的以下顾问： Jhoney Barcarolo （规划管理人员指南）， Shaffiq Essajee （妇幼卫生）， Martina Penazzato （妇幼卫生）和 Amitabh Suthar (成人，实施和服务提供)。 Ian Grubb 提供了最重要的写作支持和撰写工作中的协调。 David Breuer 负责技术层面的文字修改。下列世卫组织顾问也参与了本指南的制定过程： April Baller, Sally Girvin , Kathleen Fox , Elizabeth Marum , Priya Shetty 和 Michelle Williams 。下列世卫组织职员为本指南制定做出了贡献： Jhoney Barcarolo (Guidance for Programme Managers), Shaffiq Essajee (Maternal and Child Health), Martina Penazzato (Maternal and Child Health) 及 Amitabh Suthar (Adult and Operational and Service Delivery). Ian Grubb provided overarching writing support and coordination of writing activities. David Breuer technically edited the text. The following WHO consultants were also involved in developing these guidelines: April Baller, Sally Girvin, Kathleen Fox, Elizabeth Marum, Priya Shetty 及 Michelle Williams。

WHO Civil Society Reference Group: Eddie Banda (Malawi Network of People Living with HIV/ AIDS (MANET+), Malawi), Mabel Bianco (Fundación para el Estudio e Investigación de la Mujer (FEIM), Argentina), Tung Bui (Youth Voices Count, Thailand), Michaela Clayton (AIDS and Rights for Southern Africa, Namibia), Lee Hertel (International Network of People Who Use Drugs, USA), Ruth Mery Linares Hidalgo (Ciudad Quesada, Costa Rica), Noreen Huni (Regional Psychosocial Support Initiative (REPSSI), South Africa), Matthew Kavanagh (Health Gap, USA), JoAnne Keatley (University of California at San Francisco, USA), Sharonann Lynch (Doctors without Borders, USA), Babalwa Mbono (Mothers to Mothers (M2M), South Africa), Gitau Mburu (International HIV/AIDS Alliance, United Kingdom), Othoman Mellouk (orum on MSM and HIV, Morocco), Luís Mend ã o (European AIDS Treatment Group, Portugal), Noah Metheny (Global Forum on MSM and HIV, USA), Carlo Oliveras (Caribbean Treatment Action Group, Puerto Rico), Rachel Ong (Communities Delegation to the Board of the Global Fund to Fight AIDS, Tuberculosis and Malaria, Singapore), Asia Russell (Health Gap, USA), Leickness Simbayi (Human Sciences Research Council, South Africa), Felly Nkweto Simmonds (Population Council, Zambia), Lucy Stackpool-Moore (International Planned Parenthood Federation, United Kingdom), Ruth Morgan Thomas (Global Network of Sex Workers Projects, United Kingdom) and Mary Ann Torres (International Council of AIDS Service Organizations, Canada).

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

世卫组织下列实习生也为本指南制定提供了支持： Rachel Baggaley (Department of HIV), Silvia Bertagnolio (Department of HIV), Jesus García Calleja (Department of HIV), Agnes Chetty (WHO Regional Office for the Eastern Mediterranean), Irina Eramova (WHO Regional Office for Europe), Nathan Ford (Department of HIV), Masami Fujita (WHO Regional Office for the Western Pacific), Haileyesus Getahun (Stop TB Department), Vincent Habiyambere (Department of HIV), Chika Hayashi (Department of HIV), Masaya Kato (WHO Regional Office for the Western Pacific), Lali Khotenashvili , (WHO Regional Office for Europe), Ying-Ru Lo (WHO Regional Office for the Western Pacific), Frank Lule (WHO Regional Office for Africa), Viviana Mangiaterra (Department of Reproductive Health and Research), Hernan Julio Montenegro (Department of Health Policy, Development and Services), Lisa Nelson (Department of HIV), Morkor Newman (WHO Regional Office for Africa), Boniface Dongmo Nguimfack (Department of HIV), Linh Nguyen (Stop TB Department), Kevin O’ Reilly (Department of HIV), Brian Pazvakavambwa (WHO Regional Office for Africa), Razia Pends e (WHO Regional Office for South-East Asia), Fran ç oise Renaud-Théry (Department of HIV), Bharat B. Rewari (WHO Regional Office for South-East Asia), Nigel Rollins (Department of Maternal, Child and Adolescent Health), Anita Sands (Department of Essential Medicines and Health Products), Yves Souteyrand (WHO Regional Office for the Eastern Mediterranean), Isseu Diop Toure (WHO Regional Office for Africa), Annette Verster (Department of HIV), Gundo Weiler (Department of HIV) 及 Stefan Wiktor (Department of Pandemic and Epidemic Diseases)。世卫组织下列实习生也为本指南制定提供了支持： Grace Akol , Hanna Yemane Berhane , Jayne Ellis 和 Valentin Petey。 Hayet Souissi 和Jasmin Leuterio 负责世卫组织行政支持工作。 Oyuntungalag Namjilsuren , Sarah Russell 及 Glenn Thomas 负责沟通支持工作。 MaryannNnenkai Akpama , AfrahAl-Doori , Adriana De Putter, Lydia Mirembe Kawanguzi , Jane Ndanareh , L aurent Poulain 和 Ophelia Riano 提供了其他的行政和管理支持。

赞助方本指南获得美国疾控中心、比尔 ·梅琳达盖茨基金会、德国国际合作机构、联合国艾滋病规划署统一预算、结果和问责框架处、美国国际发展署的资助以及通过世卫组织职员时间获得的特别经费。世卫组织谨此一并感谢在指南制定过程中奉献了员工时间和其他同等贡献的机构。

前言

前言本书的出版标志着世卫组织首次发行应用抗病毒药物预防和治疗艾滋病毒感染的综合指南。本指南立意深远却又简单易行，而且具有深厚的证据基础。指南还利用了若干最新趋势，其中包括一种首选治疗方案，将治疗方案简化为固定剂量复合制剂，每日服用一次，该方案更加安全且更经济。指南还参考和应用了抗病毒治疗具备多种益处的证据。目前，通过使用正确的治疗方案，在正确的时间开始治疗， HIV感染者就可以展望更长且更健康的人生。同时，由于病毒传播风险大大降低，他们还可以保护自己的性伴和婴儿。在不断达到更高的目标和获得更好的成绩的大趋势下，指南也有超前的飞跃。截至2012年底，在非洲受艾滋病流行冲击最严重的地区，估计有750万人正接受治疗，而十年前却只有5万人。在全球范围内，约有970万人正接受治疗，这表明 “到2015年底为1500万人提供抗病毒治疗” 的全球目标具有可行性。现有成绩展示了挽救生命的公共卫生措施史上最飞速的扩展过程。根据指南的建议，加速进展的重要方法就是更早的开始治疗。现有证据表明，早治疗可以带来双重收益，既可以使人们获得更长的健康寿命，又可以显著减少病毒传播给他人的风险。早治疗还有一个益处，即简化规划的运行需求。指南建议孕妇和5岁以下儿童应在诊断后立即开始治疗，建议包括患有结核病、肝炎和其他合并感染在内的所有成年HIV感染者使用相同的日服一次的固定剂量复合制剂。指南的补充建议旨在使规划服务更贴近患者的家庭，更快获得实验室检测结果，以及将艾滋病治疗与产前保健、结核病治疗和药物依赖等相关服务更加紧密的整合，通过更大范围内的卫生工作者提供治疗、随访和关怀服务。有国家要求世卫组织提供抗病毒药物的简明使用指南。我相信这本综合指南最终能够满足这一要求。指南适用于所有年龄组和各种人群；综合提出了临床建议、实施和规划方面的建议；涵盖从HIV检测到患者纳入和保持，从艾滋病一般关怀到并发症的管理等关怀和治疗的重要领域。新指南要求规划进行一些重大的改变，同时也要求增加投入。我个人深信未来应对艾滋病将会延续现有模式，即积极主动，持续发展已有成绩，不断迎击新挑战。世卫组织估计指南会产生前所未有的影响：指南在全球范围内实施后，从现在开始到2025 年之间将避免300万例的额外死亡，这一数字高于2010年指南的相应数据，指南的应用还将避免约350万例的新发感染。这样的前景 ― 这在几年前仍是不可想象的 ― 将成为推动艾滋病流行持续而不可逆的减弱的动力之源。我强烈建议各国及其发展伙伴抓住这一无可比拟的机会，使我们的事业更上一层楼。

世卫组织总干事陈冯富珍博士

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

执行概要本综合指南旨在为诊断人类免疫缺陷病毒（艾滋病毒）感染、关怀艾滋病毒感染者以及使用抗病毒药物治疗和预防艾滋病毒感染提供指导原则。整个指南的结构按照艾滋病关怀体系提供流程设计，即艾滋病检测、关怀和治疗。行为学、结构学和生物学干预策略在抗逆转录病药物使用中并未涉及，因而本指南未涵盖其相关内容。 2013年指南综合并统一了来自世卫组织出台的相关系列指南及其他文件的建议，其中包括 2010年成人、青少年和儿童及婴儿使用抗病毒药物指南，对艾滋病毒感染孕妇进行抗病毒治疗和预防婴儿感染指南。本综合指南针对所有年龄组和不同人群包括成人、孕妇和哺乳妇女、青少年、儿童和其它重点人群提供了使用抗病毒药物的指导。本指南还致力于统一及更新临床、服务提供和规划实施等方面的指导意见。 2013年指南反映了在过去三年在艾滋病应对领域中的重要进展。自2010年以来随着包括 CD4+T淋巴细胞即时检测在内的新技术和新服务提供方式的创新，艾滋病检测和治疗监测得以通过多样化的方式开展，并且可以在更基层的地方开展。更简单、更安全、每日一次、每次一片的抗病毒治疗方案适合于大部分人群和大多数年龄组，在中低收入国家也越来越可负担，且更易于获得。各国正在朝着尽早启动三药联用的治疗方案、预防母婴传播项目变得更简单的方向前进；该强调更长期地促进艾滋病毒感染孕妇/母亲的健康状态，并且预防她们的孩子感染艾滋病毒。人们已经意识到抗病毒治疗可以带来更多的预防收益，包括：除改善健康状况和延长生命外，抗病毒治疗可以预防艾滋病毒的性传播；而通过抗病毒治疗进行暴露前预防扩大了艾滋病预防方法的选择范围，并且在某些特定人群和特定背景中暴露后预防发挥了很重要的作用，包括那些遭受性侵犯的人群。尽管各国的抗病毒治疗覆盖程度和执行2010世卫组织指南的进程不尽相同，但当前全球的趋势是一致的，那就是及早启动抗病毒治疗。与之前的世卫指南一致， 2013年指南仍以公共卫生措施为基础，进一步扩大了抗病毒药物在治疗和预防艾滋病毒感染中的使用，该措施考虑了不同资源有限环境中的可行性和有效性。本指南中的新临床建议提倡扩大抗病毒治疗的适用范围，对所有CD4+T淋巴细胞计数等于或低于500个/mm3的成人、青少年和儿童启动抗病毒治疗。对于严重或晚期艾滋病毒疾病患者和 CD4+T淋巴细胞计数等于或低于350个/mm 3的人，可优先启动抗病毒治疗。对感染艾滋病毒的特定人群，不论其CD4+T淋巴细胞计数是多少，均建议启动抗病毒治疗，包括活动性结核病患者、乙肝病毒合并感染严重慢性肝病者、单阳配偶、孕妇、哺乳妇女和5岁以下儿童。建议尽可能统一成人和儿童的抗病毒治疗方案，并且首选一线抗病毒治疗方案。特别强调在成人和青少年一线抗病毒治疗方案中不再使用司他夫定（d4T）。推荐将病毒载量检测作为监测抗病毒治疗取得成功或失败的首选方法，同时将接受抗病毒治疗患者的临床和免疫学指标作为辅助指标进行判断。本指南强调应该在更广泛的艾滋病关怀服务体系内使用抗病毒药物。本指南还针对社区艾滋病毒检测和咨询服务，以及青少年艾滋病毒检测提供了新建议。除了新建议，本指南还提供了关于艾滋病检测咨询、艾滋病预防、艾滋病病人常规关怀、常见的合并合并感染和并发症处理、药物不良反应监测及处理等方面的世卫组织指导意见的总结和关联。需要对当前的一些建议进行更新，并需要在今后若干年内随着新证据的出现，对这些新建议进行评价。抗病毒治疗的适用范围得以扩大，抗病毒药物的应用方案更加广泛，这些变化带来挽救生命、改善临床结局及减少新发感染的新机遇。同时也对许多国家的决策者和执行者提出了挑战。 2013年新的实施指南就加强艾滋病治疗关怀、改善整个卫生系统内部的相互联系的关键环

执行概要

节提供了建议。艾滋病毒该指南的重点是使艾滋病毒感染诊疗服务能够更好地提高抗病毒持续性和依从性；将提供抗病毒治疗工作下沉分散到初级卫生保健机构，将抗病毒治疗与孕产妇和儿童健康机构服务整合、与结核病医院和药物依赖治疗机构提供的服务整合。本指南还阐述了新临床建议对实验室服务以及抗病毒药物和其它物品的采购供应系统的影响。本指南为艾滋病毒相关规划管理人员提供的指导描述了如何战略性使用抗病毒药物的决策和规划以及与国家整体进程、艾滋病流行情况、卫生系统能力、可获得的财政资金以及伦理和人权考量。针对所有主要新建议本指南均列出了与规划管理人员特别有关的实施层面的考量。本指南还包含了一个关于监测与评估的章节，就如何监测指南的新建议和执行情况提供了初步的指导意见。按照世卫组织指南审查委员会建立的程序，对2013年指南进行了复审。根据GRADE （推荐、评估、制定和评价）方法对证据和决定过程进行了审查，从而建立了本指南中新的临床和操作建议。建立模型、专家咨询及开展个案研究所获得的建议均为临床、操作及规划指导意见提供了参考。这些过程也发现了知识鸿沟，将为未来的研究议程提供指导意见。除了根据GRADE系统方法获得新建议之外，本指南还对当前世卫组织制定的其他相关指南进行了总结。这些指南大部分根据GRADE系统方法制定，或者根据GRAD系统方法对建议的强度和证据的质量进行分级，并据此进行修改。本指南的主要目标人群是国家级别的艾滋病规划管理人员，特别是中低收入国家的规划管理人员。本指南旨在协助各国进行决策并制定扩展抗病毒治疗的规划。本指南也为临床工作着提供了有用的资源；并为发展机构、国际组织、非政府组织和其他合作伙伴在未来若干年内选择优先领域提供了信息。 2013年指南提出了重要步伐，迈出该步伐可实现可普遍获得用于治疗和预防艾滋病的抗病毒药物，提高抗病毒治疗规划的有效性、影响力及可持续性，从而实现消除艾滋病的终极目标。

执行概要

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

新建议摘要下表总结了根据2013年世卫组织指南关于艾滋病检测咨询、抗病毒治疗和艾滋病服务提供等方面所形成的新建议。下表也对第十章针对规划管理人员的指导意见进行了总结。下表也清楚地阐明，对抗病毒治疗的指导意见仍与2010年相关指南一致，尚无修改。该表并非完整列表，未包括本指南中可以查阅的所有世卫组织建议，特别是来自其它摘自现有世卫组织指南的建议。本指南中可以查阅的现有世卫组织的建议包括：第五章关于艾滋病检测咨询与预防；第六章关于艾滋病感染者的一般关怀；第八章关于常见的合并感染和其他并发症的处理；以及第七章第四节（7.4）关于药物毒性的处理的建议。

艾滋病毒检测和咨询主题和人群以社区为基础的检测建议滋病毒高度流行地区，除医务人员主动提供的检测和咨询外，建议以社区为基础开展艾滋病毒检测和咨询，并与预防、保健和治疗服务紧密联系（强烈推荐，低质量证据）。时具有各种艾滋病毒流行类型的地区，同除医务人员主动提供的检测和咨询外，建议以社区为基础对重点人群进行艾滋病毒检测和咨询，并与预防、保健和治疗服务紧密联系（强烈推荐，低质量证据）。青少年艾滋病毒检测和咨询a 所有艾滋病流行类型（HIV高度、中度及低流行）地区，建议对重点人群中的青少年进行艾滋病毒检测和咨询，并与预防、治疗和保健服务紧密联系（强烈推荐，极低质量证据）。高度流行地区，艾滋病毒建议对所有青少年进行艾滋病毒检测和咨询，并与预防、治疗和保健服务建立联系（强烈推荐，极低质量证据）。 IV低流行和中度流行地区， H 艾滋病毒我们建议提供艾滋病毒检测和咨询，并与预防、治疗和保健服务建立联系，使所有青少年都可以获得（有条件推荐，极低质量证据）。我们建议，艾滋病毒向青少年说明公开其艾滋病毒感染状况的潜在好处和风险，向他们赋权并提供支持，使他们自己决定是否、何时、如何以及向谁公开其感染状况（有条件推荐，极低质量证据）。

新建议摘要

何时对艾滋病毒感染者启动抗病毒治疗？主题和人群何时对成人和青少年启动抗病毒治疗a 建议作为重点，应对所有严重或晚期艾滋病（根据世卫组织标准处于临床三期或四期）患者和CD4+T淋巴细胞计数等于或低于（强烈推荐，中等质量证据）。 350个/mm3者启动抗病毒治疗应对所有CD4+T淋巴细胞计数高于350个/mm3但等于或低于不论其根据世卫组织标准处 500个/mm3 者启动抗病毒治疗，于临床几期（强烈推荐，中等质量证据）。 . 对所有CD4 T淋巴细胞计数高于350个/mm3但等于或低于应不论其根据世卫组织标准处 500个/mm3 者启动抗病毒治疗，于临床几期（强烈推荐，中等质量证据）。患活动性结核病的艾滋病毒感染者（强烈推荐，低质量证据）；滋病毒和乙肝病毒双重感染且出现严重慢性肝病者艾（强烈推荐，低质量证据)；应向单阳配偶中的艾滋病毒感染者提供抗病毒治疗，以减少艾滋病毒传播给未感染一方（强烈推荐，高质量证据）。何时对孕妇和哺乳妇女启动抗病毒治疗滋病毒应对所有艾滋病毒感染孕妇和哺乳妇女启动三联抗艾病毒治疗，并至少在存在母婴传播风险的整个阶段维持治疗。符合治疗条件的妇女应终生维持抗病毒治疗（强烈推荐，中等质量证据）。考虑到规划和实施的原因，特别是在HIV高度流行地区，所有艾滋病毒感染孕妇和哺乳妇女均应启动抗病毒治疗，并终生维持（有条件推荐，低质量证据）。一些国家，在对于那些因个人健康原因，不符合抗病毒治疗条件的妇女而言，可以考虑在存在母婴传播风险的阶段结束后停止抗逆转录病毒用药（有条件推荐，低质量证据）。 +

抗逆转录病毒和哺乳期

与2010年确定的主要原则和建议一致，包括：应由国家或省市卫生主管部门决定卫生服务机构针对艾滋病毒感染产妇的策略：母乳喂养同时接受抗逆病毒治疗性干预或者根据个人情况完全避免母乳喂养。如国家卫生主管部门决定其孕产妇和儿童健康服务机构将主要推动并支持母乳喂养和抗逆病毒治疗性干预，因为该做法最有可能提高已知艾滋病毒感染产妇所生婴儿的无艾滋病毒感染生存机会，则：知感染艾滋病毒的产妇已（及其未感染或不知是否感染艾滋病毒的婴儿）应进行六个月纯母乳喂养，随后适当添加辅食，并持续母乳喂养到孩子1岁。只有在能够获得不包括母乳的营养充足的安全膳食时，才停止母乳喂养（强烈推荐，有关前六个月建议的证据质量高，有关12个月建议的证据质量低）。

青少年指10岁至19岁的人。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

何时对艾滋病毒感染者启动抗病毒治疗？（续）主题和人群建议应对所有5岁以下艾滋病毒感染儿童启动抗病毒治疗，不论其 + 也不论其根据世卫组织标准处于 CD4 T淋巴细胞计数是多少，临床几期。 1 岁前确诊的婴儿（强烈推荐，中等质量证据） 1 岁至5岁之间感染艾滋病毒的儿童（有条件推荐，极低质量证据）对所有5岁及以上感染艾滋病毒且CD4+T淋巴细胞计数等应不论其根据世于或低于500个/mm 3的儿童启动抗病毒治疗，卫组织标准处于临床几期。 C D4 T淋巴细胞计数等于或低于350个/ mm3 （强烈推荐，中等质量证据） C D4 T淋巴细胞计数在350个到500个/mm3之间（有条件推荐，极低质量证据）应对所有艾滋病毒感染且出现严重或晚期症状，根据世卫组织标准处于临床三期或四期）的儿童启动抗病毒治疗，不论其 + （强烈推荐，中等质量证据）。 CD4 T淋巴细胞计数是多少应对任何临床初步诊断为艾滋病毒感染的18个月以下幼儿启动抗病毒治疗（强烈推荐，低质量证据）。 + +

何时对儿童启动抗病毒治疗

新建议摘要

启动抗病毒治疗时应使用哪种用药方案？主题和人群成人和青少年一线抗病毒治疗方案建议线抗病毒治疗应包括两种核苷类逆转录酶抑制剂加上一种一非核苷类逆转录酶抑制剂。荐用替诺福韦+拉米夫定推（或恩曲他滨） +依非韦伦固定剂量复合制剂作为启动抗病毒治疗的首选方案（强烈推荐，中等质量证据）。患者情况禁用替诺福韦+拉米夫定如（或恩曲他滨） +依非韦伦，或该复合制剂无法获得，建议选用以下方案之一：齐多夫定+拉米夫定+依非韦伦齐多夫定+拉米夫定+奈韦拉平诺福韦+拉米夫定替（或恩曲他滨） +奈韦拉平（强烈推荐，中等质量证据）。于普遍了解的司他夫定的代谢性毒性，鉴各国应停止在一线方案中使用司他夫定（强烈推荐，中等质量证据）。孕妇、哺乳妇女及其婴儿的一线抗病毒治疗议以一天一次替诺福韦+拉米夫定建（或恩曲他滨） +依非韦伦固定剂量复合制剂作为孕妇和哺乳妇女的一线抗病毒治疗方案，包括妊娠头三个月的孕妇和育龄妇女。该建议既适用于终生治疗也适用于为预防母婴传播而启动并于该阶段结束后终止的抗病毒治疗（强烈推荐，低至中等质量证据：一般而言针对成人证据质量为中等，但针对孕妇、哺乳妇女和婴儿等特定人群的证据质量低）。亲正接受抗病毒治疗同时进行母乳喂养的婴儿应每天一次母奈韦拉平进行六周预防性治疗。接受替代喂养的婴儿应进行四至六周预防性治疗，方案是每天一次奈韦拉平（或每天两次齐多夫定）。应在婴儿出生后或产后发现艾滋病毒暴露时即启动预防性治疗（强烈推荐，针对母乳喂养婴儿的证据质量中等；强烈推荐，针对仅进行替代喂养的婴儿的证据质量低）。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

启动抗病毒治疗时应使用哪种用药方案？（续）主题和人群 3岁以下儿童一线抗病毒治疗建议对于所有3岁（36个月）以下艾滋病毒感染儿童，均应使用以洛匹那韦/利托那韦为基础的用药方案进行一线抗病毒治疗，不论其非核苷类逆转录酶抑制剂暴露情况如何。如洛匹那韦/ 利托那韦方案不可行，则应启用以奈韦拉平为基础的用药方案（强烈推荐，中等质量证据）。可以进行病毒载量监测的情况下，在可以考虑在实现持续抑制艾滋病毒之后使用一种非核苷类逆转录酶抑制剂替代洛匹那韦/利托那韦（有条件推荐，低质量证据）。对于感染艾滋病毒的3岁以下婴幼儿，如在使用含奈韦拉平或洛匹那韦/利托那韦的治疗方案时出现结核病，建议选择阿巴卡韦+拉米夫定+齐多夫定方案。一旦完成结核病治疗，即应停止该方案，并恢复最初的用药方案（强烈推荐,中等质量证据）。于感染艾滋病毒的3岁以下婴幼儿，对进行抗病毒治疗的核苷类逆转录酶抑制剂骨干用药方案应当是阿巴卡韦+拉米夫定或齐多夫定+拉米夫定（强烈推荐，低质量证据）。 3岁及以上儿童一线抗逆转录病毒治疗对于感染艾滋病毒的3岁及以上儿童（包括青少年），依非韦伦是进行一线治疗的首选非核苷类逆转录酶抑制剂，奈韦拉平为其替代选择（强烈推荐，低质量证据)。对于3岁至10岁之间（或体重35公斤以下的青少年）感染艾滋病毒的儿童，进行抗病毒治疗的核苷类逆转录酶抑制剂骨干用药方案应当是以下之一，排列顺序亦为选择优先顺序：阿巴卡韦+拉米夫定齐多夫定或替诺福韦+拉米夫定（或恩曲他滨）

