Management of HIV Infection and Antiretroviral Therapy in Adults and Adolescents
A Clinical Manual
WHO Technical Publication No. 58
Management of HIV Infection and Antiretroviral Therapy in Adults and Adolescents A Clinical Manual 2007
WHO Library Cataloguing-in-Publication data World Health Organization, Regional Office for South-East Asia. Management of HIV infection and antiretroviral therapy in adults and adolescents: a clinical manual. (Technical Publication Series No. 58) 1. Acquired Immunodeficiency Syndrome—drug therapy. 2. Antiretroviral Agents—therapeutic use—pharmacology. 3. Antiretroviral Therapy, Highly Active. 4. HIV infections—drug therapy. 5. Adult. 6. Adolescent. 7. Manuals.
ISBN 978 92 9022 289 7
(NLM classification: WC 503.2)
This publication is available on the internet at www.searo.who.int/hiv-aids publications. Copies may be requested from the HIV Unit, Department of Communicable Diseases, World Health Organization, Regional Office for South-East Asia, Indraprastha Estate, Mahatma Gandhi Marg, New Delhi-110 002, India, e-mail: hiv@searo.who.int. Editorial support: Dr Bandana Malhotra, New Delhi, India Layout and typesetting: Macrographics, New Delhi, India
© World Health Organization 2007 All rights reserved. Requests for publications, or for permission to reproduce or translate WHO publications—whether for sale or for noncommercial distribution—can be obtained from Publishing and Sales, World Health Organization, Regional Office for South-East Asia, Indraprastha Estate, Mahatma Gandhi Marg, New Delhi-110 002, India (fax: +91 11 23370197; e-mail: publications@ searo.who.int). 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 they 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 names of 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. This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization. Printed in India
ACKNOWLEDGEMENTS The World Health Organization Regional Office for South-East Asia expresses its sincere gratitude to Anupong Chitwarakorn, Senior Expert in Preventive Medicine, Department of Communicable Disease Control, Ministry of Public Health, Bangkok, Thailand and Somsit Tansuphaswadikul, Chief of Medicine Section, Bamrasnaraduras Hospital, Nonthaburi, Thailand for facilitating the first meeting of the writing committee for revision of this guideline. The committee included Chris Duncombe, The HIV-Netherlands Australia Thailand Research Collaboration (HIVNAT), The Thai Red Cross, Research Centre, Chulalongkorn University; Nagalingeswaran Kumarasamy, YRG Care Centre for AIDS Research and Education, Tharamani, Chennai, India; Dilip Mathai, Christian Medical College, Vellore, Tamil Nadu, India; Samsuridjal Djauzi, Dharmais Cancer Hospital and Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; Htin Aung Saw, Wai Bagi Infectious Disease Hospital, Yangon, Myanmar; Kulkanya Chokephaibulkit, Department of Pediatrics, Siriraj Hospital, Bangkok, Thailand; Koen Frederixon, Arlene Chua and David Wilson, MSF Belgium, Bangkok, Thailand; and Karyn Kaplan, Thai AIDS Treatment Action Group. We thank the following contributors who provided comments: Rachel Burdon, Family Health International, Viet Nam; Lisa Stevens, Family Health International, Nepal; Jintanat Ananworanich, South-East Asia Research Collaboration with Hawaii (SEARCH), Bangkok, Thailand; Anchalee Avihingsanon and Nittaya Phanuphak, HIVNAT, The Thai Red Cross, Research Centre, Chulalongkorn University, Bangkok, Thailand; Po-Lin Chan and Bharat Rewari from WHO India Country Office; Charlie Gilks, Micheline Diepart and Marco Vitoria, Department of HIV/AIDS, WHO Headquarters, Geneva, Switzerland. Special thanks go to Chris Duncombe, HIVNAT and Veronique Bortolotti, former Short-term Professional HIV/AIDS, WHO Nepal Country Office, for preparing the initial drafts and integrating the final comments and contributions from the review panel. The work was coordinated by Ying-Ru Lo, Regional Advisor HIV/AIDS, WHO Regional Office for South-East Asia.
Acronyms and abbreviations 3TC AB ABC ACTG AFB AIDS ALT ANC APV ART ARV AST ATV AUC AZT BMI CD4 count CMV CNS CPK CSF CTX CXR d4T ddI DNA DOT DRV EC EFV EPTB FBC FPV lamivudine antibody abacavir AIDS Clinical Trials Group acid-fast bacilli acquired immunodeficiency syndrome alanine aminotransferase absolute neutrophil count amprenavir antiretroviral therapy antiretroviral (drug) aspartate aminotransferase atazanavir area under the curve zidovudine (also known as ZDV) body mass index CD4+ T-lymphocyte count cytomegalovirus central nervous system creatine phosphokinase cerebrospinal fluid co-trimoxazole chest X-ray stavudine didanosine deoxyribonucleic acid directly observed treatment darunavir enteric coated efavirenz extrapulmonary tuberculosis full blood count fos-amprenavir
FTC GI GGT HDL Hb HBsAg HBV HCP HCV hgc HIV HPV HSV IDV IDU IFN INH IRIS JCV KOH LDH LPV MAC MSM MTCT NFV NNRTI nPEP NRTI NSAID NVP OHL OI OST Pap PCP
emtricitabine gastrointestinal gamma glutamyl transpeptidase high-density lipoprotein haemoglobin hepatitis B surface antigen hepatitis B virus health-care provider hepatitis C virus hard-gel capsule human immunodeficiency virus human papillomavirus herpes simplex virus indinavir injecting drug user interferon isoniazid immune reconstitution inflammatory syndrome JC virus (virus that causes progressive multifocal leukoencephalopathy [PML]. JC are the two initials of a patient with PML.) potassium hydroxide lactate dehydrogenase lopinavir Mycobacterium avium complex men who have sex with men mother-to-child transmission (of HIV) nelfinavir non-nucleoside reverse transcriptase inhibitor non-occupational post-exposure prophylaxis nucleoside reverse transcriptase inhibitor non-steroidal anti-inflammatory drug nevirapine oral hairy leukoplakia opportunistic infection opioid substitution treatment Papanicolaou Pneumocystis jiroveci pneumonia (earlier known as Pneumocystis carinii)
PEP PGL PI PK PLHA PML PMTCT PPE PTB /r RBV REE RNA RPR RTI RTV SDN SOP SQV STI SW TB TDF TLC TPHA ULN VDRL WBC WHO ZN
post-exposure prophylaxis persistent generalized lymphadenopathy protease inhibitor pharmacokinetic people living with HIV/AIDS progressive multifocal leukoencephalopathy prevention of mother-to-child transmission (of HIV) pruritic papular eruption pulmonary tuberculosis low-dose ritonavir ribavirin resting energy expenditure ribonucleic acid rapid plasma reagin (test) reverse transcriptase inhibitor ritonavir single-dose nevirapine standard operating procedure saquinavir sexually transmitted infection sex worker tuberculosis tenofovir disoproxil fumarate total lymphocyte count Treponema pallidum haemagglutination (test) upper limit of normal Venereal Disease Research Laboratory (test) white blood cell count World Health Organization Ziehl–Neelsen
contents Introduction ............................................................................................................................1 1. Laboratory diagnosis of HIV infection in.................................................................2 adults and adolescents 2. Assessment of adults and adolescents....................................................................4 with HIV infection 3. Assessment and management after the.............................................................. 12 diagnosis of HIV infection is confirmed 4. Prophylaxis for opportunistic infections.............................................................. 14 5. When to start antiretroviral therapy (ART) in...................................................... 18 adults and adolescents 6. Recommended first-line antiretroviral regimens.............................................. 21 7. Adherence .................................................................................................................... 28 8. Clinical and laboratory monitoring prior to........................................................ 32 commencing and on first-line ART 9. Antiretroviral drug toxicities..................................................................................... 34 10. ART for pregnant women and those with............................................................ 43 childbearing potential 11. Antiretroviral therapy in tuberculosis/HIV coinfection................................... 45 12. Injecting drug users..................................................................................................... 47 13. HIV and hepatitis coinfection................................................................................... 54 14. ART failure and when to switch therapy............................................................... 56 15. Choice of second-line regimens for treatment failure..................................... 60 16. Clinical and laboratory monitoring prior to........................................................ 61 commencing and on second-line ART 17. Syndromic approach to the management of..................................................... 64 opportunistic infections 18. Nutritional support. ...................................................................................................... 74
19. Palliative care in HIV infection ................................................................................. 77 20. Management of occupational exposure including.......................................... 86 post-exposure prophylaxis 21. Management of non-occupational exposure including...............................105 post-exposure prophylaxis Annexes Annex 1: Criteria for HIV-related clinical events in................................................111 adults and adolescents Annex 2: Dosages of antiretroviral drugs for adults.............................................117 and adolescents Annex 3: Storage of antiretroviral drugs...................................................................119 Annex 4: Drugs that interact with antiretroviral....................................................121 therapy Annex 5 Drug interactions between opiates and.................................................125 antiretrovirals and other drugs Annex 6: Clinical diagnosis and management of..................................................127 common opportunistic infections Annex 7: Tuberculosis case definitions and treatment........................................132 Annex 8: Clinical diagnosis and management of..................................................135 skin conditions Annex 9: Severity grading of selected clinical and................................................142 laboratory toxicities References .............................................................................................................................146 Index . .......................................................................................................................... 155
Introduction This document updates the World Health Organization, Regional Office for South-East Asia’s guideline The use of antiretroviral therapy: a simplified approach for resource-constrained countries, published in July 2002. This new document provides a simplified and standardized approach to the clinical management of people living with HIV/AIDS (PLHA) and use of antiretroviral therapy (ART) as part of comprehensive HIV care. The term adult is used for persons 18 years of age and above and the term adolescent for those 10–18 years of age. Whether to treat adolescents following the paediatric guidelines or adult/adolescent guidelines depends on the treating physician. The objectives of this clinical manual are (i) to guide medical doctors and other health-care providers in the clinical management of HIV and ART; (ii) to serve as a source of reference for AIDS programme managers and health planners in planning HIV care and treatment programmes and in developing national HIV care and treatment guidelines; and (iii) to provide a source of reference for PLHA, caregivers and communitybased organizations. The following related publications from WHO Regional Office for SouthEast Asia should be consulted in conjunction with this manual: Laboratory guidelines for enumerating CD4 T lymphocytes in the context of HIV/AIDS, 2007. Antiretrovirals for HIV: a compilation of facts and product information, 2007. Antiretroviral therapy of HIV infection in infants and children in resourcelimited settings: a clinical manual, 2006. Training toolkit – HIV care and antiretroviral treatment recording and reporting system, 2006. Guidelines for HIV diagnosis and monitoring of antiretroviral therapy. Revision, 2005. The full set of WHO guidelines is available at www.searo.who.int/hiv-aids publications and http://www.who.int/hiv/pub/guidelines/en/index.html.
1
Laboratory Diagnosis of HIV Infection in Adults and Adolescents
Figure 1. HIV testing algorithm
Person who agreed to HIV testing
HIV antibody test [a]
Negative
Risky behaviour completely stopped [b] Yes
No
Offer next HIV test after 6 months. Counsel for risk reduction [c]
Positive
Counsel HIV-negative Counsel for risk reduction [c] Negative Inconclusive. Continue according to national HIV testing guidelines for adults
Confirmatory HIV antibody test [c] Positive
Signs and Negative symptoms suggestive of HIV
Confirmatory HIV antibody test [d]
Negative Inconclusive. Continue according to national HIV testing guidelines for adults [e]
Yes Counsel HIV-positive Counsel for risk reduction
Yes Counsel HIV-positive Counsel for risk reduction
Laboratory diagnosis of HIV infection in adults and adolescents
Notes [a] HIV testing procedures should follow each country’s national guidelines. WHO recommends that the HIV tests used should have a sensitivity of at least 99% and a specificity of 98%. The specific test combinations need to be evaluated in the context in which they will be used before wide-scale implementation. Tests selected should be of assured quality, and a number of these are evaluated against standard panels by designated reference laboratories. The introduction of highly sensitive, specific, simple-to-use, rapid antibody tests that do not require sophisticated laboratory services, running water or electricity is recommended in settings where immediate provision of test results is important. Accurate results can be available within a much shorter time than for traditional enzyme-linked immunosorbent assays (ELISA). ELISA may be preferable in settings where large numbers of tests need to be performed, and where immediate provision of test results is less important.1.2 [b] Antibodies against HIV appear from 2 weeks to 3 months after first exposure to HIV (97%). This period is called the window period. Therefore, if the initial negative HIV test was conducted within the first 3 months of possible exposure, a repeat test should be considered, in particular, when there is continued risky behaviour such as (i) unprotected sex in persons with a history of sexually transmitted infection (STI), sex workers (SWs) and their clients, men who have sex with men (MSM) and sex partners of people living with HIV/AIDS (PLHA) as well as (ii) sharing of injecting equipment among injecting drug users (IDUs). [c] WHO recommends serial testing algorithms as shown in Figure 1. If the result of the first test is negative, the HIV antibody test is reported as negative. If the test result is positive, the specimen is tested with a second test using different antigens and/or platform from the first. Tests that are exactly the same but sold under different names should not be used in combination. A second positive test result is considered to indicate a true positive result in populations with an HIV prevalence of 5% or more. WHO and UNAIDS recommend serial testing in most settings because it is cheaper and a second test is only required when the initial test is reactive. [d] In low-prevalence settings (<5%) where false-positive results are more likely, a third confirmatory test may be required.1 [e] If the result remains inconclusive following the initial and confirmatory tests, it is repeated two weeks later. If it is still inconclusive, follow-up testing may be required. Conduct a careful risk assessment and provide counselling on HIV prevention. If the person is at high risk, consider retesting at 6 and 12 months. If the results remain inconclusive after 1 year, the person is considered HIV negative if no HIV exposure has occurred in the previous 12 months.1
2
Assessment of Adults and Adolescents with HIV Infection
2.1 Clinical assessment At entry into care and prior to starting ART, the medical history should be taken and clinical assessment performed (Tables 1, 2): To determine the clinical stage of HIV infection To identify past HIV-related illnesses To identify current HIV-related illnesses that require treatment To determine the need for ART and prophylaxis for opportunistic infection (OI) To identify coexisting medical conditions and treatments that may influence the choice of therapy.
The recognition of HIV-related clinical events facilitates staging of a patient’s disease and decisions on when to initiate OI prophylaxis and ART. Annex 1 details those conditions which should alert the physician that the patient may have HIV infection. Many conditions require only a clinical diagnosis. Conditions that come under WHO stages 1, 2 and 3, with the exception of moderate anaemia, can be readily recognized clinically. For WHO stage 4 conditions, definite diagnostic criteria are recommended for diseases such as lymphoma and cervical cancer where a clinical diagnosis is not possible.3
Medical history (Table 1) Many individuals with HIV infection are unaware of their status (i.e. whether they are HIV-positive or negative). HIV testing should be performed for any patient who requests it following pre-test counselling. Other indications for HIV testing include the presence of sexually transmitted infections (STIs), pregnancy, active tuberculosis (TB) and signs and symptoms suggestive of HIV infection.
Assessment of adults and adolescents with hiv infection
Box 1: Risk factors for HIV infection
Male or female sex worker (SW) Present or past injecting drug user (IDU) Men who have sex with men (MSM) and transgenders Present or past unprotected sex, particularly with a female or male SW Present or past STI Present or past recipient of blood or blood products Injections, tattooing, ear piercing or body piercing using non-sterile instruments.
Table 1: Medical history checklist HIV testing
HIV risk
Ever tested for HIV in the past? Date and place of first HIV test Reason for the test Documentation of the result Date of last negative HIV test result Prior CD4+cell counts (if available) Prior viral load (if available) Systemic review Unexplained weight loss Swollen lymph nodes Night sweats and fever Unusual headaches or poor concentration Changes in appetite Skin rashes Sores or white spots in the mouth Pain on swallowing Chest pain, cough, shortness of breath Stomach pain, vomiting, diarrhoea Numbness or tingling in the hands and feet Muscle weakness and changes in vision TB history Last chest X-ray (CXR) History of past TB Treatment given (drugs and duration) History of exposure to TB
Unprotected sexual contact Injecting drug use Men who have sex with men (MSM) Occupational exposure Perinatal transmission Recipient of blood products Unknown Past history of HIV-related illnesses
Oral or osophageal candidiasis Persistent diarrhoea Varicella zoster (shingles) Oral hairy leukoplakia (OHL) Pneumocystis jiroveci pneumonia (PCP) Recurrent bacterial pneumonia Cryptococcal meningitis Toxoplasmosis Kaposi sarcoma Disseminated Mycobacterium avium complex (MAC) disease Cytomegalovirus (CMV) infection TB Invasive cervical cancer Sexually transmitted infections (STIs) Genital ulcer or other lesion Genital discharge (abnormal vaginal
discharge in women) Lower abdominal pain
Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 1 (contd): Medical history checklist Gynaecological history Last Papanicolaou (Pap) smear Menstrual irregularities Pelvic pain or discharge
General medical history Any other past medical condition such
as diabetes, hypertension, cardiovascular disease, hepatitis B, hepatitis C Vaccination history
Pregnancy and contraception history Previous pregnancies and terminations
BCG of pregnancy Hepatitis A vaccine Children and HIV status of children (living Hepatitis B vaccine
and dead)
Exposure to antiretroviral drugs (ARV)
during pregnancy Drugs taken and duration of ART Contraception used Last menstrual period
Medication
Allergies
Past drugs and reasons for taking them Known allergies to drugs or other substances or materials Current drugs and reasons for taking them Traditional remedies taken in the past or
currently being taken Opioid substitution therapy (OST)
ART history Current and past exposure to ART Which drugs taken and for how long Understanding and readiness to
Psychosocial history Family history, e.g. other immediate
commence ART if never taken
family member with known HIV infection Social history, e.g. marital status, education, occupation, source of income Financial and family support status Disclosure status, readiness to disclose Care and treatment support available Functional status
Substance use Alcohol, stimulant, opiate and other
Able to work, go to school, do
drug use Smoking history
housework Ambulatory but not able to work Bedridden Amount of day-to-day care needed
History-taking is followed by physical examination.
Assessment of adults and adolescents with hiv infection
Table 2: Physical examination checklist Record vital signs: body weight, temperature, blood pressure, pulse rate, respiratory rate Appearance Unexplained moderate or severe weight loss, HIV wasting
(see Annex 1) Rapid weight loss is suggestive of active OI, especially if
associated with fever. Gradual weight loss (not caused by malnutrition or other
obvious illness) is suggestive of HIV infection. Gradual weight loss, fever and anaemia are common
presentations of infection with MAC. “Track marks” and soft tissue infections are common in
IDUs. Consider conditions other than HIV Skin Malaria, TB, syphilis, gastrointestinal (GI) infections, bacterial
pneumonia, pelvic inflammatory disease, viral hepatitis Look for signs of HIV-related and other skin problems.
These include diffuse dry skin, typical lesions of pruritic papular eruptions (PPE) especially on the legs, seborrhoeic dermatitis on the face and scalp. Look for herpes simplex and herpes zoster, or scarring suggestive of previous herpes zoster. Lymph nodes Start with the posterior cervical nodes. Persistent generalized lymphadenopathy (PGL) typically
presents as multiple bilateral, soft, non-tender, mobile cervical nodes. Similar nodes may be found in the armpits and groins. Tuberculous lymph nodes typically present as unilateral, painful, hard, enlarging nodes with constitutional symptoms such as fever, night sweats and weight loss. Mouth Look for signs suggestive of HIV infection including white
plaques on the tongue, cheeks and roof of the mouth (oral candidiasis), white striped lesions on the side of the tongue (OHL) and cracks at the corners of the mouth (angular cheilitis). Chest The most common problems are PCP and TB. Signs and symptoms are cough, shortness of breath,
haemoptysis, weigh loss, fever, congestion or consolidation. Do a chest X-ray if possible. Abdomen Look for hepatosplenomegaly, masses and local tenderness. Jaundice may indicate viral hepatitis. Difficulty in swallowing is commonly caused by
oesophageal candidiasis.
Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 2 (contd): Physical examination checklist Anogenital Look for herpes simplex and other genital sores/lesions,
vaginal or penile discharge. Perform a Pap smear if possible.
Neurological examination
Focus on the visual fields and look for signs of
neuropathy (bilateral, peripheral or localized mononeuropathies). Assess for focal neurological deficit.
MAC Mycobacterium avium complex IDU injecting drug user PPE pruritic papular eruptions PGL persistent generalized lymphadenopathy OHL oral hairy leukoplakia PCP Pneumocystis jiroveci pneumonia Pap Papanicolaou TB tuberculosis
2.2 Revised WHO clinical staging of HIV-related disease in adults and adolescents aged 15 years or more The revised WHO clinical classification of HIV-associated disease is designed to be used in patients with confirmed HIV infection (Tables 3 and 4). Along with measurement of the CD4 count, where available, the staging system is used to guide decisions on when to start OI prophylaxis and when to start and switch ART. Table 3: Revised WHO clinical staging of HIV-related disease in adults and adolescents aged 15 years or more Clinical stage 1 (Asymptomatic) Asymptomatic PGL Clinical stage 2 (Mild disease) Unexplained moderate weight loss (<10% of presumed or measured body weight) Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media and pharyngitis) Herpes zoster Angular cheilitis Recurrent oral ulcerations Pruritic papular erruptions (PPE) Seborrhoeic dermatitis Fungal nail infections
Assessment of adults and adolescents with hiv infection
Table 3 (contd): Revised WHO clinical staging of HIV-related disease in adults and adolescents aged 15 years or more Clinical stage 3 (Moderate disease) Unexplained severe weight loss (>10% of presumed or measured body weight ) Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (above 37.5°C, intermittent or constant, for longer than one month) Persistent oral candidiasis Oral hairy leukoplakia (OHL) Pulmonary TB Severe bacterial infections (such as pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Unexplained anaemia (<8 g/dl ), neutropenia (<0.5 x 109/litre) or chronic thrombocytopenia (<50 x 109/litre)
Clinical stage 4 (Severe disease) HIV wasting syndrome Pneumocystis jiroveci pneumonia (PCP) Recurrent severe bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal, of more than one month’s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of the trachea, bronchi or lungs) Extrapulmonary TB (EPTB) Kaposi sarcoma Cytomegalovirus (CMV) infection (retinitis or infection of other organs) Toxoplasmosis of the central nervous system (CNS) HIV encephalopathy Extrapulmonary cryptococcosis including meningitis Disseminated non-tuberculous mycobacterial infection Progressive multifocal leukoencephalopathy (PML) Penicilliosis Chronic cryptosporidiosis Chronic isosporiasis Disseminated mycosis (extrapulmonary histoplasmosis, coccidiodomycosis) Recurrent septicaemia (including due to non-typhoidal Salmonella) Lymphoma (cerebral or B-cell, non-Hodgkin) Invasive cervical carcinoma Atypical disseminated leishmaniasis Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy
10
Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 4: Signs and symptoms suggestive of HIV infection General conditions
Weight loss of >10% of baseline body weight Fever (continuous or intermittent, oral temperature >37.5ºC) for more than one month Diarrhoea (continuous or intermittent) for more than one month Generalized lymphadenopathy
Skin conditions PPE* and diffuse dryness of skin* are strongly suggestive of HIV infection. Some conditions, such as genital warts, folliculitis and psoriasis, are common in HIV-infected patients but are not necessarily HIV related (see Annex 8). Infections Fungal infections oral candidiasis (thrush)* seborrhoeic dermatitis* vaginal candidiasis (recurrent) herpes zoster (recurrent or involving more than one
Viral infections
dermatome)* genital herpes (recurrent) molluscum contagiosum condyloma (genital warts)
Respiratory conditions
cough for more than one month dyspnoea TB recurrent pneumonia chronic or recurrent sinusutis
Neurological manifestations
worsening headache (continuous and unexplained) febrile convulsion declining cognitive function
* These conditions are strongly suggestive of HIV infection.
Assessment of adults and adolescents with hiv infection
11
2.3 Immunological assessment A CD4 count is the most reliable way of assessing the patient’s immune status. The CD4 cell count complements clinical assessment. It can detect immune deficiency requiring intervention with OI prophylaxis and ART before the patient’s disease progresses. CD4 counts vary from day to day and with intercurrent illness. Splenectomy results in falsely raised CD4 counts. In this case, the CD4% should be used to guide decision-making. If possible, CD4 testing should be repeated before a major management decision is taken, such as commencing ART. Better access to CD4 testing is promoted by WHO but the absence of CD4 testing is not a barrier to initiating ART. CD4 counts are also used to monitor response to ART.
2.4 Total lymphocyte count In the absence of a CD4 cell count, a total lymphocyte count (TLC) may be used as a surrogate marker of immune function. It is not employed in many ART programmes and is useful in only one clinical situation (patients with WHO stage 2 disease when facilities for measuring the CD4 count are not available). Decision-making is otherwise simple. ART is recommended for all patients with WHO stages 3 and 4 disease, and not recommended for asymptomatic patients (stage 1). WHO recommends that TLC be phased out. It is not useful and is not recommended for monitoring the response to ART or for deciding whether ART is failing. There is more evidence for its utility in deciding when to initiate ART in children and has been included in the current WHO paediatric ART guidelines.
3
Assessment and Management after the Diagnosis of HIV Infection is Confirmed Visit 1
Table 5: Determining eligibility for ART Medical history Symptom checklist Physical and laboratory examination (see chapters 5–8) CXR if chest symptoms present Behavioural/psychosocial assessment – Education level, employment history, financial resources – Social support, family/household structure – Disclosure status, readiness to disclose – Understanding of HIV/AIDS, transmission, risk reduction, treatment options Nutritional assessment Family/household assessment to determine if there are other HIV-infected family members who may need care Condom use recommended at every visit Eligible for ART Visit 2 (in less than 2 weeks)
Not eligible now for ART
History (new problems) Symptom checklist Examination Co-trimoxazole prophylaxis (see chapter 4) Psychosocial support Adherence counselling; more than one session may be needed prior to commencing ART (see chapter 7)
History (new problems) Symptom checklist Examination Psychosocial support
Visit 3 (2 weeks after previous visit) Commence ART if stable on co-trimoxazole
and patient is ready (see chapter 6) Commence lead-in dose of nevirapine (NVP)
200 mg once daily (see chapter 6.3) Clinical evaluation
Assessment and management after the diagnosis of HIV infection is confirmed
13
Visit 4 (2 weeks after previous visit)
History (new problems) Clinical evaluation Haemoglobin if on zidovudine (AZT) If on NVP, any side-effects (rash, fever, signs of liver toxicity) Dose escalation of NVP to 200 mg 2 times per day (see chapter 6.3) Adherence assessment/support (see chapter 7)
Visit 5 (2 weeks after previous visit)
History (new problems) Symptom checklist Examination Adherence assessment/support (see chapter 7)
Follow up
History (new problems) Symptom checklist Examination Adherence assessment/support Psychosocial support Visits every 1–3 months and more often as needed CD4 count every 3–6 months if available Assess condom use
History (new problems) Symptom checklist Examination Psychosocial support
4
Prophylaxis for Opportunistic Infections
4.1 Co-trimoxazole prophylaxis Randomized clinical trials, studies using historical controls and observational cohort studies have demonstrated the effectiveness of co-trimoxazole prophylaxis in reducing mortality and morbidity across varying levels of background resistance to co-trimoxazole and prevalence of malaria. It is therefore recommended that all HIV-infected adolescents and adults who fulfil the clinical and immunological criteria for commencing ART should also receive co-trimoxazole prophylaxis to prevent the first episode of PCP and toxoplasmosis (Table 6). Table 6: Summary of recommendations for co-trimoxazole prophylaxis, 20064 When to commence primary co-trimoxazole prophylaxis CD4 count not available WHO clinical stages 2, 3, 4 (including all patients with TB disease) CD4 count available Any WHO clinical stage and CD4 count <200 cells/mm3 OR WHO clinical stage 3 or 4 irrespective of CD4 level* Secondary co-trimoxazole prophylaxis Secondary prophylaxis for the prevention of relapse is recommended for all patients who have completed successful treatment for Pneumocystis jiroveci pneumonia (PCP). Start co-trimoxazole prophylaxis first. Start ART two weeks later if the individual tolerates cotrimoxazole and has no symptoms suggestive of allergy (rash, hepatotoxicity).§ One double-strength tablet or two single-strength tablets once daily. Total daily dose is 960 mg (800 mg sulfamethoxazole [SMZ] + 160 mg trimethoprim [TMP]).
Timing the initiation of co-trimoxazole in relation to initiating ART Dosages of co-trimoxazole in adults and adolescents
Prophylaxis for opportunistic infections
15
Table 6 (contd): Summary of recommendations for co-trimoxazole prophylaxis, 20064 Co-trimoxazole in Women who fulfil the criteria for co-trimoxazole pregnant/lactating women prophylaxis should continue on it throughout their pregnancy.5 If a woman requires co-trimoxazole prophylaxis during pregnancy, it should be started regardless of the stage of pregnancy.6 Breastfeeding women should continue to receive cotrimoxazole prophylaxis. Patients allergic to sulfabased medications Dapsone 100 mg per day can be given. Co-trimoxazole desensitization may be attempted but not in patients with a previous history of severe reaction to co-trimoxazole or other sulfa-containing drugs. No specific laboratory monitoring is required for patients receiving co-trimoxazole. Co-trimoxazole prophylaxis may be considered for all patients with active TB and HIV-infected persons from certain high-risk populations such as IDUs and SWs who typically present late with advanced disease and are less likely to have access to facilities for CD4 counts.
Monitoring Universal option
* Option 2: Any WHO clinical stage and CD4 count <350 cells/mm3 where the aim of co-trimoxazole prophylaxis is reduction in the morbidity and mortality associated with bacterial infections and malaria, in addition to the prevention of PCP and toxoplasmosis. This will help in differentiating between the similar side-effects caused by co-trimoxazole and ART (especially if starting an NVP-containing regimen). §
4.2 Co-trimoxazole desensitization Co-trimoxazole desensitization has been shown to be successful and safe in approximately 70% of patients with previous mild-to-moderate hypersensitivity.7,8 Desensitization should not be attempted in individuals with a previous history of severe reaction to co-trimoxazole or other sulfonamides (Table 7). If a reaction occurs, the desensitization regimen should be stopped. Once the patient recovers fully, dapsone 100 mg per day may be tried. Some patients may be allergic to both co-trimoxazole and dapsone.There are no other drug options for prophylaxis in resourcelimited settings.
16
Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 7: Protocol for co-trimoxazole desensitization Step Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Dose 80 mg SMX + 16 mg TMP (2 ml oral suspension) 160 mg SMX + 32 mg TMP (4 ml oral suspension) 240 mg SMX + 48 mg TMP (6 ml oral suspension) 320 mg SMX + 64 mg TMP (8 ml oral suspension) One single-strength SMX–TMP tablet (400 mg SMX + 80 mg TMP) Two single-strength SMX–TMP tablets or one double-strength tablet (800 mg SMX + 160 mg TMP) Source: Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings: recommendations for a public health approach. Geneva, World Health Organization, 2006.
Note: Co-trimoxazole oral suspension contains 200 mg SMX + 40 mg TMP per 5 ml.
4.3 Starting and stopping prophylaxis for opportunistic infections The purpose of prescribing preventive therapy for OIs is to prevent the first-ever episode (primary prophylaxis) or to prevent recurrence (secondary prophylaxis) of an OI (Table 8). Table 8: Criteria for starting and stopping OI prophylaxis Opportunistic infection Primary prophylaxis indicated when CD4 is [a] <200 cells/ mm3 [a] <200 cells/ mm3 Not indicated in most settings (see chapter 4.4) Not indicated Drug of choice Discontinue primary prophylaxis when CD4 is [b] >200 cells/mm3 >200 cells/mm3 >100 cells/mm3 Discontinue secondary prophylaxis when CD4 is [b] >200 cells/mm3 >200 cells/mm3 >100 cells/mm3
PCP Toxoplasmosis Cryptococcus meningitis
TMP–SMX 1 DS tablet once daily TMP–SMX 1 DS tablet once daily Fluconazole
Oral and oesophageal candidiasis
Not applicable
Not applicable
Not applicable
PCP Pneumocystis jiroveci pneumonia TMP–SMX trimethoprim–sulfamethoxazole DS double strength
Prophylaxis for opportunistic infections
17
Note [a] Co-trimoxazole prophylaxis may be initiated in two different contexts. “Classic” prophylaxis, where the target is the prevention of PCP and toxoplasmosis, is recommended for all HIV-infected adults with WHO stages 2–3 and 4 HIV disease or with a CD4 count <200 cells/mm3. If the targets of prophylaxis are reduction in the morbidity and mortality associated with bacterial infections and malaria, in addition to the prevention of PCP and toxoplasmosis, co-trimoxazole is recommended for HIV-infected adults with a CD4 count <350 cells/mm3 or with the same clinical criteria (WHO stages 2–3 or 4). [b] Discontinue when two consecutive CD4 counts are more than that listed in the table, the patient is on ART for more than 6 months and adherence is good. Reintroduce prophylaxis if the CD4 count falls below the starting level.
4.4 Prophylaxis for cryptococcosis Primary prophylaxis for cryptococcosis should be considered in countries where cryptococcal meningitis is a common OI and fluconazole is available and affordable. Secondary prophylaxis for prevention of relapse after treatment should be considered for all patients with a previous history of episodes of cryptococcal disease (Table 9). Table 9: Summary of recommendations for prophylaxis of cryptococcal infection When to start Primary prophylaxis CD4 count <100 cells/ mm3 OR WHO stage IV Secondary prophylaxis After completion of initial treatment for cryptococcosis What to start When to stop Fluconazole 400 mg Sustained increase of CD4 once weekly count >100 cells/mm3 after at least 6 months of ART If CD4 count not done Fluconazole 200 mg continue lifelong once daily secondary prophylaxis
5
When to Start Antiretroviral Therapy in Adults and Adolescents
5.1 CD4 count not available In the absence of facilities for measuring the CD4 count, all patients with WHO stages 3 and 4 disease should start ART. Those with WHO stages 1 and 2 disease should be monitored carefully, with a minimum of three-monthly clinical reviews, and at any time if new symptoms develop (Table 10). Table 10: Starting antiretroviral therapy based on clinical staging WHO clinical stage 1 2* 3 4 Recommendation Do not treat Do not treat Treat Treat
* Consider starting treatment in patients with WHO stage 2 disease and TLC <1200 cells/mm3
5.2 CD4 count available The optimum time to commence ART is prior to patients becoming unwell or presenting with their first OI. Disease progression is greater in patients who commence ART with a CD4 cell count <200 cells/ mm3 compared with those who start therapy at counts above this level.9,10,11,12,13,14 If facilities for CD4 count measurement are available, ART should be started before the CD4 count drops below 200 cells/mm3. The optimum time to initiate ART in patients with a CD4 cell count of 200–350 cells/mm3 remains unknown, and patients with CD4 counts in this range require regular clinical and immunological evaluation. Initiation of ART is recommended for all patients with pulmonary TB or severe bacterial infections and CD4 counts <350 cells/mm3. Initiation of ART is also recommended for all pregnant women with any stage 3 disease and a CD4 count <350 cells/mm3 (Table 11).
When to start antiretroviral therapy in adults and adolescents
19
Table 11: Starting antiretroviral therapy by CD4 count WHO clinical staging 1 2 3 CD4 count available Treat if CD4 count <200 cells/mm3 General principles Consider treatment if CD4 count <350 cells/mm3 but initiate before CD4 count drops below 200 cells/mm3 In the case of pregnancy or TB Start ART in all HIV-infected pregnant women with WHO stage 3 disease and CD4 count <350 cells/mm3 Start ART in all HIV-infected patients with CD4 count <350 cells/mm3 and pulmonary TB (WHO stage 3) or severe bacterial disease 4 Treat irrespective of CD4 count (extrapulmonary TB is WHO stage 4 disease)
The decision to initiate ART in adults and adolescents is based on clinical and immunological assessment. In many resource-limited settings, clinical staging alone will be available to guide the decision of when to start ART. Measuring viral load (HIV RNA) is not recommended to guide decision on when to start ART. The process of initiating ART involves assessment of patient readiness to commence therapy and an understanding of its implications (lifelong therapy, adherence, toxicities). Access to nutritional and psychosocial support, and family and peer support groups is important when making decisions about initiating ART.
5.3 Commencing ART in the presence of active opportunistic infections Do not start ART in the presence of an active OI. In general, the OI should be treated or stabilized before commencing ART (see chapters 11 and 17). An exception is MAC, in which commencing ART may be the preferred option, especially in situations where specific therapy for MAC is not available. Other conditions that may regress after ART is started include candidiasis and cryptosporidiosis. The OIs and HIV-related illnesses that need treatment or stabilization before ART is started are given in Table 12.
20
Management of HIV infection and antiretroviral therapy in adults and adolescents
5.4 Managing opportunistic infections before starting antiretroviral therapy Table 12: Managing opportunistic infections before starting antiretroviral therapy Clinical situation Any undiagnosed active infection in a patient who has fever and is unwell TB PCP Invasive fungal diseases: oesophageal candidiasis, cryptococcal meningitis, penicilliosis, histoplasmosis Action Diagnose and treat first; start ART when stable.
Treat TB first; start ART as recommended in the section on TB (see section 11 and Annex 6). Treat PCP first; start ART when PCP treatment has been completed. Treat oesophageal candidiasis first; start ART as soon as the patient can swallow comfortably. Treat cryptococcal meningitis, penicilliosis, histoplasmosis first; start ART when treatment has been completed. Treat pneumonia first; start ART when treatment has been completed. Treat malaria first; start ART when treatment has been completed. Do not start ART during an acute reaction. Diagnose and treat acute diarrhoea first; start ART when diarrhoea has been stabilized or controlled.
Bacterial pneumonia Malaria Drug reaction Significant acute diarrhoea which may reduce absorption of ART
Non-severe anaemia (Hb >8 g/dl) Start ART if no other cause for anaemia is found (HIV is often the cause of the anaemia); avoid zidovudine (AZT). Skin conditions such as PPE and seborrhoeic dermatitis, psoriasis, HIV-related exfoliative dermatitis Suspected MAC, cryptosporidiosis and microsporidiosis CMV infection Start ART (ART may resolve these problems).
Start ART (ART may resolve these problems).
Treat if drugs available. If not available, start ART.
6 1. 2.
Recommended First-line Antiretroviral Regimens
6.1 Recommended first-line ARV regimens Box 2: Principles for selecting the antiretroviral drug Choose lamivudine (3TC), plus Choose one nucleoside reverse transcriptase inhibitor (NRTI). Zidovudine (AZT) or tenofovir disoproxil fumarate (TDF) are preferred.
Table 13: Selecting antiretroviral drugs for first-line regimens Recommendation Preferred first-line regimen Regimen AZT + 3TC + NVP Comments AZT may cause anaemia and WHO recommends haemoglobin monitoring, but AZT is preferred to stavudine (d4T) because of d4T toxicity (lipoatrophy, lactic acidosis, peripheral neuropathy). Patients, particularly women with CD4+ cell counts >250 cells/mm3 at initiation of NVP therapy, are at higher risk for the development of symptomatic hepatic events, often associated with rash. The risk of symptomatic hepatic events regardless of severity is greatest during the first 6 weeks of therapy.15 Alternative firstline regimens AZT + 3TC + EFV Efavirenz (EFV) is substituted for NVP if there is intolerance and if the patient is receiving rifampicin. EFV should not be used in patients with raised alanine aminotransferase (ALT) levels of grade 4 or higher. Pregnancy should be avoided in women treated with EFV. Women with childbearing potential should undergo pregnancy testing before initiation of therapy with EFV.15 d4T +3TC + (NVP or EFV) d4T may continue to be used by many programmes because it is available and does not require laboratory monitoring.
22
Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 13 (contd): Selecting antiretroviral drugs for first-line regimens Other options TDF + 3TC + (NVP or EFV) ABC + 3TC + (NVP or EFV) Availability of tenofovir disoproxil fumarate (TDF) is limited in most countries. The current cost is high. Abacavir (ABC) is registered in many countries and currently the cost is high.
FTC can be Emtricitabine (FTC) is not available in many substituted for countries but this may change. 3TC in any first-line A co-formulation of FTC/TDF is available. regimen
6.2 Choice of nucleoside reverse transcriptase inhibitors (NRTIs) Table 14: Choice of nucleoside reverse transcriptase inhibitors (NRTIs) NRTI Lamivudine (3TC) Advantages Good safety profile, nonteratogenic Once-daily regimen Effective against hepatitis B Widely available, including in fixed-dose combinations Emtricitabine (FTC) FTC is an alternative to 3TC Good safety profile Same efficacy against HIV and hepatitis B as 3TC and the same resistance profile16 Available as a fixed-dose combination with TDF Tenofovir disoproxil fumarate (TDF) Good efficacy and safety profile Once-daily regimen Metabolic complications such as lactic acidosis and lipoatrophy are less common than with d4T Zidovudine (AZT) Generally well tolerated Widely available, including as fixed-dose combinations Metabolic complications less common than with d4T Reports of renal dysfunction17,18 Safety in pregnancy not established. Adverse effects on fetal growth and bone density reported Limited availability Initial headache and nausea Severe anaemia and neutropenia Haemoglobin monitoring recommended FTC is not yet on the WHO list of essential medications Low genetic barrier to resistance Disadvantages
Recommended first-line antiretroviral regimens
23
Table 14 (contd): Choice of nucleoside reverse transcriptase inhibitors (NRTIs) Abacavir (ABC) Good efficacy profile and oncedaily regimen Causes the least lipodystrophy and lactic acidosis compared with other NRTIs Stavudine (d4T) Good efficacy profile and cheap No or limited laboratory monitoring needed Widely available as fixed-dose combinations Severe hypersensitivity reaction in 2–5% of adult patients Currently the cost is high Consistently associated most often with lactic acidosis, lipoatrophy and peripheral neuropathy
6.3 Starting and stopping non-nucleoside reverse transcriptase inhibitors (NNRTIs) Table 15: Starting nevirapine (NVP) Lead-in NVP dose for the first 2 weeks* Morning Fixed-dose combination AZT or d4T + 3TC + NVP Evening AZT or d4T + 3TC OR Fixed-dose combination AZT or d4T +3TC Escalate to full NVP dose after 2 weeks Fixed-dose combination AZT or d4T + 3TC + NVP Fixed-dose combination AZT or d4T + 3TC + NVP
* Start NVP 200 mg once daily for the first 14 days. If there is no rash and there are no signs of hepatic toxicity, increase the dose to 200 mg twice daily. Starting treatment with a reduced dose is necessary because during the first two weeks of treatment NVP induces its own metabolism. The lead-in dose also decreases the risk of rash and early NVP-induced hepatitis. If NVP is restarted after more than 14 days of treatment interruption, lead-in dosing (200 mg once daily for 2 weeks, then 200 mg twice daily) is again necessary.
Box 3: Stopping either nevirapine (NVP) or efavirenz (EFV)
Stop NVP or EFV. Continue NRTI backbone (2 drugs only) for 7 days then stop all drugs. This is done to cover the long half-life of the NNRTI and reduce the risk of NNRTI resistance.
24
Management of HIV infection and antiretroviral therapy in adults and adolescents
6.4 Triple NRTI-based regimens Triple NRTI regimens are inferior to NRTI/NNRTI regimens.19,20,21,22, AZT+3TC+ABC may be considered in patients with intolerance or resistance to NNRTIs when protease inhibitor (PI)-based regimens are unavailable, to preserve second-line options for the treatment of HIV-2 infection and for the treatment of HIV/TB co-infected patients receiving rifampicin.
6.5 Use of protease inhibitors in initial therapy PIs are not recommended in first-line regimens because the use of PIs in an initial treatment regimen essentially rules out second-line options in the setting of limited drug availability. PIs may be considered in first-line regimens (with a standard dual NRTI backbone) for the treatment of HIV2 infection, in women with a CD4 count >250 cells/mm3 who require ART and who cannot take EFV, or in patients with NNRTI intolerance.
6.6 ARV combinations that are not recommended Table 16: Antiretroviral (ARV) combinations that are not recommended ARV combinations Monotherapy or dual therapy to treat chronic HIV infection d4T + AZT d4T + didanosine (ddI) Reason not to use Rapid development of resistance Antagonism (reduced levels of both drugs) Overlapping toxicities (pancreatitis, hepatitis, lipoatrophy) Deaths reported in pregnant women 3TC + FTC TDF + 3TC + ABC or TDF + 3TC + ddI Interchangeable, but should not be used together These ARV combinations will increase K65R mutation and are associated with a high incidence of early virological failure High incidence of early virological failure
TDF + ddI + any NNRTI
Recommended first-line antiretroviral regimens
25
6.7 Immune reconstitution inflammatory syndrome (IRIS) Table 17: Immune reconstitution inflammatory syndrome (IRIS) Definition A collection of signs and symptoms resulting from the ability to mount an immune response associated with immune recovery while on ART. It is a paradoxical reaction against a foreign antigen (live or dead) in patients who have started ART and have undergone a reconstitution of their immune responses against this antigen. M. tuberculosis accounts for approximately one-third of all IRIS events.23 10% of all patients initiating ART Up to 25% of patients initiating ART with a CD4 cell count <50 cells/mm3 24,25 Typically within 2–12 weeks of initiation of ART but may present later Unexpected deterioration in clinical status soon after commencing ART Unmasking of subclinical infections such as TB, which present as new active disease Worsening of co-existing infections such as a flare-up of hepatitis B or C infection 60% of IRIS events are related to infection with M. tuberculosis, MAC or Cryptococcus neoformans 26 IRIS may be mild and resolve without treatment. Continue ART if the patient can tolerate it. Treat unmasked active OI, such as TB. This may mean a temporary interruption of ART in patients with severe IRIS until the patient is stable on TB drugs, then reintroduction of ART. If the patient is receiving rifampicin and is on NVP, switch to EFV* if available. ABC is a second alternative. Switching back to the original regimen can be considered once the rifampicin-containing regimen is completed. When switching back from EFV to NVP, no lead-in dose of NVP is required. Switching back should be done with caution if the patient’s CD4 count has increased since the last time NVP was taken. If EFV or ABC is not available or contraindicated, continue NVP-based ART with close clinical monitoring and symptom-directed liver function tests. Corticosteroid treatment to suppress exaggerated inflammatory response may be indicated; for example, an acute hepatic flare where coinfection with viral hepatitis is known or suspected. If the patient is taking NVP, clinical hepatitis and/or rising hepatic enzymes in association with rash and fever is more likely to be due to NVP than IRIS and switching to EFV is recommended. Prednisone (or prednisolone) 0.5 mg/ kg/day for 5–10 days is suggested in moderate to severe cases of IRIS.27,28
Frequency Timing Signs and symptoms
Most common IRIS events Management
* Pregnancy should be avoided in women under treatment with EFV. Women with childbearing potential should undergo pregnancy testing before initiation of therapy with EFV.15
26
Management of HIV infection and antiretroviral therapy in adults and adolescents
Figure 2. Management of immune reconstitution inflammatory syndrome Unexpected deterioration in clinical condition with signs and symptoms of inflammation/infection soon after commencing ART (typically 2–12 weeks) Suspect IRIS Reported IRIS events Cryptococcal meningitis TB meningitis or abscess Toxoplasmosis PML CMV Lymphoma
CNS symptoms
Hepatobiliary symptoms
Fever without localizing signs
Reported IRIS events Disseminated TB Invasive fungal disease MAC infection CMV infection
Focal adenopathy
Respiratory symptoms with worsening CXR changes
Reported IRIS events Pulmonary TB Invasive fungal pneumonia PCP (if not on co-trimoxazole)
Mucocutaneous conditions
Autoimmune diseases
Reported IRIS events Sarcoidosis Graves disease Guillain–Barré syndrome Reiter syndrome
Recommended first-line antiretroviral regimens
27
Principles of management 1. Continue ART if possible. Reported IRIS events Flare-up of hepatitis B or C Visceral leishmaniasis TB abscess 2. Discontinue ART and prioritize treatment of the pathogen in patients who are severely ill. 3. Treat the specific pathogen in order to decrease the antigen load. Reported IRIS events Extrapulmonary TB MAC infection Kaposi sarcoma Histoplasmosis 4. Consider corticosteroids in moderate-to-severe cases of IRIS (prednisone or prednisolone) at 0.5 mg/kg/day orally or IV for 5–10 days or longer, depending on the severity of the inflammation. 5. Aspirate and drain lymph nodes and abscesses (may need to be repeated several times). 6. Perform emergency surgical decompression in cases of tracheal or intestinal obstruction.
Reported IRIS events Herpes zoster and herpes simplex HPV infection (warts) Molluscum contagiosum Kaposi sarcoma Psoriasis Eczema, folliculitis, PPE Leprosy Mucocutaneous leishmaniasis
7
Adherence
The most common reason for failure of ART is poor adherence. Adherence should be routinely assessed and reinforced at every clinic visit. A high degree of adherence to ARV drugs is necessary for optimal virological suppression. Studies indicate that 90–95% of the doses should be taken for optimal suppression; lesser degrees of adherence are more often associated with virological failure.29 Maintaining this level of adherence is difficult. Imperfect adherence is common and a survey indicated that one-third of patients missed doses within 3 days of the survey.30 Factors associated with poor adherence include a poor patient–clinician relationship, high pill burden, forgetfulness, mental depression, lack of patient education, inability of patients to identify their medications, drug toxicity and being too ill.31 Prior to starting therapy, the patient’s willingness and understanding to take such therapy should be clearly established. A treatment plan should be made which the patient understands and can commit to. The importance of taking medicines on a regular basis and the implications of non-compliance should be explained to the patient. Written instructions should be given to literate patients to help them understand the benefits of the prescribed drugs. Pill pictures and cartoons are useful tools to show patients visually how to take their ART correctly. Possible sideeffects should be explained in advance. Educating the patient’s family and friends may be helpful. A patient suffering from active substance abuse or mental illness may benefit more from ART if these problems are taken care of prior to starting ART. The process of offering information, counselling and adherence support must be carried out by staff (counsellors and/or PLHA) who understand the problems in the lives of PLHA. There are three steps in this process. In some cases, all three steps may be carried out during one session.
Adherence
29
Step 1: Giving information Clients are given basic information that enables them to understand the need for a high level of commitment to treatment and adherence. Information can be provided to a group of PLHA if the facilitator has some understanding of group dynamics and is able to stimulate group discussion.
Step 2: Counselling – in one or more individual sessions (Box 4) Help the client explore his/her feelings. Many clients will be preoccupied with problems related to family, job, relationships, etc. and cannot focus on strict adherence until they have released negative feelings about these problems. Many have no private place to store their medicines and are not able to take them in secret. Not wanting others to know their HIV status is by far the commonest reason that providers come across for poor adherence. The client needs to be realistic about who needs to know their HIV status and how to tell them.
Step 3: Solving practical problems and creating a treatment plan
Where will the ARV drugs be stored? At what time will they be taken? Who will remind the client to take the medication if they forget? What will the client do if their normal routine is interrupted?
A time should be arranged to meet or telephone the client within a few days of starting ART to discuss any problems. A trusting and caring relationship between the patient and health-care provider (HCP) is essential. Regular appointments and follow-up visits help in the continued care of the patient. Provider attitudes that are supportive and non-judgemental will encourage patients to be honest about their adherence. The health-care team should have up-to-date knowledge of ART and adherence, and should undertake training if necessary. New medical problems may influence adherence. Temporary discontinuation of all medicines may be less harmful than uncertain adherence.
30
Management of HIV infection and antiretroviral therapy in adults and adolescents
Box 4: Elements of counselling for treatment adherence
Establish a trusting relationship with the patient. Provide necessary information and advice. Encourage peer participation and help to identify persons for treatment support. Develop an individual treatment plan fitting ART into the patient’s lifestyle/ daily events and identify treatment reminders. Assess the readiness and commitment of patients for ART. Readiness to commence ART may be assessed by: – past ability to attend regular clinic visits and not miss appointments – past ability to take OI prophylaxis such as co-trimoxazole – past ability to complete a full course of TB therapy – adequate understanding. Ensure strict adherence to treatment. This means that missing >3 doses per month is associated with an increased risk of drug resistance and failure. If doses are repeatedly missed or taken late, reinforce adherence counselling. Enlist community outreach teams and peer support groups of PLHA as appropriate. Emphasize that treatment has to be continued for life. Explain that the timing of drug intake is critical (e.g. drugs taken twice daily must be taken every 12 hours + 1 hour). Tell the patient that missed doses can be taken up to 6 hours later in a twicedaily regimen. If >6 hours elapse, the dose should be skipped and the next usual dose taken. Explain how the drugs are to be taken (some drugs have to be taken with food, some on an empty stomach, and some require an increased intake of water). Explain the side-effects of the drugs and ensure that the patient understandes these before commencing ART. Emphasize that people on ART need to continue to use condoms regularly and use safe injecting equipment. Inform the patient that other medications, including herbal products, may interact with ART. Patients need careful counselling about which medications are allowed with their ART and which are not. Impress on the patient that regular clinic attendance for monitoring of efficacy, side-effects and adherence is essential. Make a call or a home visit if a patient cannot keep the clinic appointment.
Adherence
31
The treatment regimen should be simplified by reducing the number of pills and frequency of therapy (such as once- or twice-daily dosing), and minimizing side-effects. Simple regimens improve adherence. Adherence may be measured by the patient’s self-report, pill count and the report of the primary care provider. During therapy, people taking ART need repeated adherence counselling (Box 5). Box 5: Checklist to assess treatment adherence Ask for Number of doses missed in the past 3 days Number of doses missed since the last visit Whether dose taken at correct time (if no, ask for delay in hours/days) If correct dose taken Why there was an interruption or modification/failure to take the doses Another method could include estimating the proportion of doses taken using the visual analogue scale (Figure 3).