（有条件推荐，低质量证据）对于体重35公斤及以上的感染艾滋病毒的青少年（10岁～19 岁），进行抗病毒治疗的核苷类逆转录酶抑制剂骨干用药方案应当与成人用药方案一致，为以下之一，排列顺序亦为选择优先顺序：替诺福韦+拉米夫定（或恩曲他滨）齐多夫定+拉米夫定阿巴卡韦+拉米夫定（强烈推荐，低质量证据）。

新建议摘要

监测抗病毒治疗效果并对治疗失败做出判断主题和人群所有人群建议

建议将病毒载量作为判断并确认抗病毒治疗失败的首选监测指标（强烈推荐，低质量证据)。不能定期检测病毒载量，如应使用CD4+T淋巴细胞计数和临床监测确定治疗是否失败（强烈推荐，中等质量证据)。

二线抗病毒治疗：转换为何种抗病毒治疗方案主题和人群成人和青少年转换为哪种抗病毒治疗方案（包括孕妇和哺乳妇女）建议成人二线抗病毒治疗应包括两种核苷类逆转录酶抑制剂加上一种利托那韦增强型蛋白酶抑制剂。建议按以下顺序使用二线核苷类逆转录酶抑制剂方案：以替诺福韦+拉米夫定在（或恩曲他滨）为基础的一线用药方案失败后，二线方案以齐多夫定+拉米夫定为骨干核苷类逆转录酶抑制剂。以齐多夫定或司他夫定+拉米夫定为基础的一线用药方在案失败后，二线方案以替诺福韦+拉米夫定（或恩曲他滨）为骨干核苷类逆转录酶抑制剂。建议以核苷类逆转录酶抑制剂固定剂量复合制剂为首选（强烈推荐，中等质量证据）。热稳定固定剂量复合制剂阿扎那韦/利托那韦和洛匹那韦/ 利托那韦是进行二线抗病毒治疗的首选增强型蛋白酶抑制剂（强烈推荐，中等质量证据)。儿童应转换为哪种抗病毒治疗方案（包括青少年）在以非核苷类逆转录酶抑制剂为基础的一线治疗方案失败后，建议二线抗病毒治疗方案使用一种增强型蛋白酶抑制剂加两种核苷类逆转录酶抑制剂；洛匹那韦/利托那韦为首选增强型蛋白酶抑制剂（强烈推荐，中等质量证据）。在以洛匹那韦/利托那韦为基础的一线用药方案失败后，建议 3岁以下儿童仍坚持使用一线用药方案，但应采取改进依从性的措施（有条件推荐，极低质量证据）。在以洛匹那韦/利托那韦为基础的一线用药方案失败后，建议 3岁及以上儿童应转换为包括一种非核苷类逆转录酶抑制剂和两种核苷类逆转录酶抑制剂的二线用药方案；依非韦伦为首选非核苷类逆转录酶抑制剂（有条件推荐，低质量证据）。在阿巴卡韦或替诺福韦+拉米夫定（或恩曲他滨)的一线治疗方案失败后，二线抗病毒治疗的首选骨干核苷类逆转录酶抑制剂是齐多夫定+拉米夫定（强烈推荐，低质量证据）。在包含齐多夫定或司他夫定+拉米夫定（或恩曲他滨)的一线用药方案失败后，二线抗病毒治疗的首选骨干核苷类逆转录酶抑制剂为阿巴卡韦或替诺福韦+拉米夫定（或恩曲他滨）（强烈推荐，低质量证据）。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

三线抗病毒治疗主题和人群所有人群建议

各国相关规划应制定三线抗病毒治疗政策（有条件推荐，低质量证据）。三线用药方案应包括与之前所用药物交叉耐药风险最小

的新药，如整合酶抑制剂和二代非核苷类逆转录酶抑制剂和蛋白酶抑制剂（有条件推荐，低质量证据）。二线治疗即将失败且没有新的抗病毒药物可选择的患者应继续使用可耐受治疗方案（有条件推荐，极低质量证据）。针对儿童的特殊考虑

如二线治疗失败，需探索能够平衡对儿童利弊的策略。大童有更多的治疗选择，或许可以利用成人所使用的新药（如恩替卡韦（ETV）、达芦那韦(DRV)和拉替拉韦（RAL））形成三线抗逆转录病毒用药方案。二线治疗即将失败且没有新抗逆转录病毒选择的儿童应继续使用耐受用药方案。如已停止抗病毒治疗，仍需预防机会性感染，缓解症状并减轻痛苦。

业务运作和服务提供主题优化抗逆转录病毒治疗依从性的干预措施服务整合与连接建议为促进依从性策略的一系列措施之一，作可考虑利用手机短信提醒，以提高抗病毒治疗依从性（强烈推荐，中等质量证据）。在艾滋病毒高度流行地区，妇幼保健机构应对符合条件的孕产妇和婴儿启动并维持抗病毒治疗，并酌情与正在进行的艾滋病毒诊疗和抗病毒治疗服务建立联系和转介机制（强烈推荐，极低质量证据）。在艾滋病毒和结核病负担高的地区，结核病治疗机构应对艾滋病毒感染者启动抗病毒治疗，并与正在进行的艾滋病毒艾滋病毒诊疗和抗病毒治疗服务建立联系（强烈推荐，极低质量证据）。艾滋病毒艾滋病毒和结核病负担高的地区，在艾滋病毒艾滋病毒诊疗机构应对已确诊结核病的艾滋病毒艾滋病毒感染者提供抗结核治疗（强烈推荐，极低质量证据）。应在提供阿片类药物替代疗法的机构对符合条件的艾滋病毒感染者启动并维持抗病毒治疗（强烈推荐，极低质量证据）。治疗和关怀服务下沉应考虑按以下方案分散启动和维持抗病毒治疗：医院启动抗病毒治疗，在在外围卫生机构维持抗病毒治疗（强烈推荐，低质量证据）。在外围卫生机构启动并维持抗病毒治疗（强烈推荐，低质量证据）。在外围卫生机构启动抗病毒治疗，在社区水平（即卫生机构以外的场所，如外展服务点、卫生站、居家服务或社区组织）维持治疗，期间定期到卫生机构就诊随访（强烈推荐，中等质量证据）。

新建议摘要

业务运作和服务提供主题职责分工调整建议可由经过培训的非医师临床工作人员、助产士和护士启动一线抗病毒治疗（强烈推荐，中等质量证据)。由经过培训的非医师临床工作人员、可助产士和护士维持抗病毒治疗（强烈推荐，中等质量证据)。在定期就诊间隔期，可由经过培训并接受监督的社区卫生工作者分发抗病毒治疗药物（强烈推荐，中等质量证据）。

给规划管理人员的指导主题给规划管理人员的指导指导为临床和实施做出决定，建议如下：国家主管部门决策时应遵循透明、开放和知情决定的进程。该进程应包括广泛利益相关方的参与，包括来自受影响社群的有意义参与，同时考虑到有关建议的具体情况。策过程应考虑国家和地方艾滋病毒流行病学数据、决现行抗病毒治疗规划现状以及社会经济、政策和法律状况，包括预算和人力需求以及卫生系统等影响因素，即确定当前有哪些投入和系统可用以及哪些领域需要额外投资。策过程应考虑伦理、决公平和人权以及不同实施方案的影响、成本效益、机遇和风险。

引言

01 36 36 37 37 38 38 38 38 39 39

1.1 背景和环境 1.2 综合指南的理论依据 1.3 目标 1.4 目标人群 1.5 范围及内容 1.5.1 概述章节 1.5.2 临床指南 1.5.3 实施和服务提供指南 1.5.4 规划管理者指南 1.5.5 监控与评估

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

1. 引言 1.1 背景和环境世卫组织于2002年首次出版了关于在成人和青少艾滋病感染者中使用抗病毒药物的指南（1）；于2001年首次出版关于使用抗病毒药物预防HIV母婴传播的指南，并于2004年再次出版（2）。世卫组织于2006年对这些指南（3-5）进行了更新，引进了公共卫生措施，使用更简单且统一的抗病毒治疗方案。这些出版物大部分在2010年再次更新（7-10）；各国在过去的十年内已经在按比例扩展抗病毒治疗规划，这些指南则为各国提供了重要的指导。 2013年世卫组织首次对上述指南以及其他与抗病毒治疗相关的文件进行修订，并且整合到一本综合指南之中，此综合指南旨在阐明基于广泛的艾滋病关怀服务体系，对所有年龄组及不同人群如何使用抗病毒药物进行艾滋病预防和治疗。这些指南于2012年底及2013年初再次更新。与以往任何时候相比，当前可用的抗逆转录病毒用药方案变得更为安全、简单、更有效且更经济，即使在最贫困的国家亦是如此。目前新的检测策略和措施使得早期诊断HIV感染成为现实，并且可以在更广泛的机构中获取该服务；同时，新的更可负担的用于监测抗病毒治疗效果的技术也即将出现。各国正在推广用于预防HIV母婴传播的三药联用治疗方案和更简单的规划，其强调已感染艾滋病毒的孕妇、母亲及其婴儿的长期健康。重要的是，新的证据已经表明抗病毒治疗可带来预防HIV传播的显著的收益（10）。尽管各国抗病毒治疗的覆盖范围及实施世卫组织2010年相关指南（7-9）的进程不尽相同，且在研究领域仍存在明显差距，但是全球存在一致的趋势，即扩大抗病毒治疗的可及性并及早开始抗病毒治疗。抗病毒治疗的适用范围得以扩大，抗病毒药物的应用方案更加广泛，这些变化带来挽救生命及减少新发感染的机遇，同时也使许多中低收入国家的决策者和执行者面临重要的技术、实施、规划及伦理方面的挑战。这些机遇和挑战包括实施综合性策略，以确保既可在卫生机构也可在社区场所及时确诊HIV感染。同时需要在不同治疗机构之间建立有效地衔接和转介，服务下沉、创新性提供抗病毒治疗服务、有效的依从性支持和干预措施，以确保患者可以维持长期的关怀。可靠、有质量保证及可负担的实验室监测工具，充足的卫生人力资源以及不间断的药物供应也是必不可少的。各国在实施艾滋病防治规划时，经常陷入无法接触最需要抗病毒治疗的人群的困境。他们面临困难的选择，如何分配有限的资源及如何确定规划的优先领域，以最大限度的利用抗病毒药物，并与其他艾滋病预防措施一起联合应用，以期获得最佳的治疗和预防效果。国家级艾滋病规划可能需要通过评估成本及收益，证明抗病毒治疗规划中增加的投入所带来的收益，同时阐明这些投入对HIV感染率、艾滋病发病人数和死亡率带来何种影响。

1.2 综合指南的理论依据本综合指南将带来以下预期收益。在艾滋病相关预防、治疗及关怀体系内使用抗病毒药物的指导意见。除了提供抗病毒治疗的临床建议，本指南还对艾滋病相关关怀的其他主要环节提出了指导意见。针对不同年龄组和所有人群的抗病毒药物使用指南。将之前相互独立的世卫组织关于成人和青少年的抗病毒治疗指南和针对儿童和预防HIV母婴传播的几份指南相整合，统一了抗病毒治疗方案和治疗手段，以尽可能覆盖不同年龄组和不同人群。

1. 引言

统一新的和现有的指导意见。合并过程使得新建议可与现有的世卫组织相关指导意见相互统一。合并过程促使不同机构的措施和衔接相互一致。合并建议的过程有助于促进抗病毒药物及其相关服务的不同提供机构之间的衔接，并且促进不同机构的相关措施相互统一。这些服务包括艾滋病特殊关怀，初级保健，以社区为基础的关怀服务，妇幼保健服务，结核病防治服务以及对吸毒者提供的服务。更新将变得更加及时并更具综合性。合并指南使得在抗病毒药物应用过程中新学科和新兴举措在临床、实施及规划等方面所产生的关键影响得以每两年在全人群、不同年龄组及不同环境中进行一次全面评估。

1. 引言

1.3 目标本综合指南的目标包括：供最新的、提以证据为基础的临床建议，阐明一项在艾滋病关怀体系中提供抗病毒药物用于治疗艾滋病及预防HIV传播，并特别关注卫生系统能力及资源有限的地区的公共卫生措施。 ; 需要解决的实施及服务提供方面的关键议题提供指导意见，为以提高艾滋病服务可及性、加强艾滋病持续关怀，并进而将抗病毒药物供应纳入卫生系统的服务内容当中。为国家级别的决策人员和规划制定人员提供有关采纳临床及实施方面的建议，确定其优先领域，落实并监控其执行情况和影响等方面的系统指导意见。

1.4 目标人群本指南的主要目标使用对象为国家级的艾滋病规划管理人员。下列目标人群也是本指南所感兴趣的：国家级的艾滋病治疗和预防咨询委员会；国家级别的结核病规划管理人员；孕产妇、新生儿、儿童健康及生殖健康规划管理人员；临床及其他卫生服务提供者；国家实验室服务管理人员；艾滋病感染者及社区组织；以及为资源有限地区的艾滋病规划提供财政和技术支持的国际及双边机构组织。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

1.5 范围及内容本指南应对使用抗病毒药物进行艾滋病治疗和预防所涉及的临床、实施和规划方面的问题（详见图1.1）。

1.5.1 概述章节本指南包括若干概述章节。第一章：描述本指南的背景、环境、理论依据、目标和目标人群。第二章：阐明贯穿指南的指导原则。第三章：描述制定指南的方法和过程。第四章：阐述用于表达新建议的格式。

1.5.2 临床指南第五、六、七章的建议针对在艾滋病关怀体系（包含从诊断到治疗与关怀服务）内对所有年龄组和全人群使用抗病毒药物进行艾滋病治疗和预防所涉及的关键问题。第五章：通过结合现有世卫组织指导意见，本章总结了艾滋病检测咨询方法。此外，本章还结合现有世卫组织指导意见，总结了在实施综合艾滋病预防措施的场所中，使用抗病毒药物预防 HIV传播的方法。值得注意的是本章指南不包括行为、组织和生物学干预措施，因为本章所述及的抗病毒药物的应用过程不涉及这些干预措施。第六章：总结了针对个体的艾滋病综合关怀措施，从个体被确诊为HIV感染之时起，到其启动抗病毒治疗，包括将确诊为HIV感染的人群转介至艾滋病治疗和关怀服务的措施，这是综合关怀服务包的组成部分，促使个体做好启动抗病毒治疗的准备。第七章：包括针对成人（含孕妇及哺乳妇女）、青少年、儿童的抗病毒治疗建议，包括适合于大部分人群的关于启动抗病毒治疗的最佳时机的最新建议；关于最有效及最可行的一线及二线抗病毒治疗方案的最新建议（启动治疗时使用何种方案，转换至何种治疗方案）；监控及处理抗病毒药物毒性反应的最新建议；以及对三线抗病毒治疗方案进行讨论。第八章：结合现有的世卫组织指导意见，总结了针对艾滋病相关的常见机会性感染、其他合并感染和并发症的预防和处理方法。

1.5.3 实施和服务提供指南第九章：包含了针对6个主要的实施和服务提供提供的建议，为在整个卫生系统进一步扩展抗病毒药物规划并确保其有效性和可持续性，在这些领域所必需采取行动。这些领域包括：使患者保留在关怀队列中；使患者坚持抗病毒治疗；人力资源；服务提供模型，重点是将抗病毒治疗分散至初级卫生保健机构，并将抗病毒治疗纳入结核病治疗、产前保健、孕产妇及儿童保健规划以及药物依赖干预服务；实验室服务；药物供应管理。

1. 引言

1.5.4 规划管理者指南第十章：致力于协助各国决策及规划制定人员。规划实施将涉及各类政策组合，根据当地实际政策组合不尽相同。需要考虑的当地实际包括： HIV感染流行情况和变化趋势； HIV传播模式；卫生系统机构和能力；相对收入；以及当前干预措施的覆盖程度。本章提出了在国家层面确保公平、包容及透明决策的步骤；还就成本核算和制定规划的工具提出了建议。本章还针对指南中所提及的在整个卫生系统内部实施、特别及重点建议的考虑进行了讨论。

1.5 范围及内容

1.5.5 监控与评估第十一章：提供了针对本指南中重要的新建议可能产生的影响进行监测的指导意见。本章提出了用于追踪新建议的执行情况的系列指标，以及用于监控跨持续关怀体系规划的绩效的指标。第十一章也强调新建议提供了审核及加强监控评估体系的机会。

图1.1 综合指南的主要内容做什么 • HIV检测与咨询 •基于抗病毒药物的预防措施 • 综合艾滋病关怀服务 • 何时启动ART？ •启动ART时使用何种方案？ •如何监测？（ART治疗效果和毒性） • 如何换药（二线ART） •合并感染和并发症的处理怎么做 • ART的依从性 •使患者保留在关怀队列中

临床

运营

•提供服务的创新模式（整合，分散化，职责调整） • 人力资源 • 实验室和诊断服务 • 采购及供应管理系统

规划

如何确定该做些什么，在哪里及何时做 • 决策（过程、所需数据和关键参数） • 实施考虑因素 • 针对成本核算和规划制定的有用工具

监控与评价 • 对新建议可能产生的影响进行监控 •监控扩大抗病毒药物可及性的产出和结局 •其他监控考虑（耐药性和抗病毒药物毒性监测） • 加强监控和评价体系

指导原则

02 42 42 42 42 43 43

2.1 对全球卫生目标的贡献 2.2 公共卫生措施 2.3 通过学习和创新加强卫生系统 2.4 提高规划的效率和效果 2.5 促进人权和卫生公平 2.6 因地制宜

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

2. 指导原则 2.1 对全球卫生目标的贡献指南的实施有助于达成如下两个政治宣言中阐明的目标，即2006年关于艾滋病毒/艾滋病问题的政治宣言（1）和2011年关于艾滋病毒/艾滋病问题的政治宣言：加大行动力度，消除艾滋病毒/艾滋病（2），使人们普遍获得HIV的预防、关怀、治疗和支持。指南还将有助于实现20112015年全球卫生部门艾滋病毒/艾滋病战略（3）中设定的卫生部门的具体目标。指南对于致力在2015年前消除儿童新发HIV感染和使感染HIV的母亲持续生存的全球计划（4），也不无裨益。 2015年的目标包括：与2009年相比， 15-25岁青年的HIV感染率减少50%；儿童新发HIV感染者人数减少90%； HIV相关疾病的死亡人数减少25%； HIV相关的孕产妇死亡人数减少一半；与2004年相比，结核病死亡人数减少一半；在中低收入国家为1500万人提供抗病毒治疗。从远期来看，指南将促进实现 “人人享有健康” 的目标，这是2015年后发展日程的重要支柱之一。

2.2 公共卫生措施与世卫组织自2002年以来其他的HIV相关指南相同，本指南同样基于公共卫生措施，旨在扩大抗病毒药物的使用，以治疗和预防艾滋病（5）。公共卫生措施力图通过经简化的标准方法，确保有需要的人群能够普遍获得高质量的服务，并在实施已证实的最佳关怀标准和资源有限的地区可能大规模推行的服务之间找到平衡。

2.3 通过学习和创新加强卫生系统实施指南中与提供服务有关的改革和建议，应以加强HIV持续关怀体系和强化广义的卫生体系为目的，尤其要加强基本关怀和长期关怀。在很多高负担地区，艾滋病防治服务已纳入基层卫生机构的日常工作，而预防HIV母婴传播（PMTCT）服务正日益成为妇幼卫生服务的核心元素。艾滋病、结核病、肝炎、药物依赖和减低伤害等卫生服务也实现了程度不一的整合。随着接受抗病毒治疗者的老龄化， HIV感染逐渐变为一种慢性可控的疾病，促进HIV服务与非传染性疾病关怀的整合就显得尤为重要。为应对这些趋势，本指南着力推动服务提供模式的改变，以加强HIV关怀体系，在多种环境和条件下促进需要者及时开始抗病毒治疗，确保需要者转诊到适宜的服务机构且保持和依从终身治疗。国家级的艾滋病规划应该考虑进行实施性研究，确定如何更好的采纳指南的建议，使其适应各地的具体环境，大规模的开展高效而有益的服务。

2.4 提高规划的效率和效果在资金来源有限、卫生体系受限和存在优先权竞争的地区，面临使用抗病毒药物降低HIV的发病率、死亡率和减少传播等方面的层出不穷的抉择问题，各国常常进退维谷。本指南的基本原则是，各国应采取战略性手段应用抗病毒药物，进一步提高和优化艾滋病规划的效率和效果，方法包括：优先向符合治疗标准的最需要帮助的HIV感染者提供抗病毒药物；探索机遇，通过在某些人群中更早的开始治疗，加强抗病毒药物预防HIV传播的作用；

2. 指导原则

战略性的综合运用有质量保证的多种HIV检测方法，提高治疗依从性和保持率，创新服务提供方式，将抗病毒治疗与更多且更广泛的机构服务相整合，加强各种服务之间的衔接。通过这些方法，加强艾滋病关怀体系中抗病毒药物规划的有效性和可及性；同时采取短期和长期行动，优化并统一药物治疗方案，同时降低其价格，开发和实施更加简单经济的即时诊断方法和实验室服务。

2. 指导原则

2.5 促进人权和卫生公平应将获得艾滋病预防、治疗、关怀和支持服务作为实现人人享有健康权的基础。本指南应在核心人权和伦理学原则的基础上实施。总之，艾滋病规划应保证包括孕妇、儿童和重点人群在内的最需要的人群能够获得抗病毒药物及相关干预措施，并应采用可最大限度减少耻辱和歧视的服务提供方式。应做到知情同意—众所周知应用于HIV检测，但启动抗病毒治疗时也应征得患者的知情同意。应制定充分的安全措施以做到保密。一些受资源和本国卫生体系制约的国家在实施指南的过程中可能会面临重大的伦理挑战，其中一个重要的挑战可能是需要优先保证为最严重的患者提供抗病毒治疗和为已开始治疗者继续提供抗病毒药物，而同时又要努力放宽治疗的适用条件。每个国家都需要制定符合本国国情的方法，确保现有的抗病毒药物规划不会中断，同时公平合理的提高药物可及性。

2.6 因地制宜要因地制宜实施指南中的建议，要考虑的当地实际情况包括艾滋病流行形势、可用资源、卫生系统的组织结构和能力，以及预期的成本效益等。不能简单的认为指南中强烈建议的某项特定的服务提供方法是公认模型，可以完全替代国内现有的有效服务模式。

指南的编制方法和过程

03 46 46 47 47 47 48 50 50

3.1 概述 3.2 资料来源 3.3 外部参与 3.3.1 指南制定小组和同行评议过程 3.3.2 利益冲突

3.4 建议的制定过程 3.5 其他方法 3.6 发布

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

3. 指南编制的方法和过程 3.1 概述本2013年综合指南合并了新建议、现有建议以及其他与艾滋病持续关怀相关的指南。本指南以公共卫生措施为基础，包括艾滋病毒检测、艾滋病综合关怀和有策略地应用抗病毒药物治疗和预防艾滋病毒感染。本指南的制定遵守世卫组织指南审查委员会（1）所定规程，且基于 GRADE （推荐、评估、制定与评价分级）体系（2-11），提出了新的临床和实施方面的建议。其中引自现有指南的建议绝大多数根据GRADE方法编制而成。少数未使用GRADE方法而获得的建议，在本指南中会注明。由于第十章对规划的指导意见中不包含任何正式的建议，故该章未使用 GRADE方法。