Figure 3. Visual analogue scale – Adherence self-assessment instrument Instructions for the patient: Put an “X” on the line below at the point showing your best guess about how much of each drug you have taken in the past 4 weeks. 0% means you have taken none of the drug. 50% means you have taken half of the drug. 100% means you have taken every single dose of the drug. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
DRUG A:
DRUG B:
0% 10%
20% 30% 40%
50%
60% 70%
80% 90% 100%
DRUG C:
0% 10%
20% 30% 40%
50%
60% 70%
80% 90% 100%
DRUG D:
0% 10%
20% 30% 40%
50%
60% 70%
80% 90% 100%
8 Evaluation
Clinical and Laboratory Monitoring Prior to Commencing and on First-line ART
Table 18: Recommended clinical and laboratory monitoring prior to commencing and on first-line ART Before Week Week Week Week Week Every As needed or at 2 4 8 12 24 6 (symptom start of months directed) ART
Clinical Clinical evaluation Weight Concomitant medications Check ART adherence Laboratory HIV antibody test [a] CD4 count Haemoglobin [b] Pregnancy test [c] VDRL/RPR Serum chemistry Serum lactate HIV RNA (viral load) [d]
Clinical and laboratory monitoring prior to commencing and on first-line ART
33
Notes [a] A historically documented HIV antibody test is sufficient to commence ART. In the absence of a documented, confirmed HIV antibody test, testing prior to commencing ART is recommended. [b] For patients receiving AZT: Measurement of haemoglobin is recommended prior to commencing AZT and at weeks 4, 8 and 12, and as required thereafter. [c] Pregnancy testing for women initiating a first-line regimen containing EFV: Do not commence EFV if the pregnancy test is positive and the woman is in the first trimester. Pregnancy testing if pregnancy is suspected in a woman who is receiving an EFV-based regimen: Change to a non-EFV based regimen if the pregnancy test is positive and the woman is in the first trimester.
[d] Measurement of viral load (HIV RNA) is currently not recommended for decision-making on initiation or regular monitoring of ART in resourcelimited settings. It may be considered to make an early diagnosis of treatment failure or to assess discordant clinical findings and CD4 count results in patients suspected of failing ART.
9
Antiretroviral Drug Toxicities
9.1 Grading of antiretroviral toxicity Management of ART toxicity is based on the clinician and laboratory toxicity grading scales given in Annex 7. Grade1: Mild reactions: No change in therapy is required. Grade 2: Moderate reactions: Consider continuation of ART as long as feasible. If there is no improvement with symptomatic therapy, consider single drug substitution. Grade 3: Severe reactions: Substitute another drug for the offending one without stopping ART. Grade 4: Severe life-threatening reactions: Immediately discontinue ART and manage the medical event (symptomatic and supportive therapy) and reintroduce ART using a modified regimen by substituting the offending drug with another one when the patient is stabilized.
Antiretroviral drug toxicities
35
9.2 What toxicities to expect after commencing first-line ART Table 19: Side-effects and toxicities of antiretroviral drugs and when they occur Time Short term (the first few weeks) Side-effects and toxicities GI toxicities including nausea and vomiting, diarrhoea Rash Most rashes occur within the first 2–3 weeks Hepatoxicity More common if there is coinfection with hepatitis B or C Drowsiness, dizziness, confusion and vivid dreams are associated with the use of EFV Normally self-resolving but can take weeks to months Anaemia and neutropenia Sudden and acute bone marrow suppression due to AZT can occur within the first weeks of therapy or present as slowly progressive anaemia over months Hyperpigmentation of skin, nails and mucous membranes Lactic acidosis can occur at any time More common after the first few months Most commonly associated with d4T Peripheral neuropathy can occur at any time More common after the first few months Pancreatitis can occur at any time Lipodystrophy and lipoatrophy Dyslipidaemia Diabetes Skin, hair and nail abnormalities Common causes AZT, TDF, PIs NVP, EFV, ABC, PIs (rarely) NVP, EFV, PIs
EFV
Medium term (the first few months)
AZT
AZT d4T, ddI, AZT
d4T, ddI ddI d4T, ddI, AZT, PIs d4T, EFV, PIs Indinavir (IDV) PIs, especially IDV
Long term (after 6–18 months)
36
Management of HIV infection and antiretroviral therapy in adults and adolescents
9.3 Symptom-directed toxicity management Table 20: Management of side-effects and toxicities of antiretroviral drugs Toxicity Acute pancreatitis Causative ARVs d4T and ddI Recommendations Discontinue ART. Provide supportive treatment and laboratory monitoring. Resume ART with an NRTI with a low risk of pancreatic toxicity (AZT, ABC, TDF). Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered.
Diarrhoea
ddI (buffered formulation), NVF, lopinavir/ritonavir (LPV/r), saquinavir/ ritonavir (SQV/r) Drug eruptions (mild NVP, EFV (rarely) In mild cases, give antihistamines. to severe, including Moderate rash, non-progressive and without Stevens–Johnson mucosal involvement or systemic signs, syndrome or toxic consider a single NNRTI substitution (i.e. epidermal necrolysis) NVP with EFV). In moderate and severe cases, discontinue ART and give supportive treatment. After resolution, resume ART with 3 NRTI or 2 NRTI + PI regimens. Dyslipidaemia, PIs Consider replacing the suspected PI by drugs insulin resistance and EFV with a lower risk of metabolic toxicity. hyperglycaemia GI intolerance All ARVs Usually self-limited, no need to discontinue ART. Symptomatic treatment should be offered. Haematological AZT If severe (Hb <6.5 g% and/or absolute toxicities neutrophil count <500 cells/mm3) replace by an (particularly anaemia ARV with minimal or no bone marrow toxicity and leucopenia) (e.g. d4T, ABC or TDF) and consider blood transfusion in severely distressed persons. Hepatitis All ARVs If ALT >5-fold the basal level, discontinue ART (particularly NVP and monitor. After resolution, replace the drug and PI/r) most likely to be associated with another one. Hyperbilirubinaemia Atazanavir (ATV) Generally asymptomatic, but can cause scleral (indirect) icterus (without ALT elevation). Replace ATV with another PI. Hypersensitivity ABC Discontinue ABC and do not restart. Give reaction symptomatic treatment. Re-exposure may lead to a severe and potentially lifethreatening reaction. Lactic acidosis All NRTIs Discontinue ART and give supportive (particularly d4T treatment. After clinical resolution, resume and ddI) ART, replacing the offending NRTI. ABC, TDF and 3TC are less likely to cause this type of toxicity.
Antiretroviral drug toxicities
37
Table 20 (contd): Management of side-effects and toxicities of antiretroviral drugs Toxicity Lipoatrophy and lipodystrophy Neuropsychiatric changes Renal toxicity (nephrolithiasis) Causative ARVs All NRTIs (particularly d4T) EFV IDV Recommendations Early replacement of the suspected ARV drug (e.g. d4T for TDF or ABC). Consider aesthetic treatment and physical exercises. Usually self-limited, without need to discontinue ART. If using IDV, interrupt IDV and offer hydration, laboratory monitoring and symptomatic treatment (50% recurrence rate). Consider replacing IDV with another PI. Discontinue TDF and give supportive treatment. After clinical resolution, resume ART, replacing the offending drug with another. Consider replacement by an NRTI with minimal or no neurotoxicity (AZT, TDF or ABC). Symptomatic treatment should be considered.
Renal toxicity (renal tubular dysfunction)
TDF
Peripheral neuropathy
d4T and ddI
38
Management of HIV infection and antiretroviral therapy in adults and adolescents
9.4 Individual drug substitutions for toxicity and intolerance Table 21: Individual drug substitutions for toxicity and intolerance ARV drug ABC AZT Frequently associated toxicity Hypersensitivity reaction Severe anaemia or neutropenia Severe GI intolerance Lactic acidosis Suggested substitute AZT or TDF or d4T TDF or d4T or ABC TDF or ABC Boosted PI + NNRTI if ABC and TDF are not available (e.g. IDV/r + EFV) TDF or ABC Boosted PI + NNRTI if ABC and TDF are not available (e.g. IDV/r + EFV) AZT or TDF or ABC AZT or ABC or d4T NVP or TDF or ABC NVP or ABC EFV or TDF or ABC 1. Substitute EFV for NVP following a nonsevere NVP rash and/or hepatotoxicity; careful monitoring is needed. 2. TDF or ABC 3. PI-based regimen if ABC and TDF not available Stop all ARVs until stable. Then start TDF or a PI-based regimen
d4T
Lactic acidosis Lipoatrophy/metabolic syndrome
Peripheral neuropathy TDF EFV Renal toxicity (renal tubular dysfunction) Persistent and severe CNS toxicity Potential teratogenicity (first trimester of pregnancy or women not using adequate contraception) NVP Hepatitis
Non-severe (grade 1 or 2) moderate hypersensitivity reaction
Severe or life-threatening rash (Stevens–Johnson syndrome)
Notes The general principle is that single-drug substitution for toxicity should be made within the same ARV class, e.g. substitution of AZT or TDF for d4T for neuropathy, TDF or d4T for AZT for anaemia, or NVP for EFV for CNS toxicity or in pregnancy. If a life-threatening toxicity occurs, all ARVs should be stopped until the toxicity has resolved. A revised regimen is commenced when the patient has recovered.
Antiretroviral drug toxicities
39
9.5 Notes on stavudine (d4T) d4T is the NRTI most often associated with lactic acidosis, lipoatrophy and peripheral neuropathy (Box 6).32 Because of its current wide availability as a fixed-dose combination and lower price compared with other ARVs, d4T-containing regimens may be the most accessible option for people in resource-limited settings. Till safer first-line ART choices become available, close monitoring for d4T toxicity is recommended. After the publication of WHO’s 2006 guidelines for HIV therapy in adults and adolescents, the WHO Guidelines Development Group reviewed evidence for the use of d4T at reduced doses. Previously, the preferred d4T dosage was weight-based.The dose recommended for patients >60 kg was 40 mg twice daily; for patients <60 kg it was 30 mg twice daily. A systematic review of nine randomized trials and six observational cohort studies strongly suggests that stavudine-containing regimens maintain clinical and virological efficacy when the dose of stavudine is 30 mg twice daily, and that this reduced dose is associated with lower rates of toxicity, especially peripheral neuropathy, compared with the 40 mg twice daily dose. Complementary studies have also demonstrated a significant reduction of mitochondrial DNA depletion in patients on the 30 mg twice daily dose.33,34,35 Some countries (such as Thailand) and some treating physicians have adopted the principle of commencing treatment with a d4T-based regimen and switching to an AZT-based regimen after 6–12 months. The rationale for this is twofold. First, AZT may be contraindicated in patients with anaemia at the time of commencement of ART (common in those with advanced HIV disease). These patients can be started on d4T and then switched to AZT once the anaemia improves on ART. Second, switching from an initial d4T-based regimen to AZT as soon as signs of lipoatrophy or peripheral neuropathy appear is an appropriate way to manage these side-effects. As no clinical trial data are available to support this strategy, such trials are being planned.
40
Management of HIV infection and antiretroviral therapy in adults and adolescents
Box 6: Lipodystrophy Features of the lipodystrophy syndrome
Dyslipidaemia consisting of raised total cholesterol, low high-density lipoprotein (HDL) cholesterol and raised triglyceride (TG) levels Insulin resistance with hyperglycaemia Central fat accumulation (visceral, breast, neck) and local fat accumulation (lipomas, “buffalo hump”) Generalized diminution of subcutaneous fat mass (lipoatrophy)
Lipoatrophy is characterized by loss of subcutaneous fat from the face, arms, legs, abdomen and/or buttocks. It is most commonly associated with d4T but occurs with all thymidine NRTIs (d4T >ddI >AZT).36,37 It is also associated with PI-based regimens alone and in combination with NRTIs. Figure 4. Lipoatrophy of the face and leg
Fat accumulation can occur within the abdominal cavity, upper back, neck, breasts and subcutaneous tissue and is usually associated with PIbased regimens. It can also occur with non-PI based regimens. Management The fat loss is likely to be permanent in most cases. Alert the patient and intervene early with revision of the drug regimen if possible (e.g. switch from d4T to AZT, TDF or ABC). Switching to another drug may result in some recovery and may stop further fat loss.38,39 Lactic acidosis d4T, ddI (and, to a lesser extent, other nucleosides such as AZT, 3TC and ABC) have been associated with life-threatening lactic acidosis due to the mitochondrial toxicity induced by these drugs.40 After doing well
Antiretroviral drug toxicities
41
for six months or more on ART the patient presents with unexpected clinical deterioration characterized by weakness, weight loss, abdominal pain and distension, anorexia, nausea, vomiting and diarrhoea. Blood chemistry is abnormal, and includes raised levels of serum lactate, ALT, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and an abnormal anion gap ([Na + K] – [HCO3 +Cl]). Management Patients must be asked to report any unexpected deterioration in their general health. Stop all ARVs. Recovery is slow (1–2 months). Thiamine or riboflavin (30 mg/day) may be effective. If the patient is unwell, hospitalization may be required for institution of life-support measures. Deaths have been reported. Restart ART after full recovery using a TDFor ABC-containing regimen. Do not use d4T or AZT again. Peripheral neuropathy Peripheral neuropathy is most commonly associated with the use of d4T.41 It presents over weeks to months in the following sequence of events – numbness followed by tingling and burning and then pain, usually beginning in the lower extremities. Management Stop the drug if possible. There may be a short period, typically up to 4 or 8 weeks during which symptoms intensify after drug withdrawal. Analgesics are usually ineffective and drugs used to treat neuropathic pain (amitriptyline 25–50 mg at bedtime) may be of some use. Dyslipidaemia Dyslipidaemia is associated with all three classes of ARVs; PIs, NRTIs and NNRTIs. The increase in cholesterol and triglyceride (TG) levels is greater with d4T than with TDF. ABC is more likely to increase cholesterol and TG levels than AZT. NNRTIs cause a rise in total cholesterol and, to a lesser extent, TG levels (EFV >NVP). Insulin resistance d4T and some PIs (IDV, RTV, LPV/r) cause insulin resistance and abnormal glucose metabolism. Clinical diabetes may result.
42
Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 22: Strategies to maximize the safe use of stavudine (d4T) Training health-care professionals (HCPs) to recognize the signs and symptoms of lactic acidosis, lipoatrophy and peripheral neuropathy Switching to an alternative NRTI (such as AZT, TDF or ABC) as soon as side-effects occur may reduce the severity of d4T toxicity Commence with d4T in patients with anaemia and switch to an alternative NRTI (such as AZT, TDF or ABC) if anaemia improves on ART Adequately educating patients in the early recognition of side-effects of d4T and when to expect them WHO recommends that d4T 30 mg is given to everyone irrespective of body weight 34 For details, see the web link: <http://www. who.int/hiv/treatment/en/index.html>
9.6 Choice of NNRTIs Table 23: Choice of non-nucleoside reverse transcriptase inhibitors (NNRTIs) NNRTI Advantages Widely available including as fixeddose combination NVP Less expensive than EFV Preferred NNRTI for women when there is a potential for pregnancy or those in first trimester Once daily regimen Generally well tolerated Rash is less common than with NVP and generally self-resolving NNRTI of choice in individuals with TB/HIV coinfection receiving rifampicin Disadvantages Higher incidence of rash than with EFV Rash may be severe and lifethreatening, including Stevens– Johnson syndrome Potentially life-threatening risk of hepatotoxicity, especially in women with CD4 count >250 cells/mm3 Teratogenic and cannot be used in first trimester Use with caution in women with childbearing potential More expensive than NVP and not always widely available CNS side-effects
EFV
10 Clinical situation All women
ART for Pregnant Women and those with Childbearing Potential
10.1 ART for pregnant women and those with childbearing potential Table 24: Antiretroviral drugs in pregnancy Guiding principles Recommendations Treatment decisions are based solely Recommended first-line regimen on the woman’s medical need. is NVP plus 2 NRTIs. EFV plus 2 NRTIs may be used if women have access to consistent and reliable barrier methods of contraception or after the first trimester of pregnancy. ART is recommended for pregnant Some experts recommend that women according to the same all pregnant women with WHO eligibility criteria as for nonclinical stage 3 disease and CD4 pregnant adults. count <350 cells/mm3 should ART should be initiated in pregnant initiate ART. women with WHO clinical stage 3 or The recommended regimen is 4 disease, or those with WHO clinical 2 NRTIs plus an NNRTI. stage 1 or 2 disease before the CD4 The preferred regimen is count drops below 200 cells/mm3. AZT+3TC+NVP with careful monitoring in women with higher CD4 counts >250 cells/mm3. EFV should be discontinued and replaced by another drug.
Initiating ART in pregnant women
Women who are pregnant, are in the first trimester and are taking EFV Women who are breastfeeding
NVP is substituted for EFV with close monitoring in women with CD4 count >250 cells/mm3.15 Alternatively, a PI-based or triple NRTI regimen could be given. ART is recommended for postpartum The preferred regimen is breastfeeding women who meet the AZT+3TC+NVP. WHO criteria for initiation of therapy for their own health. Women who Women who have previously Single-dose NVP (SDN) >6 received ART received single-dose NVP prophylaxis months – NNRTI-based regimen as part of for PMTCT should be considered SDN <6 months prevention of eligible for NNRTI-based regimens. – A triple NRTI regimen or mother-to-child Alternatives may be considered for transmission women whose exposure to singlePI-based regimen also can be (PMTCT) dose NVP was <6 months before ART considered. intervention was initiated.
44
Management of HIV infection and antiretroviral therapy in adults and adolescents
Notes on NVP Women with CD4 counts >250 cells/mm3 are at increased risk for NVP hypersensitivity with fatal hepatic toxicity. This applies to both pregnant and non-pregnant women. NVP should be used with caution, and with careful clinical and liver function monitoring in this population.
10.2 ART and hormonal contraceptives NVP, RTV, nelfinavir (NFV), LPV/r and SQV/r cause a reduction in ethinylestradiol levels.42,43 Estrogen levels are slightly increased by ATV, IDV and EFV. Consistent use of condoms is recommended in all HIV-infected women taking ART. The limited data available do not show interaction between medroxyprogesterone acetate and NVP, EFV or NFV.33
10.3 Initiating ART in pregnant women Table 25: Starting antiretroviral therapy in pregnancy When to start ART in pregnant woman WHO stage CD4 count not available 1 Do not treat 2* Do not treat 3 Treat 4 Treat CD4 count available Treat if CD4 count <200 cells/mm3 Treat if CD4 count <350 cells/mm3 Treat irrespective of CD4 cell count
* Many women with a CD4 count >250 cells/mm3 will require ART within the first year post partum and the efficacy of NNRTI-based ART initiated <6 months after exposure to SDN viral suppression may be compromised due to NVP resistance.15
Close monitoring of aspartate aminotransferase (AST)/ALT levels is recom– mended during the first few months after commencing an NVP-containing regimen in pregnant women. Testing should be done at weeks 0, 2, 4, 6, 8 and then monthly until delivery. NVP should be discontinued if the ALT is >2.5 times the upper limit of normal (ULN), a lower threshold than normally recommended in adults. The preferred NRTIs for use in pregnant women are AZT and 3TC. The combination of d4T/ddI should not be used. There are no data on the use of FTC in pregnancy. Studies have shown TDF to be associated with decreased fetal growth and bone demineralization.44,45 The preferred NNRTI is NVP, due to extensive clinical experience with this drug in pregnant women and its proven efficacy in reducing MTCT. SQV/r and NFV are the preferred PIs in women who cannot tolerate NVP. EFV may be considered after the first trimester.
11 <200
Antiretroviral Therapy in Tuberculosis/HIV Coinfection
11.1 Initiating antiretroviral therapy in patients with active tuberculosis Table 26: Starting antiretroviral therapy in patients with tuberculosis CD4 cell count (cells/mm3) ART recommendations Recommend ART Recommend ART Defer ART Recommend ART Timing of ART in relation to initiation of TB treatment Between 2 and 8 weeks After 8 weeks Re-evaluate patient at 8 weeks and at the end of TB treatment 2–8 weeks
Between 200 and 350 >350 CD4 count not available
Choice of NRTI This is the same as for all HIV-infected persons. Choice of NNRTI EFV is the preferred NNRTI. EFV blood levels are decreased in the presence of rifampicin. There is evidence that the standard EFV dosage of 600 mg/day in patients weighing <60 kg is adequate.46,47,48,49,50 NVP levels are also decreased in the presence of rifampicin. However, standard NVP dosing is recommended.51,52,53,54,55 Due to concerns about hepatotoxicity, NVP-containing regimens should be used only when no alternative is available, particularly for women on rifampicincontaining regimens, with CD4 cell counts >250 cells/mm3 who need to start ART.15 A triple NRTI regimen (AZT+3TC+ABC or AZT+3TC+TDF) can be used with rifampicin. AZT, 3TC and TDF have no or minimal interactions with rifampicin but triple NRTI regimens are less potent than NNRTI-based regimens.
46
Management of HIV infection and antiretroviral therapy in adults and adolescents
11.2 Recommendations for patients on ART who develop active TB Table 27: Antiretroviral therapy in patients who develop active tuberculosis First- or second-line ART First-line ART regimen at the time TB occurs 2 NRTI + EFV 2 NRTI + NVP* ART options Continue with 2 NRTI + EFV Change to EFV or Change to triple NRTIs or Continue with 2 NRTI + NVP* Continue triple NRTI Change to or continue (if already being taken) LPV/r- or SQV/rcontaining regimen and adjust dose of RTV
Second-line
Triple NRTI 2 NRTI + PI
* Due to concerns about hepatotoxicity, NVP-containing regimens should be used only when no alternative is available, particularly for women on rifampicincontaining regimens, with CD4 cell counts >250 cells/mm3 who need to start on ART.
Switching back to NVP after treatment with rifampicin is completed can be considered. When switching back from EFV to NVP no lead-in dose is required. If a pregnant woman in the second or third trimester develops active TB, an EFV-containing ART regimen can be considered. An alternative in women with active TB in the first trimester is a triple NRTI regimen or an NVP-containing regimen, with careful monitoring in women with CD4 counts >250 cells/mm3 or when the CD4 count is unknown.
11.3 Second-line ART for patients with TB and indications of first-line ART failure Unboosted PIs cannot be used with rifampicin-containing regimens because the PI levels are subtherapeutic.56,57 If a patient needs to switch to or is already on a PI-based regimen, LPV 400 mg/RTV 400 mg twice daily in combination with rifampicin could be considered under close clinical and laboratory supervision for hepatotoxicity. An alternative is SQV 400 mg/RTV 400 mg with close clinical and laboratory monitoring. Recommendations and precautions for the use of PI-based regimens in combination with rifampicin in women with childbearing potential and pregnant women are the same as for other patients with TB.
12
Injecting Drug Users
12.1 Principles of comprehensive care for HIVinfected IDUs The key components of comprehensive care for IDUs are: Assessment and management of physical and psychological comorbidities including viral hepatitis and psychiatric conditions (such as depression) Assessment of the patient’s treatment priorities, goals and readiness to start ART if it is medically indicated Provision of opioid substitution therapy (OST) Provision of clean injecting equipment and condoms Management of injecting-related health problems.
Current or former injecting drug use is not a reason to withhold ART. Links to harm-reduction programmes The objectives of the Biregional strategy for harm reduction 2005–200958 are to ensure access to the essential prevention package and to treatment, care and support services for people who inject drugs, and create an enabling environment for harm-reduction interventions. Harm-reduction programmes have trained staff (social workers, counsellors and outreach workers) with experience in reaching out to and communicating with IDUs, and have established credibility and trust. Harm-reduction programmes should plan HIV treatment for IDUs59 with a focus on:
Outreach to potential clients for HIV testing and prevention of transmission of HIV Support for adherence to ART Follow up of patients who drop out of care Implementing OST for suitable patients Education and peer support
48
Management of HIV infection and antiretroviral therapy in adults and adolescents
12.2 Antiretroviral therapy for injecting drug users Table 28: Initiating antiretroviral therapy in substance-using patients Initiating ART The criteria for initiating ART in substance-using patients are the same as for other patients with HIV. Before starting ART, specific factors that may affect the timing of initiation and choice of ART should be considered. These include social instability, active use of illicit drugs and presence of co-morbidities such as mental problems and coinfection with hepatitis viruses. Unavailability of OST or active use of illicit drugs should not preclude access to ART for those IDUs in need of treatment. Effective links between ART and harm-reduction programmes are essential. Unless the person is severely ill, initiation of ART is not urgent. Adequate time spent on preparing to start ART, understanding treatment goals, adherence and the lifelong nature of ART will maximize treatment outcomes. WHO-recommended regimens can be chosen for the majority of IDUs. The choice of specific ARV drugs depends on: Co-morbidities (especially hepatitis B/C and psychiatric disorders) Drug interactions (methadone) Use of fixed-dose combinations and, if available, once-daily ARV regimens are preferable. AZT + 3TC + (EFV or NVP) AZT may be replaced by d4T. Hepatitis C and B infections are extremely common in IDUs. Monitoring for hepatotoxicity is strongly recommended in IDUs receiving NNRTI-based ART, especially NVP. EFV EFV is recommended by some experts due the high prevalence of coinfection with hepatitis B and C in IDUs, and the lower risk of hepatic complications with EFV compared with NVP.60 EFV is preferred in patients with clinical and/or laboratory evidence of significant (grade 3 or 4) hepatic dysfunction. EFV should be used with caution in patients with depression or other significant psychiatric conditions. NVP NVP is recommended in patients with no other significant co-morbidities; specifically, patients with no clinical signs of hepatic dysfunction or increase in hepatic transaminases (grade 3 or 4). If NVP is the only NNRTI available, use with careful clinical and laboratory (liver enzyme) monitoring. TDF + (3TC or FTC) + (EFV or NVP) Patients who are HBsAg-positive and TDF is available Recommendations are the same as for all patients with HIV. (ddI or TDF) + ABC+ PI/r or TDF + 3TC (± AZT) + PI/r
Choice of ART
Preferred first-line regimen Choice of NNRTI
Alternative first-line regimen Second-line regimen
Injecting drug users
49
Table 28 (contd): Initiating antiretroviral therapy in substance-using patients Adherence With experienced staff and adequate support, IDUs can adhere to ART and have clinical outcomes comparable with those of HIV-infected patients who do not use drugs.61,62 Administration of methadone with EFV, NVP or RTV decreases the plasma levels of methadone, which may precipitate symptoms of opiate withdrawal.63 Patients receiving methadone and commencing ART may require increased doses of methadone. True directly observed therapy (DOT) is possible only with once-daily regimens. Modified DOT with supervised daytime dosing and take-home evening doses may be an option.
Methadone
DOT
Opioid withdrawal symptoms are unspecific and often difficult to diagnose. The most common ones are nausea, muscle aches, abdominal cramps, irritability, loss of appetite, weakness, restlessness, headache, dizziness, sneezing, hot and cold flashes and, most importantly, craving for drugs.64 Choice of NNRTI component Patients, particularly women, with increased CD4+ cell counts at initiation of NVP therapy (>250 cells/mm3 in women and >400 cells/mm3 in men) are at higher risk for the development of symptomatic hepatic events, often associated with rash. The risk of symptomatic hepatic events regardless of severity is greatest during the first 6 weeks of therapy. However, hepatic events may occur at any time during treatment. In some cases, patients present with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Patients who have infection with hepatitis B or C and/or abnormal liver function tests at the start of therapy with NVP are at greater risk for later symptomatic events (6 weeks or more after starting NVP) and asymptomatic increases in AST and/or ALT. Serious psychiatric adverse events have been reported in patients treated with EFV. These include severe depression, suicidal ideation, aggressive behaviour, paranoid reactions and manic reactions.
12.3 Viral hepatitis and chronic liver disease Coinfection with hepatitis C virus (HCV) is common in HIV-infected IDUs. Chronic, active hepatitis B and alcoholic liver disease are also common.