3.2 资料来源制定新建议时使用了以下来源的资料：统综述。系世卫组织指南制定领导小组（3）使用人群、干预、对比和结局原则（Population, Intervention, Comparison and Outcome, PICO）对41个问题进行了系统综述（网络附件： www.who.int/hiv/pub/guidelines/arv2013/annexes）。这41个问题涵盖了艾滋病治疗的全过程（9个问题涉及何时启动治疗； 11个问题涉及启动治疗后做什么； 4个问题涉及治疗效果的监测； 6个问题涉及毒副反应监测； 6个问题涉及服务提供的各个方面； 5个问题涉及依从性干预）。指南制定领导小组与指南制定小组共同讨论，确定了临床证据方面综述的关键指标（即死亡率、发病率、传染情况和严重不良反应），同时也确定了服务提供方面综述的关键指标（即死亡率、发病率、传染情况、可及性、治疗持续性、病毒抑制情况以及依从性）。系统综述委托给了制定检索方案并对现有证据进行审查的研究人员。他们运用相关的关键词和检索式在电子数据库（MEDLINE/PubMed、 Embase、 CENTRAL）、会议数据库（Aegis、 AIDSearch、 NLM Gateway和手工检索）和临床试验注册中心（http:// clinicaltrials.gov, www.controlled-trials.com和http://www.pactr.org）进行检索。网络附件（http://www.who.int/hiv/pub/guidelines/arv2013/annexes）包括检索方案、有关综述问题的完全清单和GRADE表以及各主题的证据摘要。 . 标准化的GRADE证据表。该表用来对临床证据进行定量总结，并以结局为指标对每个PICO 问题进行质量评估。 GRADE方法用于评估证据的质量（4-10）和推荐的等级（11）（附件3.1 ；网络附件： www.who.int/hiv/pub/guidelines/ arv2013/annexes）。社区咨询。由国际艾滋病联盟和艾滋病毒感染者全球网络（GNP+）协作，通过在线网络调查和民间团体网络共同主持论坛讨论，对指南中重点领域的价值观和优先权进行了社区咨询。并且在乌干达和马拉维进行了专题小组讨论，讨论南非孕妇终生进行抗病毒治疗、预防母婴传播和儿童抗病毒治疗的相关经验（网络附件http://www.who.int/hiv/pub/ guidelines/arv2013/annexes）。际和民间团体的两次协商。国针对HIV中、高流行区域进行持续治疗的服务提供问题，国际社会团体和民间团体进行了两次磋商。咨询卫生工作者。对为成人和儿童服务的卫生工作者进行了一项网络调查，就指南中重点领域的价值观和优先权进行了咨询。

3. 指南编制的方法和过程

2012年WHO艾滋病药物和诊断服务中心第六次年度调查。调查80个低收入及中低收入国家的抗病毒药物使用和诊断情况（网络附件www.who.int/hiv/pub/guidelines/arv2013/ annexes）。数学建模。 HIV建模协会对不同人群和环境中早期进行抗病毒治疗的影响和成本效益建立了数学模型，同时对不同治疗监测策略进行了模型分析，其数据来自于HIV中、高流行的国家（印度、肯尼亚、南非、越南和赞比亚）（网络附件www.who.int/hiv/pub/guidelines/arv2013/ annexes）。进行影响评估。基于不同的资格标准，通过谱系模型（Spectrum Model）评估适合接受抗病毒治疗的成人和儿童的增长数量（网络附件www.who.int/hiv/pub/guidelines/arv2013/ annexes）。国家经验报告各国的实施经验报告显示，马拉维使用B+方案预防艾滋病母婴传播；赞比亚将替诺福韦（TDF）引入一线抗病毒治疗；津巴布韦将司他夫定司他夫定司他夫定（d4T）从抗病毒治疗方案中剔除；非洲南部的无国界医生组织则扩展了对病毒载量的监测工作。针对国家级终端用户的网络调查为明确世卫组织抗病毒药物使用指南中格式、表达和发布方面需要改进的地方，专门针对国家级的终端用户进行了一项网络调查（网络附件www.who. int/hiv/pub/guidelines/arv2013/annexes）。

3. 指南编制的方法和过程

3.3 外部参与 3.3.1 指南制定小组和同行评议过程整个过程由四个相互独立的外部指南制定小组（即成人组，妇幼保健组，实施和服务提供组以及规划组，共计108人）和一个一百余人的外部同行评议组共同支撑。这些成员将在致谢名单中列出。小组依照世卫组织指南制定规程（1）组建，成员包括艾滋病专家、调查研究人员、规划管理人员、指南制定方法学专家、流行病学专家、人权专家、发展机构、联合国合作伙伴以及来自社会和艾滋病毒感染者网络的代表，并且考虑了地理和性别上的代表性。社会小组成员通过公开的电话提名进行选择。完整的指南草案将分发给指南制定小组和外部同行评议小组的成员进行评阅。

3.3.2 利益冲突指南制定组和外部同行评议组的所有成员都填写了世卫组织利益声明表（包括担任咨询顾问、获得科研支持和财务投资）。共计21名指南制定小组成员和12名同行评议专家声明曾担任制药公司或顾问团队的成员，或曾收取咨询费用， 23名指南制定小组成员和13名同行评议专家声明有制药公司通过资助其科研的方式曾对其提供资金支持。 2013年指南旨在制定新的或者更新现有的关于成人、青少年、儿童和孕妇使用抗病毒治疗药物的建议。世卫组织秘书处和各指南开发组的联合主席认为，潜在利益冲突的重点在于成员被单独某家制药公司雇佣，或者参与已完成、正在进行或计划进行的试验，在某家制药公司进行抗病毒治疗期间或评估具体抗病毒治疗效果时担任重要角色。世卫组织指南制定领导小组审查了所有声明，未发现仅加入一家顾问团队、仅收取一家公司的咨询费用或科研资金仅来自于某一家制药公司资助的情况。在关键实验和研究中担任审查员的成员以后也会在指南制定小组会议中做出声明。总而言之，世卫组织指南制定领导小组和各指南制定小组的联合主席已经确认，成员的利益冲突声明是透明的，没有谁需要从此审议过程中排除。同时也向不同指南制定小组所代表的广泛的选区的全体选民声明，多数成员没有需要声明的利益驱使。因此所有已填写利益声明的人员全部继续参加指南制定小组会议或担任同行评议专家。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

3.4 建议的制定过程 2012年11月至2013年1月，指南制定小组在瑞士日内瓦召开了4次会议（2012年11月，实施和服务提供指南制定小组会议； 2012年12月，成人指南制定小组和妇幼保健指南制定小组会议； 2013年1月，规划指南制定小组会议）。会议讨论了系统综述、用GRADE方法制定的证据表以及其他在3.2节讨论过的相关内容，并在一个需密码登录的网站上发布。随后针对以下每个主题（3.1专栏）编制标准化决策制定表，对提出的建议进行考量。这些主题包括：现有和新提出的建议；证据概要；受益和风险；社区和卫生工作者的价值观和偏好；成本和涉及的资源；成本效果；可行性和实施障碍；公平、伦理和人权问题；建议推荐强度的等级（强烈推荐或有条件推荐）和证据质量；研究中存在的不足和需求；建议的总体依据等。指南制定小组不仅讨论了建议的措辞，还讨论了其推荐强度（强烈推荐或有条件推荐）。所有的决议都是在商讨并对建议达成一致意见的基础上形成的，包括推荐的强度、适合的区域、推荐附带的条件。对于分歧，则通过邮件讨论、电话会议和重新起草推荐及理论依据来解决。指南各章节的早期草案在指南制定小组成员间传阅，完整草案在指南制定小组成员间和同行评议专家间传阅，以便做出评价。对于一百余名评议专家所提出的广泛意见，尽可能采纳并整合入的指南的修订版.

专栏3.1 使用GRADE系统评估证据质量和推荐强度的方法世卫组织自2008年开始使用GRADE方法，该方法可以将证据的质量和建议的强度区分开来。证据质量是指报告的效应估计值足以支撑某具体决策或推荐的可信程度。 GRADE方法将证据质量分为高、中、低和极低四个级别（表3.1）（4-10）。随机对照试验初始被评定为高质量证据，但可能会由于某些原因被降级，如研究的局限性、研究结果不一致、间接证据、结果不精确和报告有偏倚等。观察性研究初始被评定为低质量证据，但若某干预措施效果显著、多数研究呈现相同效果、证据显示剂量反应关系或者可能导致效果显著降低的各种偏倚都可被识别时，观察性研究的质量等级可能会被提高（10）。证据的质量等级越高，越有可能被强烈推荐。推荐强度反映出指南制定小组认为采纳推荐后获得的理想效果大于潜在的不良效果的程度。推荐强度受到以下因素的影响：证据的质量、利弊的权衡、价值观和优先权、资源的利用和干预的可行性（表3.2）。 GRADE方法将推荐强度分为两种： “强烈” 和 “有条件” [11]。强烈推荐是指南制定小组确信采纳建议后的受益程度大于不良作用。有条件推荐是指南制定小组认为采纳建议后获得的受益程度可能大于不良作用，但对收益和风险间的平衡关系不够确定。表3.3总结了 “强烈推荐” 和 “有条件推荐” 分别对个人、临床医生和政策制定者的意义。有条件推荐的原因包括：缺乏高质量的证据；结果估计不精确；个体对干预结果的价值观和偏好易改变；收益低；更适应特定环境而非所有环境；收益低而成本高（包括实施该建议的成本）。

3. 指南编制的方法和过程

表3.1 GRADE证据等级分类证据等级高中等低极低依据进一步研究也几乎不可能改变我们对预计效果的确信程度进一步研究可能影响我们对预计效果的确信程度进一步研究很有可能影响我们对预计效果的确信程度，预计效果可能改变任何预计效果都很不确定

3.4 建议的制定过程

表3.2 影响推荐强度的关键维度维度收益和风险价值观和优先权（可接受性）成本和财务的影响（资源使用）可行性依据期望效果（收益）需大于不良影响（风险）。收益比风险大越多，越可能被强烈推荐如果该建议可能被广泛接受或高度评价，则可能被强烈推荐。若有充分的理由认为该推荐方法很难被接受，则更有可能被确定为有条件推荐成本（资金、基础设施、设备或人力资源）较低或成本效益较高的将更可能被强烈推荐如果一项干预可实施并且预期可获得最好效果，则更可能被强烈推荐

表3.3 强烈推荐和有条件推荐对个人、临床医生和政策制定者的意义强烈推荐个人你所处的环境中，绝大部分人希望拥有所推荐的行动路线，只有少部分人不希望绝大部分人会接受该行动路线有条件推荐你所处的环境中大部分人希望拥有所推荐的行动路线，但也有很多人不希望准备帮助个人做出与其价值观一致的决定需要利益相关者进行大量的讨论和参与

临床医生政策制定者

在大多数情况下该建议适于采纳为政策

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

3.5 其他方法现有指南中的推荐。除外基于GR ADE方法的新推荐，本指南还总结了现有的世卫组织其他指南中的相关建议。这些建议多使用GRADE方法制定，或者使用2008年之前的分级标准（A （强烈推荐）到C （可选推荐））及I–IV （证据等级）（网络附件www.who.int/hiv/pub/ guidelines/arv2013/annexes）。对于现有建议没有重新进行证据审查。对于需要更新的建议已标注，对于各指南中已计划更新之处也已明确声明。对于无法进行或不适合通过系统综述和使用GRADE方法评估证据质量来对新建议加以证明之处，已撰写了定性文献综述并发表。此方法应用于第9章的一些特定议题，包括如何促使患者保留在艾滋病关怀体系中，但该方法尚不能构成正式的建议。针对负责规划决策的规划管理人员的指导。第10章和第11章不涉及建议制定或证据质量评估，因此未使用GRADE方法。该过程涉及了两篇综述，其中一篇属叙述性综述，内容为基于证据的伦理决策过程和标准；另一篇综述是关于世卫组织相关政策、世界卫生大会决议以及利用数学建模获得的在不同人群和地区中早期进行抗病毒治疗的效果和成本效益。指南制定小组成员还进行了结构化讨论，以确定不同艾滋病流行形势（艾滋病中流行、高流行区域以及抗病毒治疗覆盖程度为低、中、高的不同区域）中关键临床建议的优先级别。

3.6 发布本指南将以联合国六种官方语言，通过出版物和世卫组织网络进行宣传。网上版本将包含所有附件。精简版概括了新的和现有的关键建议，以便于参考。网站提供了所有的支持文件和证据库。世卫组织总部将通过区域和分区域会议，与各区域和各国办事处及合作伙伴紧密联系，确保实现指南的广泛传播，同时将向各成员国提供帮助以实现指南的本土化。为了解用户对这些建议的理解程度，并发现妨碍指南有效实施的障碍，世卫组织已经开始制定一项关于用户如何实施指南的评估。本指南将于2015年进行复审。在此期间，如果发现有新的重要证据，可能会对本指南进行技术层面或规划层面的更新。

指南的结构

04 52 54 54 54 55 56 58 59

关怀体系

4.1 新建议的介绍结构 4.2 选自现有指南的建议的介绍结构 4.3 如何将指南应用于特定人群 4.3.1 孕妇和哺乳期妇女 4.3.2 青少年 4.3.3 儿童 4.3.4 重点人群

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

4. 指南的结构关怀体系

第6.2节

第9.3节

■■

持续 HIV预防 HIV综合关怀进行ART准备并感染和合并发症处

■■ ■■

HIV咨询和检测

接至关怀链体系中

■■

纳入关怀

■■ ■■

第5.1节

第5.2节

第6.1节

第6.4节

第8.1和8.2节

4. 指南的结构

第9.2和9.3节

■■

依从性和持续性

启动ART (一线) ■■ ■■

二线和三线ART 监测ART的反应监测ARV

第7.1和7.2节

第7.3和7.4节

第7.5节

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

4.1 新建议的介绍结构指南的新建议已用符号新标出。在本指南编制过程中重新进行了证据审核，据此对原有建议进行了更新，这些更新的建议也包含于新建议之中。如果原有建议未改变，也做了清晰的标示。建议按照如下格式介绍，反映了指南制定小组对新建议充分的证据讨论和审核过程。建议。描述了通过GRADE系统评估的新建议的强度和相关证据的质量。背景。描述了此前世卫组织在该领域的指南以及最近一次出版相应建议之后的主要进展。如建议涉及到特定人群，则会对该人群的主要问题进行简要总结。建议的依据和支持性证据。概述了建议的新证据和制定建议时在实施和规划方面所考虑的其他主要问题。床问题或实施考量。临列出了某些情况下与建议相关的主要临床实施问题。第10章讨论了一些主要建议的与规划经理有关的实施考虑。要的研究差距。主在某些情况下，描述和列举了需进一步研究的关键问题，这也是建议内容的一部分。各章的参考资料按章节列在指南的最后。

4.2 选自现有指南的建议的介绍结构有两个章节概述了出自现有世卫组织指南的建议：第5章HIV咨询和检测以及抗病毒药物的预防性使用；第8章HIV综合关怀，包括合并感染和合并症的预防和处理。大体上按照如下格式介绍：背景; 建议的来源补充指导（如适宜）；现有建议介绍了通过GRADE系统（或其他可选方法）评估的建议的强度和相关证据的质量。

4.3 如何将指南应用于特定人群指南包括了对成人、孕妇和哺乳期妇女、青少年、儿童和重点人群的建议。明确而详细地说明了每条建议所涉及的具体人群，还标记了适当的符号供快速查询。成人孕妇青少年表4.1-表4.4总结了对特定人群（孕妇和哺乳期妇女、青少年、儿童和婴儿、重点人群）的重点建议和指南的相关章节：表格筛选并突出强调了与各人群高度相关的议题。但是，表格并未穷举所有相关问题，而且，很多建议和指导都是与多个人群相关的。儿童重点人群

4. 指南的结构

4.3.1 孕妇和哺乳期妇女表4.1总结了与孕妇和哺乳期妇女相关的主要指导建议在指南中的位置。

4.3 如何将指南应用于特定人群

表4.1 针对孕妇和哺乳期妇女的主要建议和指导意见章第5章： HIV诊断和ARV 药物的预防应用议题卫生机构的HIV咨询和检测以社区为基础的HIV咨询和检测特定人群的HIV咨询和检测：配偶特定人群的HIV咨询和检测：孕妇和产后妇女特定人群的HIV咨询和检测：早期婴儿诊断单阳配偶的预防性抗病毒治疗第6章：将确诊为HIV感染的人纳入关怀和治疗第7章：抗病毒治疗 HIV感染者的综合关怀 HIV感染者抗病毒治疗前准备抗病毒治疗的第一个月会出现哪些情况孕期和哺乳期妇女何时开始抗病毒治疗抗病毒药物和哺乳持续时间孕妇关怀和管理的特殊考虑孕期和哺乳期妇女的一线抗病毒治疗方案和婴儿的抗病毒药物监测抗病毒治疗的反应和治疗失败的诊断（包括孕期和哺乳期妇女）监测抗病毒药物毒性和药物替换（包括孕妇和哺乳期妇女）成人和青少年的二线抗病毒治疗方案（包括孕妇和哺乳期妇女）三线抗病毒治疗（包括孕妇和哺乳期妇女）第8章：常见的合并感染和合并症的处理第9章：实施和服务提供方面的指导意见合并感染合并感染的预防、筛查和处理其他合并症的预防和处理以及HIV感染者的长期关怀节第5.1.2节第5.1.3节第5.1.4.1节第5.1.4.2节第5.1.4.3节第5.2.2节第6.3节第6.4节第6.5节第7.1.2节第7.1.3节第7.1.3节，专栏7.1 第7.2.2节第7.3节第7.4节第7.5.1节第7.6节第8.1节第8.2节

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。抗病毒治疗的依从性：孕妇和产后妇女在产前保健和妇幼保健机构提供抗病毒治疗任务下沉和职责分工调整第9.2.1节第9.4.2.1节第9.4.3节和第9.5.2节

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

表4.1 针对孕妇和哺乳期妇女的主要建议和指导意见（续）章第10章：针对规划经理的指导意见议题节

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。主要建议的实施考虑：努力为所有孕妇和哺乳期妇女提供终身抗病毒治疗新建议的监测含义附录1. 世卫组织关于儿童、青少年和成人艾滋病的临床分期附录3. 2013年孕期和哺乳期妇女的建议原则附录6. 准备情况评估表：努力为孕期和哺乳期妇女提供抗病毒治疗附录7. 青少年和成人推荐抗病毒药物的剂量（包括孕期和哺乳期妇女）第10 .6节，专栏10.4 第11.2节第12章

第11章：监测和评估附录

4.3.2 青少年 WHO将青少年定义为10岁～19岁。 HIV青少年感染者包括围产期感染的幸存者、因性活跃而新近感染、或通过注射吸毒和其他不安全注射行为发生暴露，以及通过输血而感染的人。青少年可以在多种机构获得HIV关怀服务，包括儿科和产前保健门诊、成人门诊。但是很少有卫生系统提供专门的青少年服务，这种情况对青少年获取卫生保健服务和保持治疗依从性提出了挑战。总之，指南中针对成人的临床和综合关怀建议也适用于青少年。在针对儿童的建议中涉及青少年的指导意见时，也有明确指示。有4条针对咨询和检测的具体建议摘自最新的青少年指南。 2013年青少年HIV咨询检测和青少年感染者关怀指南包含了为青少年提供HIV检测咨询和服务的建议。（表4.2）

4. 指南的结构

表4.2 孕期和哺乳期妇女的主要建议和指导章第5章： HIV诊断和ARV 药物的预防性使用议题卫生机构的HIV咨询和检测以社区为基础的HIV咨询和检测特定人群的HIV咨询和检测：青少年第6章：将确诊为HIV感染的人纳入关怀和治疗第7章：抗病毒治疗 HIV感染者的综合关怀 HIV感染者抗病毒治疗前准备抗病毒治疗的第一个月会出现哪些情况成人和青少年何时开始抗病毒治疗三岁及以上儿童一线抗病毒治疗方案（包括青少年）儿童HIV感染者合并结核病的联合治疗监测抗病毒治疗的反应和治疗失败的确定（包括青少年）监测抗病毒药物毒性和药物替换（包括青少年）主要抗病毒药物的相互作用（包括青少年）成人和青少年的二线抗病毒治疗方案包括青少年的儿童二线抗病毒治疗方案第8章：常见的合并感染和合并症的处理第9章：实施和服务提供方面的指导意见合并感染的预防、筛查和处理其他合并症的预防和处理以及HIV感染者的长期关怀成人和青少年感染者的营养关怀与支持节第5.1.2节第5.1.3节第5.1.4.4节第6.3节第6.4节第6.5节第7.1.1节第7.2.4节第7.2.5节第7.3节第7.4节表7.16 第7.5.1节第7.5.2节第8.1节第8.2节第8.2.4.1节

4.3 如何将指南应用于特定人群

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。抗病毒治疗的依从性：青少年任务下沉和职责分工调整第9.2.1节第9.4.3节和第9.5.2节

第10章：针对规划经理的指导意见

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。规划经理对主要建议的实施考虑：将成人和青少年开始抗病毒治疗的 C D 4 +T 淋巴细胞计数标准从 350个/mm3提高到500个/mm3 新建议的监测含义附录1. 世卫组织关于儿童、青少年和成人艾滋病的临床分期附录2. 2013原则年成人和青少年的建议原则附录7.青少年和成人抗病毒推荐药物的剂量第12章第10.6节，专栏10.2 第11.2节

第11章：监测和评估附录

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

4.3.3 儿童表4.3总结了重要的儿童（10岁以下）专门指导建议的位置。

表4.3 儿童的主要建议和指导章第5章： HIV诊断和ARV 药物的预防性使用议题卫生机构的HIV检测以社区为基础的HIV咨询和检测特定人群的HIV咨询和检测：婴幼儿和儿童第6章：将确诊为HIV感染的人纳入关怀和治疗第7章：抗病毒治疗 HIV感染者的综合关怀 HIV感染着抗病毒治疗前准备抗病毒治疗的第一个月会出现哪些情况儿童何时开始抗病毒治疗三岁以下儿童一线抗病毒治疗方案三岁及以上儿童一线抗病毒治疗方案儿童HIV感染者合并结核病的联合治疗监测抗病毒治疗的反应和治疗失败的诊断（包括儿童）监测抗病毒药物毒性和药物替换（包括儿童）主要抗病毒药物的相互作用（包括儿童）三线抗病毒治疗方案（包括儿童）第8章：常见的合并感染和合并症的处理合并感染合并感染的预防、筛查和处理免疫其他合并症的预防和处理以及HIV感染者的长期关怀成人和青少年感染者的营养关怀与支持第9章：实施和服务提供方面的指导意见节第5.1.2节第5.1.3节第5.1.4.3节第6.3节第6.4节第6.5节第7.1.4节第7.2.3节第7.2.4节第7.2.5节第7.3节第7.4节表7.16 第7.6节第8.1节第8.1.7节第8.2节第8.2.4.2节

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。抗病毒治疗的依从性：婴儿和儿童任务下沉和职责调整第9.2.1节第9.4.3节和第9.5.2节

4. 指南的结构

表4.3 儿童的主要建议和指导（续）章第10章：针对规划经理的指导意见议题节

4.3 如何将指南应用于特定人群

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。主要建议的实施考虑：扩大儿童治疗主要建议的实施考虑：逐步淘汰司他夫定司他夫定司他夫定（d4T）第10 .6节，专栏10.6 第10 .7 节，专栏10.7 第11.2节

第11章：监测和评估附录

新建议的监测含义附录1. 世卫组织关于儿童、青少年和成人艾滋病的临床分期附录4. 2013年的儿童建议原则附录5. 早期婴儿诊断原则附录7. 基于体重的儿童抗病毒药物剂量配方

第12章

4.3.4 重点人群在本指南中，重点人群包括易受感染的人群和高危人群。高危人群包括男男性行为者、变性者、注射吸毒者和性工作者等。重点人群的抗病毒治疗应遵循与成人建议相同的一般原则。以社区为基础的HIV检测中有一条建议是专门针对重点人群的。表4.4总结了重点人群（10岁以下）的专门指导建议的位置。

表4.4 重点人群的主要建议和指导章第2章指导原则第5章： HIV诊断和ARV 药物的预防性使用第6章：将确诊为HIV感染的人纳入关怀和治疗议题保证人权和促进卫生公平卫生机构的HIV检测以社区为基础的HIV咨询和检测特定人群的HIV咨询和检测：重点人群 HIV感染者的综合关怀 HIV感染者抗病毒治疗前准备抗病毒治疗的第一个月会出现哪些情况节第2.5节第5.1.2节第5.1.3节第5.1.4.5节第6.3节第6.4节第6.5节新

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

表4.4 重点人群的主要建议和指导（续）章第7章：抗病毒治疗议题成人和青少年何时开始抗病毒治疗（包括重点人群）成人的一线抗病毒治疗方案（包括重点人群）监测抗病毒治疗的反应和治疗失败的诊断（包括重点人群）监测抗病毒药物毒性和药物替换（包括重点人群）成人和青少年的二线抗病毒治疗方案（包括重点人群）三线抗病毒治疗方案（包括重点人群）第8章：常见的合并感染和合并症的处理第9章：实施和服务提供方面的指导意见合并合并感染的预防、筛查和管理合并合并感染和并发症的预防和处理吸毒及相关疾患抗病毒的依从性：高危人群（包括性工作者、男男性行为者、变性者和注射吸毒者）鸦片类毒品替代治疗机构提供抗病毒治疗，整合和链接相关服务任务下沉和职责调整第10章：针对规划经理的指导意见节第7.1.1节第7.2.1节第7.3节第7.4节第7.5.1节第7.5.3节第8.1节第8.2节第8.2.3节第9.2.1节第9.4.2.3节第9.4.3节和第9.5.2节

本章所有指南均与多个人群相关。在此列出与特定人群相关的议题。社会经济学、政策和法律环境伦理、公平和人权主要建议的实施考虑：将成人开始抗病毒治疗的 CD4+T淋巴细胞计数标准从350个/mm3提高到500 个/mm3 主要建议的实施考虑：逐步淘汰司他夫定司他夫定（d4T）第10.3.4节第10.4.1节第10 .6节，专栏10.2 第10 .7 节，专栏10.7 第11.2节

第11章：监测和评估附录

新建议监测的含义附录1. 世卫组织关于儿童、青少年和成人艾滋病的临床分期附录7. 抗病毒药物的推荐剂量

第12章

HIV感染的诊断与抗病毒药物的预防性应用 5.1 HIV检测与咨询 5.1.1 前言 5.1.2 医疗机构开展的HIV检测与咨询 5.1.3 社区开展的HIV检测与咨询 5.1.4 特定人群HIV检测与咨询 5.2.1 使用口服药物进行暴露前预防 5.2.2 单阳配偶抗病毒治疗预防HIV传播 5.2.3 职业暴露和非职业暴露的暴露后预防 5.2.4 HIV综合性预防

贯穿关怀体系的临床指南：

05 62 62 63 64 65 74 74 74 75 75

5.2 应用抗病毒药物预防HIV

本章目标为广泛实施艾滋病关怀服务体系的地区，特别针对卫生系统能力和资源有限的地区和场所，总结现有及最新循证临床建议，概述致力于确诊HIV感染以及预防性抗病毒治疗的公共卫生措施。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

贯穿关怀体系的临床指南： 5.