50
Management of HIV infection and antiretroviral therapy in adults and adolescents
Hepatotoxicity associated with these conditions complicates the choice of ART. NRTIs with the most hepatotoxicity are AZT, ddI and d4T. Both the available NNRTIs can cause hepatotoxicity. NVP is more commonly associated with severe hepatotoxicity and should be avoided if possible in all patients with chronic liver disease.65 EFV can be administered in full doses in patients with liver insufficiency. PIs are also associated with hepatotoxicity, and the dosing is complex in patients with hepatic insufficiency.66 If drugs are available, the recommended treatment for HIV/hepatitis B virus (HBV) coinfection is TDF alone or in combination with 3TC or FTC as part of the ART regimen. 3TC should not be used alone due to rapid development of resistance by HBV. Fatal cases of an acute flare-up of HBV infection have been documented in HIV/HBV co-infected patients who discontinue 3TC monotherapy.67,68 Drugs for treating hepatitis C are often not available in resource-limited settings and pegylated interferon (IFN) and ribavirin (RBV) are used. There is no other treatment for hepatitis C. Patients should be stable on ART with CD4 counts >200 cells/mm3 before pegylated IFN and RBV are started. AZT levels are increased by RBV and patients should be closely monitored for hepatic toxicity, neutropenia and anaemia. Other causes of hepatic dysfunction need to be considered in addition to viral hepatitis. Alcohol use/dependency has the same implication for treatment options and monitoring as viral hepatitis. Where possible, the least hepatotoxic ARV should be used and hepatic enzymes monitored in all patients with hepatic dysfunction.
12.4 Opioid substitution therapy OST is the most effective treatment for opioid dependence, and results in substantially higher retention rates, suppression of drug use and improved psychosocial functioning. Its use in the context of HIV treatment has been associated with improved adherence to and outcomes of treatment. Detoxification and abstinence-based programmes are unlikely to achieve similar levels of clinical effectiveness and may prove counterproductive in the context of ART. If possible, stabilization of substance use with substitution treatment is recommended prior to commencement of ART. Where substitution therapy is available,
Injecting drug users
51
consideration should be given to offering HIV care and dispensing HIV medication at the same site where substitution therapy is delivered. This approach can achieve maximal levels of treatment supervision which should enhance efficacy and reduce the risk of HIV drug resistance. In addition, co-location of these services facilitates the management of drug–drug interactions between methadone and ART. Outcomes of OST in a structured programme include:
Decreased heroin use and reduced chaotic drug-taking Decreased needle-sharing Stabilization of clients’ lives Improved quality of life and the chance to lead a productive life in the community Improved ability to commence and adhere to ART
OST programmes generally use either methadone liquid or buprenorphine sublingual tablets. Methadone and buprenorphine are included in the WHO Essential Drugs List. (http://www.who.int/medicines/publications/essentialmedicines/en/ index.html) Methadone Methadone, an orally administered long-acting opiate agonist, is the most commonly used pharmacological treatment for opiate addiction. Methadone is inexpensive and widely available.
12.5 ARV dose adjustments in patients receiving methadone There are two relevant interactions. Methadone and NNRTIs Methadone levels are decreased by up to 50% in those receiving EFV and NVP, and clinical signs of opiate withdrawal may be precipitated. Signs and symptoms of opiate withdrawal typically occur 4–8 days after starting NNRTI-based ART. Patients receiving methadone replacement therapy and NNRTI-based ART require a step-wise increase in the daily
52
Management of HIV infection and antiretroviral therapy in adults and adolescents
dose of methadone by 5−10 mg until they are comfortable (Table 29). Precipitating opiate withdrawal may trigger relapse to heroin use, distrust of medical providers, and unwillingness to take ART. The levels of EFV and NVP are not affected by methadone. Methadone and NRTIs ddI concentrations are reduced by approximately 60% when admini– stered with methadone. This may lead to subtherapeutic levels of ddI and the combination should be avoided. The levels of enteric-coated (EC) ddI are not affected by methadone. Methadone and PIs PI levels are generally not affected by methadone, except for amprenavir (APV), which is reduced by 30%. Administration of APV, NFV, LPV and RTV Table 29: Methadone maintenance therapy Contraindications for methadone use
Known hypersensitivity to methadone Acute asthma (or other unstable medical condition) Alcoholism (unstable alcohol use) Treatment with monoamine oxidase inhibitor (MAOI) antidepressants (or unstable psychiatric condition) Severe hepatic impairment History of biliary or renal tract spasm (relative contraindication) Usually 20–30 mg per day The initial dose should be reduced if there is concomitant benzodiazepine or alcohol use or dependence; the dose should be carefully increased in the first 2 weeks of treatment. Review before the third dose. 5–10 mg at a time (keep 5 days between each dose increase) if the client has discomfort or requires a higher dose. Individualized Doses of 60–120 mg per day are more effective in achieving treatment outcomes (no relapse) than lower doses.
Initial dose
Follow up Dose escalation
Usual maintenance dose
Termination of treatment
The minimum duration of treatment should be one year. Three years or more of treatment are likely to have improved long-term outcomes.
Injecting drug users
53
results in a significant decrease in methadone levels and may result in symptoms of opiate withdrawal (see Annex 5). Buprenorphine Buprenorphine is administered as a single daily dose in the range of 8– 34 mg/day. The average dose for most patients is 16 mg/day but doses up to 34 mg/day may be required. Tablets should be placed under the tongue until they are dissolved. Swallowing the tablets reduces the bioavailability of the drug. There are two sublingual formulations, buprenorphine alone and bupre– norphine combined with naloxone. Addition of the opioid antagonist naloxone is intended to deter injecting of the crushed dissolved tablets. Interactions between ART and buprenorphine are less well researched than with methadone (see Annex 5). Emerging evidence indicates that PIs including RTV and ATV inhibit buprenorphine metabolism resulting in a clinically significant effect. The dose of buprenorphine may need to be reduced in this context.60
13 Choice of ART Preferred firstline ART Alternatives if TDF is unavailable
HIV and Hepatitis Coinfection
13.1 Hepatitis B infection Table 30: Principles of therapy for HIV/HBV coinfection Drugs with anti-HBV activity should be included in the first-line ART regimen for HIV-infected patients who are HBsAg-positive and HBeAg-positive if known. TDF + (3TC or FTC) + EFV (AZT or d4T) + (3TC or FTC) + EFV (AZT or d4T) + (3TC or FTC) + NVP (see Choice of NNRTI below) In this case, 3TC (or FTC) will be the only drug with activity against HBV. EFV is the preferred NNRTI option. NVP should be used with care and regular monitoring in patients
Choice of NNRTI
who have known HIV/HBV coinfection and grade 1, 2 or 3 increase in ALT/AST. NVP is not recommended for patients with grade 4 or greater increase in ALT/AST. Second-line regimen HBV resistance 3TC should be continued as part of second-line ART following initial ART failure, even if it was used in the first-line regimen. Ideally, 3TC should be used either with TDF or not at all. This may not be feasible in resource-limited settings. HBV resistance to 3TC will develop in 50% of patients after two
years and in 90% after four years of treatment if 3TC is the only active anti-HBV drug in the ART regimen. Therapy outcomes Hepatic flares FTC HBV seroconversion (loss of HBeAg and development of HBeAb) occurs in 11–22% of HBeAg-positive HIV-infected patients who are treated with 3TC for one year. Starts soon after initiation of ART as part of IRIS Discontinuation of 3TC may also result in hepatic flares
FTC has a similar rate of suppression of HBV and a similar safety profile and resistance pattern as 3TC.
Note: ARV programmes in areas of the world with a high seroprevalence of HBV and no capacity to screen for HBV may consider the use of TDF plus either FTC or 3TC as the preferred initial NRTI combination if these drugs are available.
HIV and hepatitis coinfection
55
Hepatic flares Hepatic flares may occur Following initiation of ART as part of IRIS When ART is stopped. Flares typically present as an unexpected increase in ALT/AST levels and symptoms of clinical hepatitis (fatigue, nausea, abdominal pain and jaundice) within 6–12 weeks of commencing ART. Flares may be difficult to distinguish from ART-induced hepatic toxicity. Drugs active against HBV should preferably be continued during a suspected flare. If it is not possible to distinguish between a serious hepatitis B flare and grade 4 drug toxicity, all ART should be stopped until the patient stabilizes.
13.2 Hepatitis C infection Table 31: Principles of therapy for HIV/HCV coinfection HCV therapy No ARVs are directly active against HCV. However, ART has been shown to delay the progression of HCV liver disease in HIV/HCV coinfection. The only effective treatment is pegylated IFN and RBV, which are generally not available in resource-limited settings.69 Clinical trial outcomes HCV genotype 1: 15–28% sustained virological response rates HCV genotypes 2 and 3: 60–70% virological response rates Up to 60% of individuals treated with IFN will experience mental health problems, most commonly depression. Monitor mental health closely. Commence anti-HCV therapy before the CD4 count drops to levels
Therapy outcomes Side-effects of IFN Timing of HCV therapy
where ART is required. If ART is required in HCV-positive patients, they should be stable on
Preferred first-line ART regimen
Drug interactions
ART with a CD4 count >200 cells/mm3 before anti-HCV therapy is considered.60 The choice of NRTI is the same as for HCV-uninfected patients. EFV is the preferred NNRTI. NVP should be used with care and regular monitoring in patients who have known HIV/HCV coinfection and grade 1, 2 or 3 increase in ALT/AST. NVP is not recommended for patients with grade 4 or higher increase in ALT/AST. RBV and d4T/ddI – pancreatitis/lactic acidosis Do not co-administer. RBV and AZT – anaemia Monitor closely. IFN and EFV – depression Monitor closely.
Hepatic flares
Soon after initiation of ART as part of IRIS
14 Yes
ART Failure and when to Switch Therapy
14.1 Determining ART failure Figure 5. Determining ART failure Does the patient have good adherence to ART? (see chapter 7) No Intense adherence support Continue the same first-line regimen, give OI prophylaxis if necessary and follow closely. Start second-line therapy only after good adherence can be assured.
Patient has been on ART for at least 6 months
No
Continue first-line regimen. Exclude and treat OI and IRIS. (see pages 64–73, 25)
Yes
CD4 count available
No
Diagnose treatment failure if OI present and on ART >6 months with good adherence if CD4 count not available.
Yes
CD4 count indicating failure of treatment (see page 58) Yes
No
Exclude other causes such as OI and IRIS. Continue first-line ART.
Prepare the patient for second-line regimen. The regimen is likely to be more complex. Make sure the patient understands the new drugs, how to take them and possible side-effects. Reinforce adherence.
ART failure and when to switch therapy
57
Switching to a second-line regimen is not an emergency. Review the patient’s OI prophylaxis. Patients on a failing regimen with WHO stage 2, 3 or 4 disease or CD4 count <200 cells/mm3 need to restart cotrimoxazole. While a failing regimen may retain some anti-HIV activity, the more time that the patient remains on a failing regimen, the more resistance mutations will accumulate, reducing the chances of success of the second-line regimen. The decision to switch is based on clinical, immunological or virological definitions of failure (presented below) and the availability of second-line ARVs.
14.2 Defining failure Definitions Clinical failure: New or recurrent WHO stage 4 condition after at least 6 months of ART. Exceptions are TB, oesophageal candidiasis and severe bacterial infections which may not always represent ART failure. Review the response to therapy first and if the response is good, do not switch. Virological failure: Viral load >10 000 copies/ml after at least 6 months on ART. ART failure cannot be diagnosed based on clinical criteria alone in the first 6 months of taking ART. Clinical events that occur during the first 6 months of therapy often represent IRIS and not failure.
58
Management of HIV infection and antiretroviral therapy in adults and adolescents
14.3 Immunological criteria for failure Figure 6. Pattern of immunological failure of ART CD4 count
Pattern 3
Pattern 2
50 or 100 cells/mm 3 Pattern 1
6 months
12 months
Pattern 1: CD4 count <100 cells/mm3 (some experts recommend <50 cells/mm3) after one year of therapy Pattern 2: Return to or a fall below the pre-therapy baseline CD4 count after one year of therapy Pattern 3: 50% decline from the on-treatment peak CD4 value (if known)
ART failure and when to switch therapy
59
CD4 cell count can also be used to determine when not to switch therapy. For example, in a patient with a new clinical stage 3 event for whom a switch is being considered, switching is not recommended if the CD4 cell count is >200 cells/mm3. Virological criteria for failure are included here as some countries in the Region (such as India and Thailand) have increasing capacity to perform affordable viral load testing. Viral load remains the most sensitive indicator of ART failure. Recognizing early failure facilitates switching before multiple resistance mutations have developed to drugs in the first-line regimen. The optimal viral load value at which ART should be switched has not been defined. However, values >5000–10 000 copies/ ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline.70,71,72,73
15
Choice of Second-line Regimens for Treatment Failure
The entire treatment regimen needs be changed in the setting of treatment failure (Table 32). Table 32: Which second-line regimens to choose First-line regimen Second-line regimen Reverse transcriptase Protease inhibitor inhibitor (RTI) (PI) component component* ddI + ABC or TDF + ABC or TDF + 3TC (± AZT)
Preferred regimen AZT or d4T + 3TC + NVP or EFV § Alternative regimen
PI/r *
AZT or d4T + 3TC + EFV or NVP ± ddI TDF or ABC¶
* Boosted PI/NRTI combinations: An RTV-boosted PI (PI/r) such as ATV/r, fosamprenavir (FPV)/r, IDV/r, LPV/r or SQV/r is the backbone of all second-line regimens. Unboosted PIs are not recommended with the exception of NFV if RTV is not available. NFV is less potent than a boosted PI. Two unused NRTIs are added to the PI/r; ddI is a preferred NRTI.76 § If AZT or d4T are used in the first-line regimen (as may be the case in many countries), TDF or ABC are included in all preferred second-line regimens. If these drugs are not available, the choices are limited, and ddI + 3TC (± AZT) may be the only option. If preferred NRTIs are not available, some experts recommend supporting the boosted PI component of the second-line regimen with ddI plus retaining 3TC (± AZT), even though it was used in the first-line regimen. The use of 3TC reduces HIV fitness even if there is resistance to 3TC. The combination of TDF and ddI plus an NNRTI is not recommended due to reports of early virological failure,77 falling CD4 counts despite an undetectable viral load78,79 and safety concerns. TDF increases ddI exposure by 60% and intracellular ddI levels twofold.80 ¶ For those who received a triple NRTI first-line regimen, the recommended combination is a boosted PI plus an NNRTI with the option of adding ddI and/ or 3TC to the boosted PI/NNRTI combination.81,82
16 Evaluation Clinical Clinical evaluation Weight Concomitant medications Check ART adherence Laboratory CD4 count Haemoglobin [a] Pregnancy test [b] Creatinine [c] Fasting lipids [d] Fasting glucose [e] Serum lactate HIV RNA (viral load) [f ]
Clinical and Laboratory Monitoring Prior to Commencing and on Second-line ART
Table 33: Clinical and laboratory monitoring prior to commencing and on second-line ART Before Week Week Week Week Week Every As needed or at 2 4 8 12 24 6 months (symptomART directed) switch
Notes [a] For patients receiving AZT, haemoglobin monitoring should be done prior to commencing AZT and at weeks 4, 8 and 12, and as required. [b] Pregnancy testing should be done for women before switching to a PI-based second-line ART and if pregnancy is suspected in women receiving an EFVbased regimen. Change to a non-EFV based regimen if the pregnancy test is positive and the woman is in the first trimester. [c] For patients taking TDF, baseline and 6-monthly monitoring of creatinine is recommended.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
[d] All PIs can raise levels of cholesterol and triglycerides. Monitor 6-monthly. [e] Only for patients taking IDV, baseline and 6-monthly fasting glucose should be tested. [f ] HIV RNA measurement is currently not recommended for decision-making on initiation or regular monitoring of ART in resource-limited settings. It may be considered to make an early diagnosis of treatment failure or to assess discordant clinical findings and CD4 counts in patients suspected of failing ART. Table 34: Symptom-directed management of toxicities of second-line antiretroviral drugs Toxicity Acute pancreatitis Causative ARVs Recommendations ddI NVF, ddI (buffered formulation), LPV/r SQV/r Discontinue ART. Provide supportive treatment and laboratory monitoring. Start new regimen replacing ddI with ABC or TDF if available. Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered. NFV is most commonly associated with diarrhoea. Replace NFV with another PI. Cholesterol and TG levels raised to grade 1 or 2: Monitor, diet, exercise Cholesterol and TG levels raised to grade 3 or 4: Treat raised TG with fibrates (fenofibrate 600 mg 1–2 times per day). Treat increased cholesterol with statins. Avoid simvastatin as it interacts with PIs (see Annex 4). Switch to a different PI. Ask the patient to drink 3 litres of fluid per day. Consider switching to another PI. Usually self-limited, without need to discontinue ART. Symptomatic treatment should be offered. If severe (Hb <6.5 g/dl) stop AZT and consider blood transfusion. If ALT >5-fold the basal level, discontinue ART and monitor. After resolution, try a different PI. Generally asymptomatic, but can cause scleral icterus (without ALT increase). Replace ATV or IDV with another PI.
Diarrhoea
Dyslipidaemia
PIs
Insulin resistance and IDV hyperglycaemia Renal colic and calculi GI intolerance IDV All ARVs
Haematological toxicities AZT (particularly anaemia and leucopenia) LPV/r and less Hepatitic dysfunction commonly other PIs Hyperbilirubinaemia (indirect) ATV, IDV
Clinical and laboratory monitoring prior to commencing and on second-line art
63
Table 34 (contd): Symptom-directed management of toxicities of second-line antiretroviral drugs Toxicity Hypersensitivity reaction Causative ARVs Recommendations ABC Discontinue ABC and do not restart. Give symptomatic treatment. Re-exposure may lead to a severe and potentially life-threatening reaction.
Lactic acidosis
Discontinue ART and give supportive treatment. All NRTIs After clinical resolution, resume ART, replacing (particularly d4T the offending NRTI. ABC, TDF and 3TC are less and ddI) likely to cause this type of toxicity. All NRTIs (particularly d4T) and PIs Replace the suspected ARV drug with another. TDF and AZT are less likely to cause lipodystrophy than d4T and ddI. Among the protease inhibitors, atazanavir (ATZ) may cause less lipodystrophy than the other PIs. Discontinue TDF and give supportive treatment. After clinical resolution, resume ART, replacing the offending drug. AZT, ddI or ABC may be substituted for TDF.
Lipoatrophy and lipodystrophy
Renal toxicity (renal tubular dysfunction)
TDF
17
Syndromic Approach to The Management of Opportunistic Infections
17.1 Dysphagia Figure 7. Management of dysphagia Dysphagia
Treat presumptively for oesophageal candidiasis [a]
Improved after 7 days Yes
No
Treat presumptively for HSV [b]
Improved after 7 days Yes
No
Oesophagoscopy for diagnosis [c]
Continue fluconazole for 14 days. Recurrence is likely unless ART is started. Consider prophylaxis with fluconazole 200 mg twice weekly.
Continue acyclovir for 14 days. Recurrence is likely unless ART is started. Consider prophylaxis with acyclovir 400 mg twice daily.
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65
Notes [a] Oesophageal candidiasis Candidiasis may infect the oesophagus in immune-compromised patients, causing difficulty and pain on swallowing.The diagnosis is based on clinical symptoms and response to systemic antifungal therapy. Endoscopy is not required unless the patient fails to respond to treatment. Treatment
Fluconazole 200 mg daily for 14 days or Itraconazole 400 mg daily for 14 days or Ketoconazole 200 mg daily for 14 days
[b] Acyclovir 400 mg every 4 hours [c] Failure of treatment Other causes of oesophagitis are CMV infection, Kaposi sarcoma and lymphoma. Non-HIV related causes include acid reflux. Endoscopy is required for diagnosis.
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17.2 Lymphadenopathy Figure 8. Management of lymphadenopathy Lymphadenopathy
Single node or asymmetrical lymph node Yes
No
Persistent generalized lymphadenopathy Suggestive of HIV-associated PGL [a] No specific treatment Assess clinical and immunological stage for co-trimoxazole and ART
Suggestive of extrapulmonary TB [b] Yes
No
Treat for TB (see Annex 7)
Lymph node biopsy available
No
Refer for further diagnosis
Yes Treat as extrapulmonary TB if biopsy AFB positive (see Annex 7 ) AFB acid-fast bacilli
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67
Notes [a] Persistent generalized lymphadenopathy (PGL) is common in HIV-infected patients. In an asymptomatic patient no further investigation or treatment is required. However, in patients with recently symptomatic lymphadenopathy, rapidly enlarging nodes, marked nodal asymmetry and constitutional symptoms, further evaluation and treatment is necessary. Causes of lymphadenopathy (other than HIV) include TB, cryptococcosis, histoplasmosis, lymphoma and Kaposi sarcoma.
[b] Extrapulmonary TB (EPTB) is common in HIV-infected patients. Clinical suspicion of TB is raised by the presence of the following signs and symptoms: fever, weight loss, unilateral nodes increasing in size, and matted and fluctuant nodes. Treat according to the national TB guidelines.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
17.3 Chronic diarrhoea Figure 9. Management of chronic diarrhoea without blood Chronic diarrhoea with no blood in stool [a] Empirical treatment with quinolones for 7 days [f]
Dehydrated [b]
No
Stool microscopy and culture available [d] Yes Treat as indicated [e]
No
Yes
Correct with oral fluids and rehydration salts or IV fluids Give constipating drug unless blood in stool or fever [c]
Improvement Yes
No
Empirical treatment with metronidazole for 7 days [f]
Continue to complete 14 days total treatment
Notes [a] Definition of chronic diarrhoea: liquid stool three or more times a day, continuously or episodically for more than one month [b] Assessment of dehydration General appearance Pulse Respiration Skin elasticity Eyes Mucous membranes Urine Restless, irritable Rapid Deep, may be rapid Pinched skin retracts slowly Sunken Dry Reduced in amount and dark in colour
In the case of moderate dehydration, correct with oral fluids and oral rehydration salts (ORS), prescribe intravenous fluids in case of severe dehydration. Supplemental feeding should be given slowly with multiple and divided feeding, along with intravenous fluids (minimum 1.5 litres of water a day).
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[c] Symptomatic treatment Loperamide, 4 mg initially, followed by a further 2 mg after each unformed stool (maximum daily dosage 16 mg). Constipating agents should not be used in patients with bloody diarrhoea, because of the risk of inducing toxic megacolon.
[d] Multiple stool examinations (each day for 3 days) increase the diagnostic yield. [e] Specific treatment for diarrhoea due to common pathogens Disease Salmonellosis and shigellosis Campylobacteriosis Giardiasis Amoebiasis Isosporiasis Strongyloidiasis Mycobacterium avium complex Drug used Dosage (per day) Treatment duration 7–10 days 7–10 days 5 days 5 days 7–10 days 7 days 3 days
Ciprofloxacin 500 mg 2 times Ofloxacin 400 mg 2 times Erythromycin 500 mg 4 times Metronidazole 500 mg 3 times Metronidazole 500 mg 3 times TMP–SMX 860 mg 4 times Thiabendazole 3 times 25 mg/kg body weight For treatment, see Annex 6
Cryptosporidiosis: There is currently no established effective treatment except ART. Maintenance of fluid and electrolyte balance is of greatest importance, and agents that aid constipation may also be useful. In HIVinfected patients, salmonellosis, shigellosis, Campylobacter infection and isosporiasis often relapse. If relapse occurs after an initial course of antimicrobial therapy, a 6–12-week course of therapy should be administered. [f ] If the patient improves after 7 days of therapy with metronidazole, the drug should be continued for a total of 14 days. If there is no improvement, consider other HIV-associated chronic diarrhoea including the possibility of starting ART (see Annex 1). Empirical treatment for chronic diarrhoea without blood Option Drug used 1 Ciprofloxacin 500 mg OR Ofloxacin 400 mg 2 Metronidazole 500 mg Dosage/day 2 times 2 times 3 times Treatment duration 7–10 days 7–10 days 7 days
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17.4 Respiratory symptoms Figure 10. Management of respiratory symptoms Respiratory symptoms and severe dyspnoea [a]
Oxygen and CXR
Fever
No
Consider pulmonary embolism ? Signs of venous thrombosis ? IDU
Yes Productive cough >2–3 weeks Yes Sputum smear for AFB [c] Positive Treat as pulmonary TB [d] AFB acid-fast bacilli
No
Consider PCP Treat with high-dose co-trimoxazole [b]
Negative
Consider bacterial pneumonia CXR if available Treat with ampicillin [e]
Notes [a] Common respiratory symptoms in patients with HIV infection and immunodeficiency are fever, dry cough (typical of PCP), productive cough with sputum and/or haemoptysis (typical of pneumonia and TB), shortness of breath and severe respiratory distress.
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71
Causes of respiratory symptoms Infections Mycobacterium tuberculosis (cough for >2–3 weeks) Pneumocystis jiroveci pneumonia (cough, often for 1–2 months) Bacterial pneumonia Fungal infection (cryptococcosis, histoplasmosis) Atypical mycobacteria (MAC) CMV pneumonitis Malignancies: lymphoma, Kaposi sarcoma Others Pleural effusion/empyema (TB, bacterial infection or malignancies) Pneumothorax (TB or PCP) Pulmonary embolism (common among IDUs) Pericardial effusion (often associated with TB)
[b] PCP: Typically has a slow onset over weeks to months of dry cough, fever and shortness of breath. Clinical diagnosis supported by CXR findings is preferred for the diagnosis of PCP (see Annex 6). [c] Sputum examination for acid-fast bacilli (AFB) is indicated in patients with cough for >2–3 weeks. At least two separate sputum smear examinations are recommended. [d] TB: No CXR pattern is absolutely typical of pulmonary TB. The classical pattern is more common in HIV-negative patients; the atypical pattern is more common in HIV-positive patients. Pleural effusion is a prominent feature. Pleural tap and microscopic examination of the pleural fluid may be helpful for diagnosis. Treat according to national TB guidelines. Classical pattern Upper lobe infiltrates Cavitation Pulmonary fibrosis Atypical pattern Interstitial infiltrates (especially lower zones) Bilateral infiltrates No cavitation
[e] Bacterial pneumonia: The typical presentation is with productive cough, purulent sputum and fever for 1–2 weeks. PCP presents more slowly and there is normally non-productive cough. The typical CXR finding is lobar consolidation. Gram-positive pyogenic bacteria are the most probable cause of bacterial pneumonia. Amoxycillin 500 mg 3 times per day or erythromycin 500 mg 4 times per day for 7 days can be given if the clinical presentation suggests bacterial pneumonia and not PCP.
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17.5 Neurological signs and symptoms Figure 11. Management of neurological signs and symptoms Neurological signs and symptoms [a]
Focal neurological signs [b]
Clinical signs of meningeal irritation [b] Yes
No
Treat empirically for cryptococcal meningitis [d]
Yes CSF examination available Cerebral CT available No Treat empirically for bacterial meningitis [e]
Yes Bacteria, WBC, AFB, India-ink stain Treat as indicated [c, d, e] No
Yes
Treat based on clinical examination and CT findings
Treat for toxoplasmosis [c]
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73
Notes [a] Causes of headache include cryptococcal meningitis,tuberculous meningitis, cerebral toxoplasmosis, chronic HIV meningitis, bacterial meningitis and lymphoma. Causes of headache not related to HIV infection include migraine, syphilis, tension, sinusitis, refractive disorders, dental disease, anaemia and hypertension. Other infectious diseases such as malaria, typhoid fever, dengue fever and rickettsiosis may also cause headache.
[b] Neurological examination Evidence of meningeal irritation (photophobia, neck stiffness) or raised intracranial pressure (high blood pressure and slow pulse in the presence of fever) Changes in mental state Focal neurological deficits including paresis, cranial nerve palsies, movement disorders, ataxia, aphasia and seizures [c] Toxoplasmosis (for treatment, refer to Annex 6). [d] Cryptococcal meningitis (for treatment, refer to Annex 6). [e] Bacterial meningitis Benzyl penicillin 1.2–2.4 million IU daily by IV injection every 4 hours in divided doses. Treat for a minimum of 7 days or for 4–5 days after the patient becomes afebrile. Ceftriaxone 2–4 g daily by intravenous infusion or by deep intramuscular injection can be used if the patient is allergic to penicillin, ampicillin or chloramphenicol.
18
Nutritional Support
Depending upon the stage of the disease, HIV causes the following: Reduction in food intake Difficulties related to digestion Difficulties related to absorption Altered metabolism of nutrients (e.g. metabolism of carbohydrates/ lipids may be altered in HIV-infected persons) Altered body functions: inability to produce saliva, other digestive juices Improper utilization of fats.
Increased resting energy expenditure (REE) is observed in HIV-infected adults.
Energy requirements are likely to increase by 10% to maintain body weight and physical activity in asymptomatic HIV-infected adults, and maintain growth in asymptomatic children. Once HIV infection becomes symptomatic, and subsequently after the development of AIDS, energy requirements increase by approximately 20–30% to maintain adult body weight.
Nutritional counselling must be provided every time PLHA visit the clinic. It is aimed at providing the following necessary practical guidelines on nutrition to PLHA and their caregivers: 1. Simple steps on food handling and safety:
Cook food thoroughly. Eat cooked food immediately. Store food carefully. Re-heat cooked food thoroughly. Avoid contact between raw and cooked food. Wash your hands thoroughly before and after cooking.
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75
Keep kitchen surfaces clean. Protect food from rodents, insects and animals. Use clean water.
2. Commonly available food items and their nutritional content 3. Recommendations on which food items to avoid:
Raw eggs Food that has not been thoroughly cooked, especially meat and chicken Unboiled water or juices made with unboiled water. Alcohol and coffee Stale food
4. Symptom-based nutritional care and support (Table 35 ) 5. Nutrition and ART, including food–drug interactions Paying greater attention to diet and nutrition may enhance the acceptability and effectiveness of ART, as well as adherence to it. Give counselling on correct nutrition and foods that can enhance the wellbeing of PLHA. Food can affect the absorption, metabolism, distribution and excretion of medication. Medication too can affect the metabolism of food.
High-fat meals reduce the absorption of IDV (unboosted). High-fat meals increase the bioavailability of TDF. RTV causes changes in fat metabolism. The side-effects of medication may adversely affect the consumption and absorption of food, e.g. AZT causes nausea, anorexia and vomiting; ddI causes vomiting, diarrhoea and dryness of the mouth. The combination of certain medications and alcohol can produce side-effects, e.g. taking ddI together with alcohol may result in pancreatitis. Take AZT with low-fat meals. Take ddI on an empty stomach. Avoid alcohol with any medication.
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Table 35: Symptom-based nutritional care Symptoms Loss of appetite Management Eat small, frequent meals (5–6 meals/day) Eat nutritious snacks Drink plenty of liquids Take walks before meals—the fresh air helps to stimulate appetite Have family or friends assist with the preparation of food Take light exercise and do light activity Add flavour to drinks and food
Mouth ulcer
Avoid citrus fruits, and acidic and spicy foods Eat food at room temperature Eat soft and moist food Avoid caffeine and alcohol mashed vegetables, apple juice, milk)
Candidiasis
Eat soft, cool and bland foods (such as rice porridge, oatmeal, Add garlic (optional) Avoid sugar (glucose, cane sugar), yeast, caffeine, spicy food,
carbonated drinks and alcohol Nausea and vomiting Eat small, frequent meals Avoid being on an empty stomach as this makes the nausea
Constipation
Anaemia
worse Eat bland food Avoid food with strong or unpleasant odours Drink plenty of liquids Rest and relax after meals Avoid lying down immediately after eating Avoid coffee and alcohol Eat fibre-rich and sprouted food Take light exercise and do light activity Drink plenty of water Take warm drinks Eat meat and fish Eat cereals Eat a variety of green leafy vegetables. The best way for the body to utilize iron from plant sources is to combine food rich in iron with a food rich in vitamin C, such as oranges, lemons, tomatoes and papaya
19
Palliative Care in HIV Infection83
19.1 Definition Palliative care is an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification, and impeccable assessment and treatment of pain and other problems – physical, psychosocial and spiritual. Palliative care extends, if necessary, to support in bereavement. Palliative care in HIV:
is family and patient-centred; optimizes the quality of life by active participation, prevention and treatment of suffering; involves an interdisciplinary team approach throughout the continuum of illness, placing critical importance on the building of respectful and trusting relationships; addresses physical, intellectual, emotional, social and spiritual needs.
The availability of ART and palliative care has made HIV a chronic, manageable disease for many. Apart from regular management of pain, nutritional support and management of OIs, palliative care includes giving support for drug failure and severe toxicities due to ART. Special attention needs to be given to the following HIV-related conditions, which may present as terminal illnesses. These conditions can be managed with proper medical care and support. 1. Severe oral and oesophageal candidiasis, leading to severe pain and weight loss. 2. Cryptococcal meningitis and toxoplasma encephalitis.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
19.2 Components of palliative care The main components of palliative care include the following:
Pain management Symptom management Nutritional support Psychosocial support Spiritual support End-of-life care Bereavement counselling.
19.3 Management of pain (1) Assess the patient for pain:
Determine the severity, site and nature of the pain (bone pain, mouth pain, shooting nerve pain, colicky pain, severe muscle spasms). If there is infection, prompt management of infection is the main step in controlling the pain (e.g. treating severe oral and oesophageal candidiasis with fluconazole relieves the pain). The severity of the pain can be graded with the help of the tool below (Figure 10).
GO BY WHAT THE PATIENT SAYS IS HURTING: Do not disregard the patient’s complaint of pain just because there is no apparent physical cause. Figure 12. Visual scale to assess pain intensity The following format may be used for assessing pain in any patient.
Pain Intensity Scale
No Pain Mild Pain Discomfort
Distress
Intense Excruciating
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79
(2) The treatment strategies for pain are shown in Figure 13. Figure 13. Strategies for treatment of pain By mouth If possible, administer painkiller by
By the clock Give painkillers at fixed time intervals
mouth (rectal administration is an alternative – avoid the intramuscular route).
(by the clock or radio or sun). Start with a small dose, and then titrate
the dose against the patient’s pain until the patient is comfortable. The next dose should be given before the effect of the previous one wears off. For breakthrough pain, give an extra “rescue” dose, in addition to the regular schedule.
C By the analgesic ladder:
pers Pain s
ists o
rease r inc asing
s d Pain ecre
asing
d Pain se crea s or in rsist e p Pain g easin decr Pain
ecre
3
2
1
Opioid for mildto-moderate pain (codeine) ± Non-opioid (aspirin or paracetamol or ibuprofen)
Opioid for moderateto-severe pain (oral morphine)
Non-opioid (aspirin or paracetamol or ibuprofen)
± Non-opioid
The right dose is the dose that relieves the patient’s pain. Source: Palliative care: symptom management and end-of-life care. Integrated management of adolescent and adult illness. Interim guidelines for first-level facility health workers. Geneva, WHO, 2004.
(3) Use opioid and non-opioid analgesics: Give only one drug from the opioid and non-opioid groups at a time. The exception is codeine – if it cannot be given, use aspirin every four hours combined with paracetamol every four hours – overlap the two so that one is given every two hours.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 36: Use of analgesics in pain relief Analgesics Non-opioid Paracetamol (also lowers fever) 2 tablets of 500 mg every 4–6 hours (skip dose at night or give another analgesic to keep the total to 8 tablets) Only 1 tablet may be required in the elderly or very ill, or when combined with an opioid. Mild pain may be controlled with 6-hourly dosing. Do not exceed 8 tablets of 500 mg in 24 hours (more can cause serious liver toxicity). Starting dose in adults Range Side-effects/ precautions
STEP 1
Aspirin (acetylsalicylic acid) (also antiinflammatory and lowers fever)
300 mg (2 tablets) every 4 hours
Avoid use if gastric problems. Stop if epigastric pain, indigestion, black stools, petechiae or bleeding. Avoid if any bleeding is present. Maximum dose 8 tablets per day
Ibuprofen (also antiinflammatory, lowers fever, relieves bone pain)
400 mg every 6 hours
Opioid for mild-to-moderate pain (give in addition to aspirin or paracetamol) Codeine (if not available, consider alternating aspirin and paracetamol) 30 mg every 4 hours 30–60 mg every 4–8 hours Maximum daily dose for pain 180–240 mg as it causes constipation – if so, switch to morphine. Give laxative to avoid constipation unless there is diarrhoea.
STEP 2
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81
Table 36 (contd): Use of analgesics in pain relief Analgesics Starting dose in adults Range Side-effects/ precautions
Opioid for moderate-to-severe pain Oral morphine 5 mg/5 ml or 50 mg/5 ml. Drop into mouth. Can also be given rectally (by syringe) 2.5–5 mg every 4 hours (dose can be increased by 1.5 mg or doubled after 24 hours if pain persists) According to need of patient and breathing. There is NO ceiling dose. Give laxative to avoid constipation unless there is diarrhoea.
STEP 3
Source: Palliative care: symptom management and end-of-life care. Integrated management of adolescent and adult illness. Interim guidelines for first-level facility health workers. Geneva, WHO, 2004.
19.4 Medications to control special pain problems Pain may be due to special conditions, which can be relieved by specific medications (Table 37). Provide specific treatment in combination with drugs from the analgesic ladder.
19.5 Additional methods for pain control Combine these with pain medications if the patient agrees and it helps:
Emotional support Physical methods: touch (stroking, massage, rocking, vibration); ice or heat; deep breathing Cognitive methods: distraction such as playing a radio, music, imagining a pleasant scene Prayer (with respect to the patient’s practice) Traditional practices which are helpful and not harmful – get to know what can help in the local setting.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 37: Medications for special types of pain Special pain problems For burning pain; pain due to abnormal sensation; severe, shooting pain with relatively little pain in between; pins and needles For painful muscle spasms or paralysis Herpes zoster (or the shooting pain following it) Refer patients with ophthalmic zoster Gastrointestinal pain from colic only after intestinal obstruction has been excluded (i.e. vomiting, no passage of stool and flatus, visible bowel movements) Bone pain or renal colic or dysmenorrhoea Pain from: Swelling around tumour Severe oesophageal ulceration and cannot swallow Nerve or spinal cord compression Persistent severe headache (likely from increased intracranial pressure) Medication Low-dose amitriptyline (25 mg at night or 12.5 mg twice daily; some start with 12.5 mg daily) – wait 2 weeks for response, then increase gradually to 50 mg at night or 25 mg twice daily. Diazepam 5 mg orally or rectally 2–3 times per day Low-dose amitriptyline Early eruption: acyclovir if available; apply gentian violet if ruptured vesicles Codeine 30 mg every 4 hours or antispasmodics such as hyoscine (buscopan) 10 mg three times daily (can increase up to 40 mg three times daily) Ibuprofen (or other non-steroidal antiinflammatory drug [NSAID] When giving end-of-life care and referral not desired, can consider use of steroids under careful clinical supervision.
Source: Palliative care: symptom management and end-of-life care. Integrated management of adolescent and adult illness. Interim guidelines for first-level facility health workers. Geneva, WHO, 2004.
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19.6 Symptom management Table 38: Management of symptoms with medications and home care Symptoms Nausea and vomiting Medications to give Give an antiemetic: metoclopramide (10 mg every 8 hours). Give only for a day at a time or haloperidol (1–2 mg once daily) or chlorpromazine (25–50 mg every 6–12 hours). Home care The patient should Eat small, frequent meals. Avoid an empty stomach as this makes the nausea worse. Eat bland foods. Avoid foods with strong or unpleasant odours. Drink plenty of liquids. Rest and relax after and between meals. Avoid lying down immediately after eating. Avoid coffee and alcohol. Remove bits of food stuck in the
Painful mouth ulcers or pain on swallowing
If Candida: give fluconazole,
nystatin or miconazole orally Topical anaesthetics can provide some relief. Pain medication may be regulated according to analgesic ladder For aphthous ulcers: crush one 5 mg prednisone tablet and apply a few grains. Smelly mouth/breath (halitosis) from oral cancer or other lesions: metronidazole 400 mg twice a day or chlorhexidine gluconate 1% 10 ml mouthwash four times a day or hexetidine 0.1% 10 ml four times a day or benzydamine 0.5% mouthwash or sodium bicarbonate mouthwash (1 tsp in 1 pint warm water) For herpes simplex: Acyclovir 400 mg every four hours for 5 days
mouth with cotton wool, gauze or soft cloth soaked in salt water. Rinse the mouth with diluted salt water (a finger pinch of salt or 1/2 teaspoon sodium bicarbonate in a glass of water) after eating and at bedtime. Mix 2 tablets of aspirin in water and rinse the mouth up to 4 times a day. Eat a soft diet to decrease discomfort such as rice porridge, oatmeal, depending on what the sick person feels is helpful. More textured foods and fluids may be easier to swallow than fluids. Avoid extremely hot or cold or spicy foods.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Table 38 (contd): Management of symptoms with medications and home care Symptoms Bed sores Medications to give All patients need skin care to
Home care For small sores, clean gently with
avoid pressure problems. Check for signs of infection. For smelly tumours or ulcers, sprinkle metronidazole powder – enough to cover the area and keep dry.
salt water and allow to dry. Apply honey to bedsores that are
not deep and leave the wound open to the air. If painful, give painkillers such as paracetamol or aspirin regularly. For deep or large sores, clean daily gently with diluted salt water, fill the bedsore area with pure honey and cover with a clean light dressing to encourage healing.
Source: Palliative care: symptom management and end-of-life care. Integrated management of adolescent and adult illness. Interim guidelines for first-level facility health workers. Geneva, WHO, 2004.
19.7 End-of-life care “ How people die lives on in the memory of those left behind.” The terminal phase is defined as the period when day-to-day deterioration occurs, particularly of strength, appetite and awareness. It is difficult to predict when death will occur and it is better not to do so. The aim of care at this stage should be to ensure the patient’s comfort holistically, and a peaceful and dignified death. Provide psychosocial and spiritual support to the patient:
Active listening, counselling and social/emotional support Spiritual support is very important: – Be prepared to discuss any matter the patient would like to. – Learn to listen with empathy. – Understand reactions to the patient’s losses in life (the different stages of grief ). – Be prepared to “absorb” some reactions, for example, anger projected onto the health-care provider. – Do not impose your own views. – Share religious beliefs with the appropriate person (e.g. religious leader, spiritual counsellor, etc.) as required.
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Empower the family to provide care: – Help the family come to terms with the fact that the patient is leaving them soon: let family members be around to see and talk to the patient. – Deal gently with their anxieties and fears. – Give information and teach skills. Actions Encourage communication within the family. Discuss worrying issues such as custody of children, family support, future school fees, old quarrels, funeral costs. Tell the patient that they are loved and will be remembered. Talk about death if the person wishes to (keep in mind cultural taboos if not in a close relationship). Make sure the patient gets help with feelings of guilt or regret. Connect with a spiritual counsellor or arrange for pastoral care as the patient wishes. Approach, be present and compassionate. Make an outreach visit regularly and offer home-based care. Someone needs to hold the hand, listen, converse with the patient and family. Provide comfort and physical contact by light touch, holding
Table 39: Management of end-of-life care issues Steps Preparing for death
Presence
Caring Comfort measures near the end of life
hands (if appropriate). Moisten lips, mouth, eyes. Keep the patient clean and dry and prepare for incontinence of
the bowel and bladder. Give only essential medications – pain relief, antidiarrhoeals, and
treat fever and pain (e.g. paracetamol round-the-clock), etc. Control symptoms with medical treatment as needed to relieve
suffering (including antibiotics and antifungals). Eating less is acceptable. Ensure hydration. Take care of the skin; turn the patient every 2 hours or more
frequently to prevent bed sores. Signs of imminent death Decreased social interaction – sleeps more, acts confused, coma Decreased food and fluid intake – no hunger or thirst Changes in elimination – reduced urine and bowel movements,
incontinence Respiratory changes – irregular breathing, “death rattle” Circulatory changes – cold and greyish or purple extremities,
Signs of death
decreased heart rate and blood pressure Breathing stops completely Heart beat and pulse stop Totally unresponsive to shaking, shouting Eyes fixed in one direction, eyelids open or closed Changes in skin tone – white to grey
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Management of Occupational Exposure Including Postexposure Prophylaxis84
20.1 Introduction Avoiding occupational exposure to blood is the primary way to prevent transmission of HIV, HBV and HBC in health-care settings. Hepatitis B immunization and appropriate post-exposure management are integral components of a programme to prevent infection following exposure to blood-borne pathogens. Appropriate post-exposure management guidelines form an important element of workplace safety. These guidelines should describe the risks of infection, preventive measures and procedures to be followed after occupational exposure. These guidelines should address the following aspects of occupational exposure to blood:
Who is at risk? What is the risk? What practices may influence this risk and how can the risk be minimized? What is the role of antiretroviral agents in reducing this risk? Issues about the safety of drugs for post-exposure prophylaxis (PEP) and their use in pregnancy Operational recommendations to develop a comprehensive programme for implementation of PEP with 24-hour access to the needed drugs.
20.2 Definitions Occupational exposure refers to exposure to potential blood-borne infections (HIV, HBV and HCV) that occurs during the performance of job duties.
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Post-exposure prophylaxis refers to the comprehensive management given to minimize the risk of infection following potential exposure to bloodborne pathogens (HIV, HBV, HCV). This includes counselling, risk assessment, relevant laboratory investigations based on informed consent of the source and exposed person, first aid and, depending on the risk assessment, the provision of short-term (4 weeks) ARV drugs, with follow up and support. The term health-care personnel (HCP) includes any person, paid or unpaid, working in health-care settings, who is potentially exposed to infectious materials (e.g. blood, tissue and specific body fluids, and medical supplies, equipment,or environmental surfaces contaminated with these substances). If required, PEP can also be given to public safety workers, including law enforcement personnel, prison staff, fire-fighters, workers in needleexchange programmes and workers in international HIV programmes. Exposure that may place an HCP at risk for a bloodborne infection is defined as:
A percutaneous injury (e.g. needle-stick or cut with a sharp instrument) Contact with the mucous membranes of the eye or mouth Contact with non-intact skin (particularly when the exposed skin is chapped, abraded, or afflicted with dermatitis), or Prolonged contact (e.g. several minutes or more) with intact skin contaminated with blood or other potentially infectious body fluids.
20.3 Principles of providing PEP Non-discrimination: The decisions about whether to provide PEP should be based only on the clinical consideration of risk. Providers should give information, services and education without discrimination. Confidentiality: The provision of information regarding PEP should be confidential, including information about HIV testing, PEP provision and the reasons for seeking PEP. Informed consent: Informed consent for taking PEP needs to be obtained as for any other medical procedure.This should be taken in writing. Consent for HIV testing in the context of HIV exposure and/or taking PEP needs to conform to the national counselling and testing guidelines.
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20.4 Who is at risk? Professionals with frequent exposure to blood:
Interns and medical students Nurses and nursing students Physicians Surgeons Labour and delivery room personnel Emergency care providers Dentists Laboratory technicians Pathologists, autopsy staff Health facility cleaning staff and clinical waste handlers.
20.5 Infectious body fluids Not all body fluids are considered to carry a risk for HIV transmission (Table 40). Table 40: Potentially infectious body fluids Exposure to body fluid considered “at risk” Blood Semen Vaginal secretions Cerebrospinal fluid Synovial, pleural, peritoneal, pericardial fluid Amniotic fluid Exposure to body fluid considered “not at risk” Tears Sweat Urine and feces Saliva unless these secretions contain visible blood
Any direct contact (i.e. contact without barrier protection) to concentrated virus in a research laboratory or production facility requires clinical evaluation. For human bites, clinical evaluation must include the possibility that both the person bitten and the person who inflicted the bite were exposed to bloodborne pathogens. Transmission of HIV infection after human bites has rarely been reported.
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20.6 What is the average risk of acquiring HIV, HBV or HBC infection after an occupational exposure? The average risk of acquiring HIV infection after different types of occu– pational exposure is low compared with the risk of acquiring HBV or HCV infection. In terms of occupational exposure the important routes are needle-stick exposure (0.3% risk for HIV, 9–30% for HBV and 1–10% for HCV) and mucous membrane exposure (0.09% for HIV).
20.7 Practices that influence risk and how to reduce risk (occupational exposure) Certain work practices increase the risk of needle-stick injury such as:
Recapping needles (most important) Transferring a body fluid from one container to another Failing to dispose of used needles properly in puncture-resistant sharps containers Poor health-care waste management practices. Avoid the use of needles where safe and effective alternatives are available. Avoid recapping needles. Plan for safe handling and disposal of needles before using them. Promptly dispose of used needles in appropriate sharps disposal containers. Report all needle-stick and sharps-related injuries promptly to ensure that you receive appropriate follow-up care. Participate in training related to infection prevention. Help your institute select and evaluate devices with safety features that reduce the risk of needle-stick injury. Use devices with safety features provided by the institute (wherever possible). Record and monitor injuries by means of an injury register in each location of health-care setting.
Protecting oneself from needle-stick/sharps injuries
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20.8 Preventing exposure to and transmission of HIV and other viruses Staff information: All categories of HCP within the hospital should be informed about how to protect themselves against HIV and other pathogens transmitted by blood or body fluids. The knowledge must be reinforced on a regular basis. All staff share an individual and collective responsibility in this regard. The medical director/dean/principal/person responsible for hospital policies must constitute a hospital infection control committee which will conduct regular training and monitor hospital infection control including universal standard precautions, and implementation of PEP and quality control. The medical director must ensure that the hospital has a written protocol and standard operating procedure (SOP) for handling occupational exposure and that these are disseminated to all relevant personnel/departments. Key information:
The universal standard precautions to be followed in the health services (Box 7) Use of personal protective equipment Other preventive measures to be taken against these viruses (including vaccination) SOPs to be followed in case of accidental exposure to blood and body fluids.
Minimize the use of sharps/injections: All medical staff should try to minimize the use of invasive interventions, for example, use oral drugs in place of injections wherever possible. Where the use of sharps is indicated try to use safer alternatives where practical and possible within the limitations of the system. Protection against HBV: All HCP should be vaccinated against HBV. The schedule comprises three doses; initial dose on day 0, second dose after one month and third dose after six months. Seroconversion after completing the full course is 99% (see p. 100).
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Box 7: Universal standard precautions Universal standard precautions are intended to prevent exposure of HCP and patients to bloodborne pathogens. These must be practised with regard to the blood and body fluids of all patients, regardless of their infection status. Universal standard precautions include:
Hand-washing before and after all medical procedures. Safe handling and immediate safe disposal of sharps: not recapping needles; using special containers for sharps disposal; using a needle cutter/destroyer; using forceps instead of the fingers for guiding sutures; using vacutainers where possible. Safe decontamination of instruments. Use of protective barriers whenever indicated to prevent direct contact with blood and body fluids such as gloves, masks, goggles, aprons and boots. An HCP who has a cut or abrasion should cover the wound before providing care. Safe disposal of contaminated waste.
20.9 Management of the exposed person Table 41: Summary of dos and don’ts Do Remove gloves, if appropriate Wash the exposed site thoroughly with running water Irrigate with water or saline if the eyes or mouth have been exposed Wash the skin with soap and water Do not Do not panic Do not put the pricked finger in the mouth Do not squeeze the wound to bleed it
Do not use bleach, chlorine, alcohol, betadine, iodine or other antiseptics/ detergents on the wound
Do: Consult the designated physician immediately for management of the occupational exposure as per institutional guidelines.
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20.10 Steps for managing occupational exposure Step 1: Manage the exposure site – First aid Step 1: Manage exposure site
Wash wound and surrounding skin with water and soap
OR
Irrigate exposed eye immediately OR with water or normal saline
Rinse the Refer to mouth physician thoroughly, using water or saline and spit again
Step 6: Follow up and monitor adherence
Step 5: Laboratory evaluation
Step 4: Prescribe PEP
Step 3: Counsel for PEP
Step 2: Establish eligibility for PEP
For the skin – if the skin is broken after injury with a needle-stick or sharp instrument:
Immediately wash the wound and surrounding skin with water and soap, and rinse. Do not scrub. Do not use antiseptics or skin washes (bleach, chlorine, alcohol, betadine). For unbroken skin: – Wash the area immediately with water and soap, and rinse. Do not scrub. – Do not use antiseptics or skin washes (bleach, chlorine, alcohol, betadine). For the eye: – Irrigate the exposed eye immediately with water or normal saline. – Sit on a chair, tilt the head back and ask a colleague to gently pour water or normal saline over the eye. – If wearing a contact lens, leave it in place while irrigating, as it forms a barrier over the eye and will help protect it. Once the eye is cleaned, remove the contact lens and clean it in the normal manner. This will make it safe to wear again. – Do not use soap or disinfectant in the eye.
After a splash of blood or body fluids:
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For the mouth: – Spit out fluid immediately. – Rinse the mouth thoroughly, using water or saline and spit again. Repeat this process several times. – Do not use soap or disinfectant in the mouth.
Consult the designated physician of the institution immediately for management of the exposure. Step 2: Establish eligibility for PEP Step 1: Manage exposure site Step 2: Establish eligibility for PEP
Exposure within 72 hours
Assess Assess exposed exposure individual source
Assess Determine Determine type of risk of eligibility exposure transmission for PEP Step 4: Prescribe PEP Step 3: Counsel for PEP
Step 6: Follow up and monitor adherence
Step 5: Laboratory evaluation
A risk assessment to establish eligibility for PEP should be undertaken by a trained person as soon as possible after every occupational exposure, no matter what time of the day it occurs. The risk assessment is conducted to determine the severity of the exposure and whether any immediate medical action (such as the provision of PEP) is required. An appropriate risk assessment should be performed as close to the workplace as possible, depending on the competency of workplace support. Local protocols must designate the person or position to be contacted to perform a risk assessment. If there is no one on duty with the necessary skills, this could be performed over the telephone, or radio (or other method of communication over a distance) if a skilled person or service has been identified in the protocol.
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The first dose of PEP should be administered within the first 72 hours of exposure and the risk evaluated as soon as possible. If the risk is insignificant, PEP could be discontinued if already commenced. Even if the exposure is not considered to be significant for HIV transmission, prompt intervention including assessment and communication of risk can significantly reduce the anxiety a worker may experience after an exposure. Two main factors determine the risk of infection: the status of the source patient and the type of exposure. Box 8: Eligibility criteria for PEP 1. 2. 3. 4. Exposure less than 72 hours ago, and Exposed individual not known to be HIV-infected, and Source of exposure HIV-infected or of unknown status, and Exposure was to blood, body tissues, visibly blood-stained fluid, concentrated virus, cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid or amniotic fluid, and Exposure penetrated the skin with spontaneous bleeding or deep puncture, or a significant amount of fluid splashed onto a mucous membrane, or there was prolonged contact of at-risk substance with non-intact skin, and (If skin penetration) Exposure was from a recently used hollow-bore needle or other sharp object visibly contaminated with blood.