HIV感染的诊断与抗病毒药物的预防性应用

5.1 HIV检测与咨询 5.1.1 前言 HIV咨询检测是人们获得HIV治疗、关怀和预防服务的重要入口。据估计，目前全球大约有一半的HIV感染者不知道自己的感染状况。了解自己感染状况的人通常检测较晚，而且HIV检测咨询到关怀之间的衔接较差―包括未能迅速获得抗病毒治疗准入资格―这意味着很多人开始治疗时已经明显出现免疫功能低下，因而导致健康结局不理想，同时导致HIV持续传播。对于一个在全国范围内实施的艾滋病规划而言， HIV检测与咨询服务的总体目标应该是尽可能让更多的HIV 感染者在感染后尽早确诊，并及时地通过合适的方式转介至预防、关怀和治疗服务体系。经检测未感染的人群应转介到合适的预防服务体系，如在撒哈拉以南非洲地区一些重点国家开展的男性自愿包皮环切医疗服务，或者对吸毒人群提供减少危害服务，鼓励他们于一段时间后进行重复检测。提供多样化的HIV检测咨询服务模式可提高获得HIV诊断服务的可及性，包括在卫生保健机构设立咨询检测点，设立多个独立的咨询检测服务点以及大范围的以社区为基础的服务点。这些服务模式在《2012年世卫组织HIV检测与咨询策略框架》（1）中有详细叙述。 HIV快速诊断试验可用于现场即时检测，目前已成为一项重要策略，提高了检测可及性和当天获得结果的比例，并促使患者得以合理转介和随访。各国应根据当地的实际情况、 HIV流行现状、成本效果以及可获取的资源，确定包含不同服务模式的综合策略，使公众得以公平获取HIV检测与咨询服务。这种综合性的检测服务应促使尽可能多的HIV感染者得以尽早诊断，并且能够及时获得抗病毒治疗服务。这些策略要覆盖那些最脆弱的人群、高危人群和边缘人群（专栏5.1）。只开展1次HIV检测不足以确诊HIV感染；必须按照世卫组织于2012年更新的HIV检测策略（程序）（1）中规定的步骤进行确诊。要将检测结果的假阳性率和假阴性率控制到最低，必须建立一个质量保证体系。否则，将有可能得到不准确的检测结果，从而可能产生长期的严重不良后果。对于咨询过程而言，质量保证和质量改进措施也非常重要，可保证HIV检测咨询总是采用可接受的有效方式来开展。

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

专栏5.1 HIV检测咨询：指导原则所有形式的HIV检测与咨询服务都必须遵循 “5C” 原则：知情同意（Consent）、保密 (Confidentiality)、咨询（counselling）、结果准确(correct result)以及与关怀、治疗和预防服务相链接(connections to care, treatment and prevention services)。检测绝对不能以强制性和胁迫性形式开展，无论这种胁迫是来自于卫生保健人员还是伴侣或家庭成员。以下主要原则适用于各种场合、各种形式的HIV检测咨询。为人们提供HIV检测咨询服务之前必须征得其知情同意（口头知情同意即可，不要求必须有书面的知情同意书）。应告知他们HIV检测咨询的过程以及他们有拒绝检测的权利。 HIV检测咨询服务是保密的，这意味着未经求询者同意， HIV检测咨询服务人员和求询者之间的谈话内容不得泄露给任何外人。尽管要尊重保密权，但也不应过于强调秘密、歧视和羞耻感。咨询员应通过其他议题，了解求询者可能希望把检测结果告知什么人，以及通过何种方式告知。与一个伴侣或家庭成员分享秘密，相信他人并与卫生保健人员分享秘密通常是非常有益的。 HIV检测咨询服务必须配套高质量的检测前咨询（在一些场合下可以通过集体进行检测前咨询的方式提供）和检测后咨询。为保证提供高质量的咨询服务，必须建立质量保证机制以及支持性的监督指导体系。 HIV检测咨询员应力求提供高质量的检测服务，同时建立质量保证机制以保证提供准确的检测结果。质量保证机制要包括内部和外部措施，并在必要时能够获得国家参比实验室的支持。与预防、关怀和治疗服务的衔接要包含提供有效的转介服务，使患者获得适宜的随访服务，包括长期的预防和治疗支持服务。无论采用何种形式的检测咨询服务，质量保证措施均必不可少。

5.1.2 医疗机构开展的HIV检测与咨询背景世卫组织建议在医疗机构提供常规HIV检测与咨询服务（即所谓的医务人员主动提供的检测和咨询， PITC）作为一种高效实用方式，诊断HIV感染者并使之从治疗中获益。

建议依据：生机构医务人员主动提供HIV检测咨询指南。卫日内瓦，世卫组织， 2007。 (http://whqlibdoc.who.int/publications/2007/9789241595568_eng.pdf) （2）。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

目前建议（2）在高流行地区，建议向以下医疗机构所有就诊者（成人、青少年和儿童）提供PITC服务：医疗手术机构；性传播疾病、肝炎及结核门诊；公立及私立医疗机构；住院部及门诊；流动或外展医疗服务机构；为孕妇提供卫生服务的机构（产前门诊、计划生育门诊和妇幼保健机构）；重点人群服务机构；婴儿和儿童服务机构；以及生殖健康服务机构。在中度流行区和低流行地区，建议对所有医疗机构对下列人群提供PITC服务：到医疗机构就诊的成人、青少年和儿童，有症状、体征或医学情况可能提示HIV感染，包括结核病；暴露于HIV的儿童、 HIV阳性妇女所产婴儿以及有症状的婴儿和儿童。在性病、肝炎和结核病门诊、产前保健门诊以及重点人群服务点（特别是男男性行为人群、变性人群、性工作者和注射毒品人群），应考虑提供PITC服务。

5.1.3 社区开展的HIV检测与咨询除了医疗机构，还可以在社区多种场所提供HIV检测与咨询服务。

最新建议（2013）

新

在HIV高度流行区，除了PITC服务之外，建议提供以社区为基础的HIV检测与咨询服务，并开展预防、关怀和治疗服务。（强烈建议，证据质量较低）在不同HIV流行情况下，除PITC服务之外，均建议为重点人群提供以社区为基础的 HIV检测咨询服务，并开展预防、关怀和治疗服务。（强烈建议，证据质量较低）

背景这些指南扩大了感染HIV的儿童、青少年、成人和孕妇及哺乳妇女的抗病毒治疗适用标准。为使这些建议所提及的个人及公众健康的利益最大化，必须尽可能在HIV感染的早期阶段发现并转介至治疗关怀服务。尽管在医疗机构开展检测是一个重要途径，但在医疗场所中诊断的HIV感染者通常已处于感染晚期，同时一些人群包括男性和青少年，特别是重点人群，对卫生保健服务的利用率通常很低。与医务人员主动提供HIV检测咨询相比，以社区为基础的HIV检测方式可能在HIV感染早期发现感染者，同时可以将检测服务扩展至那些通常情况下不去医疗机构就诊的人群。 HIV快速诊断试验应用指尖血检测，可由接受过培训的咨询员和社区卫生工作者开展检测，这种方式可促进社区场所HIV检测咨询服务的扩展；社区场所包括家庭、客运站、宗教机构、中学、大学、工作场所以及运动场馆等重点人群频繁出入的地方。持续扩大社区HIV检测咨询作为医疗机构HIV检测咨询服务的补充，这是一项非常重要的策略，有助于实现普遍知晓HIV感染状态、早期诊断并获得关怀和治疗服务。以社区为基础的HIV检测与咨询服务包括应用流动外展服务、走家窜户、推荐、开展运动和以工作场所及学校为基础等多种方式提供HIV检测与咨询服务。（1）

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

理论依据与支持性证据这些建议均有证据支持，同时也得到实施规划的证明。系统性综述纳入了四项随机化研究（3,4）和八项观察性研究（5-10），对高流行区地区的以社区为基础的检测和以医疗机构为基础检测两者进行了比较（网络附件： www.who.int/hiv.pub/guidelines/arv2013/annexes）。研究结论是，以社区为基础的检测方式提高了人们首检率以及CD4+T淋巴细胞计数超过350/ mm3的成年人的诊断率。但是，医疗机构的阳性结果检出率要高于社区场所。系统综述发现，通过社区HIV检测咨询服务（通过走家串户方式或者流动外展服务方式）与医疗机构HIV检测咨询服务相结合的方式，地区级的HIV 检测咨询服务的覆盖率明显提高。另外一项综述主要针对重点人群，选择了三项研究，对重点人群的社区检测服务和医疗机构检测服务进行了对比（11-13）。经分析发现，两种方式下调查对象首检率基本相当，而以社区为基础的检测方式的接受率较高。 15项研究对以社区为基础的检测服务可能存在的负面影响进行了分析（10， 14-25）。这些研究对检测对象获得阳性结果的经历及其忧虑进行了讨论。 8篇文章报告称，少数调查对象拒绝 HIV检测咨询的原因是担心自己的感染状况被暴露或者歧视（10， 14-17， 21， 23， 25）。这些研究并没有对社区检测会减少还是会增加歧视或恐惧或者其他伤害进行阐述。若干项研究分析比较了医疗机构检测服务和社区检测服务的单位（/人）服务成本，结果发现，两种方式的单位服务成本基本相当（网站附件： www.who.int/hiv/pub/guidelines/ arv2013/annexes）。虽然上述综述提供的总体证据质量较低，但编写组成员一致认为，社区HIV检测咨询具有重要的规划优势，同时上述综述对社区HIV检测咨询的价值、优势、成本和可行性进行了分析，从而提供了充足的依据，使指南编写组得以提出重要建议。社区HIV检测咨询服务应作为医务人员主动提供检测咨询服务的有效补充。同时需要多种方式并重，包括独立检测点、家庭检测、流动外展服务检测（包括工作场所、学校、大学、专项检测运动和活动）以及为获得流行病学和社会学基础数据而开展的多种疾病调查活动。

5.1 HIV检测与咨询

5.1.4 特定人群HIV检测与咨询 5.1.4.1 配偶背景多个国家开展的研究表明，配偶HIV检测咨询是可接受、可行及有效的检测咨询方式。这种检测咨询方式可以发现单方阳性配偶，对已感染的一方可转介至治疗服务使之获得治疗依从性支持。同时，对尚未感染的另一方可提供预防性干预使之受益。这项服务的对象应包括夫妇或同居配偶、有婚前性行为的情侣、一夫多妻或一妻多夫家庭以及其他伴侣关系的人群。与所有HIV 检测咨询方式一样，伴侣HIV检测咨询也必须遵循自愿原则。医务人员必须了解亲密伴侣间发生暴力的可能性，同时当他们不愿和伴侣同时检测时应提供相应支持。伴侣HIV检测咨询可以在所有提供HIV检测咨询的场所开展，包括产前保健和结核病门诊。鼓励HIV感染者的伴侣进行检测也是发现更多HIV感染者的有效途径，如发现其感染还可向其者提供治疗服务而使之受益。伴侣 HIV检测咨询还可作为一种重要的干预方式，使HIV感染者更早获得抗病毒治疗，从而使抗病毒治疗覆盖更多感染者。通过向单方感染或双方均感染HIV的家庭提供检测咨询，可使更多之前未知晓感染状态的儿童、青少年和其他家庭成员获得诊断结果。新

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

建议依据：侣HIV检测咨询，伴包括单方阳性配偶的抗病毒治疗和预防。日内瓦，世卫组织， 2012 （http://whqlibdoc.who.int/publications/2012/9789241501972_ eng.pdf）（26）。

目前建议（26）配偶和伴侣的HIV检测咨询应遵循自愿原则，并支持相互告知检测结果（强烈建议，证据质量较低）。在产前保健门诊应为配偶和伴侣提供HIV自愿检测咨询，并支持相互告知检测结果（强烈建议，证据质量较低）。应对已知晓自身HIV感染状况的个人及其伴侣提供配偶和伴侣HIV自愿咨询检测，并支持相互告知检测结果（对于所有流行水平下所有HIV携带者均强烈建议，但证据质量较低；对于HIV阴性人群，则建议根据各国HIV流行状况而定，有条件者开展，但证据质量较低）。

5.1.4.2 孕妇及产妇背景医务人员主动对孕妇提供检测咨询并开展预防和关怀治疗，有助于改善母亲健康和预防新生儿感染，并有助于配偶检测策略的实施。

建议依据：生机构医务人员主动提供HIV检测咨询指南。卫日内瓦，世卫组织， 2007 （http://www.who.int/hiv/pub/vct/pitc2007/en）（2）。

目前建议（26）高流行水平地区建议将女性PITC服务作为产前保健、分娩、产后及儿科保健场所保健服务包的常规内容。由于孕期感染HIV的危险性较高，建议在孕期后三个月、分娩时或产后短期内重新检测HIV。

中、低流行水平地区应考虑向孕妇提供PITC服务。许多国家将PITC服务作为与加强基本妇幼保健系统同等重要的优先规划在产前门诊开展，视之为预防HIV母婴传播措施的关键组成部分，并有效地将HIV检测和梅毒筛查、肝炎检测及与产前检查有关的其他重要检测相结合协同开展。

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

5.1.4.3 婴儿和儿童背景暴露于HIV的婴儿及18月以下儿童在出生四到六周之内要进行HIV检测，以便检测结果阳性的婴幼儿及时开始抗病毒治疗。感染HIV而未经治疗的婴儿在一岁以内的病死率非常高。因此及早进行HIV检测、及时反馈结果并迅速启动治疗非常必要。在此类人群中， HIV感染只能通过病毒学检测进行确认，因为母体HIV抗体可以在儿童体内持续存在15-18个月。病毒学检测包括病毒核酸检测试验（HIV、 DNA、 RNA或总核酸）或p24抗原检测试验。目前，最常用的病毒学检测是干血斑（DBS）样本检测，可通过现场采样，运送至中心实验室进行检测。尽管早期检测比例逐渐得到提高，但是结果获取、反馈以及结果阳性婴儿的早期治疗问题还面临着更大挑战。进一步开展现场即时病毒学检测有望极大改善早期诊断和治疗问题。由于一些婴儿的HIV暴露状况未被发现或者未能给予产后随访，婴儿保健机构因此要开展PITC服务，以便发现更多病例。要确保在母婴传播的危险期之内（母乳喂养阶段）完成确诊，如果一个已知有过HIV暴露的婴儿其HIV抗体检测结果为阴性，若无后续暴露则可认为该婴儿没有感染HIV。（见附件5：小于18个月龄幼儿的HIV感染诊断原则。）对于18个月龄及以上儿童（未进行母乳喂养或者至少6周前终止母乳喂养），标准的HIV血清学检测如快速检测可用于有效判断HIV感染状况。世卫组织建议，对所有营养不良、患有结核病、住院治疗或者有其他HIV感染症状或体征的儿童开展PITC。为提高HIV感染儿童的发现机会，一些地区也尝试了其他方法，比如对接受儿童免疫接种规划的所有儿童均进行HIV检测。未来期间将对婴幼儿HIV感染诊断方面的建议进行评估。

5.1 HIV检测与咨询

表5.1 婴儿HIV检测推荐方法汇总（27) 分类明确 HI V暴露史的健康婴儿 H I V暴露史不明确的婴儿健康且在9个月月龄时有过HIV暴露的婴儿检测需求出生后4周 — 6周内开展病毒学检测母亲HI V血清学检测或婴儿HIV血清学检测 HIV血清学检测（最后一次免疫接种通常在 9月龄开展）目的诊断HIV 诊断或确定 HIV暴露确定婴儿HI V 抗体持续存在还是发了生血清学转变措施若感染则开展抗病毒治疗若有HIV暴露则需进行病毒学检测 HIV血清学阳性需要进行病毒学检测并持续随访；若HIV阴性，则认定未感染，若持续母乳喂养则需复查如果<18月龄实施病毒学检测应对―启动HIV关怀和抗病毒治疗感染HIV的婴儿及5 岁以下儿童，需要启动HIV关怀，包括抗病毒治疗

具有HI V感染症状或体征的婴幼儿 > 9 月且 <18 月龄的 H I V血清学阳性的儿童，不论健康或患病完全终止母乳喂养的婴幼儿

HIV血清学检测病毒学检测

确认暴露诊断HIV感染

终止母乳喂养6周或更长时间后重复检测，通常应用血清学检测，并对HIV阳性儿童和不足18月龄儿童进行病毒学检测

暴露结束后排除HIV感染

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

建议依据：卫组织关于婴幼儿HIV感染的诊断建议。世日内瓦,世卫组织， 2010 （http://whqlibdoc. who.int/publications/2010/9789241599085_eng.pdf）（27） 2岁以下儿童HIV检测结果告知咨询指南。 1 日内瓦，世卫组织， 2011 （http://whqlibdoc. who.int/publications/2011/9789241502863_eng.pdf）（28）

目前建议（27）烈建议卫生保健机构对所有未知或未确定HIV暴露状况的婴儿在分娩时或分娩前后强或产后第一次随访（通常出生后4周 ― 6周内）时，或在儿童健康随访时，进行HIV暴露状况确认（强烈建议，证据质量高）。烈建议所有HIV暴露婴儿在出生后4周 ― 6周内或其后及早进行HIV病毒学检测强（强烈建议，证据质量高）。于初次病毒学检测结果阳性婴儿，对强烈建议立即开始抗病毒治疗，并同时采集第二份血样证实最初的阳性病毒学检测结果。不能延误抗病毒治疗。立即启动抗病毒治疗，挽救婴儿生命，尽管还在等待确证结果，也不能因此推迟治疗（强烈建议，证据质量高）。烈建议具有HIV感染症状或体征的婴儿采取HIV血清学检测，强如果结果阳性（应对），则开展病毒学检测（强烈建议，证据质量较低）。烈建议有HIV暴露史的健康婴儿在9月龄强（或者在最后一次免疫接种随访时）前后采取HIV血清学检测。 9月龄血清学试验阳性反应婴儿应进行病毒学检测，以确证婴儿 HIV感染状况，并对结果阳性者开展抗病毒治疗（强烈建议，证据质量较低）。烈建议疑有HIV感染或HIV暴露的18月龄及以上儿童，强按照成人HIV血清学标准诊断原则开展HIV血清学检测（强烈建议，证据质量高）。

目前建议（28）将学龄儿童的HIV阳性状况告知其本人、应父母或监护人；学龄前儿童HIV感染状况的告知要循序渐进，待其认知能力、情绪逐渐成熟，可以应对全面揭示HIV感染状况之后再进行告知（强烈建议，证据质量较低）。

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

5.1.4.4 青少年背景在许多艾滋病规划中，为青少年提供的服务总是匮乏的，为青少年提供服务并未赋予优先级别；青少年对HIV检测咨询服务的可及性较差，接受检测率低，也难以获得后续的预防及关怀服务。感染HIV的青少年包括围产期感染后仍存活的和进入性活跃期后通过性传播感染，以及由于注射吸毒、其他不安全注射感染和输血等途径感染的青少年人群。在高流行地区，通过早期HIV 诊断和治疗将使那些预防母婴传播规划中未诊断出的垂直感染婴儿受益。在许多情况下，青年女孩和重点人群中的青少年很容易受到HIV感染，但他们可受益于包括HIV检测咨询服务在内的具有可接受性且有效的HIV服务。在一些地区，知情同意问题可能会成为青少年接受HIV服务的障碍， 2013年世卫组织出版的关于青少年的相关指南对此问题进行了详细讨论（29）。

5.1 HIV检测与咨询

建议依据：青少年HIV检测咨询及青少年HIV感染者关怀指南。日内瓦，世卫组织， 2013，新闻报道（29）。

最新建议（2013）（29）

新

议在不同HIV流行水平地区建（高、中、低流行），均为重点人群中的青少年提供HIV检测咨询服务，并提供预防、治疗和关怀服务（强烈建议，证据质量非常低）。议向HIV高度流行区的所有青少年提供HIV检测咨询服务，建并提供预防、治疗和关怀服务（强烈建议，证据质量非常低）。议在中、建低流行地区的所有青少年均接受到HIV检测咨询服务，并获得预防、治疗和关怀服务（建议有条件时开展，证据质量非常低）。们建议向青少年提供相关咨询服务，我包括公开自身HIV感染状况可能带来的利益和风险，同时鼓励和帮助青少年决定是否、何时、如何以及向谁公开自身HIV感染状况（建议有条件开展，证据质量非常低）。新

理论依据与支持性证据这些建议是青少年HIV防治最新指南的一部分，由世卫组织、联合国教科文组织、联合国人口活动基金会、联合国儿童基金会和全球HIV感染者网络于2013年发布，依据对当前证据的系统综述、对青少年和卫生保健人员价值和偏好的团体讨论评估以及各个指南编制组的慎重考虑意见编制而成。大多数情况下，针对青少年HIV防治建议缺少已公开发布的证据；在这些指南中，专家意见、青少年及其卫生保健人员的价值和偏好以及工作人员的现场经验占据了相当大的分量。青少年HIV检测咨询和青少年HIV感染者关怀指南（29）中有关证据汇总的部分对此做了详细描述。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

5.1.4.5 重点人群背景自最初开发出HIV检测技术以来， HIV检测咨询服务就优先覆盖重点人群。世卫组织于2006 年发布了注射毒品人群HIV检测指南，于2009年发布了羁押人群和难民HIV检测指南，于2011年发布了男男性行为人群和变性人群HIV检测指南，于2012年发布了性工作者HIV检测指南。对于重点人群，特别是罪犯， HIV检测咨询服务有时是通过惩罚性或强制性方式提供。因此，关于这些高危人群和脆弱人群在HIV检测咨询方面的当前建议和最新建议均重点强调知情同意和保密，并保证HIV检测咨询成为预防、关怀和治疗综合规划的组成部分。 2012年世卫组织HIV检测咨询策略框架（1）对所有这些人群（亚群）的HIV检测咨询指南进行了汇总（表5.2和表5.3）。

补充指南：低收入国家性工作者HIV及其他性传播疾病的预防和治疗：中公共卫生措施建议。日内瓦, 世卫组织， 2012 （http://apps.who.int/iris/bitstream/10665/77745/1/ 9789241504744_eng.pdf）（30）性行为人群及变性人群HIV及其他性传播疾病的预防和治疗：男公共卫生措施建议。日内瓦，世卫组织， 2011.(http://whqlibdoc.who.int/publications/ 2011/9789241501750_ eng.pdf) (31)

表5.2 高流行地区HIV检测咨询建议汇总检测谁医疗机构的所有就诊者何时检测与其他诊疗服务相整合何地检测所有场所，包括初级卫生保健机构、门诊和外科病房、产前保健和妇幼保健机构、结核病防治机构、计划生育机构和性病诊疗机构。初级卫生保健机构、自愿咨询检测点、抗病毒治疗门诊、产前保健机构、计划生育门诊、性病诊疗门诊、社区及流动外展服务点、家里初级卫生保健机构、抗病毒治疗机构、妇幼保健机构和产前保健机构、家里、社区以及流动外展服务点世卫组织相关指南卫生机构医务人员主动提供HIV检测咨询指南（2）