5.
6.
Assess status of the exposed individual The exposed individual should be assessed for pre-existing HIV infection as PEP is intended for people who are HIV-negative at the time of their potential exposure to HIV. Exposed individuals who are known or discovered to be HIV-positive should not start or continue PEP. In the case of unknown HIV status PEP should be started before the test result is known. Assessing the status of the exposure source If the source person’s HIV infection status is unknown at the time of exposure, use of PEP should be decided on a case-by-case basis, after
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considering the type of exposure and the clinical and/or epidemiological likelihood of HIV infection of the source. Identification and HIV testing of the source of the exposure is only necessary if the results are likely to change the clinical management of the exposed worker. If the exposure is assessed as having no or very low risk of HIV transmission, there is no need to test the source. If the HIV status of the source is not already known or available by rapid testing, the decision to commence PEP should be based on the factors listed above. Waiting for the results of the source’s test will jeopardize the timeliness of commencing PEP. Therefore, PEP should be given after a significant exposure if there is a possibility that the source is HIVpositive. Source testing should be encouraged using standard national HIV testing and counselling protocols. The source could consent to testing but PEP should be started without waiting for the results. Source testing in all workplace settings requires consent. The exposed worker must not be involved in obtaining consent from the source for HIV testing. If the source can be tested and consents to testing, the test results should be a part of the decision as to whether to continue PEP if commenced. If the source is HIV antibody negative at the time of the incident, assessment should be made as to whether the person could possibly be in the window period before the HCP makes a decision to discontinue PEP if commenced. In the case of a source who is unknown, or unable or unwilling to be tested, universal standard precautions dictate that all sources should be regarded as potentially HIV-infected and PEP should be initiated if indicated by the severity of the exposure. If the source is known to be HIV-positive the treating physician should be consulted for the history of and response to ART.
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Assessing the nature of exposure and risk of transmission Table 42: Factors to be considered in a risk assessment Type of exposure – sharps injury The type (solid or hollow-bore) and size of the needle or sharp object What the needle or sharp object was used for The severity of the injury Whether the penetration site bled The type of blood or body substance the person was exposed to The amount of blood or body substance the person was exposed to Whether the injury occurred through gloves or clothing When the exposure occurred How recently the sharp had been used
Type of exposure – splash The type of body fluids the person was exposed to Whether the fluid the person was exposed to contained blood The amount of blood or body substance the person was exposed to Whether non-intact skin or mucous membrane was exposed When the exposure occurred
Source (of the blood or body fluid or tissue) Known or unknown HIV status (if known) Stage of HIV infection (if known) HIV RNA viral load (if known) ART history (if known) Estimated population prevalence of HIV (this includes geographical region and
country prevalence, and also prevalence within the cultural, ethnic or behavioural group) Wearing of gloves during any of these accidents constitutes a protective factor.
Note In case of an accidental exposure to blood with material such as discarded sharps/needles contaminated for over 48 hours, the risk of infection becomes negligible for HIV, but still remains significant for HBV. HBV survives longer than HIV outside the body.
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Step 3: Counsel for PEP Step 1: Manage exposure site Step 2: Establish eligibility for PEP Step 3: Counsel for PEP
Provide information on HIV and PEP Step 6: Follow up and monitor adherence
Obtain consent for PEP Step 5: Laboratory evaluation
Offer special leave from work Step 4: Prescribe PEP
Exposed persons should receive appropriate information and counselling about what PEP is and the risks and benefits of PEP in order to provide informed consent. It should be clear that PEP is not mandatory. Special leave from work should be considered and offered for a period of time, e.g. two weeks (initially), then as required based on an assessment of the exposed person’s mental state, side-effects of PEP and other requirements. Step 4: Prescribe PEP Step 1: Manage exposure site Step 2: Establish eligibility for PEP Step 4: Prescribe PEP Step 3: Counsel for PEP
Assess source patient's ARV status
Check for pregnancy if exposed female HCP
Explain sideeffects of ARVs
Explain postexposure measures against HBV and HCV Step 5: Laboratory evaluation
Step 6: Follow up and monitor adherence
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The drugs used for PEP should be aligned with the formulary adopted in the country. AZT, 3TC and boosted PIs are the most common ARV drugs used in these situations. An alternative NRTI that can be considered is d4T. NVP is NOT recommended for PEP due to the risk of severe reactions reported in these situations. EFV should be avoided due to its CNS side-effects and should not be given to pregnant women or women with childbearing potential. There is also no evidence that a three-drug PEP regimen is superior to a two-drug one.
A two-drug regimen is used for all exposures that may have a potential risk of HIV transmission. A three- or more drug regimen is used for all exposures that may have a potential risk of HIV transmission where the source is known or suspected to have ARV resistance.
Selection of the PEP regimen when the source patient is known to be on ART: The physician should consider the comparative risk represented by the exposure and information about the source of the exposure, including history of and response to ART based on clinical response, CD4 cell counts, viral load measurements (if available), and current disease stage (WHO clinical staging and history). When the source person’s virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, it is recommended that drugs to which the source person’s virus is unlikely to be resistant be selected. Refer to an expert for opinion. If this information is not immediately available, initiation of PEP, if indicated, should not be delayed. Give the two-drug (basic) regimen (Table 43). Changes in the PEP regimen can be made after PEP has been started, as appropriate. Re-evaluation of the exposed person should be considered within 72 hours post exposure, especially as additional information about the exposure or source person becomes available. Table 43: PEP regimens Preferred Two-drug regimen (basic PEP regimen) First choice: AZT + 3TC Alternative Second choice: d4T + 3TC
Three-drug regimen (expanded PEP regimen): consult an expert before starting a third drug, e.g. LPV/r, NFV or IDV. Not recommended ddI + d4T combination NNRTIs such as NVP should not be used for PEP.
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More information on alternative schedules is available in the latest update of the Updated US Public Health Service (USPHS) Guidelines issued on 30 September 2005. (http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5409a1.htm) or www.who.int PEP during pregnancy If the exposed person is pregnant, the risk of infection and need for PEP should be evaluated as with any other person who has had an exposure to HIV. However, the decision to use any ARV drug during pregnancy should involve a discussion between the woman and her physician regarding the potential benefits and risks to her and the fetus. Data regarding the potential effects of ARV drugs on the developing fetus or neonate are limited. There is a clear contraindication for EFV (first 3 months of pregnancy) and IDV (prenatal). In conclusion, for a female HCP considering PEP, a pregnancy test is recommended if there is any chance that she may be pregnant. It is recommended that pregnant HCP begin the basic two-drug regimen, and if a third drug is needed, NFV is the drug of choice. Side-effects and adherence to PEP Studies of HCP taking PEP have reported more side-effects than PLHA taking ART, most commonly nausea and fatigue. Possible sideeffects occur mainly at the beginning of treatment and include nausea, diarrhoea, muscular pain and headache. The person taking the treatment should be informed that these may occur and should be dissuaded from stopping treatment as most side-effects are mild and transient, though possibly uncomfortable (see Tables 19, 20). Anaemia and/or leucopenia and/or thrombocytopenia may occur during the month of treatment. A complete blood count and liver function tests (transaminases) may be performed at the beginning of treatment (as baseline) and after 4 weeks. In practice and from HCP studies, many HCP do not complete the full course of PEP because of side-effects. Side-effects can be reduced by prescribing regimens that do not include a PI, by giving medications
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to reduce nausea and gastritis, and by educating clients about how to reduce side-effects, e.g. taking PEP medications with food. It is important that side-effects should be explained before initiating PEP so that the symptoms are not confused with symptoms of seroconversion to HIV. Information on adherence and psychological support are essential. More than 95% adherence is important to maximize the efficacy of PEP. Dispensing PEP All clients starting on PEP must take four weeks (28 days) of medication. In all cases, the first dose of PEP should be offered as soon as possible, once the decision to give PEP has been made. HIV testing can be done later and results of the source’s HIV test can follow. As usage of PEP drugs is not frequent and the shelf-life is 1–1.5 years, it is proposed that starter packs for 7 days can be put in the emergency department with instructions to go to a designated clinic/officer within 1–3 days for a complete risk assessment, HIV counselling and testing, and dispensing of medications and management. At least three such kits should be provided in the casualty department. Post-exposure measures against hepatitis B and C Hepatitis B All health staff should be vaccinated against HBV. Unvaccinated persons or persons known to not have responded to a complete hepatitis B vaccine series should receive both hepatitis B immune globulin (HBIG) and hepatitis B vaccine as soon as possible after exposure (preferably <24 hours) if the exposure source is known to be HBsAg-positive. Hepatitis B vaccine may be administered simultaneously with HBIG at a separate injection site.85 Schedule for hepatitis B vaccination Vaccine Engerix-B Recombivax HB Age <20 years ≥20 years ≥ 20 years Dose 10 µg 20 µg 10 µg Volume 0.5 ml 1 ml 1 ml No. of doses 3 3 3 Schedule 0, 1–2, 4 months* 0, 1, 6 months* 0, 1, 6 months
* Double-dose regimen is recommended in the context of HIV infection.
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Unvaccinated persons should receive the hepatitis B vaccine series with the first dose initiated as soon as possible after exposure, preferably <24 hours if the exposure source has an unknown HBsAg status. The vaccine series should be completed using the age-appropriate dose and schedule.85 Hepatitis C There is presently no vaccine available against hepatitis C. There is no post-exposure prophylaxis for HCV disease. Step 5: Laboratory evaluation Step 1: Manage exposure site Step 2: Establish eligibility for PEP Step 5: Laboratory evaluation Step 3: Counsel for PEP Step 4: Prescribe PEP
Provide HIV pre-test counselling
Check immunization status for hepatitis B
Offer HIV, HBV, HBC test
Draw blood to include CBC, liver function tests, pregnancy test, if applicable
Provide HIV post-test counselling
Step 6: Follow up and monitor adherence
The reason for HIV testing soon after an occupational exposure is to establish a “baseline” against which to compare future test results (Table 44). If the worker is HIV-negative at the baseline test, it is in principle possible to prove that subsequent infection identified by follow-up testing is related to the occupational exposure (depending on the
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timing of infection and consideration of other risks or exposures). When offered HIV testing, the exposed person should receive standard pretest counselling according to the national HIV testing and counselling guidelines, and should give informed consent for testing. Confidentiality of the test result must be assured. There are different reasons for possibly delaying HIV testing: the HCP may be unable to give informed consent immediately after the exposure due to anxiety, the exposure occurs outside working hours or in settings where HIV testing is not readily available. The HIV test may be done up to several days after the exposure, with assurance and respect for confidentiality, based on informed consent and with pre- and post-test counselling. Providing PEP should not be delayed if HIV testing is not available. Table 44: Recommended baseline laboratory evaluation Timing Baseline (within 8 days after accidental exposure to blood) In persons taking PEP (standard regimen) Antibodies: HIV, HCV, HBV in unvaccinated HCP Complete blood count Transaminases In persons not taking PEP Antibodies: HIV, HCV, HBV in unvaccinated HCP
HIV RNA testing by polymerase chain reaction (PCR) during PEP has a very poor positive predictive value and should be strongly discouraged. Pregnancy testing should also be available, but its unavailability should not prevent the provision of PEP. Other laboratory testing such as haemoglobin measurement should be available, especially when AZT is used for PEP in areas where anaemia is common. The absence of baseline laboratory testing should not delay the commencement of PEP. Testing for other bloodborne diseases such as syphilis, malaria and kala-azar may also be useful, depending on the nature of risk, symptoms of the source patient, local prevalence and laboratory capacity.
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Step 6: Follow up of an exposed person Step 1: Manage exposure site Step 2: Establish eligibility for PEP Step 6: Follow up and monitor adherence Step 3: Counsel for PEP Step 4: Prescribe PEP Step 5: Laboratory evaluation
Recordkeeping
Follow-up visits for clinical assessment at 2 weeks and hepatitis B vaccination if needed
HIV test at 3 and 6 months
The treating physician should document the findings of steps 1–5 in the patient record and findings from follow-up visits. Whether or not PEP prophylaxis has been started, follow up is indicated to monitor for possible infections and provide psychological support. The exposed person must be monitored for the eventual appearance of signs indicating HIV seroconversion: acute fever, generalized lymphadenopathy, cutaneous eruptions, pharyngitis, non-specific ’flu-like symptoms and ulcers in the mouth or genital area. These symptoms appear in 50–70% of individuals with primary (acute) HIV infection and almost always within 3–6 weeks after exposure. An exposed person should be advised to use precautions (e.g. avoid blood or tissue donations, breastfeeding, unprotected sexual relations or pregnancy) to prevent secondary transmission, especially during the first 6–12 weeks following exposure. Use of condoms is recommended. Counselling for adherence and side-effects should be provided and reinforced at every follow-up visit. Psychological support and mental health counselling are often required.
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Follow-up HIV testing: Exposed persons should be offered HIV testing following national guidlines. A baseline HIV test and testing at 3 months and again at 6 months is recommended. Very few cases of seroconversion after 6 months have been reported. Hence, no further testing is recommended if the HIV test at 6 months is negative. Psychological support: Many people feel anxious after exposure. Every exposed person needs to be informed about the risks and measures that can be taken. This will help to relieve part of the anxiety, but some may require further specialized psychological support.
21
Management of Non-occupational Exposure Including Post-exposure Prophylaxis
21.1 Definition Non-occupational exposure refers to exposure to potential bloodborne infections (HIV, HBV, HCV) outside the work setting. Table 45: Estimated risk for acquisition of HIV by exposure route86 Exposure type (sexual exposure assumes no condom use) Blood transfusion Needle-sharing injecting drug use Receptive anal intercourse Percutaneous needle-stick injury Receptive penile–vaginal intercourse Insertive anal intercourse Insertive penile–vaginal intercourse Risk per 10 000 exposures to an infected source 9000 67 50 30 10 6.5 5
21.2 Situations where non-occupational postexposure prophylaxis (nPEP) may be provided
Unprotected sexual exposure including rape Needle-sharing by IDUs (single event); Injuries from needles discarded in public places with visible blood on them, and87 Human bite injuries.
21.3 Situations where nPEP should not be provided nPEP should not be provided in case of persistent potential exposure to HIV such as discordant sex partners who rarely use condoms, repeated unprotected sex with sex workers or other non-regular partners, and IDUs who often share injecting equipment. Persons who engage in frequent, recurrent, high-risk behaviour should be counselled and provided with appropriate risk-reduction interventions.
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21.4 Evidence for providing nPEP In Sao Paulo, Brazil 180 women presenting within 72 hours of assault were treated for 28 days with AZT and 3TC (for those without mucosal trauma) or AZT, 3TC and IDV (for those with mucosal trauma or those subjected to unprotected anal sex). None of the women seroconverted. However, 4/145 women (2.7%) who were not treated seroconverted.88 Four hundred eighty HIV-negative rape victims in South Africa received AZT and 3TC and were followed up for at least 6 weeks. A woman who was started on AZT + 3TC 96 hours after the assault was the only one who seroconverted.86 In Brazil, nPEP (AZT + 3TC) was offered to 200 homosexual and bisexual men. Among the men who took nPEP, only one seroconverted, while among those who did not, 11 seroconverted.89,90
21.5 Evaluation of persons with potential nonoccupational exposure to HIV This evaluation should include:
HIV status of the person potentially exposed to HIV Timing and characteristics of the most recent exposure Frequency of potential exposures to HIV HIV status of the source if it can be ascertained Concomitant STIs.
21.6 Initiating nPEP The same schedule is recommended as for occupational PEP; commence ARVs as soon as possible after the exposure, within 72 hours, and continue for 28 days. There are no data to support the use of PEP started after 72 hours.
21.7 HIV status of the source When the HIV status of the source is unknown, determine whether the source is available for HIV testing. If the risk associated with the exposure is considered substantial, nPEP can be started pending determination of
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the HIV status of the source and then stopped if the source is determined to be non-infected. When the source is known to be from a group with a high prevalence of HIV infection (e.g. a homosexual or bisexual man, an IDU, or a sex worker), the risk of transmission is increased. In the case of sexual violence, the source person may not be identifiable. Where the HIV status of the source is unknown and cannot be determined, nPEP should be offered following risk evaluation and counselling of the exposed person by a trained HCP. In case of sexual violence the steps for PEP may differ from those of other other non-occupational exposure and are described elsewhere.91 If the source person is known to be HIV-positive, nPEP is indicated and a two-drug regimen should be given unless there is evidence that the source person has a current or past history of ARV use with poor adherence, or is known to have failed first-line ART. A three-drug PEP regimen is recommended in this case.
21.8 ARVs for nPEP The choice of ARVs is the same for both occupational and non-occupati– onal PEP (Table 43).
21.9 Counselling
Assess the extent, frequency and timing of risk exposure. Try to ascertain the HIV status of the source (often unknown). Evaluate for STI syndromes. Assess the need for and offer emergency contraception (“morningafter” pill). Give pre-HIV test counselling. Carry out baseline tests for the following: – HIV – Hepatitis B and C – Swabs and cultures for gonorrhoea and chlamydia, if available – Syphilis (Venereal Disease Research Laboratory [VDRL] and Treponema pallidum haemagglutination [TPHA]) – Pregnancy test (if available) following appropriate counselling.
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Counsel the individual that they must not give blood and must practise safe sex and safe injecting practices and not breastfeed until the outcome is known. Review and give baseline results. Offer hepatitis B vaccination if the individual has not been vaccinated, was known not to have responded to a complete hepatitis B vaccine series or has no antibodies against HBV showing past or current infection. Offer tetanus toxoid vaccination if there are any tears, cuts or abrasions in case of sexual assault. Offer PEP for STIs.
21.10 Emergency contraception91 Emergency contraceptive pills can be used for up to 5 days after unprotected intercourse. However, the sooner they are taken, the more effective they are. Several regimens are available, using levonorgestrel or combined oral contraceptive pills. A second option for emergency contraception is insertion of a copperbearing IUD within 5 days of the rape. This will prevent more than 99% of pregnancies. The IUD may be removed during the woman’s next menstrual period or left in place for continued contraception. If an IUD is inserted, make sure to give full STI treatment as recommended below. If more than 5 days have passed, counsel the woman on the availability of abortion services (in most countries, post-rape abortion is legal). A woman who has been raped should first be offered a pregnancy test to rule out the possibility of a pre-existing pregnancy.
21.11 Presumptive treatment of STIs Another concrete benefit of early medical intervention following rape is the possibility of treating the person for a number of STIs. STI prophylaxis can be started on the same day as emergency contraception, although the doses should be spread out (and taken with food) to reduce sideeffects such as nausea.
Management of non-occupational exposure including post-exposure prophylaxis
109
The incubation periods of different STIs vary from a few days for gonorrhoea and chancroid to weeks or months for syphilis and HIV. Treatment may thus relieve a source of stress, but the decision regarding whether to provide presumptive treatment or wait for the results of STI tests should be made in consultation with the treating physician. Table 46 lists treatment options that are effective whether taken soon after exposure or after the appearance of symptoms. (Women often do not develop symptoms.) Table 46: Treatment of sexually transmitted infections Coverage Option 1 All single dose, highly effective. Choose one from each box (= 3 or 4 drugs) Option 2 Effective substitutes – possible resistance in some areas, or require multiple dosage If patient is pregnant, breastfeeding or under 16 years of age Choose one from each box (= 3 or 4 drugs) Benzathine penicillin [a] 2.4 million units by single intramuscular injection Cefixime 400 mg orally as a single dose, or ceftriaxone 125 mg by intramuscular injection Erythromycin 500 mg orally 4 times a day for 7 days
Syphilis
Benzathine penicillin [a] 2.4 million units by single intramuscular injection Cefixime 400 mg orally as a single dose, or ceftriaxone 125 mg by intramuscular injection Azithromycin 1 g orally as single dose
Doxycycline [b] 100 mg orally twice a day for 14 days (in case of penicillin allergy only) Ciprofloxacin [c] 500 mg orally as a single dose, or spectinomycin 2 g by intramuscular injection Doxycycline [b] 100 mg orally twice a day for 7 days, or tetracycline 500 mg orally 4 times a day for 7 days Tinidazole 2 g [e] orally as a single dose
Gonorrhoea/ chancroid
Chlamydia/ lymphogranuloma venereum
Trichomoniasis
Metronidazole [d] 2 g orally as a single dose
Metronidazole 2 g [d] orally as a single dose, or 400–500 mg 3 times a day for 7 days
Source: Sexually transmitted and other reproductive tract infections. Geneva, WHO, 2005:141–150.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Notes [a] Benzathine penicillin can be omitted if treatment includes either azithromycin 1 g or 14 days of doxycycline, tetracycline or erythromycin, all of which are effective against incubating syphilis. [b] These drugs are contraindicated in pregnant or breastfeeding women. [c] The use of a quinolone should take into consideration the patterns of Neisseria gonorrhoeae resistance, such as in the WHO South-East Asia and Western Pacific Regions. [d] Metronidazole should be avoided in the first trimester of pregnancy. Patients taking metronidazole should be cautioned to avoid alcohol. [e] Patients taking tinidazole should be cautioned to avoid alcohol.
Annex
1
Criteria for HIV-related Clinical Events in Adults and Adolescents Clinical diagnosis Definitive diagnosis
Clinical event Clinical stage 1 Asymptomatic
No HIV-related symptoms reported Not applicable and no signs on examination Persistent generalized Painless enlarged lymph nodes >1 cm, Histology lymphadenopathy in two or more non-contiguous sites (excluding inguinal), in absence of (PGL) known cause and persisting for ? 3 months Clinical stage 2 Moderate Reported unexplained weight loss. In Documented weight loss unexplained weight pregnancy failure to gain weight <10% of body weight loss (<10% of body weight) Recurrent bacterial Symptom complex, e.g. unilateral Laboratory studies where upper respiratory tract face pain with nasal discharge available, e.g. culture of infections (current (sinusitis), painful inflamed eardrum suitable body fluid event plus one or (otitis media), or tonsillo-pharyngitis more in the past sixwithout features of viral infection (e.g. month period) coryza, cough) Herpes zoster Painful vesicular rash in dermatomal Clinical diagnosis distribution of a nerve supply; does not cross midline Angular cheilitis Splits or cracks at the angle of the Clinical diagnosis mouth not due to iron or vitamin deficiency, and usually responding to antifungal treatment Recurrent oral Aphthous ulceration, typically painful Clinical diagnosis ulcerations (two or with a halo of inflammation and a more episodes in the yellow-grey pseudomembrane past six months) Papular pruritic Pruritic papular eruptions lesions, Clinical diagnosis eruptions (PPE) often with marked post-inflammatory hyperpigmentation Seborrhoeic dermatitis Itchy, scaly skin condition, particularly affecting hairy areas (scalp, axillae, upper trunk and groin) Clinical diagnosis
112 Clinical event
Management of HIV infection and antiretroviral therapy in adults and adolescents
Clinical diagnosis Paronychia (painful, red and swollen nail bed) or onycholysis (separation of the nail from the nail bed) of the fingernails (white discoloration – especially involving proximal part of nail plate – with thickening and separation of nail from nail bed) Reported unexplained weight loss (>10% of body weight or body mass index <18.5). In pregnancy weight loss may be masked Chronic diarrhoea (loose or watery stools three or more times daily) reported for longer than one month
Definitive diagnosis Fungal culture of nail/nail plate material
Fungal nail infections
Clinical stage 3 Severe unexplained weight loss (>10% of body weight) Unexplained chronic diarrhoea for longer than one month
Documented loss of >10% of body weight
Unexplained persistent fever (intermittent or constant and lasting for longer than one month)
Oral candidiasis
Oral hairy leukoplakia (OHL)
Not required but confirmed if three or more stools observed and documented as unformed, and two or more stool tests reveal no pathogens Reports of fever or night sweats Documented fever for more than one month, either >37.6 °C with negative intermittent or constant with reported blood culture, negative lack of response to antibiotics or Ziehl–Neelsen (ZN) stain, antimalarials, without other obvious negative malaria slide, foci of disease reported or found normal or unchanged on examination. Malaria must be chest X-ray (CXR) and no excluded in malarial areas other obvious focus of infection Persistent or recurring creamy-white Clinical diagnosis curd-like plaques which can be scraped off (pseudomembranous), or red patches on tongue, palate or lining of mouth, usually painful or tender (erythematous form) Fine white, small, linear or corrugated Clinical diagnosis lesions on lateral borders of the tongue, which do not scrape off
Annex 1: Criteria for HIV-related clinical events in adults and adolescents
113 Definitive diagnosis Isolation of M. tuberculosis on sputum culture or histology of lung biopsy (together with compatible symptoms)
Clinical event Pulmonary TB (current)
Clinical diagnosis Chronic symptoms: (lasting ≥2–3 weeks) cough, haemoptysis, shortness of breath, chest pain, weight loss, fever, night sweats, PLUS either positive sputum smear OR
Negative sputum smear AND compatible chest radiograph (including but not restricted to upper lobe infiltrates, cavitation, pulmonary fibrosis and shrinkage). No evidence of extrapulmonary disease Severe bacterial Fever accompanied by specific infection (e.g. symptoms or signs that localize pneumonia, infection, and response to appropriate meningitis, empyema, antibiotic pyomyositis, bone or joint infection, bacteraemia, severe pelvic inflammatory disease ) Acute necrotizing Severe pain, ulcerated gingival ulcerative gingivitis or papillae, loosening of teeth, necrotizing ulcerative spontaneous bleeding, bad odour and periodontitis rapid loss of bone and/or soft tissue Clinical stage 4 HIV wasting syndrome Reported unexplained weight loss (>10% body weight), with obvious wasting or body mass index <18.5 PLUS EITHER
Isolation of bacteria from appropriate clinical specimens (i.e. usually sterile sites)
Clinical diagnosis
Documented weight loss >10% of body weight; PLUS
Two or more unformed Unexplained chronic diarrhoea (loose stools negative for or watery stools three or more times pathogens daily) reported for longer than one OR month Documented temperature OR >37.60C with no other Reports of fever or night sweats cause of disease, negative for more than one month without blood culture, negative other cause and lack of response to malaria slide and normal antibiotics or antimalarials. Malaria or unchanged CXR must be excluded in malarial areas
114 Clinical event Pneumocystis pneumonia
Management of HIV infection and antiretroviral therapy in adults and adolescents
Clinical diagnosis Dyspnoea on exertion or nonproductive cough of recent onset (within the past 3 months), tachypnoea and fever; AND Chest X-ray evidence of diffuse bilateral interstitial infiltrates AND
Definitive diagnosis Cytology or immunofluorescent microscopy of induced sputum or bronchoalveolar lavage (BAL), or histology of lung tissue
No evidence of a bacterial pneumonia. Bilateral crepitations on auscultation with or without reduced air entry Recurrent bacterial Current episode plus one or more pneumonia previous episodes in the past 6 (this episode plus one months. Acute onset (<2 weeks) of symptoms (e.g. fever, cough, or more episodes in dyspnoea and chest pain) PLUS new the past 6 months) consolidation on clinical examination or CXR. Response to antibiotics Chronic herpes Painful, progressive anogenital or simplex virus (HSV) orolabial ulceration; lesions caused by infection (orolabial, recurrent HSV infection and reported genital or anorectal) for more than one month. History of more than one of previous episodes. Visceral HSV month’s duration requires definitive diagnosis Oesophageal Recent onset of retrosternal pain or candidiasis difficulty in swallowing (food and fluids) together with oral candidiasis Extrapulmonary TB (EPTB)
Positive culture or antigen test of a compatible organism
Positive culture or DNA (by PCR) of HSV or compatible cytology/ histology
Macroscopic appearance at endoscopy or bronchoscopy, or by microscopy/histology Systemic illness (e.g. fever, night M. tuberculosis isolation sweats, weakness and weight loss). or compatible histology Other evidence of extrapulmonary or from appropriate site, disseminated TB varies by site: pleural, together with compatible pericardial, peritoneal involvement, symptoms/signs (if culmeningitis, mediastinal or abdominal ture/histology is from lymphadenopathy, osteitis respiratory specimen then must have other evidence Miliary TB: diffuse, uniformly distributed, small miliary shadows or of extrapulmonary disease) micronodules on CXR Discrete cervical lymph node M. tuberculosis infection is usually considered a less severe form of EPTB Typical appearance in skin or oropharynx of persistent, initially flat patches with a pink or bloodbruise colour, skin lesions that usually develop into violaceous plaques or nodules
Kaposi sarcoma
Macroscopic appearance at endoscopy or bronchoscopy, or by histology
Annex 1: Criteria for HIV-related clinical events in adults and adolescents
115 Definitive diagnosis Positive serum Toxoplasma antibody AND (if available) single/ multiple intracranial mass lesion on neuro-imaging Diagnosis of exclusion: and (if available) neuroimaging (CT or MRI)
Clinical event CNS toxoplasmosis
Clinical diagnosis Recent onset of a focal neurological abnormality or reduced level of consciousness AND response within 10 days to specific therapy
HIV encephalopathy
Clinical finding of disabling cognitive and/or motor dysfunction interfering with activities of daily living, progressing over weeks or months in the absence of a concurrent illness or condition other than HIV infection which might explain the findings Extrapulmonary Meningitis: usually subacute fever cryptococcosis with increasingly severe headache, (including meningitis) meningism, confusion, behavioural changes that respond to cryptococcal therapy Disseminated non-tuberculous mycobacterial infection No presumptive clinical diagnosis
Progressive multifocal No presumptive clinical diagnosis leukoencephalopathy (PML)
Cryptosporidiosis No presumptive clinical diagnosis (with diarrhoea lasting for more than one month) Chronic isosporiasis No presumptive clinical diagnosis Disseminated mycosis No presumptive clinical diagnosis (coccidioidomycosis, histoplasmosis)
Isolation of Cryptococcus neoformans from extrapulmonary site or positive cryptococcal antigen test (CRAG) on CSF/blood Diagnosed by finding atypical mycobacterial species from stool, blood, body fluid or other body tissue, excluding lung Progressive neurological disorder (cognitive dysfunction, gait/speech disorder, visual loss, limb weakness and cranial nerve palsies) together with hypodense white matter lesions on neuroimaging or positive polyomavirus (JCV) PCR on CSF Cysts identified on modified ZN microscopic examination of unformed stool Identification of Isospora Histology, antigen detection or culture from clinical specimen or blood culture
116 Clinical event
Management of HIV infection and antiretroviral therapy in adults and adolescents
Clinical diagnosis No presumptive clinical diagnosis
Definitive diagnosis Blood culture
Recurrent non-typhoid Salmonella bacteraemia Lymphoma (cerebral or B cell non-Hodgkin) or other solid HIVassociated tumours Invasive cervical carcinoma Visceral leishmaniasis
No presumptive clinical diagnosis
No presumptive clinical diagnosis No presumptive clinical diagnosis
Histology of relevant specimen or neuroimaging techniques for CNS tumours Histology or cytology Diagnosed by histology (amastigotes visualized) or culture from any appropriate clinical specimen Renal biopsy Cardiomegaly and evidence of poor left ventricular function confirmed by echocardiography
HIV-associated nephropathy HIV-associated cardiomyopathy
No presumptive clinical diagnosis No presumptive clinical diagnosis
Source: 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, 2006.
Annex
2
Dosages of Antiretroviral Drugs for Adults and Adolescents Dose 300 mg twice daily or 600 mg once daily 250 mg or 300 mg twice daily [a] 200 mg once daily >60 kg: 400 mg once daily <60 kg: 250 mg once daily 150 mg twice daily or 300 mg once daily 30 mg twice daily irrespective of weight 300 mg once daily 600 mg once daily 200 mg once daily for 14 days, followed by 200 mg twice daily 300 mg/100 mg once daily 700 mg/100 mg twice daily 800 mg/100 mg twice daily Capsule Three capsules twice daily lopinavir 133.3 mg + (400/100 mg twice daily) ritonavir 33.3 mg four capsules twice daily when combined with EFV or NVP (533/133.33 mg twice daily)
Generic name Nucleoside RTIs (NsRTIs) Abacavir (ABC) Zidovudine (AZT) Emtricitabine (FTC) Didanosine (ddI) [b] buffered tablets or enteric-coated (EC) capsules Lamivudine (3TC) Stavudine (d4T) Nucleotide RTIs (NtRTIs) Tenofovir (TDF) Non-nucleoside RTIs (NNRTIs) Efavirenz (EFV) Nevirapine (NVP) Protease inhibitors (PIs) Atazanavir/ritonavir (ATV/r) [c] Fos-amprenavir/ritonavir (FPV/r) Indinavir/ritonavir (IDV/r) [d]
Lopinavir/ritonavir (LPV/r) [e] Tablet (heat-stable formulation) lopinavir 200 mg + ritonavir 50 mg Nelfinavir (NFV) Saquinavir/ritonavir (SQV/r) [e] Darunavir (DRV) 1250 mg twice daily 1000/100 mg twice daily 600/100 mg twice daily Two tablets twice daily (400/100 mg twice daily) Three tablets twice daily when combined with EFV or NVP (600/150 mg twice daily)
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Notes [a] AZT 250 mg 2 times per day is included as an option in the 2006 WHO guidelines for adult ART and is available as the fixed-dose combination of AZT 250 mg/3TC 150 mg/NVP 200 mg (Gpovir-Z). New data from Thailand may support a dose of 200 mg 2 times per day in the Thai population.92 [b] The dose of ddI should be adjusted when co-administered with TDF. If the weight is >60 kg, the recommended dose is 250 mg once daily. If the weight is <60 kg, there are no data to make a recommendation. (Some preliminary pharmacokinetic [PK] studies suggest 125–200 mg once daily.93) Buffered ddI needs to be taken on an empty stomach. [c] In resource-limited settings, PIs are not recommended in first-line regimens. If for some special reason such as intolerance to all NNRTIs ATV is given to a treatment-naive patient, the dose is 200 mg once daily (without RTV). [d] Other dosage regimens in clinical use are 600 mg/100 mg,94 and 400 mg/100 mg.95 [e] See the section on TB for TB-specific dose modifications of LPV/r and SQV/r.
Annex
3
Storage of Antiretroviral Drugs Storage requirements Room temperature Room temperature Room temperature for tablets and capsules Reconstituted buffered powder should be refrigerated; oral solution for children is stable after reconstitution for 30 days if refrigerated.
Generic name Nucleoside RTIs (NsRTIs) Abacavir (ABC) Zidovudine (AZT) Didanosine (ddI)
Emtricatabine (FTC) Lamivudine (3TC) Stavudine (d4T)
Room temperature Room temperature Room temperature. After reconstitution, oral solution should be kept refrigerated; if so, it is stable for 30 days. Room temperature Room temperature Room temperature
Stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP) Zidovudine (AZT) + lamivudine (3TC) + abacavir (ABC) Zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP) Nucleotide RTIs (NtRTIs) Tenofovir (TDF) Non-nucleoside RTIs (NNRTIs) Efavirenz (EFV) Nevirapine (NVP) Protease inhibitors (PIs) Atazanavir (ATV) Indinavir (IDV) Fos-amprenavir (FPV) Lopinavir/ritonavir (LPV/r) capsules Lopinavir/ritonavir (LPV/r) heat-stable tablets Nelfinavir (NFV)
Room temperature Room temperature Room temperature Room temperature Room temperature Room temperature Refrigerate for long-term storage At room temperature: stable for 30 days Room temperature Room temperature
120 Generic name Ritonavir (RTV)
Management of HIV infection and antiretroviral therapy in adults and adolescents
Storage requirements Refrigerate capsules until dispensed Stable at room temperature for 30 days
Room temperature for oral solution (do not refrigerate) Saquinavir – hard gel capsules (SQVhgc) Room temperature Darunavir (DRV) Room temperature Room temperature is defined as 15–30°C. Refrigeration is defined as 2–8°C.
ARV
NVP
EFV
LPV/r
NFV
SQV
Annex
4
Antimycobacterials Rifampicin ↓NVP level by 20– 58%. Virological consequences are uncertain; the potential for additive hepatotoxicity exists. Careful monitoring is required during co-administration. Rifabutin ↓NVP level by 16% No dose adjustment ↓EFV level by 25% Standard dosing of EFV recommended ↓LPV AUC by ↓NFV level by 82% 75% Should not be coShould not be co- administered administered ↓SQV level by 84% Severe liver impairment with co-administration reported Should not be coadministered
Drugs that Interact with Antiretroviral Therapy
EFV level unchanged; rifabutin level ↓ 35% Dose: ↑rifabutin dose to 450–600 mg once daily or 600 mg thrice weekly EFV: Standard
Rifabutin AUC ↑ 3-fold ↓ rifabutin dose to 150 mg once daily or thrice weekly LPV/r: Standard
↓NFV level by 82% Levels: ↓SQV by Should not be co- 40% administered Contraindicated unless SQV/RTV Dose: Rifabutin 150 mg once daily or thrice weekly
122
ARV ↓Clarithromycin level by 39% Monitor for efficacy or use alternative drugs ↑Clarithromycin No data AUC by 75%, adjust clarithromycin dose if renal impairment Without RTV, ↑ clarithromycin level by 45%, ↑SQV level by 177% RTV can ↑ clarithromycin level by 75% No clarithromycin dose adjustment needed for unboosted SQV. For boosted SQV if renal impairment – no data
NVP
EFV
LPV/r
NFV
SQV
Clarithromycin
None
Antifungals Ketoconazole No significant changes in ketoconazole or EFV levels
↑Ketoconazole level by 63% ↑NVP level by 15–30% Co-administration not recommended
↑LPV AUC No dose adjustment ↑Ketoconazole level necessary 3-fold Do not exceed 200 mg/day ketoconazole
Management of HIV infection and antiretroviral therapy in adults and adolescents
Fluconazole
↑NVP Cmax, AUC, Cmin by 100% No change in fluconazole level Possible increase in hepatotoxicity with co-administration; requires monitoring of NVP toxicity No data
No data
No data
↑SQV level 3-fold No dose adjustment necessary if given unboosted For RTV-boosted SQV – no data (RTV treatment dose can increase ketoconazole level 3-fold) No data
ARV No data ↑Itraconazole level Do not exceed 200 mg/day itraconazole No data but potential for bidirectional inhibition, monitor toxicities Bidirectional interaction has been observed. May need to decrease itraconazole dose. Consider monitoring SQV level (especially if given unboosted with RTV) No data for unboosted SQV RTV treatment dose can ↓level of ethinylestradiol by 41% Unknown, but may markedly ↓ SQV levels Monitor anticonvulsant levels and consider obtaining SQV level
NVP
EFV
LPV/r
NFV
SQV
Itraconazole
No data
Annex 4: Drugs that interact with antiretroviral therapy
↑Ethinylestradiol level by 37%. Use alternative or additional methods of contraception Unknown. Use with caution
Oral contraceptives Ethinylestradiol ↓Ethinylestradiol level by 20% Use alternative or additional methods of contraception Anticonvulsants Carbamazepine Use with caution. Phenytoin One case report showed low EFV concentrations with phenytoin ↓Ethinylestradiol level by 42% Use alternative or additional methods of contraception ↓Levels of norethindrone by 18% and ethinylestradiol by 47% Unknown, but may decrease NFV levels substantially Monitor anticonvulsant levels and virological response
123
Many possible interactions: Carbamazepine: ↑ levels when coadministered with RTV. Use with caution. Monitor anticonvulsant levels. Phenytoin: ↓levels of LPV, RTV and↓ levels of phenytoin when administered together Avoid concomitant use or monitor LPV level
124
ARV Potential large ↑ in statin level Avoid concomitant use ↑Simvastatin AUC by 505% Potential large ↑ in lovastatin AUC Avoid concomitant use Potential large ↑ in statin level Avoid concomitant use
NVP
EFV
LPV/r
NFV
SQV
Lipid-lowering agents Simvastatin, No data lovastatin
Atorvastatin
No data
↑Atorvastatin AUC 5.88-fold Use lowest possible starting dose with careful monitoring
↑Atorvastatin AUC by 74% Use lowest possible starting dose with careful monitoring
↑Atorvastatin level by 450% when used as SQV/RTV Use lowest possible starting dose with careful monitoring
Pravastatin
↑Pravastatin AUC by No data ↓Pravastatin level by 33% 50% No dose adjustment No dose adjustment needed needed Proton-pump inhibitors. All the PIs and EFV can ↑ levels of cisapride and non-sedating antihistamines (astemizole, terfenedine), which can cause cardiac toxicity. Co-administration is not recommended.
No data
↓ Simvastatin level by 58% EFV level unchanged Adjust simvastatin dose according to lipid response, do not exceed the maximum recommended dose ↓Atorvastatin AUC by 43% EFV level unchanged Adjust atorvastatin dose according to lipid response, do not exceed maximum recommended dose No data
Management of HIV infection and antiretroviral therapy in adults and adolescents
AUC area under the curve Cmax maximum concentration Cmin minimum concentration Note: Concomitant use of fluticasone with RTV results in significant reduction of serum cortisol concentrations. Co-administration of fluticasone with RTV or any RTV-boosted PI regimen is not recommended unless the potential benefit outweighs the risk of systemic corticosteroid side-effects. (Adapted from Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents, 4 May 2006. www.aidsinfo.nih.gov)
Annex
5
Drug Interactions between Opiates and Antiretrovirals and other Drugs Effect on methadone None reported
Interaction between methadone and antiretroviral drugs ARV NRTIs Didanosine (ddI) Concentrations decreased by 60% when buffered tablet taken, but not with EC capsule Avoid use of ddI buffered tablets Use EC capsule if available
Effect on ARV
Comments
No dosage Buffered tablet adjustments Enteric-coated (EC) capsule necessary NNRTIs Decrease in methadone level by up to 60% Efavirenz (EFV) Symptoms of opiate withdrawal common Decrease in methadone level by up to 50% Nevirapine (NVP) Symptoms of opiate withdrawal common PIs Lopinavir/ritonavir (LPV/r) Decrease in methadone level by up to 50% Decrease in methadone level by 37%
Unknown
Observe for symptoms of methadone withdrawal and increase dosage as necessary
None reported
Considerable increase in methadone dose up to 50% commonly required
None reported
Ritonavir (RTV)
Dose adjustment may be required
May require increase in methadone dose Studies limited Observe for signs of methadone withdrawal
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Interactions between methadone and other drugs Drug Rifampicin
Indication TB
Effect on methadone Decrease in methadone level by 33–68% and may induce symptoms of opiate withdrawal Increase in methadone levels by 26%
Comments Increase in methadone dose required if withdrawal symptoms present Associated with cardiac rhythm disturbances, caution when used with methadone
Sertraline
Antidepressant
Carbamazepine and phenytoin
Anticonvulsants
Decrease in methadone levels Increase in methadone dose and may cause symptoms of may be required methadone withdrawal Consider using sodium valproate as an alternative
Interactions between buprenorphine and antiretroviral drugs ARV Effect on buprenorphine Effect on ARV Comments
NRTIs/ NNRTIs No significant interactions reported PIs Inhibition of Ritonavir (RTV) buprenorphine None reported metabolism resulting in a clinically significant Atazanavir (ATV) increase in buprenorphine levels
Buprenorphine dose may need to be reduced
Opportunistic infection Diagnosis Treatment
Clinical features
Annex
6
Preferred treatment Co-trimoxazole (trimethoprim– sulfamethoxazole, TMP 15 mg plus SMZ 75 mg/kg daily) in 4 divided doses, orally or intravenously, for 21 days
Dry cough
Co-trimoxazole should be given IV in severely ill patients. Patients can switch to oral co-trimoxazole once they improve clinically
Shortness of breath
Fever
Pneumocystis jiroveci pneumonia (PCP) (previously known as Pneumocystis carinii pneumonia)
Night sweats
Subacute presentation over 1–2 months
Chest X-ray is abnormal in more than 90% cases of PCP, Oral doses are 480 mg, 2 tablets 4 times daily and typically shows (patient <40 kg) and 3 tablets 4 times daily bilateral interstitial (patient >40 kg) infiltrates Alternative treatment Clindamycin 600 mg IV or 450 mg orally 3 times per day + primaquine 15 mg orally once daily for 21 days if allergy to sulfonamides Prednisolone 20 mg 4 times daily, with slow reduction of the dose over 7–10 days, depending on response to therapy, is recommended for severely ill patients
Clinical Diagnosis and Management of Common Opportunistic Infections
128
Opportunistic infection Diagnosis Typical clinical appearance on physical examination Nystatin pessaries 100 000 IU, to be sucked every 4 hours for 7 days or Nystatin oral suspension 100 000 IU, three times a day for 7 days or
Clinical features
Treatment
Oral candidiasis
White mucosal plaques ± erythema in the oral cavity
Candidiasis
Microscopic demonstration Amphotericin B oral suspension, 1 spoon three times of psuedohyphae in a day for 7 days or potassium hydroxide (KOH) Miconazole 2% oral gel, 2 spoons 3 times daily for 7 preparation days
Oesophageal candidiasis
Cryptococcosis
Typical clinical presentation and response Fluconazole 200 mg daily for 14 days or to antifungal therapy Dysphagia Itraconazole 400 mg daily for 14 days or Endoscopy should be done Ketoconazole 200 mg daily for 14 days ± retrosternal chest pain if available Preferred treatment Occipital headache, meningeal irritation, photophobia, neck IV amphotericin B (0.7 mg/kg/day) for 2 weeks stiffness or raised intracranial followed by itraconazole 200 mg 2 times daily or Raised intracranial pressure fluconazole 400 mg daily for 8 weeks pressure and on lumbar puncture, Fever Alternative treatment protein in CSF Changes in mental state Fluconazole 400 mg daily for 8–12 weeks Organisms demonstrated Maintenance therapy Itraconazole 200 mg/day or fluconazole 200 mg/day from CSF or skin lesions with India-ink stain and on light microscopy
Management of HIV infection and antiretroviral therapy in adults and adolescents
Disseminated disease with papulonecrotic skin lesions resembling molluscum contagiosum associated with fever and pulmonary infiltrates
Opportunistic infection Diagnosis Preferred treatment Microscopy of skin biopsy or lymph node aspirate Organism demonstrated with Wright or Cotton blue Maintenance therapy stain Itraconazole 400 mg daily IV amphotericin B (0.7mg/kg daily) for 2 weeks followed by itraconazole 400 mg orally daily for 8–10 weeks
Clinical features
Treatment
Penicilliosis
Papulonecrotic skin lesions associated with systemic features of fever, lung involvement, cough, weight loss, anaemia and lymphadenopathy
70% of patients with disseminated Penicillium marneffei infection will have skin lesions Preferred treatment Focal neurological signs
Headache
Drowsiness
Cerebral toxoplasmosis
Fever
Focal neurological abnormality
Annex 6: Clinical diagnosis and management of common opportunistic infections
Seizures
Pyrimethamine loading dose 75–100 mg, then 25–50 mg daily plus sulfadiazine, 4 g daily in 4 divided Single or multiple ringdoses enhancing lesions on CT (if Folic acid 15 mg every second day if available available) Treat for 6 weeks Response to presumptive treatment can be used to Maintenance therapy support the diagnosis Pyrimethamine 25 mg daily plus sulfadiazine, 2 g daily in 4 divided doses Usually self-limiting and may not require treatment Typical clinical appearance Local care of the lesion, such as with gentian violet and chlorhexidine If indicated, acyclovir 200–400 mg 5 times daily for 7 days can be given
Herpes simplex virus (HSV) infection
Clusters of typical blisters, usually in genital area or face
Systemic involvement (such as HSV oesophagitis, encephalitis) is possible
129
130
Opportunistic infection Diagnosis Treatment
Clinical features
Herpes zoster
Typical painful blisters in clusters along dermatomes Can involve the eye Clinical appearance Sputum examination for AFB Chest X-ray Classic chest X-ray pattern Upper lobe infiltrates, cavitation Atypical pattern Bilateral interstitial infiltrates Pleural effusion Pleural tap for AFB
Local care of the lesion, such as with gentian violet and chlorhexidine. Acyclovir 800 mg 5 times daily orally for 7 days, commenced within 72 hours of onset of blisters. Famciclovir and valaciclovir are alternatives. Acyclovir ointment applied in the eye every 4 hours for ophthalmic herpes zoster
Pulmonary TB
Cough, fever, weight loss, fatigue
Tuberculosis
Treat according to national TB guidelines. For WHO recommendations see Annex 7
Extrapulmonary TB
Enlarged lymph nodes or spleen
Management of HIV infection and antiretroviral therapy in adults and adolescents
CNS or GI symptoms
Unilateral nodes increasing in size, matted nodes, fluctuant nodes, fever, weight loss, splenomegaly, diarrhoea and abdominal pain
Opportunistic infection Diagnosis Preferred treatment Azithromycin 500–600 mg once a day, or clarithromycin 500 mg twice a day plus ethambutol 15 mg/kg/day plus rifabutin 300 g once a day Isolation of organism from blood or other sites Unexplained anaemia Maintenance therapy Clarithromycin 500 mg twice a day or azithromycin 500 mg once a day plus ethambutol 15 mg/kg once a day The condition may resolve with ART
Clinical features
Treatment
Mycobacterium avium complex (MAC) disease
Chronic or recurrent fever Weight loss Fatigue
Chronic diarrhoea Stool specimen stained with modified AFB stain
Cryptosporidiosis
Cramps and vomiting
ART is the preferred treatment
Annex 6: Clinical diagnosis and management of common opportunistic infections
Right upper quadrant pain
131
Annex
7
Tuberculosis Case Definitions and Treatment
1. Case definitions
TB suspect. Any person who presents with symptoms or signs suggestive of TB, in particular, cough of long duration (>2–3 weeks). Case of TB. A patient in whom TB has been bacteriologically confirmed or diagnosed by a clinician. Any person given treatment for TB should be recorded as a case. Incomplete “trial” TB treatment should not be used as a method for diagnosis. Definite case of TB. A patient with two sputum smears positive for AFB. In countries where culture is routinely available, a patient with a positive culture for Mycobacterium tuberculosis complex is also considered a “definite” case.
2. Site of TB disease (pulmonary and extrapulmonary) In general, recommended treatment regimens are similar irrespective of site. The importance of defining the site is primarily for recording and reporting purposes. Pulmonary TB (PTB) refers to disease involving the lung parenchyma. Therefore, tuberculous intrathoracic lymphadenopathy (mediastinal and/or hilar) or tuberculous pleural effusion, without radiographic abnormalities in the lungs, constitutes a case of extrapulmonary TB (EPTB). A patient with both PTB and EPTB should be classified as a case of PTB. Extrapulmonary TB (EPTB) refers to TB of organs other than the lungs, e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, meninges. Diagnosis should be based on one culture-positive specimen, or histological or strong clinical evidence consistent with active EPTB, followed by a decision by a clinician to treat with a full course of TB chemotherapy. The definition of a case with EPTB with several sites affected depends on the site representing the most severe form of the disease.
Annex 7: Tuberculosis case definitions and treatment
133
Pulmonary TB, sputum smear-positive (PTB+) a. Two or more initial sputum smear examinations positive for AFB, or b. One sputum smear examination positive for AFB plus radiographic abnormalities consistent with active PTB as determined by a clinician, or c. One sputum smear positive for AFB plus sputum culture positive for M. tuberculosis. Pulmonary TB, sputum smear-negative (PTB–) a. At least two negative sputum specimens for AFB, and b. Radiographic abnormalities consistent with active TB, and c. Decision by a clinician to treat with a full course of anti-TB chemotherapy, or d. Sputum smear negative for AFB but culture positive for M. tuberculosis. 3. First-line anti-TB drugs First-line anti-TB drugs Mode of action Potency Recommended dose (mg/kg of body weight) Daily Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Streptomycin (S) Ethambutol (E) Bactericidal Bactericidal Bactericidal Bactericidal Bactericidal High High Low Low Low 5 10 25 15 15 Intermittent (3 times a week) 10 10 25 15 30
Letters in parentheses are the standard abbreviations of the names of the drugs.
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Management of HIV infection and antiretroviral therapy in adults and adolescents
4. Possible alternative treatment regimens for each TB treatment category TB Type of TB patient diagnostic category I
Alternative treatment regimens Initial phase (daily Continuation or 3 times per phase (daily or 3 week) [ a] times per week) 4 HR or 6 HE daily [c]
II
New smear-positive PTB; 2 HRZE [b] new smear-negative PTB with extensive parenchymal involvement; severe concomitant HIV disease or severe forms of EPTB Previously treated sputum 2 HRZES/1 HRZE smear-positive PTB: Relapse Treatment failure [d] Treatment after interruption New smear-negative PTB (other than in Category I); less severe forms of EPTB Chronic and multidrugresistant (MDR) TB cases (still sputum-positive after supervised re-treatment) [f ] 2 HRZE [e]
5 HRE
III
4 HR or 6 HE daily [c]
IV
Specially designed standardized or individualized regimens are suggested for this category
In the standard code for TB treatment regimens, each anti-TB drug has an abbreviation: streptomycin (S), isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). A regimen consists of two phases. [a] [b] Direct observation of drug intake is required during the initial phase of treatment in smearpositive cases, and always in treatment that includes rifampicin. Streptomycin (provided that sterile syringes and needles, and sharps disposal are available) may be used instead of ethambutol. In meningeal TB, ethambutol should be replaced by streptomycin. This regimen may be associated with a higher rate of treatment failure and relapse compared with the six-month regimen with rifampicin in the continuation phase. Whenever possible, drug sensitivity testing is recommended before prescribing Category II treatment in failure cases. It is recommended that patients with proven MDR-TB use Category IV regimens. Ethambutol may be omitted during the initial phase of treatment for patients with noncavitary, smear-negative PTB who are known to be HIV-negative, patients known to be infected with fully drug-susceptible bacilli, and young children with primary TB. Contacts of patients with culture-proven MDR-TB should be considered for early culture and sensitivity testing.