伴侣和配偶

婚前、孕期、分居后、有新伴侣时以及开始抗病毒治疗和关怀时；对于HIV单方阳性配偶中的阴性方，每 6个月～12个月检测一次在家庭成员诊断HIV 感染后尽早检测

伴侣HIV检测咨询，包括单阳配偶应用抗病毒疗法治疗和预防HIV （26）成人HIV检测结果告知及重复检测咨询信息告知（32）

有指示病例的家庭

HIV检测咨询（HTC）的服务提供方式： H TC规划策略框架（1）家庭HIV检测的计划、实施和督导（33）

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

表5.2 高流行地区HIV检测咨询建议汇总（续）检测谁重点人群：注射吸毒人群、男男性行为人群、变性人群、性工作者和注射吸毒者的伴侣何时检测每 6个月～12个月检测一次何地检测初级卫生保健机构、性病诊疗机构和外展服务点，包括减轻危害服务点和为重点人群提供服务的其他场所世卫组织相关指南中低收入国家性工作者HIV 及其他性传播疾病的预防和治疗：公共卫生措施建议（30）男男性行为人群和变性人群 HIV及其他性传播疾病的预防和治疗：公共卫生措施建议（31） HIV检测咨询（HTC）的服务提供方式： H TC规划策略框架（1）成人HIV检测结果告知及重复检测咨询信息告知（32）孕妇和男性伴侣首次产前保健就诊时；孕期后三个月或围产期再次检测；为伴侣提供检测产前保健机构、分娩机构和产后保健机构卫生机构医务人员主动提供HIV检测咨询指南（2）成人HIV检测结果告知及重复检测咨询信息告知（32）伴侣HIV检测咨询，包括单阳配偶应用抗病毒疗法治疗和预防HIV （26）婴儿及＜18月龄幼儿母亲HI V 阳性或HI V 状况未知婴儿在出生后4周～6周内进行早期诊断； 18月龄以及/ 或者母乳喂养结束后确证婴儿HIV感染状况每次就诊均是为其确定是否感染HIV的机会与其他诊疗服务相整合；性活跃期每年一次；有新性伴时妇幼保健服务机构；儿科门诊；计划免疫门诊世卫组织关于婴儿及儿童 HIV感染诊断的建议（27）

5.1 HIV检测与咨询

儿童

儿童病房和门诊；计划免疫门诊

卫生机构医务人员主动提供HIV检测咨询指南（2）

青少年

初级卫生保健机构，门诊病人，住院病人，自愿咨询检测点，面向青少年的服务机构，计划生育机构，性病诊疗机构

成人HIV检测结果告知及重复检测咨询信息告知（32）青少年HIV检测咨询及青少年HIV感染者关怀治疗指南（29）

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

表5.3 中、低流行地区HIV检测咨询建议汇总检测谁具有HIV感染症状或体征者何时检测与其他诊疗服务相整合何地检测性病诊疗机构、结核病防治机构、病房、其他门诊临床机构，包括初级卫生保健机构、抗病毒治疗门诊、结核病防治机构、产前保健机构、性病诊疗门诊、自愿咨询检测门诊抗病毒治疗门诊、妇幼保健机构和产前保健机构、家里、社区以及流动外展服务点世卫组织相关指南卫生机构医务人员主动提供HIV检测咨询指南（2）

HIV感染者的配偶

配偶确诊感染HI V 后应对另一方尽早检测；对单方阳性配偶中的阴性方，每 6 个月～12个月检测一次在家庭成员诊断 H I V感染后尽早检测

伴侣HIV检测咨询，包括单阳配偶应用抗病毒疗法治疗和预防HIV （26）成人HIV检测结果告知及重复检测咨询信息告知（30）

有指示病例的家庭

HIV检测咨询（HTC）的服务提供方式： HTC规划策略框架（1）家庭HIV检测的计划、实施和督导（33）伴侣HIV检测咨询，包括单阳配偶应用抗病毒疗法治疗和预防HIV （26）

重点人群：注射吸毒人群、男男性行为人群、变性人群和性工作者

每 6 个月～12个月检测一次

性病诊疗机构、重点人群外展服务点和减轻危害服务机构

中低收入国家性工作者HIV 及其他性传播疾病的预防和治疗：公共卫生措施建议（30）男男性行为人群及变性人群 HIV及性传播疾病预防与治疗：公共卫生措施建议 HIV检测咨询（HTC）的服务提供方式： HTC规划策略框架（1）成人HIV检测结果告知及重复检测咨询信息告知（32）

孕妇

首次产前保健就诊时

产前保健机构

卫生机构医务人员主动提供HIV检测咨询指南（2)

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

表5.3 中、低流行地区HIV检测咨询建议汇总（续）检测谁婴儿及＜18月龄幼儿何时检测母亲HIV阳性或 HI V状况未知婴儿在出生后4周―6 周内进行早期诊断； 18月龄以及/或者母乳喂养结束后确证婴儿H I V感染状况与其他诊疗服务相整合何地检测妇幼保健服务机构；儿科门诊；计划免疫门诊世卫组织相关指南世卫组织关于婴儿及儿童 HIV感染诊断的建议（27）

5.1 HIV检测与咨询

有HIV感染症状或体征的儿童，或者有感染 HIV的家庭成员的儿童

所有医疗场所

卫生机构医务人员主动提供HIV检测咨询指南（2）

重点人群中的青少年

每 6 个月―12个月检测一次

面向青少年的服务机构，性病诊疗机构，外展服务点

成人HIV检测结果告知及重复检测咨询信息告知（32）青少年HIV检测咨询及青少年HIV感染者关怀治疗指南（29）

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

5.2 应用抗病毒药物预防HIV

5.２.1 使用口服药物进行暴露前预防背景使用口服药物进行暴露前预防（PrEP）是指未感染HIV人群每天口服抗病毒药物以避免感染。临床试验表明，在单方阳性配偶（34）、男男性行为人群（35）、高危异性恋配偶（36）、注射毒品人群（37）中，每天口服药物进行暴露前预防具有显著效果。

建议依据：方阳性配偶、单与HIV高危男性发生性行为的男性和变性女性人群使用口服药物进行暴露前预防指南：示范规划使用建议。日内瓦，世卫组织， 2012.(http://apps.who.int/iris/ bitstream/10665/75188/1/9789241503884_eng.pdf) (38)。

目前建议（38）世卫组织当前建议（38）是为示范规划中应用口服药物进行暴露前预防而制定，针对单方阳性配偶、与HIV高危男性发生性行为的男性和变性女性人群。方阳性配偶。单当确定单方阳性配偶后，同时需要其他HIV预防选择时，可以每天口服药物（TDF或TDF+FTC联合用药）进行暴露前预防，并将此作为针对未感染配偶的一项附加干预措施。如果使用口服药物进行暴露前预防的对象是同性恋、男男同性恋的单阳配偶中的未感染方，则需要TDF+FTC联合用药，因为目前对男男插入性性行为人群的治疗方案中仅此疗法其有效性和安全性得以证实。性和变性女性。男男性和变性女性在与男性发生性行为时可传播HIV，如果需要其他 HIV预防选择时，可以考虑将每天口服药物（特别是TDF+FTC联合用药）进行暴露前预防作为一项有效干预措施（建议有条件时开展，证据质量高）。 1

第七章中详述抗病毒药物预防的其他方面内容，包括预防母婴传播。

5.2.2 单阳配偶抗病毒治疗预防HIV传播建议依据：伴侣HIV检测咨询，包括单阳配偶应用抗病毒疗法治疗和预防HIV。日内瓦，世卫组织， 2012 （http://whqlibdoc.who.int/publications/2012/ 9789241501972_eng.pdf） (26)。

目前建议（26）该在单阳配偶中的HIV感染者为自身健康开始抗病毒治疗时告知，应抗病毒治疗也推荐用于降低将HIV传播给未感染配偶的风险（强烈建议，证据质量高）。单阳配偶中CD4计数≥350/mm3的HIV感染者提供抗病毒治疗，向降低其将HIV传播给未感染配偶的风险（强烈建议，证据质量高）。

5. 贯穿关怀体系的临床指南： HIV感染的诊断与抗病毒药物的预防性应用

5.2.3 职业暴露和非职业暴露的暴露后预防背景暴露后预防是指无论是由于职业暴露还是性行为，在可能暴露后通过短期使用抗病毒治疗减少感染HIV的可能性。在卫生系统内部，暴露后预防应作为普遍预防综合服务的组成部分，以降低发生暴露的工作人员的感染风险。自2006年以来，世卫组织一直未对职业暴露后预防指南进行评估， 2014年将对该指南进行更新。目前建议HIV感染的暴露后预防的疗程是28天，第一剂药物应在暴露后72小时内尽早应用。暴露后预防药物应根据各国针对HIV的一线抗病毒治疗方案进行选择。一项最新建议（39）特别提及性侵的暴露后预防。

5.2 应用抗病毒药物预防HIV

建议依据：对女性的亲密伴侣间暴力和性暴力应对：针临床与政策指南。日内瓦，世卫组织，新闻报道（39）。

目前建议（2013）（39）女性在遭遇性侵72小时内要考虑采取HIV暴露后预防措施。与受害人共同讨论以决定 HIV暴露后预防是否合适（强烈建议，证据质量非常低）。

5.2.4 HIV综合性预防背景人们对预防HIV的需求在其一生中是有所改变的。一套综合措施有助于人们在不同时期获得最适宜的干预措施。综合措施也可能产生协同效应，较单项干预措施产生更大的影响。尽管抗病毒药物在HIV预防中发挥了重要作用，但仍需与以下多种适宜措施联合应用。他生物医学干预措施，其这些措施可减少HIV危险行为和/或每次接触事件传播HIV的可能性，包括： • 用和女用安全套。男如果坚持并正确使用男用安全套，可至少减少80%的异性传播，并可为64%在男男同性恋人群中进行的肛交行为提供保护。针对女用安全套有效性的数据很少，但证据表明女用安全套和男用安全套有类似的保护效果（41）。针具交换规划和注射吸毒人群HIV传播降低高度相关（42）。沙酮或丁丙诺啡替代阿片类药物治疗是治疗阿片类药物依赖最有效的方式，美同时也有效减少了HIV高危行为的发生，降低了注射吸毒传播HIV的发生。阿片类药物替代疗法也提高了抗病毒治疗人群的依从性（43-44）。性自愿进行包皮环切使男性感染HIV的风险至少降低了66%，男同时可提供显著的终身保护效果（45）。

• •

•

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

行为干预减少了可能导致传播的事件的发生频率，包括以下措施： • 有针对性的宣传教育。这些规划通过不同的交流方式—例如学校性教育、同伴咨询和社区咨询及人际咨询—来传播行为改变信息，鼓励人们减少那些可增加HIV风险的行为、增加保护性行为（如安全药品使用、推迟首次性行为、减少多性伴无保护性行为频率、正确坚持使用男用和女用安全套、了解自己和性伴的HIV感染状况）。

构性和支持性干预可影响行为学和生物医学干预措施的可及性、结接受度和持续性。此类干预措施解决与HIV传播有关的关键的社会、法律、政策和环境问题，包块法律和政策改革、减少歧视及侮辱、促进性别平等和预防性暴力、加强经济赋权、入学、以及致力于加强转介、依从、保持力和社区动员的支持性干预措施。

确诊HIV感染者的后续关怀与治疗服务 6.1 前言 6.2 衔接关怀服务的最佳实践措施 6.3 HIV感染者的综合关怀服务 6.4 HIV感染者抗病毒治疗准备 6.5 抗病毒治疗最初几个月的预期效果

贯穿关怀体系的临床指南：

06 78 78 78 81 82

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

6. 贯穿关怀体系的临床指南：将确诊HIV感染者转介至关怀与治疗服务 6.1 前言对于HIV感染者而言，及早接受HIV关怀治疗至关重要。这样他们就能够尽早接受抗病毒治疗适宜性评估并及时启动抗病毒治疗，同时获得干预服务，以预防HIV二代传播，预防其他感染和并发症，从而减少失访。 2012年世卫组织HIV检测咨询规划策略框架（1）特别强调，保证HIV检测咨询规划与预防、治疗、关怀和支持服务之间有效衔接的重要性。 .

6.2 衔接关怀服务的最佳实践措施对于能够促进与治疗关怀衔接的干预措施，需要进一步严格评估。但是，多项系统综述和观察性研究表明，有多种最佳措施可促进与治疗关怀的衔接（2-4）。这些措施包括：将HIV检测咨询与关怀服务进行整合；提供现场或即时CD4检测并当日反馈结果；如果抗病毒治疗场所和HIV 检测咨询点的距离比较远，要提供交通帮助；利用社区外展工作人员寻找失访人员；保证来自于有经验病人和同伴病人的支持；以及使用诸如手机短信等新技术。

6.3 HIV感染者的综合关怀服务各国应专门建立一套针对HIV感染者的综合关怀干预服务包，而不仅限于抗病毒治疗服务，从而减少HIV传播，预防发病并提高感染者的生活质量。并不是所有的HIV感染者都适合开展抗病毒治疗，同时也不是所有适合开展抗病毒治疗的感染者都能及时得到治疗。一些人可能会选择推迟抗病毒治疗。将HIV感染者纳入关怀范围有利于拉近临床与实验室监测和抗病毒治疗适宜性评估的距离，及时启动抗病毒治疗，达到最大可能减少失访的目的。许多治疗关怀干预措施在整个持续关怀过程中是相互关联的，包括HIV暴露个体、 HIV感染者治疗前及治疗阶段。综合关怀包括HIV基本预防、 HIV感染者健康促进和筛查、 HIV相关合并感染和并发症的预防和处理。世卫组织对综合关怀和预防措施制定了简要指南（5-7），同时于2008年推荐了一系列针对资源有限地区感染HIV的成人及青少年的预防干预措施，共包含13项预防干预内容（5）。这些建议包括： (1)社会心理学咨询及支持； (2)告知及伴侣告知； (3)复方新诺明预防性治疗； (4) 结核病咨询、筛查和预防性治疗； (5)预防常见真菌感染； (6)预防性传播疾病并提供生殖健康支持，包括预防和筛查宫颈癌； (7)疟疾（复方新诺明、蚊帐以及预防孕妇感染疟疾）； (8)特定疫苗可预防疾病； (9)营养； (10)计划生育； (11)预防母婴传播； (12)注射吸毒人群的针具交换规划；以及(13)饮水及清洁卫生问题。根据各地HIV流行类型、受影响人群和合并感染情况、其他并发症和健康问题的不同，综合关怀服务也有所差异。表6.1中对HIV感染者关怀服务包要素进行了概括总结。 8.1节中根据世卫组织现有指南，对最常见的合并感染、并发症和其他健康问题的筛查、预防和抗病毒治疗时机等方面的主要建议进行了总结。

6. 贯穿关怀体系的临床指南：将确诊HIV感染者转介至关怀与治疗服务

表6.1 HIV感染者持续关怀综合服务要素一览表服务规划 HIV诊断时期w 关怀登记时期启动抗病毒治疗时期实施抗病毒治疗期间治疗失败及更换方案期内容及参考文献

6. 贯穿关怀体系的临床指南：将确诊HIV感染者转介至关怀与治疗服务

综合关怀 WHO临床分期过去及现存HIV 相关问题怀孕状况计划生育与避孕预防母婴传播告知和伴侣告知支持风险减少咨询与 H I V综合预防措施并发症与非传染性疾病的筛查、预防和处理精神卫生和药物滥用问题筛查、预防及处理疼痛及症状处理 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ 8.2.6.1节 7.1.2节及 7.2.2节 5.1.4节 ✓ ✓ ✓ 附件1

✓

5.2.4节

✓

8.2.1节

✓

8.2.2节及 8.2.3节

✓

8.2.5节

营养评估与咨询

✓

8.2.4节

儿童和青少年营养、生长发育评估婴儿及儿童喂养

✓

7.1.3节 8.2.4节

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

表6.1 HIV感染者持续关怀综合服务要素一览表（续）服务规划 HIV诊断时期w 关怀登记时期启动抗病毒治疗时期实施抗病毒治疗期间治疗失败及更换方案期内容及参考文献

合并感染的预防和治疗复方新诺明预防性治疗 ✓ ✓ ✓ ✓ ✓ 8.1.1节

加强结核病例发现

✓

8.1.2节

异烟肼预防性治疗

✓

8.1.2节

隐球菌感染筛查与真菌感染预防

✓

8.1.3节

乙肝、丙肝筛查

✓

8.1.4节

预防疟疾（用杀虫剂处理蚊帐并进行预防性治疗）性传播疾病筛查

✓

8.1.5节

✓

8.1.6节

子宫颈癌预防和筛查

✓

8.1.7节

疫苗可预防疾病评估

✓

8.1.7节

6. 贯穿关怀体系的临床指南：将确诊HIV感染者转介至关怀与治疗服务

表6.1 HIV感染者持续关怀综合服务要素一览表（续）服务规划 HIV诊断时期w 关怀登记时期 ✓ 启动抗病毒治疗时期 ✓ 实施抗病毒治疗期间治疗失败及更换方案期内容及参考文献 6.4节

6.4 HIV感染者的抗病毒治疗准备

抗病毒治疗准备

依从性准备、评估及支持服务

✓

6.4节 9.2节

目前的药物治疗

✓

7.4.6节

6.4 HIV感染者的抗病毒治疗准备在开始抗病毒治疗之前，首先要和他们进行一次详细的讨论，包括抗病毒治疗的意愿、是否做好抗病毒治疗前的准备、抗病毒治疗方案、药物剂量和服药计划、可能的收益及潜在的副作用以及必要的随访监测等。对于儿童感染者，要直接与其监护人讨论这些问题，同时还要讨论儿童感染状况的告知问题（见第5章）。在开始抗病毒治疗之前，首先要对HIV感染者重新进行一次检测，这样可以更好地保证诊断的准确性。启动抗病毒治疗时还应总是考虑患者的营养状况、合并症以及药物交互作用，以便考虑到禁忌症和药物剂量调整等问题。最终接受还是拒绝抗病毒治疗还要由患者本人或他/她的监护人来决定，如果他们选择推迟抗病毒治疗，在后续的的随访过程中可以再次提议开展抗病毒治疗。如果患者存在精神健康问题、药物滥用或其他影响依从性的重大问题，需要向他们提供适当的支持措施，同时定期评估其抗病毒治疗准备状况。丰富多彩的有关其他病人的信息材料和社区及病友的支持可帮助患者做好准备并做出启动抗病毒治疗的决定。开始抗病毒治疗的患者及其监护者要认识到，一线抗病毒治疗方案具有抑制病毒和修复免疫系统的最佳效果，而要成功实现治疗效果则需要他们完全按照处方要求服用药物。需要告知他们许多副作用是暂时的，并可治疗处理，有问题的抗病毒药物通常可用其他药物替换（见9.2节，抗病毒治疗依从支持策略）。对于接受抗病毒治疗的患者及其监护人，要定期询问其他药物的服用情况，包括中药和营养制剂。接受抗病毒治疗的患者要认识到，尽管抗病毒药物可以降低HIV传播的风险，但不能完全依靠抗病毒治疗来预防他人感染HIV。应建议他们采取安全性行为（包括使用安全套），避免诸如共用针具等其他高危行为，以防止将HIV传播给他人。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

6.5 抗病毒治疗最初几个月的预期效果尽管抗病毒治疗是一项终生行为，但治疗的前六个月尤为重要。如果患者坚持抗病毒治疗，有望获得临床和免疫学的改善，实现病毒抑制，但也可能出现机会性感染和/或免疫重建炎性综合征（IRIS），以及早期药物副作用，例如药物过敏，特别是在抗病毒治疗的前三个月。总体而言，抗病毒治疗可有效降低病死率，但在抗病毒治疗的前三个月其病死率是最高的。如果患者开始抗病毒治疗时已处于艾滋病晚期，存在严重免疫缺陷、合并感染和/或并发症、严重低血红蛋白、低体重指数以及CD4+T淋巴细胞计数非常低或严重营养不良等问题，这些并发症更常见。

CD4计数恢复大多数成人和儿童在开始抗病毒治疗及出现免疫重建后， CD4+T淋巴细胞计数会升高。通常而言，在治疗的第一年， CD4+T淋巴细胞计数会升高并进入增长停滞期，在治疗第二年继续升高（10）。但是一些治疗患者，特别是那些开始治疗时CD4+T淋巴细胞计数非常低的患者，会持续出现严重的免疫抑制，而CD4+T淋巴细胞计数未见升高。对于未实现CD4+T淋巴细胞计数恢复的患者，卫生保健人员应警惕患者是可能存在依从性问题，还是主要由于对抗病毒治疗无反应，并应考虑对患者继续提供抗机会性感染的预防性治疗，如复方新诺明预防性治疗。

免疫重建炎性综合征（IRIS）免疫重建炎性综合征通常认为是由于对抗病毒治疗产生应答而引起的，一系列与免疫重建相关的临床症状和体征。这是一种常见现象，在10%～30%开展抗病毒治疗的患者中都会出现，通常发生在开始治疗的前4-8周（11,12）。可通过两种不同的方式出现： “治疗矛盾型IRIS” ，在抗病毒治疗前已经出现机会性感染或肿瘤，最初对治疗产生反应，接着在开始抗病毒治疗后恶化； “暴露型IRIS” ，抗病毒治疗引发了治疗前未出现临床表现的疾病。只有当患者出现一些临床表现，但不是新感染所致，也不能为已知感染和药物毒性的预期病程所解释时，才应当考虑免疫重建炎性综合征。 IRIS的临床表现多种多样，已报道的IRIS包括多种感染性疾病、肿瘤和非感染性疾病（11,12）。最严重并造成生命威胁的治疗矛盾型IRIS包括结核病、隐球菌病、卡波济肉瘤和带状疱疹。在常规接种卡介苗的地区， HIV感染婴儿可能会出现卡介苗相关IRIS （局部或全身）。开展治疗时 CD4+T淋巴细胞计数较低（<50个/mm3）、扩散型机会性感染或肿瘤以及抗病毒治疗前抗机会性感染治疗时间过短为主要危险因素（11,12）。免疫重建炎性综合征通常是自限性的，终止抗病毒治疗基本不会显示效果，但患者出现长期症状时要消除其疑虑，避免终止抗病毒治疗或者治疗依从性下降。减少IRIS发生的最重要措施包括：早期诊断HIV感染，并在CD4+T淋巴细胞计数降低到200 3 个/mm 之前启动抗病毒治疗；提高抗病毒治疗前开展机会性感染筛查，特别是结核病和隐球菌感染；以及在启动抗病毒治疗前对机会性感染进行合理治疗。存在机会性感染的患者选择抗病毒治疗时机时要权衡利弊：早期启动治疗出现IRIS风险较大，而一旦延误ART则死亡几率较高。第 8章总结了世卫组织当前关于结核病（见8.1.2节）和隐球菌感染（见8.1.3节）患者抗病毒治疗最佳时机的建议，这些建议基于临床随机对照试验所获得的证据。

抗病毒治疗 7.1 何时启动抗病毒治疗

贯穿关怀体系的临床指南：

07 84 85 92 95 98 102 103 105 110 114 118 119 119 120 124 124 125 127 128 129 129 132 132 136 138

7.1.1 成人及青少年的抗病毒治疗何时启动 7.1.2 孕妇及哺乳妇女的抗病毒治疗何时启动 7.1.3 抗病毒药物与哺乳期 7.1.4 儿童的抗病毒治疗何时启动 7.2.1 成人的一线抗病毒治疗 7.2.2 怀孕及哺乳妇女的一线抗病毒治疗及其婴儿的抗病毒药物 7.2.3 不满3岁儿童的一线抗病毒治疗 7.2.4 3岁及以上儿童及青少年的一线抗病毒治疗 7.2.5 HIV与结核合并感染儿童的治疗 7.3.1 启动抗病毒治疗前后进行实验室监测 7.3.2 抗病毒治疗效果监测及治疗失败判断 7.4.1 指导原则 7.4.2 抗病毒药物毒性的主要类型 7.4.3 替诺福韦（TDF）毒性监测 7.4.4 其他抗病毒药物的毒性监测 7.4.5 因抗病毒药物毒性更换药物 7.4.6 主要抗病毒药物交互作用 7.5.1 成人与青少年的二线抗病毒治疗 7.5.2 儿童及青少年的二线抗病毒治疗

7.2 抗病毒治疗起始方案（一线抗病毒治疗）

7.3 抗病毒治疗效果监测及治疗失败判断

7.4 抗病毒药物毒性监测与药物更换

7.5 更换至何种（二线）抗病毒治疗方案

7.6 三线抗病毒治疗

本章目标为实施艾滋病关怀服务体系的地区提供基于证据支持的最新临床建议，概述抗病毒治疗的公共卫生措施，并重点关注资源受限及能力不足的地区。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

贯穿关怀体系的临床指南： 7. 抗病毒治疗 7.1 何时启动抗病毒治疗尽早启动治疗有利于HIV的预防和治疗，能够在群体水平提高生存率并减少HIV感染的发生。 2013版指南制定小组建议，对于CD4+T淋巴细胞计数结果≤500/mm3的所有确诊HIV感染者，国家艾滋病规划都应提供抗病毒治疗。而且，应当对重症或晚期艾滋病患者（见附录1）、以 3 及CD4+T淋巴细胞计数≤350/mm 者优先启动抗病毒治疗。另外，对于活动性结核病患者、合并感染乙肝病毒的重症慢性肝病患者、感染HIV的孕妇和哺乳妇女、不满5岁的HIV感染儿童、以及HIV单阳配偶中的感染方，无论其CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗（见表7.1）

表7.1 成人、青少年、怀孕及哺乳妇女及儿童何时启动抗病毒治疗的建议总结人群建议 CD4+T淋巴细胞计数≤500/mm3时应当启动抗病毒治疗：

• 重症或晚期艾滋病患者（WHO临床3期或4期）、或者CD4+T淋巴细胞计数≤350/mm3者应当优先启动抗病毒治疗成人、青少年（10岁及以上）无论CD4+T淋巴细胞计数结果或WHO临床分期如何，都应当启动抗病毒治疗者包括：

• 活动性结核病患者 • 合并感染乙肝病毒的重症慢性肝病患者 • 感染HIV的孕妇和哺乳妇女 • H IV单阳配偶中的感染方（以降低HIV传播风险） CD4+T淋巴细胞计数≤500/mm3时应当启动抗病毒治疗：

• 重症或晚期艾滋病患儿（WHO临床3期或4期）或CD4+T淋巴细胞儿童（5岁及以上）计数≤350/mm3的患儿应当优先启动抗病毒治疗无论CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗者包括：

• W HO临床3期或4期患儿 • 活动性结核病患儿无论CD4+T淋巴细胞计数结果或WHO临床分期如何，均应启动抗病毒治疗： a 儿童（1岁～5岁）

• 所有1岁～2岁HIV感染患儿、重症或晚期艾滋病患儿（WHO临床3 （以两者之期或4期）、 CD4+T淋巴细胞计数≤750/mm3或＜25% 间的数值较低者为准）的所有患儿都应当优先启动抗病毒治疗

a 婴幼儿（不满1岁）

无论CD4+T淋巴细胞计数结果或WHO临床分期如何，均应启动抗病毒治疗

对于临床初步诊断为HIV感染的不满18月龄患儿都应当启动抗病毒治疗。

7.贯穿关怀体系的临床指南：抗病毒治疗

7.1.1 成人及青少年的抗病毒治疗何时启动最新建议（2013）对重症或晚期艾滋病患者（WHO临床3期或4期）以及CD4+T淋巴细胞计数 ≤350/mm3者，应当优先启动抗病毒治疗（强烈建议、中等质量证据）。无论WHO临床分期如何，对CD4+T淋巴细胞计数＞350/mm3而≤500/mm3 a 的所有人，都应当启动抗病毒治疗（强烈建议、中等质量证据）。对于下列HIV感染者，无论其CD4+T淋巴细胞计数结果及WHO临床分期如何，都应当启动抗病毒治疗：新新

7. 贯穿关怀体系的临床指南：抗病毒治疗

• 患有活动性结核病的HIV感染者（强烈建议、低质量证据） b • HIV与乙肝病毒合并感染的重症慢性肝病患者（强烈建议、低质量证据）

新

• H IV单阳配偶中的感染方应当给予抗病毒治疗，以降低对未感染方的HIV 传播风险（强烈建议、高质量证据）

• 感染HIV的孕妇和哺乳妇女（具体建议见7.1.2部分）

新

对于下列各种情况，没有充分证据或风险效益评估结果支持在CD4+T淋巴细胞计数＞500/mm3时，或者不考虑CD4+T 淋巴细胞计数结果及WHO临床分期就启动抗病毒治疗： HIV感染者超过50岁、 HIV-2型感染者或HIV-1型与HIV-2型合并感染者、 HIV与丙肝病毒合并感染者、以及具有高传播风险的重点HIV感染人群（如注射吸毒者、男男性行为者、变性者以及性工作者）。因此，对于这些人群，抗病毒治疗的启动应当遵循与其他成人HIV感染者相同的原则及建议。对于HIV与乙肝病毒合并感染者，没有充分证据或风险效益评估结果支持在CD4+T淋巴细胞计数＞500/mm3时，或者不考虑CD4+T淋巴细胞计数结果及WHO临床分期就启动抗病毒治疗。因此，不考虑CD4+T淋巴细胞计数结果就启动抗病毒治疗的情况应当针对肝病进展或死亡风险较高的重症慢性肝病患者。对于没有重症慢性肝病的人群，抗病毒治疗的启动应当遵循与其他成人HIV感染者相同的原则及建议。

新

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

表7.2 成人、青少年何时启动抗病毒治疗的建议总结目标人群重症或晚期艾滋病患者（WHO临床 3期或4期 HIV感染（WHO临床1或2期）建议无论CD4+T淋巴细胞计数结果如何都应当启动抗病毒治疗 CD4+T淋巴细胞计数≤500/mm3时启动抗病毒治疗（CD4+T淋巴细胞计数≤350/mm3时应当优先启动抗病毒治疗）结核病对于患有活动性结核病的HIV感染者，无论CD4+T 淋巴细胞计数结果如何，都应当启动抗病毒治疗（同 a 2010版建议（2））都对于CD4+T淋巴细胞计数≤500/mm3的所有人，应当启动抗病毒治疗；对于重症慢性肝病患者，无论CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗b HIV单阳配偶对于其中的感染方，无论CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗，以降低对未感染方的HIV 传播风险（现行2012版建议（49））

合并乙肝病毒感染

应当首先启动结核治疗，随后尽早（于结核治疗启动头8周之内）启动抗病毒治疗。对于CD4+T淋巴细胞计数＜50/mm3 的患者，应当于结核治疗启动后的2周之内启动抗病毒治疗（见8.1.2部分）。重症慢性肝病包括肝硬化及终末期肝病，并分为代偿期和失代偿期。失代偿期肝硬化即出现了门静脉高压的严重临床并发症（腹腔积液、食道静脉曲张破裂出血及肝性脑病）或肝功能不全（黄疸）。

背景 2002年以来，对于尽早启动抗病毒治疗的支持性证据逐渐增多，世卫组织制定的抗病毒治疗指南也随之不断更新（1）。根据2010版世卫组织关于成人及青少年指南（2）建议，无论其世卫组织关于HIV感染状态的临床分期（以下简称 “WHO临床分期” ）如何，对CD4+T淋巴细胞计数≤350/mm3的所有人（包括孕妇）以及无论其CD4+T淋巴细胞计数结果如何，对所有重症或晚期艾滋病患者（WHO临床3期或4期），都应当启动抗病毒治疗。这一强烈建议基于一些随机对照试验（3,4）以及一些观察性研究（5-8）的中等质量证据。这些研究表明，在此CD4阈值及以下启动抗病毒治疗，能够降低死亡率、延缓疾病（包括结核病）进程、减少HIV垂直传播并避免出现药物严重不良反应。数学模型模拟结果也显示，如果治疗覆盖率及依从性较高，尽早启动抗病毒治疗对HIV的性传播和垂直传播都能够产生影响（9）。根据2010版指南（2）建议，对于活动性结核病患者以及乙肝病毒合并感染并需进行乙肝治疗者，无论其CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗。至2011年底，对于达到2010版治疗纳入标准（CD4+T淋巴细胞计数≤350/mm3）的所有人，全球范围的抗病毒治疗覆盖率已达54%，纳入人数超过八百万（10）。但覆盖率随地区不同有所差异（15%~68%）（11）。仅有9个低收入及中等收入国家报告的覆盖率超过80%。 68个国家报告的覆盖率低于50%。尽管如此，各国相关政策均发生了非常明显的变化。最新一项涉及92 个国家的调查（见网络附录www.who.int/hiv/pub/guidelines/arv2013/annexes）表明，超 3 过90%的国家都采纳了CD4+T淋巴细胞阈值350/mm 及以下时启动抗病毒治疗的建议。另有

7.贯穿关怀体系的临床指南：抗病毒治疗

几个国家采用了高于350/mm3的CD4阈值。在几乎所有国家（包括高收入国家），虽然启动抗病毒治疗的CD4+T淋巴细胞计数中位数都在上升，但其仍远低于350/mm3（12,13）。而且，治疗启动的延误会导致较高的过早死亡率及较低的关怀队列维持率（6,14）。提高对HIV感染状况的知晓率、加强检测与治疗服务间的有效衔接以及确保患者长期维系治疗与依从的理想效果，对于很多国家而言仍然是主要的挑战。

7.1 何时启动抗病毒治疗

理论依据与证据支持自2010年以来，相关证据与规划经验都将风险效益比朝着有利于尽早启动抗病毒治疗的方向推进。另外，越来越多证据表明， HIV感染状态如果不进行治疗，可能会导致一些非艾滋病范畴的疾病（包括心血管疾病、肾病、肝病、癌症、神经认知障碍）（15-17），而尽早启动抗病毒治疗可以减少这些病症的出现并提高生存率。最新的证据（18）还表明，抗病毒治疗能够大大减少 HIV单阳配偶中性传播的发生（但并非所有研究都报道了生存效益）。而且，毒性更低、更为便捷的治疗方案逐渐被广泛采纳，抗病毒治疗的成本也不断下降。但关于抗病毒治疗的启动应当提早到什么程度，目前仍在争论当中。指南制定小组也对相关评估予以持续关注，以确定新版建议在个体水平及群体水平的潜在风险和效益。

对CD4+T淋巴细胞计数≤350/mm3的有症状及无症状艾滋病患者优先启动抗病毒治疗对于有症状的艾滋病患者以及CD4+T淋巴细胞计数更低的患者来说，启动抗病毒治疗具有最大效益。 2013版指南制定小组对2010版指南（2）中这一建议的证据质量与推荐强度未予变更。来自两项随机对照试验以及几项观察性研究的中等质量证据表明，在CD4+T淋巴细胞阈值 3 350/mm 及以下启动抗病毒治疗，能够大大降低死亡率、延缓疾病进展并减少机会性疾病（尤其是结核和非艾滋病范畴的疾病）的发生（2）。

当CD4+T淋巴细胞计数在350～500/mm3之间时启动抗病毒治疗本指南中，关于CD4+T淋巴细胞计数在350～500/mm 3之间时启动抗病毒治疗，其风险效益分析方面存在一定争议。指南制定小组一致同意，相关证据有力证明了这一建议对HIV传播的预防作用。由于相关研究所依据的主要是观测数据，而且数据大多来自高收入国家，所以采用GRADE系统进行评估时，尽早启动抗病毒治疗的临床效益证据被确定为中等质量。指南制定小组强烈建议将尽早启动抗病毒治疗作为一项公共卫生措施加以应用。如果该建议的具体实施存在可行性问题，指南制定小组建议在实施过程中开展实施性研究，对诸如可行性、治疗服务链接、治疗维系、依从性以及资源配置等具体问题进行评估。 CD4+T淋巴细胞计数在350～500/mm 3之间时启动抗病毒治疗的建议，依据的是一项采用了GRADE证据评估方法的系统综述（见网络附录www.who.int/hiv/pub/guidelines/ ar v2013/annexes）。该系统综述涉及21项观察性研究（8,19 -39）和3项随机对照试验（3,18,40），这些研究的结果数据包括发病率、死亡率、免疫学结果及病毒学结果。该系统综述采用GRADE系统对这些研究的证据质量及强度进行了评估，结果表明，当CD4+T淋巴细胞计数＞350/mm3时启动抗病毒治疗与≤350/mm3时相比，前者降低了病程发展至艾滋病或死亡、结核及非艾滋病范畴内的疾病的风险，并增加了免疫恢复的可能性。虽然没有研究表明尽早启动抗病毒治疗会对个体造成伤害，但这些研究所覆盖的时长都相对较短。对上述观察性研究的汇总分析发现：在13项研究（21-23,26,29-31,34-39）中，尽早启动抗病毒治疗显著降低了死亡风险；而在9项研究（21,23,26,27,30,33,34,36,39）和3项随机对照试验（3,18,40）中，则降低了病程发展至艾滋病或死亡的风险。但这些发现的异质性水平都较低，所以支持尽早启动治疗的这些证据被定为中等质量。进一步的亚组分析表明，将启动抗病毒

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

治疗的CD4阈值定为500/mm3能够降低死亡风险。但其对免疫恢复的影响并不十分显著，其证据被定为低质量或极低质量（20,24,28）。在较高的CD4+T淋巴细胞计数启动治疗与较低时相比，在病毒抑制（＜500拷贝/ml）、病毒学失败和病毒反弹风险等方面， 2项研究未发现两者之间存在显著性差异（20,36）。对两项随机对照试验（3,18）的汇总分析发现：关于在较高CD4阈值启动治疗可以降低死亡率、减缓疾病进展以及（在其中一项试验中）减少非艾滋病范畴疾病的发生，存在低质量的证据 ii 支持。而在药物严重不良反应风险方面没有发现显著性差异。但3级和4级实验室异常风险在一项随机对照试验（40）中有所上升。在其中一项SMART试验中（3），其延迟启动组在CD4+T淋 3 3 巴细胞计数达到250/mm 以下时（而非350/mm 时以下）才启动治疗；出于其不精密性和不直接性，该临床效益证据被定为低质量。另一系统综述（41）发现，在1项随机临床试验（18）和2项观察性研究（42,43）中，对于 3 CD4+T淋巴细胞计数＞350/mm 时启动抗病毒治疗的个体，结核患病风险较低。抗病毒治疗还会使结核复发率降低50% （44）。动态模型显示， CD4+T淋巴细胞计数＞350/mm3时启动抗病毒治疗在群体水平能够更大程度地降低结核患病率（45）。最后，在一项随机对照试验（18）中，存在高质量的证据表明，尽早启动抗病毒治疗可以显著降低向阴性配偶或性伴传播HIV的风险。另外一项试验结果也支持了这一发现，其中对感染者启动抗病毒治疗后，向阴性配偶或性伴传播HIV的风险降低了92% （46）。

成本及成本效益关于在CD4+T淋巴细胞计数≤350/mm 3 时、 ≤500/mm 3 时以及对于成人HIV感染者无论其CD4+T淋巴细胞计数如何即启动抗病毒治疗，指南制定小组回顾了针对各自成本及流行病学效益进行的数学模拟研究。模型显示，将CD4+T淋巴细胞计数≤500/mm3作为抗病毒治疗的纳入标准能够产生显著的卫生效益，而且对于疫情高流行和疫情中等流行地区都具有很好的成本效益。因尽早启动抗病毒治疗所需增加成本，一部分可以由其所带来的成本降低（如减少住院、提高生产率）及预防新发HIV感染等效益所抵消（见网络附录www.who.int/hiv/pub/ guidelines/arv2013/annexes）。但是，产生这些效益的前提是高HIV检测率、高治疗覆盖率、持续依从性以及高关怀队列维持率。模型还显示，由于最大的成本与全面实施2010版抗病毒治疗指南（2）（当CD4+T淋巴细胞计数≤350/mm3时启动抗病毒治疗）相关，因此，将启动抗病毒治疗的CD4+T淋巴细胞计数标准从≤350/mm3改为≤500/mm3，所需增加的成本其实相对较小，对于那些已有很多CD4+T淋巴细胞计数≤350/mm3并且正在接受抗病毒治疗的HIV感染者的国家而言就更是如此。同时，这些模型的结果支持对CD4+T淋巴细胞计数≤350/mm3的成人及青少年HIV感染者优先启动抗病毒治疗。但是，由于各国的治疗覆盖率彼此不同、各地方政府也可能出于各种原因有自己的成本考量，所以对地区及国家水平的相关成本问题还需要进一步研究。

潜在危害并非所有观察性研究结果都一致支持该结论：尽早启动抗病毒治疗能够降低死亡率，并减少与慢性炎症及病毒复制相关的非艾滋病范畴疾病的发生。因此，需要更长时间的随访对其潜在危害与效益进行评估。另外，需要对抗病毒治疗的长期安全性以及尽早启动治疗对药物毒性和耐药的影响进行密切监测。

3级和4级实验室异常被认为是药物严重不良反应，通常需要中断抗病毒治疗，直至病人状况稳定、并找到合适的替代药物（见网络附录www.who.int/hiv/pub/guidelines/arv2013/annexes）。

7.贯穿关怀体系的临床指南：抗病毒治疗

可行性根据国家规划和队列数据，将启动治疗的CD4+T淋巴细胞计数标准从≤350/mm 3 改为 ≤500/mm 3后，需要进行治疗的人数会增加25% （47,48）（见网络附录www.who.int/hiv/ pub/guidelines/arv2013/annexes）。但各国经验也表明，如果没有更高的HIV咨询及检测率、更好的从检测到治疗服务的衔接、足够的治疗监测以及可持续的依从性支持，提高启动抗病毒治疗的CD4阈值未必能够迅速实现实际接受治疗人数的显著增加。关于CD4+T淋巴细胞计数在350～500/mm3之间时启动抗病毒治疗，其具体实施可能需要额外的人员、设施及资金投入，这些具体内容将在第十章予以详细介绍。

7.1 何时启动抗病毒治疗

无论CD4+T淋巴细胞计数结果如何都启动抗病毒治疗的情况 iii HIV单阳配偶中的感染方

HPTN052研究（18）的结果强烈支持使用抗病毒治疗来防止HIV在HIV单阳配偶中的传播。因此，指南制定小组支持2012版指南中关于HIV单阳配偶的HIV检测咨询以及使用抗病毒药物进行治疗和预防的建议，即对于HIV单阳配偶中的感染方，无论其CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗。 iv 活动性结核病的治疗

2010年，世卫组织建议对于所有患有活动性结核病的HIV感染者，无论其CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗；而且应当首先启动抗结核治疗，随后尽早（于抗结核治疗启动8周之内）启动抗病毒治疗。根据3项随机临床试验的结果，患有严重免疫缺陷（CD4+T淋巴细胞计数≤50/mm3）的结核病患者，如果在结核治疗启动头8周之内启动抗病毒治疗，其临床效益要高于在8周之后再启动抗病毒治疗（50-52）。指南制定小组对这些研究证据进行了回顾，并对2010版建议给予了支持。整合服务可能有利于艾滋病和结核病管理相关建议的实施（见第九章）。 v HIV与乙肝病毒合并感染的重症慢性肝病患者

合并感染HIV几乎对乙肝病毒感染自然病程的方方面面都有影响。其中包括肝病转为慢性的比例增高、乙肝病毒的自发清除现象减少、肝纤维化进程加快并且伴发肝硬化及肝癌的风险升高、肝病相关死亡率增加以及抗病毒药物治疗有效性下降（53-56）。肝病已经成为HIV与乙肝病毒合并感染者的第一死因（57,58）。 2010版世卫组织抗病毒治疗指南建议（2），对于HIV与乙肝病毒合并感染并且需要对其乙肝病毒感染（即慢性活动性肝炎）进行治疗的所有个体，无论其CD4+T淋巴细胞计数结果及 WHO临床分期如何，都应启动抗病毒治疗。但是，由于缺乏乙肝病毒常规检测，大多数人都不知道自身的乙肝病毒感染状况。另一方面，需要使用肝病临床分期诊断工具（肝组织活检、间歇性弹性成像、乙肝病毒DNA及血清生物标记）来确定是否存在慢性活动性肝病以及是否应该进行乙肝病毒治疗，但这些工具都较为昂贵，因而可及性较低。

iii

IV单阳配偶是指： H 在一对配偶当中，一方HIV阳性而另外一方HIV阴性。尽管另外一方目前HIV阴性，但并不意味着其已具有HIV免疫力或能够防止在未来被感染。动性结核病是指感染了结核菌且具有症状和临床疾病。活潜伏性结核感染是指感染了结核菌但没有症状或临床疾病。并非所有潜伏性结核感染者都会发展成结核病。但对于HIV感染者来说，感染结核菌后发展成结核病的风险则非常高。

症慢性肝病包括肝硬化和终末期肝病，重并分为代偿期和失代偿期。失代偿期肝硬化是指已出现门静脉高压的严重临床并发症（腹腔积液、食道静脉曲张破裂出血及肝性脑病）或肝功能不全（黄疸）。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

根据一项Meta分析（59）及一项随机对照试验（60）的亚组分析，对于HIV与乙肝病毒合并感染者，抗病毒治疗对肝相关疾病患病率及死亡率的总体影响方面，存在低质量的证据支持。但相关研究并未涉及在较高CD4+T淋巴细胞计数水平启动抗病毒治疗的效益问题。总体而言，指南制定小组认为，对于HIV与乙肝病毒合并感染者，没有充分证据或风险效益 3 评估结果支持在CD4+T淋巴细胞计数＞500/mm 时、或者不考虑CD4+T淋巴细胞计数结果及 WHO临床分期就启动抗病毒治疗。尽早启动抗病毒治疗还可能包含一些相关风险（肝毒性、免疫重建炎性综合征、肝炎突发等）。但指南制定小组建议，对于肝病进展或死亡风险较高的重症慢性肝病患者，应当不考虑其 CD4+T淋巴细胞计数结果就启动抗病毒治疗。这里使用 “重症慢性肝病” 一词、而非2010版指南中所使用的 “慢性活动性肝炎” 一词，是因为前者更为广泛理解并且仅通过临床标准就能够明确判断。如果具体情况下不能为CD4+T淋巴细胞计数≤500/mm3的所有HIV感染者提供抗病毒治疗，应当优先考虑对HIV与乙肝病毒合并感染者进行诊断和治疗。正如2010版WHO 抗病毒治疗指南（2）中提到，一项随机对照试验的研究数据表明，至少应当选用两种具备抗乙肝病毒作用的药物（TDF+3TC （或FTC）），以改善病毒载量反应、并减少乙肝病毒耐药的发生（61,62）。这一领域的临床研究尚需针对下列问题加强数据收集：资源受限时抗病毒治疗对乙肝病毒合并感染者肝脏的影响；以及抗病毒治疗对CD4+T淋巴细胞计数＞500/mm3的早期肝病患者的影响。

未发布任何新建议的人群对于下列各人群，指南制定小组没有发现足够证据或风险效益评估结果支持在CD4+T淋巴 3 细胞计数＞500/mm 时或者不考虑CD4+T淋巴细胞计数结果及WHO临床分期就启动抗病毒治疗；

HIV感染者超过50岁针对欧洲及北美13项队列研究的汇总分析表明，超过50岁的HIV感染者具有更高的疾病进展及死亡风险（26）。但是，这些数据并未针对CD4+T淋巴细胞计数结果进行分层，并且不支持针对该人群在CD4+T淋巴细胞计数＞500/mm3时就启动抗病毒治疗。

HIV-2型感染者目前尚缺乏关于HIV-2型感染者治疗的随机研究，因此很难确定该人群适宜何时启动抗病毒治疗。一项系统综述（见网络附录www.who.int/hiv/pub/guidelines/arv2013/annexes）对15项研究的观测数据进行了评估，发现在死亡率、疾病进展、 CD4+T淋巴细胞计数升高、病毒学反应以及耐药风险等方面，在CD4+T淋巴细胞计数≤350/mm3时启动抗病毒治疗与≤500/ mm3时相比没有显著性差异。由于这些研究结果具有不精确性（样本较少）和严重偏倚风险，其证据被定为低质量至极低质量。

HIV与丙肝病毒合并感染者相关观察性研究表明， HIV与丙肝病毒合并感染会加速丙肝病毒相关的肝纤维化进展，并造成终末期肝病发生率（63）及死亡率（63-65）升高。根据一项Meta分析的结果（66），抗病毒治疗对HIV与丙肝病毒合并感染者的肝病进展及死亡率具有明确的总体效益，但此方面仅有低质量的观测数据支持。另外9个队列研究探讨了抗病毒治疗与肝纤维化的关系，对其进行评价时发现，抗病毒治疗与肝纤维化进展速度降低相

7.贯穿关怀体系的临床指南：抗病毒治疗

关，但尚未根据CD4+T淋巴细胞计数水平对此进行评价（见网络附录www.who.int/hiv/pub/ guidelines/ arv2013/annexes）。指南制定小组支持2010版指南（2）的特别说明，即针对合并丙肝病毒感染的HIV感染人群，抗病毒治疗的启动应当遵循与HIV单独感染者相同的原则及建议。没有发现足够证据支持，因此也不建议无论其CD4+T淋巴细胞计数结果如何就启动抗病毒治疗。在无法有效获得丙肝病毒抗体检测、 RNA检测、肝病分期诊断工具（如组织活检）及丙肝病毒治疗的情况下，以及对于某些特殊人群（如注射吸毒者），丙肝病毒感染的诊断和治疗都面临着不小的挑战。但是，丙肝病毒检测及治疗的可及性问题以及较高的丙肝病毒感染率，都不应成为启动抗病毒治疗的障碍。世卫组织将于2014年发布的关于肝炎的指南将在丙肝病毒筛查、治疗和关怀等方面提供具体指导。由于丙肝病毒药物（如干扰素、病毒唑以及更新的直接效应药物）与抗病毒治疗药物之间存在潜在的药物相互作用及毒性升高风险，需要对同时接受抗病毒治疗和抗丙肝病毒药物治疗的HIV与丙肝病毒合并感染者进行密切监测。

7.1 何时启动抗病毒治疗

重点人群为了在重点人群中预防HIV感染并降低人群患病率，已经在群体水平、生态学研究中及数学模型上，对在相应人群中扩大抗病毒药物使用范围进行了评估（67-79）。其中一些研究发现，在抗病毒治疗覆盖率较高的地区和抗病毒治疗扩展迅速的地区，群体病毒载量有所降低，但未必同时伴有HIV感染率的降低。指南制定小组认为，对于重点人群，没有足够证据支持，因此也不建议无论其CD4+T淋巴细胞计数结果如何就尽早启动抗病毒治疗，其抗病毒治疗的启动应当遵循与其他成人或青少年HIV感染者相同的一般性原则及建议。

临床考量第十章第六节（10.6部分，清单10.3）介绍了将CD4阈值从350/mm3改为500/mm3后，规划管理人员要面对的具体实施问题。

尚待研究的主要问题关于尽早启动抗病毒治疗的临床效益及缺陷，目前尚需进一步研究。目前正在开展两项探讨抗病毒治疗最佳启动时机的大型随机试验，其结果有望于2014或2015年发布。在一项称作抗病毒治疗时机策略（START）的试验中，针对未服用过抗病毒药物的18岁及以上成人，是在 CD4+T淋巴细胞计数＞500/mm 3 时就立即启动抗病毒治疗，还是待CD4+T淋巴细胞计数下降到≤350/mm3或病程已发展至艾滋病期后再启动抗病毒治疗，该试验对两种策略进行了比较（80）。在科特迪瓦进行的TEMPRANO试验（成人HIV感染者早期进行抗病毒治疗和或早期使用异烟肼进行结核病的预防性治疗- ANRS 1213），考察并比较了两种策略的效益和风险，即策略一是按照2010版WHO指南的建议（CD4+T淋巴细胞计数≤350/mm3时再启动抗病毒治疗），策略二是对CD4+T淋巴细胞计数＞350/mm3的成人立即启动抗病毒治疗（81）。这些试验都将对世卫组织未来的建议产生影响。其它急需研究的问题包括：长期进行抗病毒治疗者的药物严重不良反应评估；对于在较高 CD4+T淋巴细胞计数时启动抗病毒治疗者，开展有关治疗的接受程度、治疗率、依从性及长期治疗维持情况评估；以及对重点人群立即启动抗病毒治疗的预防效益评估。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

7.1.2 孕妇及哺乳妇女的抗病毒治疗何时启动最新建议新

所有感染HIV的孕妇及哺乳妇女应当启动三联抗病毒药物治疗，并应当至少持续至母婴传播风险期结束。达到治疗纳入标准的妇女应当继续进行终身抗病毒治疗（强烈推荐、中等质量证据）。出于规划及实施方面的考虑，尤其是对于HIV高度流行的地区，所有感染HIV的孕妇及哺乳期妇女都应当进行终身抗病毒治疗（有条件推荐、低质量证据）。在一些国家，对于那些由于自身健康问题未达到抗病毒治疗纳入标准的妇女，可以考虑在母婴传播风险期结束后停止使用抗病毒药物（有条件推荐、低质量证据）。

表7.3 预防母婴传播规划的抗病毒治疗方案国家级预防母婴传播规划的治疗感染HIV的孕妇及哺乳妇女方案无论 CD 4 +T 淋巴细胞计数结果及对所有孕妇及哺 WHO临床分期如何乳妇女进行终身抗病毒治疗（B＋启动抗病毒治疗，并在分娩及哺乳期方案）后继续治疗达到治疗纳入标未达到治疗纳入标准a 准a 启动抗病毒治启动抗病毒治疗，疗，并在分娩及但在分娩及哺乳 bc 哺乳期后继续治期后终止治疗 b 疗 HIV暴露婴儿

哺乳

人工喂养

每日一次N V P 每日一次NVP 婴儿预防用药（或每日两次共6周 AZT）婴儿预防用药共4-6周

仅对达到治疗纳入标准的怀孕及哺乳妇女进行终身抗病毒治疗（B 方案）

a b

CD4+T淋巴细胞计数≤500/mm 3、或WHO临床3期或4期时启动抗病毒治疗，或者遵循各自国家指南；对于达到临床或实验室治疗失败标准的孕期或哺乳期病人，应当进行二线治疗评估； c 对于哺乳妇女，在哺乳期结束1周后终止抗病毒治疗；对于采用人工喂养者，在分娩后终止抗病毒治疗。

背景感染HIV的孕妇及哺乳妇女服用抗病毒药物的主要目的是保护母亲健康以及保护暴露婴儿免受感染，同时也可能起到预防HIV性传播的作用。 2010版世卫组织关于预防母婴传播指南（82）建议，对达到治疗纳入标准（根据2010版标准，即CD4+T淋巴细胞计数≤350/mm 3 、或WHO临床3期或4期）的妇女进行终身抗病毒治疗；对未达到治疗标准的感染HIV的妇女采取预防性抗病毒治疗来实现母婴传播阻断。对于那些未达到治疗标准的妇女，建议采取两种预防方案： A方案，母亲在孕期采用AZT，在分娩时及产后持续一周采用单剂NVP （sd-NVP）＋AZT＋3TC； B方案，孕期及哺乳期均采用三联抗病毒药物治疗。建议早在怀孕第14周就启动

7.贯穿关怀体系的临床指南：抗病毒治疗

预防用药，且两种方案都应包含针对婴儿的用药方案：围产期4周～6周使用NVP或AZT，无论母亲是否哺乳。各国应根据实际情况为自己所选的母婴阻断抗病毒治疗方案制订出全国实施策略。为了在全球资源受限地区加速推广抗病毒治疗及母婴阻断，保证孕妇公平获得抗病毒治疗机会，实现消灭婴儿新发感染及维护母亲生命的全球目标（83），需要进一步对建议进行简化、标准化和一致化。马拉维于2011年实施了一项新策略，即无论CD4+T淋巴细胞计数结果及WHO临床分期如何，均对所有感染HIV的孕妇和哺乳妇女进行终身抗病毒治疗，也就是常说的 “B＋方案” （84-86）。世卫组织于2012年4月发布了最新规划信息（87），列出了B方案及 “B＋方案” 各自的实施优势。 2013版指南建议，对所有感染HIV的孕妇和哺乳妇女在母婴HIV传播风险期实施抗病毒治疗（简化的三联用药方案），并在之后对所有妇女或根据母亲健康状态仅对达到治疗纳入标准的妇女进行终身抗病毒治疗。不再推荐使用A方案。

7.1 何时启动抗病毒治疗

基本理论与证据支持针对所有感染HIV的孕妇和哺乳妇女，采用标准化抗病毒治疗方案的优点尽管已有数据显示，预防用药A方案和B方案在临床试验中具有相似的效用（88-92），但A 方案的复杂性妨碍了母婴阻断服务在很多国家的推广，包括其治疗和预防用药方案不一致；需要检测CD4+T淋巴细胞计数来确定是否纳入治疗以及如何用药；产前、分娩时及产后采用不同的用药方案；母亲产后需要额外的抗病毒药物治疗；以及婴儿需长时间服用奈韦拉平（NVP）进行预防性治疗。相比而言，对于所有感染HIV的孕妇和哺乳妇女使用经优化的、使用固定剂量复合制剂的抗病毒治疗一线方案（TDF＋3TC （或FTC）＋EFV，具体见7.2.2部分），能够带来一些重要的规划及临床效益，包括：易于实施。对所有怀孕妇女（无论是否达到治疗纳入标准）都采用相同的简化抗病毒治疗方案，并且在孕期、分娩及产后的整个过程中一直如此。一致性。经优化的、使用固定剂量复合制剂的一线方案能够与除孕妇之外的成人的抗病毒治疗建议保持一致。抗病毒治疗覆盖率提高。该方案可确保不能进行CD4检测的免疫受损妇女及时接受抗病毒治疗：

新

• 垂直传播效益。扩大了抗病毒治疗覆盖面，最大程度预防婴儿感染； • 母亲健康效益。在治疗过程中延缓疾病进展（93）。接受程度。针对上述建议的审查发现，这一治疗策略在社区水平一般具有较高的偏好度和接受程度。性传播预防效益。抗病毒治疗可以降低HIV在性伴之间的传播（18）。指南制定小组也对一项系统综述所获得的总体证据进行了斟酌；该系统综述包含21项观察性研究（19-39）及3项随机对照试验（3,18,40），其对成人的抗病毒治疗启动时机进行了评估。（见网络附录www.who.int/hiv/pub/guidelines/ arv2013/annexes、见7.1.1部分）。在上述针对怀孕及哺乳妇女扩大抗病毒治疗适宜范围的建议中，已考虑了资源受限国家的抗病毒药物方案选择范围有限的问题。同时，指南制定小组也认识到应当对抗病毒治疗对孕妇及哺乳妇女带来的效益与其在孕期及哺乳期对母亲、胎儿及婴儿所致毒性风险进行权衡。指南制定小组所考虑的

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

其它因素还包括：成本、成本效益及卫生系统负担（94,95）、依从性及关怀队列维持率等相关问题（96）、 HIV耐药、抗病毒治疗失败及未来可选治疗方案以及确保达到现行指南中治疗纳入标准的所有人能够得到治疗等。

终身抗病毒治疗与在母婴HIV传播风险期结束后停止治疗的比较目前尚缺乏有关对所有感染HIV的妇女进行终身治疗的影响及有效性的结论性的证据。因此，对所有感染HIV的孕妇和哺乳妇女都进行终身抗病毒治疗，或是出于母亲健康考虑仅对达到治疗纳入标准的妇女继续进行抗病毒治疗，相关建议都是条件性的，需要各国根据本国具体疫情及国家规划做出抉择。对于HIV高度流行的地区以及CD4检测受限、性伴检测受限、哺乳期较长、生育率较高等情况，对所有感染HIV的孕妇和哺乳妇女都进行终身抗病毒治疗的效益十分显著，其中包括保证所有出于自身健康需要治疗的人都能够接受治疗，避免反复怀孕时药物治疗的起起停停，为未来妊娠提供早期母婴传播预防，减少HIV在单阳配偶中的传播风险以及改善母亲健康。根据CD4+T 淋巴细胞计数≤500/mm3的新治疗纳入标准，并根据自身健康状况，大约60%的HIV感染孕妇都将达到治疗纳入标准（97）。还可能有至少10%～20%的妇女在产后2年能够到达治疗纳入标准（尽管不完全符合条件）。对于HIV中等流行的国家，在方便进行CD4+T淋巴细胞检测、有足够能力为达到治疗纳入标准的孕妇及哺乳妇女提供抗病毒治疗、生育率较低或者不鼓励HIV感染母亲进行哺乳的情况下，可以考虑在母婴传播风险期结束后，对未达到抗病毒治疗纳入标准的妇女停止抗病毒药物治疗。无论采用何种治疗策略，都需要给予专项投入和支持计划，以提高依从性（尤其是在哺乳期，目前很多规划都忽视了对此期间的随访工作），并确保将感染者有效地衔接到长期治疗服务系统。针对在终身抗病毒治疗与停止抗病毒治疗之间进行抉择的国家规划，第十章提供了额外指导（专栏10.4）。在孕期及哺乳期加强抗病毒药物毒性监测，对妇女、胎儿及婴儿的治疗策略安全性评估而言十分重要。尤其是当前越来越多正开始接受抗病毒治疗的妇女怀孕，导致胎儿在孕早期就暴露于较高水平的抗病毒药物（见7.2.2部分：采用何种方案启动抗病毒治疗；和7.4部分：抗病毒药物的毒性监测与药物替换）。另外，开展实施性研究对于与终身抗病毒治疗相关的很多具体问题的发现和解决均十分重要。

由2010版指南过渡到2013版指南最新的2013版指南建议，目前按照2010版指南的要求（82）实施A方案的各国应当在适当规划下，过渡到对所有感染HIV的孕妇和哺乳妇女都启动抗病毒治疗。 2013版指南不再推荐A 方案。向B方案过渡或已在采用B方案的各国应当根据自身实际情况，充分考量向所有怀孕及哺乳妇女提供终身抗病毒治疗的优点和缺点。

临床考量关于过渡到对所有怀孕及哺乳妇女都进行终身抗病毒治疗，第十章第六节（10.6部分：重要建议的具体实施问题，专栏10.4）介绍了相关临床考量以及涉及规划管理人员的具体实施问题。为了有效对该过渡过程进行应对，现已开发出一个包含准备工作评估清单的工具包（98）（附录6）。

尚待研究的主要问题指南制定小组强调进行更多的研究，以为新版建议提供支持、为规划决策提供信息并为具体实施提供有效促进。尚待研究的主要问题如下。

7.贯穿关怀体系的临床指南：抗病毒治疗

抗病毒药物毒性监测。对孕妇、哺乳妇女及其婴儿进行终身抗病毒治疗，其安全性及可接受性仍需进行更多研究。尤其是在资源受限的国家，相比富国会存在更多的营养不良及合并症，而且监测能力也相对不足，则更应重视此方面的研究。关于母亲健康结局、妊娠结局（如死产、出生低体重及早产）、出生缺陷以及婴儿与儿童的健康结局，都需要更好的研究数据（见专栏7.2）。母亲及儿童健康结局。在哺乳期结束时对母婴传播和母亲健康等远期结局进行评估方面尚需进行更多研究。除了近期结局（如常在第6周检测的早期母婴传播率）外，对母亲抗病毒治疗的远期结局进行评估也同等重要，其中包括哺乳期结束时的最终传播率及无HIV感染生存率、（HIV感染或未感染）母亲及儿童的健康结局、（高CD4+T淋巴细胞计数及低CD4+T淋巴细胞计数个体的）关怀队列维持率、抗病毒治疗一线药物的治疗是否成功以及HIV耐药等方面的内容。依从性及关怀队列维持。对于怀孕及哺乳妇女的抗病毒治疗（包括由于自身健康原因而未达到当前治疗纳入标准的妇女，其启动了终身抗病毒治疗），如何改善治疗接受程度、依从性及关怀队列维持率，还需要进行更多研究。为了对感染HIV的孕妇和哺乳妇女的终身抗病毒治疗进行优化，还需要开展更多关于卫生体系与群体干预的研究。另外，关于抗病毒治疗的不同启动策略对不同人群的潜在影响，也需要进一步研究。

7.1 何时启动抗病毒治疗

7.1.3 抗病毒药物与哺乳期建议 2010年确定的重要原则及建议仍然有效，包括：国家及下级卫生部门应当做出决定，向已知HIV感染的母亲提供怎样的咨询和支持：出于其已感染状态，是帮助她们在哺乳的同时接受抗病毒药物干预，还是帮助她们完全放弃哺乳。如果国家已经做出决定：其母婴健康服务应当主要致力于在促进和支持在哺乳的同时进行抗病毒药物干预、并通过这一策略使已知HIV感染的母亲所生婴儿最大可能地获得无HIV感染生存的机会，那么：其婴儿未感染HIV或感染状态未知时，在已知HIV感染的母亲应当在婴儿6月龄之内只喂母乳，之后应适当引入辅食、并在婴儿12月龄之内继续进行哺乳。而后，哺乳仍应持续，直至能够提供营养足够的非母乳安全膳食（强烈建议6月龄相关建议具有高质量证据， 12月龄相关建议具有低质量证据）。

背景世卫组织针对HIV与婴儿喂养问题提出建议，其主要目的是提高HIV暴露婴儿的无HIV感染生存率，包括（主要采用抗病毒药物）降低HIV经母乳传播风险，同时避免出现营养不良以及由不安全喂养造成的婴儿及儿童严重疾病风险增加。世卫组织于2010年建议，在整个哺乳期向母亲或婴儿提供抗病毒药物，以降低产后传播 HIV的风险（82,99）。在推荐哺乳同时进行抗病毒药物干预的国家，建议HIV感染妇女应当在婴儿12月龄之内继续进行哺乳，直至能够提供营养足够的非母乳安全膳食再终止哺乳（99）。这一建议的证据包括：哺乳能够预防腹泻、肺炎、及营养不良造成的死亡，这种效益在婴儿12月龄之内最为显著；而且，在进行抗病毒药物干预的情况下，通过哺乳将HIV传播给婴儿的风险很低（100,101）。在当时，关于母亲对预防性服用抗病毒药物的依从性，以及她们能否在更长的时

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

间内（婴儿18～24月龄之内）坚持给其婴儿服用抗病毒药物都是不确定的问题。因此，婴儿12月龄之后的哺乳能否得到足够的保护以防止HIV传播也是不确定的。最后，婴儿长期暴露于母乳中的（尽管是低剂量的）抗病毒药物，其可能造成的药物不良反应问题也没有足够数据支持（102104）。自2010年以来，关于HIV感染妇女的哺乳期长短问题，来自推荐哺乳的国家的建议从12个月至24个月不等，还有些国家并不明确推荐哺乳。关于哺乳期抗病毒药物治疗的覆盖率及依从性以及产后有效母婴随访问题，目前的研究数据仍然很少。随着母婴阻断规划中产前抗病毒药物覆盖率的不断增加，因哺乳而感染婴儿的相对比例可能会有所升高，因为哺乳期抗病毒药物的覆盖率相对不足，这提示制定产后有效预防策略是非常重要的。关于上文中提到的 “无论CD4+T淋巴细胞计数结果及临床分期如何，均对所有HIV感染孕妇提供终身抗病毒治疗” （见7.1.2部分），这一策略引出一个实际问题，即是否应当对这些母亲的哺乳期长短进行限制。所以，如果实施的策略是 “无论CD4+T淋巴细胞计数结果及临床分期如何，都对HIV感染孕妇提供终身抗病毒治疗” ，指南制定小组考虑是应当坚持 “在婴儿12月龄之内持续进行哺乳” 的建议，还是应当推荐无时长限制的哺乳期。由于延长哺乳期具有潜在的实施优势，指南制定小组曾考虑对建议进行修订，包括：

针对HIV感染母亲的相关建议与针对无HIV感染母亲的建议实现一致化及简明化，将可能简化公共卫生信息、并在整个社区水平改善婴儿喂养；少歧视并可能提高母亲及群体的接受程度。减但是指南制定小组最终还是决定，不对2010版关于HIV与婴儿喂养问题相关建议进行修改。

不对2010版世卫组织关于HIV与婴儿喂养问题相关建议进行修改的基本理论总体而言，没有出现新的证据支持对2010版的该建议进行修订。对于HIV感染母亲推荐无时长限制的哺乳期，其主要顾虑是母亲可能不会在整个哺乳期坚持抗病毒治疗，从而导致其将HIV传播给婴儿的风险升高。尽管这对于婴儿哺乳期的任何时候而言均很严重，但在婴儿达到12月龄后尤为令人担忧。另外，在12月龄之前，哺乳能够显著预防腹泻、肺炎及营养不良造成的婴儿死亡。尽管哺乳在12月龄之后仍然能够继续为婴儿提供很多效益，但在降低上述各种死亡率方面已效果变得不那么显著了。世卫组织在其建议中也认识到，在婴儿12月龄之后，如果停止哺乳，一些母亲可能不能提供营养足够的安全膳食，这也就意味着应当继续进行哺乳。但是，如果此作为一项基本策略，对于额外引入的HIV感染风险，目前尚缺乏相关研究证据；而且，对于抗病毒药物可能对婴儿造成的不良健康影响，目前也缺乏相关的药物毒性监测数据。

HIV感染母亲进行哺乳的临床考量在哺乳期使用抗病毒药物的重要临床考量及具体实施问题包括：

后婴儿预防用药仍然很重要：产对于已在接受抗病毒治疗并正在哺乳的母亲，其婴儿应当接受6周NVP预防用药（见7.2.2部分）；当考虑采用某些具体干预措施应（如将随访与接种等婴儿卫生服务相结合），以改善目前大多规划都忽视的产后母婴随访；

7.贯穿关怀体系的临床指南：抗病毒治疗

于抗病毒药物治疗的同时进行哺乳的价值以及当地对哺乳期长短的考虑，关都应与当事人及相关群体进行清晰、有效的沟通。另外，对于长时间使用抗病毒药物可能产生的药物毒性，指南制定小组强调了应当进行有效监测，包括在婴儿2岁之内进行的婴儿队列哨点现场监测、其后3-5年的继续监测以及引入新药后的监测，从而对抗病毒药物的效应（尤其是对神经发育、肾脏健康及骨骼健康的影响）进行评估。

7.1 何时启动抗病毒治疗

尚待研究的主要问题于时长不同的哺乳期和要求不同的规划，对在同等抗病毒治疗条件下的产后传播风险是否存在差异；病毒药物抗（尤其是EFV和TDF）经母乳长时间、低剂量暴露的短期及长期婴儿健康结局，包括神经发育状况、营养状况（包含微量营养素）和骨代谢及发育状况；于在产后接受抗病毒药物干预的同时进行哺乳，对提高其依从性的各种干预措施，以及对所有孕妇及产妇启动终身抗病毒治疗的策略能否提高哺乳期对抗病毒药物的依从性，从而使 HIV感染妇女的哺乳期没有长度限制。

专栏7.1 孕妇治疗和管理的特殊问题（见网络附录www.who.int/hiv/pub/guidelines/arv2013/annexes）

指南参考文献： Pregnancy, childbirth, postpartum and newborn care: a guide for essential practice. Geneva, World Health Organization, 2006 www. who.int/reproductivehealth/publications/ maternal_perinatal_ health/924159084X/en/index.html). Guidance on global scale-up of the prevention of mother-to-child transmission of HIV. Geneva, World Health Organization, 2007 (www.who. int/hiv/pub/mtct/pmtct_ scaleup2007/en/index.html). IMAI/IMPAC clinical training for integrated PMTCT services. Geneva, World Health Organization, 2013 (www.who.int/hiv/topics/mtct/training/ en).

一般性指南感推荐的产前保健和孕期保健服务。染HIV的孕妇应当接受的一揽子基本服务包括：另外，还应当接受一些额外的干预措施，包括：性传播感染筛查、营养支持以及婴儿喂养与计划生育咨询。分娩过程中发生HIV传播的风险较高，可以通过下列重要原则和方法来降低风险，包括：强化推荐的产前就诊，尤其是孕晚期后段的高风险管理；促进产妇到拥有受过培训、有经验的助产人员的卫生机构进行分娩；采用产程图监测分娩，避免不必要地使用器械和造成胎膜早破；以及非侵入性吸出鼻及胃分泌物并清洗新生儿血迹。

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

专栏7.1 孕妇治疗和管理的特殊问题（续）其它减少HIV传播的方法包括：尽早发现感染HIV的母亲并向其和新生儿提供抗病毒药物，这是十分重要的。如果在即将分娩时，母亲的HIV感染状况未知，应当在分娩时及分娩后立即进行HIV 快速检测。对于检测阳性的妇女，应当根据现行治疗建议与婴儿长期预防用药考量（见7.2.2部分），向母亲及其婴儿都提供抗病毒药物。医（包括对于感染HIV的母亲）都应当采取通用预防措施。疗卫生人员对所有分娩在与分娩相关的医护过程中，应当特别注意确保服务中的非歧视及支持态度。尽管已有研究结果显示剖腹产能够防止HIV传播（尤其是当缺乏抗病毒药物时，或是在高病毒载量的情况下）。但是在资源受限的情况下，世卫组织并未特别针对HIV感染，而是针对产科及其它医疗指征而推荐是否应当采用剖腹产。对于在医疗卫生机构外进行分娩的HIV感染妇女及感染状况未知妇女，应当鼓励她们在分娩后尽早去母婴卫生机构进行医疗评估并开始或者继续进行适当的HIV干预。向HIV感染妇女及其HIV暴露婴儿提供随访、将其衔接到抗病毒治疗服务以及产后医护服务都十分重要。其婴儿的初始医护计划一般在4周～6周初次免疫接种就诊时确定，包含加强安全喂养、审查是否接受了抗病毒治疗以及早期婴儿诊断性检测。其母亲的随访医护计划最好同时确定，并应包含产后检查、计划生育咨询、抗病毒药物方案以及依从性支持服务。

7.1.4 儿童的抗病毒治疗何时启动最新建议新

对于不满5岁的所有感染HIV的儿童，无论其WHO临床分期及CD4细胞计数结果如何，都应当启动抗病毒治疗。 1岁以内确诊感染HIV的婴儿（强烈建议、中等质量证据）。 • 1岁～不满5岁的感染HIV的儿童（有条件建议a、极低质量证据）。 • 对于5岁及以上且CD4+T淋巴细胞计数≤500/mm3的所有HIV感染儿童，无论其 WHO临床分期如何，都应当启动抗病毒治疗。 CD4+T淋巴细胞计数≤350/mm3者（强烈建议、中等质量证据）。 • CD4+T淋巴细胞计数在350/mm3与500/mm3之间者（有条件建议b、极低质 • 量证据）。对于患有重症或晚期有症状疾病（WHO临床3期或4期）的所有感染HIV的儿童，无论其年龄及CD4+T淋巴细胞计数结果如何，都应当启动抗病毒治疗（强烈建议、中等质量证据）。对于不满18月龄，临床初步诊断为HIV感染的所有儿童，都应当启动抗病毒治疗（强烈建议、低质量证据）。

7.贯穿关怀体系的临床指南：抗病毒治疗这一建议被定为条件性的原因是，在这一年龄组尽早启动治疗尚缺乏证据支持。但一般认为，这一策略在免疫学检测受限、儿童HIV疾病负荷较高、儿童抗病毒治疗覆盖率较低的情况下，具有显著的规划优势，因为简化的抗病毒治疗启动标准有可能提高HIV感染儿童的抗病毒治疗覆盖率并改善其健康结局。对于不满2岁的儿童，出于其更高的死亡风险，无论其WHO临床分期及CD4+T淋巴细胞计数结果如何，都应当优先启动抗病毒治疗。对于患有晚期疾病（WHO临床3期或4 期）的2岁～5岁儿童以及（无论其WHO临床分期如何）对于CD4+T淋巴细胞计数≤750/mm3或＜25% （以两者之间的较低者为准）的2岁～5岁儿童，都应当优先启动抗病毒治疗（强烈建议、极低质量证据）（105）。这一建议被定为条件性的原因是，在这一人群中尽早启动治疗所产生的个体效益尚缺乏证据支持。但一般认为，这一策略在儿童抗病毒治疗覆盖率较高以及规划需要与成人抗病毒药物建议保持一致的情况下，具有显著的规划优势。如果没有采纳这一建议，则应当在WHO临床3期或4期、或者（无论其WHO临床分期如何）在CD4+T淋巴细胞计数≤350/mm3时启动抗病毒治疗（强烈建议、极低质量证据）（105）。

7.1 何时启动抗病毒治疗

表7.4 儿童的抗病毒治疗何时启动的建议总结年龄婴儿（不满1岁） 1岁～不满5岁何时启动治疗所有个体治疗所有个体（儿童不满2岁、或是WHO临床3期或4期、或是都应当优先启 CD4+T淋巴细胞计数≤750/mm3或＜25%时，动治疗） WHO临床3期或4期、或是CD4+T淋巴细胞计数≤500/mm3 （CD4+T淋巴细胞计数≤350/mm3时应当优先启动治疗）

5岁及以上

背景婴儿和儿童的HIV感染状态导致不良健康结局的风险非常高。在缺乏任何干预措施的情况下， 52%的儿童在2岁之前死亡（106）。缺乏治疗时的死亡及疾病进展风险在5岁之前逐步降低至与年轻成人相近的水平（107,108）。早期婴儿诊断规划的推广提高了感染HIV婴儿的检出率，但在已检出者尽早启动抗病毒治疗方面还不尽人意。大多数达到抗病毒治疗纳入标准的HIV感染儿童仍然未能得到治疗。全球儿童抗病毒治疗覆盖率（28%）远远落后于成人（57%）（11）。另外，对HIV暴露及感染儿童进行诊断并将他们维持在医护服务当中，仍然是相当艰巨的挑战，因为这些都取决于这些儿童的监护人。儿童在艾滋病关怀体系中的失访率一直相当高（109），对于已接受艾滋病关怀服务但尚未达到抗病毒治疗纳入标准的儿童，其在关怀体系中的保留尤其成问题。对于不满5岁的儿童，一些国家根据规划及实施方面的考虑，已经开始引入立即启动抗病毒治疗的策略（110,111）。对于5岁以上的儿童， 2010版世卫组织指南已将其临床及免疫学治疗纳入标准与成人保持一致（即在WHO临床3期或4期、或是CD4+T淋巴细胞计数≤350/mm3时启动治疗）（105）；并且建议，对于不满2岁的所有HIV感染儿童，无论其临床及免疫学检测结果如何，都应当启动治疗；对于2岁～5岁的儿童，应当对其中WHO临床3期或4期、或是CD4+T淋巴细胞计数≤750/ 3 mm 或＜25%的儿童启动治疗（105）。依据2013年的证据审查、具体实施方面的考量以及医护人员的价值观与偏好，最终对先前的建议进行了修订，对儿童治疗进行了简化和扩展，包括对不满5岁的所有儿童均启动抗病毒治疗、将5岁及以上儿童的启动抗病毒治疗的CD4阈值提高到与成人的新阈值一致的水平（即同为 ≤500/mm3）。新

100

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

基本理论与证据支持无论临床分期及CD4结果如何均在婴儿期后继续进行治疗的策略，尽管其在临床效益方面还缺乏证据支持，但抗病毒治疗启动标准的简化带来了显著的规划和实施优势，并由此成为上述建议的基础。同样，出于对规划的考虑，并考虑到5岁及以上儿童在疾病进程方面与年轻成人相近，将其抗病毒治疗启动标准与成人保持一致的策略被认为很有价值。

将立刻进行抗病毒治疗的年龄界限提高到5岁的证据根据CD4+T淋巴细胞计数与WHO临床分期能够确定那些疾病进展与死亡风险升高的儿童。先前的建议所依据的观察性研究表明，未经治疗的幼儿在其出生后第二年的患病率及死亡率仍然高于无HIV感染的幼儿（106）。儿童生存曲线显示， CD4结果超过25%的2岁以上儿童的死亡率每年为1%～2% （107,108）。系统性综述只获得一项与此问题相关的随机临床试验（PREDICT）（112）（见网络附录 www.who.int/hiv/pub/guidelines/arv2013/annexes）。该试验研究了300名CD4+T淋巴细胞计数超过15%、无CDC临床C期疾病的1岁～12岁（年龄中位数为6.4岁）儿童，并将他们随机分配到立即治疗组和延迟治疗组中，后者直至CD4+T淋巴细胞计数下降到低于15%时才开始治疗。不同组间的无艾滋病生存率、神经发育状况及生长参数均无差异（113）。针对5732名24月～59月龄（年龄中位数为3.3岁）未经抗病毒治疗、 CD4+T淋巴细胞计 3 数高于现行治疗纳入阈值（25%或750/mm ）的儿童， IeDEA南部非洲网络收集了前瞻性数据，并采用这些数据进行了一项因果模型研究（114）（见网络附录www.who.int/hiv/pub/ guidelines/arv2013/annexes）。这项研究在该人群中未发现尽早进行治疗的任何生存效益。但由于大多数纳入研究时CD4+T淋巴细胞计数高于750/mm 3的儿童在3年之内都达到了 CD4+T淋巴细胞计数的治疗纳入阈值，也就是说该年龄组中有很高比例的儿童都将很快达到现行治疗纳入标准。更具体而言，在该队列中，上述群体中有32%和60%分别在1年和2年之后达到了治疗纳入标准。

规划及实施优势尽管2岁～5岁儿童与2岁以下儿童相比，其疾病进展的风险较低，也尽管为所有5岁以下儿童提供抗病毒治疗而无需检测CD4+T淋巴细胞计数的策略只有低质量的证据支持，指南制定小组还是特别强调了这一策略为规划及实施所带来的优势。对5岁以下所有儿童进行治疗的策略使儿童抗病毒治疗程序得以简化，并促进了儿童治疗覆盖率的显著上升。尽管这一进步并未被作为规划结果进行评估，但规划数据表明，接受抗病毒治疗的儿童与仅接受医护服务但未开始抗病毒治疗的儿童相比，前者在关怀体系中的维持率比后者要高（109）。提高抗病毒治疗覆盖率并找出这些儿童并给予HIV持续关怀服务，可能还会促进5岁以内其它可预防的致死性疾病的治疗。这一策略可能会对当前体系增加较小的负荷（115）。但要注意的是，诊断较迟的现象仍然存在，依据 2010版建议所检出的HIV感染儿童中有很大比例均早已达到了抗病毒治疗的纳入标准。

社区价值观与偏好对每个5岁以下儿童都进行抗病毒治疗的策略已被广泛接受。对HIV感染人群、看护人员、医护人员的价值观与偏好进行的评估显示，由于一般认为尽早启动治疗能够促进家庭医护、防止失访并提高依从性，所以尽早启动治疗的策略广受欢迎（116）。尽管如此，在低龄儿童中很早启动治疗也存在耐药风险、依从性低以及药物供应差等问题；对于非常低龄的儿童就更是如此，因为其药物配方和成人非常难以一致化。但是治疗带来的效益有可能超过了上述这些潜在风险。

7.贯穿关怀体系的临床指南：抗病毒治疗

101

在免疫学检测受限、儿童HIV疾病负荷较高及儿童抗病毒治疗覆盖率较低的情况下，抗病毒治疗启动标准的简化可以显著提高HIV感染儿童的总体健康结局（117）。国家规划需要确定这一建议的最佳实施方式，是对所有5岁以下儿童全部进行治疗；还是专注于对1岁以下婴儿全部进行治疗而对1～5岁儿童则采用临床或免疫学方面的纳入标准。当抗病毒治疗从面向婴儿扩展到（无论其临床及免疫学状况如何而）面向所有5岁以下儿童时，应当对2岁以下儿童给予优先治疗，因为其具有更高的死亡风险和疾病快速进展风险。另外，扩展抗病毒治疗服务还需要保证关怀队列维持率，而且应当与提高依从性的干预措施同步扩展。

7.1 何时启动抗病毒治疗

将CD4阈值提高到500/mm3的证据 5岁以上儿童的抗病毒治疗启动标准与成人相同。关于对CD4 +T淋巴细胞计数在350 ～500/mm3之间的儿童进行治疗，尽管相关临床影响的评估数据有限，而抗病毒药物的性传播预防效益对于这一人群又不适用，但与成人标准的一致化为这一策略带来了一些规划优势。尤其是在抗病毒治疗覆盖率高的情况下，其可行性可能达到最高。如同成人一样，对CD4+T淋巴细胞计数≤350/mm3的所有儿童，都应高度优先予以治疗，因为其疾病进展的风险最高。

HIV与乙肝病毒合并感染一些同时涉及HIV疫情与乙肝病毒疫情的小型队列研究表明，感染HIV儿童的慢性乙肝病毒患病率为1%-49% （118）。乙肝病毒一般是在婴儿期或儿童早期感染，并且与成人不同，可能存在持续于整个儿童期与青少期的免疫耐受期。令人遗憾的是，关于感染HIV儿童中这一疾病的自然病程，目前还知之甚少。而且，对这些儿童尽早进行抗病毒治疗的效益也还有待评估。

扩展儿童抗病毒治疗的临床考量第十章第六节（10.6部分）介绍了涉及规划管理人员的具体实施问题（见专栏10.6）。对于医护工作者而言，具体实施中的另一个重要问题是，抗病毒治疗扩展成 “对于5岁以下儿童，不用考虑其临床或免疫学指标就启动治疗” ，在这一年龄组中免除了启动治疗所需的CD4+T淋巴细胞计数测定，从而避免了CD4检测受限时抗病毒治疗的延误。但是， CD4检测（包含基线绝对计数及百分数的测定）在缺乏病毒载量监测的情况下，对于确保治疗得到适当监测而言仍然很重要。

尚待研究的主要问题尽早启动抗病毒治疗对5岁以下儿童患病率的潜在影响与临床效益问题，以及长时期内的免疫反应及病毒学反应问题，都仍然需要更多研究数据来证实。对于非艾滋病晚期的儿童，尽早启动抗病毒治疗对关怀队列维持、依从性及潜在HIV耐药等方面的影响需要进一步的研究。而对于合并感染乙肝病毒的儿童，启动抗病毒治疗的最佳方式也需要更多的研究数据。

102

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

7.2 抗病毒治疗起始方案（一线抗病毒治疗）一线抗病毒治疗建议采用简化、毒副作用少、更便捷的治疗方案，如固定剂量复合制剂。包含非胸苷的核苷类逆转录酶抑制剂（NRTI）骨干用药（TDF＋FTC或TDF＋3TC）以及一种非核苷类逆转录酶抑制剂（EFV）的每日一次用药方案仍然是成人、青少年及3岁以上儿童的首选方案。对于3岁以下儿童，则首选采用基于蛋白酶抑制剂（PI）的方案（见表7.5）。

表7.5 成人、青少年、怀孕及哺乳妇女、及儿童的一线抗病毒治疗方案一览：一线抗病毒治疗方案首选一线方案备选一线方案 ab

成人（包括怀孕及哺乳妇女以及合并感染TB和乙肝病毒的成人） TDF＋3TC （或FTC）＋EFV 体重35kg及以上的青少年（10岁～19岁）

AZT＋3TC＋EFV AZT＋3TC＋NVP TDF＋3TC （或FTC）＋NVP AZT＋3TC＋EFV AZT＋3TC＋NVP TDF＋3TC （或FTC）＋NVP ABC＋3TC＋EFV(或NVP) ABC＋3TC＋NVP AZT＋3TC＋EFV

3岁以上～不满10岁的儿童以及体重不足35kg的青少年

ABC＋3TC＋EFV

AZT＋3TC＋NVP TDF＋3TC （或FTC）＋EFV TDF＋3TC （或FTC）＋NVP

不满3岁的儿童

ABC或 AZT＋3TC＋LPV/r

ABC＋3TC＋NVP AZT＋3TC＋NVP

a对于青少年，应当停止在一线治疗中使用d4T，而且d4T应当仅在无法使用其它抗病毒药物的情况下、在严密监督下且尽可能短时间地使用。对于儿童， d4T应当仅用于存在疑似或确诊AZT毒性且无法得到ABC或TDF时，而且包含该药的治疗方案应当尽可能短时间地使用。淘汰d4T的相关指导请见专栏10.7。 b 在特殊情况下，可以使用ABC或使蛋白酶抑制剂（ATV/r、 DRV/r、 LPV/r）增效。

7.贯穿关怀体系的临床指南：抗病毒治疗

103

7.2.1 成人的一线抗病毒治疗最新建议新

7.２抗病毒治疗起始方案（一线抗病毒治疗）

一线抗病毒治疗应当包含两种核苷类逆转录酶抑制剂（NRTI）以及一种非核苷类逆转录酶抑制剂（NNRTI）。推荐采用TDF＋3TC(或FTC)＋EFV固定剂量联合用药作为启动抗病毒治疗的首 • 选方案（强烈建议、中等质量证据）。如果不能得到TDF＋3TC(或FTC)＋EFV或存在禁忌症，建议从下列方案选择之一： •

• AZT＋3TC＋EFV • AZT＋3TC＋NVP • T DF＋3TC(或FTC)＋NVP （强烈建议、中等质量证据）。

由各国应当在一线方案中停止使用（强烈建议、中等于d4T具有众所周知的代谢毒性，质量证据）。

表7.6 成人的一线抗病毒治疗方案总结a 成人（包括怀孕及哺乳妇女、以及合并结核病和乙肝病毒感染的成人）一线抗病毒治疗方案首选方案备选方案 TDF＋3TC （或FTC）＋EFV AZT＋3TC＋EFV （或NVP） TDF＋3TC （或FTC）＋NVP c 特殊情况 a

b 包含ABC、 d4T 或增效PI

关于青少年的方案， 7.2.4部分中介绍了3岁及以上儿童（包括10岁及以上的HIV感染青少年）的一线抗病毒治疗。应当停止在一线治疗中使用d4T，而且d4T应当仅在无法使用其它抗病毒药物的情况下、在严密监督下使用且尽可能短时间地使用。 c 包括因严重毒性、预期的药物间相互作用、药品采购、供应管理等原因，无法得到或不适于采用首选口服方案的特殊情况。 b

新

背景 2010版世卫组织有关抗病毒治疗指南（2）建议，对于未接受过抗病毒治疗的成人，初始抗病毒治疗应当包含一种NNRTI （EFV或NVP）和两种NRTI （其中一种为3TC或FTC、另一种为 AZT或TDF）。对于已知具有线粒体毒性的d4T，指南强调避免将其作为一线方案中首选用药的重要性。同时，指南也强调了采用预期毒性更低、更适合大多数人的方案的重要性。出于临床、实施及规划效益的考量，最好采用固定剂量制剂用药方案。推荐方案的毒副作用低于d4T，同时在病毒学功效方面，由于没有证据显示AZT强于d4T、 AZT强于TDF、 TDF强于d4T或ABC、或 EFV强于NVP，所以推荐方案被认为在功效方面与d4T方案相似。各国从一线抗病毒治疗首选方案中淘汰d4T的过程各异。有些国家的进展迅速，有些国家则循序渐进，例如仅对刚启动抗病毒治疗者或孕妇避免使用d4T （见网络附录www.who.int/hiv/ pub/guidelines/arv2013/annexes）。

104

使用抗病毒药物治疗和预防艾滋病毒感染的综合指南

世卫组织（119,120）推荐的更为廉价、高效的治疗策略，采用简单的、单片剂的、每日服用一次的抗病毒治疗方案。 2013版指南建议，抗病毒治疗应当进一步简化，包括减少首选一线方案的数目和重点采用适合多种人群的方案。

基本理论与证据支持将首选一线方案改为TDF＋3TC （或FTC）＋EFV 将6种方案进行比较的系统综述显示，存在中等质量证据支持：每日一次的TDF＋3TC （或 FTC）＋EFV联合用药方案与其它每日一次或两次方案相比，前者更少造成药物的严重不良反应并且其病毒学及治疗反应更好（见网络附录www.who.int/hiv/pub/guidelines/arv2013/ annexes）。另一系统综述提示，服用NVP者因药物不良反应而终止治疗率为服用EFV者的两倍（121）。指南制定小组还对已发表的一项Meta分析及其补充研究（122,123）进行了回顾，上述研究结果显示： EFV与其它抗病毒药物相比，在孕早期使用时未发现造成出生缺陷风险升高（122）。 3TC与FTC在药理学方面表现相似（123）。 TDF＋3TC （或FTC）＋EFV为不同人群的治疗一致化提供了很好的条件： TDF/FTC或TDF/3TC是HIV与乙肝病毒合并感染者的首选NRTI骨干用药，并可用于结核病合并感染者及孕妇。 EFV是HIV与结核病合并感染者（因其与结核药物在药理学方面相容）以及HIV与乙肝病毒合并感染者（因其肝毒性风险更低）的首选NNRTI用药，并可用于孕妇（包括孕早期者）。如果不能采用TDF＋3TC （或FTC）＋EFV，对于未接受过抗病毒治疗者，可以采用其它包含 NNRTI的每日一次或每日两次用药方案（AZT＋3TC＋EFV、 AZT＋3TC＋NVP、 TDF＋3TC （或 FTC）＋NVP）作为备选一线方案。这些方案尽管被作为等价方案使用，但与首选方案相比各自存在一定的潜在缺陷。 ABC及增效PI等药物被用作特殊情况下的潜在后备方案，但鉴于抗病毒药物的优化原则，不推荐将这些药物用作最佳备选用药。

对孕妇人群使用奈韦拉平（NVP）一些研究显示，与服用EFV相比， CD4+T淋巴细胞计数较高的孕妇服用NVP后出现严重肝或皮肤反应的相对风险较高（124-126）。因此，关于NVP具有更高的药物不良反应风险以及将其用于CD4+T淋巴细胞计数超过250/mm3的HIV感染妇女方面一直存在广泛担忧。关于NVP 孕妇相关毒性风险的系统综述（127）及其2013年补充研究（134）显示，药物不良反应的出现频率有所升高，但并不高于一般成年人群的观测结果。关于CD4+T淋巴细胞计数较高的HIV 感染孕妇与一般HIV感染人群相比具有更高的药物不良反应风险，这一理论的证据支持较为薄弱。 NVP最初使用时需要确定起始用药剂量，并且目前没有NVP与TDF＋3TC （或FTC）的固定剂量复合制剂，这些都需要予以重点考虑。因此，将NVP应用于孕妇及可能会怀孕的妇女时应当只有当无法使用NVP时，才可以使用NVP的其它替代选项（如ABC及增效PI）。

备选方案的使用和司他夫定（d4T）的淘汰目前推荐的备选方案（如用AZT替换TDF、用NVP替换EFV）在治疗功效上与首选方案相似，但其具有一些临床及规划方面的潜在缺陷。对于采用备选方案后在临床上已经稳定且没有禁忌症的个体，可以考虑根据国家指南继续使用该方案；或者也可以改用首选方案，以简化治疗管理、降低成本、改善耐受性、提高依从性并使首选治疗方案得以更好推进。在特殊情况下也可以采用ABC及增效PI，但必须在没有其它选择时才能使用。应当停止在治疗方案中使用d4T。 d4T应当仅在无法使用其它抗病毒药物的情况下、在严密监督下且尽可能短时间地使用。当d4T方案仍然作为启动抗病毒治疗的首选方案使用时，应当实

7.贯穿关怀体系的临床指南：抗病毒治疗

105

施d4T淘汰计划，最好是过渡到使用基于TDF的一线方案（2,128,129）。关于d4T淘汰问题的详细介绍，请参见第十章第六节（10.6部分，专栏10.7）。

7.２抗病毒治疗起始方案（一线抗病毒治疗）

替诺福韦（TDF）毒性关于TDF毒性的系统综述显示，短期至中期使用TDF时，尤其对于已患有肾病或具有肾病风险者，会产生低水平的肾毒性。前瞻性队列研究数据显示， TDF与肾功能中度下降（以估算肾小球滤过率的降低程度来衡量）（130,131）及骨矿物质密度降低相关，但仍需对这些副作用的临床影响及危害程度（尤其是在长期治疗时）进行进一步研究。对于TDF毒性的实验室筛查与监测应当日常性开展、还是应当仅针对高危人群（如高血压或糖尿病患者或增效PI的服用者）进行，也还需要更多的研究。由于TDF的肾毒性通常是肾小管性的，肾小球的功能测定并不能提供直接评价，而且也没有其它简单试验能够对肾小管毒性进行测定。关于这一问题的详细介绍，请参见7.4部分。相关证据显示，对于没有继发性肾病的HIV感染者，抗病毒治疗所带来的肾功能总体改善可以抵消TDF的毒性风险。

HIV-2型感染关于HIV-2感染者治疗方案的系统综述（见网络附录www.who.int/hiv/pub/guidelines/ arv2013/annexes）将所有观察性研究的证据都确定为极低质量，具有严重的偏倚、不一致和不准确的风险。由于HIV-2型病毒对NNRTI具有自然抗性，对于未经治疗的HIV-1型与HIV-2型合并感染者，应当采用包含三种NRTI的治疗方案（TDF＋3TC （或FTC）＋AZT或AZT＋3TC＋ABC）或是采用利托那韦增效PI加上两种NRTI。若采用的是基于PI的方案，一线治疗的首选方案应当为 LPV/r，因为这是低收入国家中成人二线治疗及儿童一线治疗的共同采购药品。 SQV/r和DRV/r 是增效PI的备选方案，但这些药物都没有具备热稳定性能的固定剂量复合制剂。

7.2.2 怀孕及哺乳妇女的一线抗病毒治疗及其婴儿的抗病毒药物