[c] [d]
[e]
[f ]
Infection
Clinical features
Diagnosis
Treatment
Annex
8
Clinical
1. Pruritic (itchy) rashes Eosinophilic Erythematous, pruritic, follicular folliculitis papules/pustules on face, upper trunk, upper arms, intense itching; hyperpigmented area after healing Pruritic Hyperpigmented, hyperkeratotic papular papules and nodules which are often eruptions symmetrically distributed on the (PPE)* arms, legs, lower back, buttocks Clinical
Scabies
Clinical Diagnosis and Management of Skin Conditions
Norwegian scabies
Rash and excoriations on torso; burrows in web spaces and wrist; face spared Extensive crusting (psoriasis-like lesions) with thick, hyperkeratotic scales on the elbows, knees, palms and soles
Microscopy of skin scrapings KOH or mineral oil preparations
Treat mild disease with topical steroids and oral antihistamines.96 Treat moderate-to-severe disease with oral itraconazole, isotretinoin or phototherapy. Treatment includes mild topical steroids and systemic antihistamines to relieve the itching that often accompanies this condition. If secondary impetigo occurs, topical or systemic antibiotics may be needed. The condition improves with immune recovery on ART but scarring from old lesions may be permanent. Gammabenzene hexachloride once a week for 2–3 weeks or until the lesions have cleared OR Permethrin cream 5%: Apply from chin to toes and take a shower 10–12 hours later; repeat after 1 week OR 25% benzylbenzoate solution:97 Apply the lotion from head to toe. The application is left to dry on the skin and then repeated the next day. Treatment should be repeated weekly until all lesions have cleared. Itching can be relieved by taking chlorpheniramine 4 mg 3–4 tablets/day AND Clothes and bedding should also be washed and kept separately for 3 days to prevent re-infestation. Household contacts should be treated. After treatment, all the clothes and bed linen should be washed and dried.
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Infection
Clinical features
Diagnosis
Treatment
Scabies (contd.)
Xerosis
Dry and rough skin, sometimes with fine cracks
Clinical
Household and other close contacts require the same treatment. In severe cases, ivermectin (if available) administered in a single oral dose of 200 µg/kg may be considered.98 A moisturizing skin lotion can be used to relieve dryness and antihistamines for itching (chlorpheniramine 4 mg 3 times per day or hydroxyzine 10 mg 2 times per day). The condition improves with immune restoration on ART.99 No specific treatment is indicated for the rash or for primary HIV infection. Patient counselling, education and behaviour modification are necessary.
2. Erythematous rashes Primary HIV Generalized maculopapular rash usually infection* with fever and systemic symptoms
Management of HIV infection and antiretroviral therapy in adults and adolescents
Drug reaction
Generalized, erythematous, pruritic rash with or without fever and signs of hepatotoxicity. Severe drug reactions (Stevens–Johnson syndrome) result in blistering of skin and/or mucous membranes Typically in the first days to weeks of commencing the new drug
Serology for HIV RNA or HIV DNA May be negative in early primary HIV infection Clinical
Stop the causative drug. Give antihistamines and topical moisturizing creams. Hospitalization with cardiorespiratory support may be needed for patients with Stevens–Johnson syndrome. Most experts recommend the use of short-course systemic steroids in cases of severe drug reactions. Start with prednisone 0.5 mg/kg per day, and reduce the dose over 5–10 days.
Infection Clinical Care of the local lesion with gentian violet and chlorhexidine. Acyclovir 800 mg 5 times daily for 7 days should be started within 72 hours of onset of the blisters. Famciclovir and valaciclovir are alternative drugs. For ophthalmic herpes zoster, acyclovir ointment can be applied in the eye every 4 hours. Pain is managed with paracetamol 1 g 6-hourly; stronger analgesics can be used if necessary. Amitriptyline 25–50 mg before bedtime is useful for the control of the neuropathic pain associated with herpes zoster and for postherpetic neuralgia, which may persist for months after an episode of herpes zoster. Clinical Care of the local lesion, such as wet compresses for 15 minutes with Burow solution 4–5 times/day or gentian violet or chlorhexidine. If available, give acyclovir 200–400 mg 5 times daily for 7 days. In case of frequent recurrences, long-term suppressive therapy with acyclovir 400 mg 2 times per day may be necessary. Secondary prophylaxis or long-term suppressive therapy with acyclovir 400 mg 2 times per day may be necessary for cases with frequent recurrences. In immunosuppressed patients herpes simplex can be chronic and invasive (e.g. oesophagitis, encephalitis). An alternative is famciclovir 500 mg 2 times per day for 7 days followed by suppressive therapy with 250 mg once daily. In immunosuppressed patients herpes simplex can be chronic and invasive (e.g. oesophagitis, encephalitis).
Clinical features
Diagnosis
Treatment
3. Blisters, sores, nodules and pustules Herpes zoster* Typical painful blisters in clusters along dermatomes. Can involve the eye. HIV infection should be suspected if lesions are multidermatomal or episodes are recurrent. Prodromal symptoms include paraesthesiae and/or pain in the dermatome a few days before the rash appears. Fever, malaise and headache may precede the outbreak of blisters.
Annex 8: Clinical diagnosis and management of skin conditions
Herpes simplex
Typical blisters, with pain and tingling, usually in genital area or face. Chronic HSV infection presents as progressive, shallow, clean-based ulcers on genitalia, perianal, perioral areas.
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Infection Preferred: IV amphotericin B (0.7 mg/kg daily) + flucytosine (25 mg/kg 4 times a day) for 2 weeks, then fluconazole (400 mg daily) for 8 weeks Alternatives: IV amphotericin B (0.7 mg/kg daily) for 2 weeks, then fluconazole (400 mg daily) for 8 weeks. Secondary prophylaxis is given with fluconazole (200 mg daily) lifelong or until evidence of immune recovery on ART (CD4 cell count >100 cells/mm3). IV amphotericin B (0.7 mg/kg daily) for 2 weeks then itraconazole 400 mg orally daily for 10 weeks In mild cases, give itraconazole 400 mg orally daily for 8 weeks. Secondary prophylaxis is given with itraconazole 200 mg per day for life or until immune recovery on ART.
Clinical features
Diagnosis
Treatment
Cryptococcosis*
Generalized papulonecrotic skin lesions resembling molluscum contagiosum, associated with fever and other symptoms of disseminated cryptococcosis such as meningitis, lung infection
Penicilliosis*
Papulonecrotic skin lesions associated with systemic symptoms of fever, lung involvement, cough, weight loss, anaemia, hepatosplenomegaly and lymphadenopathy. 70% of patients with disseminated Penicillium marneffei infection will have skin lesions. Endemic in northern Thailand, Southern China, Viet Nam, Indonesia and Hong Kong Tissue biopsy Haematoxylin– eosin staining Blood or tissue culture Microscopy of tissue/skin scraping Warthin–Starry silver or Grocott–silver methenamine stain
Microscopic examination of skin biopsy, lymph node aspirate or CSF. India ink, Wright or Cotton blue staining Blood culture CXR
Histoplasmosis*
Pustules, nodules, ulcers and papules in a patient with systemic symptoms including those due to lung, CNS, gastrointestinal and ocular involvement
Amphotericin B (0.7 mg/kg daily), minimum total dose should be 2 g. Secondary prophylaxis is given with itraconazole 200 mg per day for life or until immune recovery on ART. Erythromycin (500 mg 4 times per day) is the drug of choice. Doxycycline (100 mg) is an alternative. Rifampicin (300 mg 2 times a day) may be added to erythromycin or doxycycline in patients with severe disease who are immunocompromised.
Management of HIV infection and antiretroviral therapy in adults and adolescents
Bacillary Papules or nodules resembling pyogenic angiomatosis* granuloma, nodules or plaques resembling Kaposi sarcoma. Splenomegaly, anaemia
Infection AFB on skin biopsy Blood culture Preferred therapy Azithromycin 500–600 mg once a day, or clarithromycin 500 mg twice a day plus ethambutol 15 mg/kg/day plus rifabutin 300 g once a day The condition may resolve with ART. Maintenance therapy Clarithromycin 500 mg twice a day or azithromycin 500 mg once a day plus ethambutol 15 mg/kg once a day. Primary, secondary and early latent syphilis (<1 year’s duration) Single dose of benzathine penicillin G, 2.4 million U IM Alternative treatments (only for non-pregnant, penicillinallergic patients): 2-week course of doxycycline 100 mg 2 times per day, tetracycline 500 mg 4 times per day, or erythromycin base 500 mg times per day.
Clinical features
Diagnosis
Treatment
Mycobacterium avium complex (MAC)*
Papulopustular eruptions on trunk and extremities. Systemic symptoms include fever and pulmonary symptoms, lymphadenopathy, diarrhoea, weight loss, night sweats
Annex 8: Clinical diagnosis and management of skin conditions
Primary syphilis
Painless, indurated genital ulcer (chancre) with localized lymphadenopathy. Chancres may also be seen in the mouth and anus.
Dark-field microscopy or immunofluorescent staining RPR, VDRL not positive until 7–10 days after appearance of chancre
Secondary syphilis
Late latent syphilis (>1 year’s duration), syphilis of Macular, papular or pustular rash on entire RPR, VDRL, TPHA undetermined duration and late syphilis body, especially on palms and soles CSF examination Benzathine penicillin G, 2.4 million U IM once weekly for 3 40% of these patients will have CNS Protein and cell consecutive weeks Alternative treatment: doxycycline 100 mg orally 2 times involvement with headache and meningism count per day or tetracycline 500 mg 4 times per day for 4 weeks Neurosyphilis Aqueous crystalline penicillin G, 2–4 million U IV 4-hourly for 10–14 days Alternative treatment: Procaine penicillin, 2.4 million U IM once a day, plus probenecid 500 mg 4 times per day for 10–14 days
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Infection Tissue/skin scraping Ziehl–Neelsen stain Treatment should follow the national TB treatment guidelines.
Clinical features
Diagnosis
Treatment
Cutaneous TB
TB verrucosa cutis: Asymptomatic, warty papules on hands or extremities often mistaken for verruca vulgaris. Lesions may evolve and persist for years. Disseminated TB presents as papulonecrotic lesions (indistinguishable from penicilliosis, histoplasmosis, cryptococcosis) Clinical In mild cases, use 1% hydrocortisone cream or 0.1% triamcinolone cream or a similar topical steroid cream. This condition also responds to topical antifungals. Use 2% ketoconazole shampoo to wash the hair and scalp and spread shampoo lather over the face, eyebrows, etc. Leave on for 5 minutes and wash off. Repeat daily until the lesions have cleared and use once weekly to prevent recurrence. Ketoconazole cream can also be used on the face. Alternative option: Whitfield ointment twice a day or gentian violet twice a day or miconazole 2% cream twice daily. For refractory cases, oral ketoconazole 200 mg/day for 7–14 days can be used. Clinical Remove by enucleation (with forceps) or cryotherapy; prick the centre and apply phenol. Remove by cryotherapy, cauterization or application of podophylline 25% solution (2–3 times weekly). Annual Papanicolaou (Pap) smears must be done in women as the risk of invasive cervical cancer is increased.
4. Skin rashes with few or no symptoms
Seborrhoea
Erythematous plaques with greasy scaling on the scalp, face, postauricular area and chest
Molluscum contagiosum
Raised, dome-shaped pedunculated lesions usually on face, neck, genital area and armpits
Management of HIV infection and antiretroviral therapy in adults and adolescents
Condyloma acuminata
Multiple, raised, irregular lesions with a cauliflower-like appearance typically in genital area
Clinical
Infection Clinical As no specific cause has been identified, treatment is mainly symptomatic such as antihistamines and application of emollient creams. The condition may improve with immune recovery on ART. Flucloxacillin 500 mg 4 times per day orally for 10 days
Clinical features
Diagnosis
Treatment
HIV-associated Itchy, maculopapular and generalized skin rash
5. Severe soft tissue or muscle infection Gram stain or culture or 1–2 g IV 4 times per day for 10 days Surgical drainage may be necessary for pyomyositis.
Pyomyositis and skin abscess
Abscess or affected area is fluctuant and warm. There may be discharge.
Clinical diagnosis preferred. Diagnostic test is normally not required.
Annex 8: Clinical diagnosis and management of skin conditions
*Highly suggestive of HIV infection. HIV counselling and testing should be done if the HIV status is unknown.
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Annex
9
Severity Grading of Selected Clinical and Laboratory Toxicities
(Source: Division of AIDS, National Institute of Allergy and Infectious Diseases [modified])
For abnormalities NOT found in the toxicity table use the scale below to estimate the grade of toxicity: GRADE 1 Transient or mild discomfort; no limitation in activity; no medical intervention/therapy required. GRADE 2 Mild-to-moderate limitation in activity—some assistance may be needed; no or minimal medical intervention/therapy required. GRADE 3 Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalization possible GRADE 4 Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitali– zation or hospice care. HAEMATOLOGY Haemoglobin GRADE 1 8.0–9.4 g/dl OR 80–94 g/L OR 4.93–5.83 mmol/L 1000–1500/ mm3 OR 1.0–1.5 g/L* 75 000– 99 000/mm3 OR 75–99 g/L* GRADE 1 130–135 mEq/ L OR 130–135 mmol/L GRADE 2 GRADE 3 7.0–7.9 g/dl OR 6.5–6.9 g/dl OR 70–79 g/L OR 4.3–4.92 mmol/L 750–999/mm3 OR 0.75–0.99 g/L* 65–69 g/L OR 4.03–4.30 mmol/L 500–749/mm3 OR 0.5–0.749 g/L* GRADE 4 <6.5 g/dl OR <65 g/L OR <4.03 mmol/L <500/mm3 OR <0.5 g/L* <20 000/ mm3 OR <20 g/L* GRADE 4
Absolute neutrophil count Platelets
50 000– 20 000–49 999/ 74 999/mm3 OR mm3 OR 50–74.9 g/L* 20–49.9 g/L* GRADE 2 GRADE 3
CHEMISTRIES Sodium Hyponatraemia
123–129 mEq/L 116–122 mEq/L OR OR 123–129 mmol/L
<116 mEq/L OR 116–122 mmol/L <116 mmol/L
Annex 9: Severity grading of selected clinical and laboratory toxicities
143
CHEMISTRIES (contd.) GRADE 1 Hypernatraemia 146–150 mEq/ L OR 146–150 mmol/L Potassium Hyperkalaemia 5.6–6.0 mEq/L OR 5.6–6.0 mmol/L 3.0–3.4 mEq/L OR 3.0–3.4 mmol/L Bilirubin Hyperbilirubinaemia Glucose Hypoglycaemia >1.0–1.5 X ULN 55–64 mg/dL OR 3.01–3.55 mmol/L 116–160 mg/dl OR 6.44–8.90 mmol/L —
GRADE 2 GRADE 3 151–157 mEq/L 158–165 mEq/L OR OR 151–157 mmol/L 6.1–6.5 mEq/L OR
GRADE 4 >165 mEq/L OR 158–165 mmol/L >165 mmol/L
6.6–7.0 mEq/L OR
6.1–6.5 mmol/L 6.6–7.0 mmol/L 2.5–2.9 mEq/L OR 2.0–2.4 mEq/L OR
>7.0 mEq/L OR >7.0 mmol/L <2.0 mEq/L OR <2.0 mmol/L
Hypokalaemia
2.5–2.9 mmol/L 2.0–2.4 mmol/L
1.6–2.5 X ULN
2.6–5 X ULN
>5 X ULN
40–54 mg/dl OR 2.19–3.00 mmol/L
30–39 mg/dl
Hyperglycaemia (nonfasting and no prior diabetes) Triglycerides
OR 1.67–2.18 mmol/L 161–250 mg/dl 251–500 mg/dl OR 8.91–13.88 OR 13.89–27.76 mmol/L mmol/L
<30 mg/dl OR <1.67 mmol/L >500 mg/dl OR >27.76 mmol/L
400–750 mg/dl 751–1200 mg/dl >1200 mg/dl OR OR OR 4.52–8.47 mmol/L 1.6–3.0 X ULN 8.48–13.55 mmol/L 3.1–6.0 X ULN >13.55 mmol/L >6.0 X ULN
Creatinine Transaminases AST (SGOT) ALT (SGPT) Gamma glutamyl transpeptidase (GGT) Alkaline phosphatase Amylase Pancreatic amylase Lipase
>1.0–1.5 X ULN 1.25–2.5 X ULN 1.25–2.5 X ULN 1.25–2.5 X ULN 1.25–2.5 X ULN 1.0–1.5 X ULN 1.0–1.5 X ULN >1.0–1.5 X ULN
2.6–5.0 X ULN 2.6–5.0 X ULN 2.6–5.0 X ULN 2.6–5.0 X ULN 1.6–2.0 X ULN 1.6–2.0 X ULN 1.6–3.0 X ULN
5.1–10.0 X ULN 5.1–10.0 X ULN 5.1–10.0 X ULN 5.1–10.0 X ULN 2.1–5.0 X ULN 2.1–5.0 X ULN 3.1–5.0 X ULN
>10.0 X ULN >10.0 X ULN >10.0 X ULN >10.0 X ULN >5.0 X ULN >5.0 X ULN >5.0 X ULN
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Management of HIV infection and antiretroviral therapy in adults and adolescents
Transaminases (contd.) Lactate <2.0 X ULN without acidosis >2.0 X ULN without acidosis Increased lactate with pH <7.3 without life-threatening consequences GRADE 3 Severe discomfort OR minimal intake for ≥3 days Severe vomiting of all food/fluids in 24 hours OR orthostatic hypotension OR IV treatment required Bloody diarrhoea OR orthostatic hypotension OR >7 loose stools/day OR IV treatment required GRADE 3 Dyspnoea at rest Increased lactate with pH <7.3 with life-threatening consequences GRADE 4 Hospitalization required
GASTROINTESTINAL Nausea
Vomiting
Diarrhoea
GRADE 1 Mild OR transient; reasonable intake maintained Mild OR transient; 2–3 episodes per day OR mild vomiting lasting <1 week Mild OR transient; 3–4 loose stools per day OR mild diarrhoea lasting <1 week GRADE 1 Dyspnoea on exertion GRADE 1 1+ 200 mg–1 g loss/day OR <0.3% OR <3 g/L Microscopic only
GRADE 2 Moderate discomfort OR intake decreased for <3 days Moderate OR persistent; 4–5 episodes per day OR vomiting lasting ≥ 1 week Moderate OR persistent; 5–7 loose stools per day OR diarrhoea lasting ≥1 week
Hypotensive shock OR hospitalization for IV treatment required Hypotensive shock OR hospitalization required
RESPIRATORY Dyspnoea
GRADE 2 Dyspnoea with normal activity GRADE 2 2–3+ 1–2 g loss/day OR 0.3–1.0% OR 3–10 g/L Gross, no clots
URINALYSIS Proteinuria Spot urine 24-hour urine
GRADE 3 4+ 2–3.5 g loss/day OR >1.0% OR >10 g/L Gross plus clots
GRADE 4 Dyspnoea requiring O2 therapy GRADE 4 Nephrotic syndrome Nephrotic syndrome OR >3.5 g loss/day Obstructive
Gross haematuria
Annex 9: Severity grading of selected clinical and laboratory toxicities
145 GRADE 4 >40.5°C for ≥12 continuous hours Intractable
MISCELLANEOUS Fever (oral, >12 hours)
GRADE 1 37.7–38.5°C
GRADE 2 38.6–39.5°C
GRADE 3 39.6–40.5°C
Headache
Mild, or does not require treatment Pruritus without rash Erythema, pruritus
Allergic reaction
Moderate, which responds to non-narcotic analgesics Localized urticaria Diffuse, maculopapular rash OR dry desquamation
Severe, which responds to initial narcotic analgesic Generalized urticaria, angioedema Vesiculation OR moist desquamation OR ulceration
Anaphylaxis
Rash Hypersensitivity
Fatigue
Normal Normal activity Normal activity activity reduced reduced >50%; reduced <25% 25–50% cannot work
Stevens– Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis Unable to care for self
References 1
WHO. Guidelines for HIV diagnosis and monitoring of antiretroviral therapy. Revision. New Delhi, WHO Regional Office for South-East Asia, 2005 (SEAHLM 382). WHO. Guidance on provider-initiated HIV testing and counselling in health facilities. Geneva, WHO (in press). WHO. 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, 2006. Available at http://www.who.int/ hiv/pub/guidelines/hivstaging/en/index.html (accessed on 24 January 2007) WHO. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults in resource-limited settings: recommendations for a public health approach. Geneva, World Health Organization, 2006. Available at http://www.who.int/hiv/pub/guidelines/ ctx/en/index.html (accessed on 24 January 2007) Forna F et al. Systematic review of the safety of trimethoprim– sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings. AIDS Reviews, 2006, 8:24–36. Walter J et al. Cotrimoxazole prophylaxis and adverse birth outcomes among HIV-infected women in Lusaka, Zambia. 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado. February 2006 [Abstract 126]. Carr A et al. Efficacy and safety of rechallenge with low-dose trimethoprim–sulphamethoxazole in previously hypersensitive HIVinfected patients. AIDS, 1993, 7:65–71. Absar N, Daneshvar H, Beall G. Desensitization to trimethoprim/sulfamethoxazole in HIV-infected patients. Journal of Allergy and Clinical Immunology, 1994, 93:1001–1005. Egger M et al. Prognosis of HIV1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet, 2002, 360:119–129. Gulick RM et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. New England Journal of Medicine, 1997, 337:734–739.
2
3
4
5
6
7
8
9
10
References 11
147
Hammer SM et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. New England Journal of Medicine, 1997, 337:725–733. 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. Teerawattananon Y et al. Targeting antiretroviral therapy: lessons from a longitudinal study of morbidity and treatment in relation to CD4 count in Thailand. Asia Pacific Journal of Public Health, 2006, 18:39–48. Wood E et al. When to initiate antiretroviral therapy in HIV-1 infected adults: a review for clinicians and patients. Lancet Infectious Diseases, 2005, 5: 407–414.
12
13
14
15
WHO. Antiretrovirals for HIV: a compilation of facts and product information. New Delhi, World Health Organization, Regional Office for South-East Asia 2006. Saag MS. Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B virus. Clinical Infectious Diseases, 2006, 42:126–131. Jones R et al. Renal dysfunction with tenofovir disoproxil fumaratecontaining highly active antiretroviral therapy regimens is not observed more frequently. A cohort and case–control study. Journal of Acquired Immune Deficiency Syndromes, 2004, 37:1489–1495. Izzedine H et al and Study 903 Team. Long term renal safety of tenofovir disoproxil fumarate in antiretroviral naive HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrology, Dialysis, Transplantation, 2005, 20:743–746. Gulick R, Ribaudo H, for the AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. New England Journal of Medicine, 2004, 350:1850–1861. DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS 2006, 20:1391–1399. Gallant JE et al. and the ESSS3009 Study. Early virologic non-response to tenofovir, abacavir and lamivudine in HIV-infected antiretroviral-naive subjects. Journal of Infectious Diseases, 2005, 192:1921–1930.
16
17
18
19
20
21
148 22
Management of HIV infection and antiretroviral therapy in adults and adolescents
Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naïve, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 8–11 February 2004 [Abstract number 51]. Robertson J et al. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clinical Infectious Diseases, 2006, 42:1639–1646. French MA et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Medicine, 2000, 1:107–115. Breen RAM et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax, 2004, 59: 704–707. Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Current Opinion in Infectious Diseases, 2006, 19: 20–25. McComsey GA et al. Placebo-controlled trial of prednisone in advanced HIV-1 infection. AIDS, 2001,15:321–327. Murdoch DM et al. Immune reconstitution inflammatory syndrome (IRIS) review of common infectious manifestations and treatment options. AIDS Research and Therapy, 2007, 4:9. Paterson DL et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Annals of Internal Medicine, 2000, 133:21–30. Ickovics JR, Meisler AW. Adherence in AIDS clinical trials: a framework for clinical research and clinical care. Journal of Clinical Epidemiology, 1997, 50: 385–391. Chesney MA. Factors affecting adherence to antiretroviral therapy. Clinical Infectious Diseases, 2000, 30 (Suppl 2): S171–S176. Shibuyama S et al. Understanding and avoiding antiretroviral adverse events. Current Pharmaceutical Design, 2006, 12: 1075–1090. WHO. Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: towards universal access. Recommendations for a public health approach. Geneva, World Health Organization, 2006 revision. Hill A et al. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Expert Opinion on Pharmacotherapy 2007, 8 (in press).
23
24
25
26
27
28
29
30
31
32
33
34
References 35
149
WHO. Addendum to 2006 WHO guidelines on antiretroviral therapy for HIV infection in adults and adolescents. New dosage recommendations for stavudine (d4T). (Available at http://www.who.int/hiv/treatment/en/index. html, 7 May 2007).
36
Palella FJ et al. Anthropometrics and examiner-reported body habitus abnormalities in the multicenter AIDS cohort study. Clinical Infectious Diseases, 2004, 38: 903–907. Joly V et al. Increased risk of lipoatrophy under stavudine in HIV-1infected patients: results of a substudy from a comparative trial. AIDS, 2002, 16: 2447–2454.
37
38
Martin A et al.; Mitochondrial Toxicity Study Group. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS, 2004, 18:1029–1036. Martin A, Mallon PW. Therapeutic approaches to combating lipoatrophy: do they work? Journal of Antimicrobial Chemotherapy, 2005, 55:612–615. Epub 10 Mar 2005. Cote HC et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. New England Journal of Medicine, 2002, 346: 811–820. Wulff EA, Wang AK, Simpson DM. HIV-associated peripheral neuropathy: epidemiology, pathophysiology and treatment. Drugs, 2000, 59:1251–1260. Winston A, Boffito M. The management of HIV-1 protease inhibitor pharmacokinetic interactions. Journal of Antimicrobial Chemotherapy, 2005, 56:1–5.
39
40
41
42
43
Back D, Gibbons S, Khoo S. Pharmacokinetic drug interactions with nevirapine. Journal of Acquired Immune Deficiency Syndromes, 2003, 34 (Suppl 1): S8–S14. Tarantal AF et al. Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). Journal of Acquired Immune Deficiency Syndromes, 2002, 29: 207–220. Hazra R et al. Safety, tolerability, and clinical responses to tenofovir DF in combination with other antiretrovirals in heavily-treatment-experienced HIV-infected children: data through 48 weeks. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 8–11 February 2004 [Abstract 928].
44
45
150 46
Management of HIV infection and antiretroviral therapy in adults and adolescents
Almond L et al. A retrospective survey of the Liverpool TDM Service: factors influencing efavirenz concentrations in patients taking rifampicin. 6th International Workshop on Clinical Pharmacology of HIV therapy, Quebec, April 2005 [Poster 2.12]. Patel A et al. Safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with tuberculosis and HIV-1. Journal of Acquired Immune Deficiency Syndromes, 2004, 37: 1166–1169. Pedral-Sampaio D et al. Efficacy and safety of efavirenz in HIV patients on rifampin for tuberculosis. Brazilian Journal of Infectious Diseases, 2004, 8:211–216. Manosuthi W et al. A randomized controlled trial of efavirenz 600 mg/ day versus 800 mg/day in HIV-infected patients with tuberculosis to study plasma efavirenz level, virological and immunological outcomes: a preliminary result. XV International AIDS Conference, Bangkok, Thailand, July 2004 [Abstract MoOrB1013]. Sheehan NL, Richter C. Efavirenz 600 mg is not associated with subthera– peutic efavirenz concentrations when given concomitantly with rifampin. 6th International Workshop on Clinical Pharmacology of HIV therapy, Quebec City, Canada, 28–30 April 2005. Autar RS et al. What is the clinical relevance of the drug interaction between nevirapine and rifampin? XV International AIDS Conference, Bangkok, Thailand, July 2004 [Abstract B11784]. Oliva J et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. AIDS, 2003, 17: 637–642. Ribera E et al. Pharmacokinetic interaction between nevirapine and rifampin in HIV-infected patients with tuberculosis. Journal of Acquired Immune Deficiency Syndromes, 2001, 28: 450–453. Dean GL, Back DJ, De Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma concentrations. AIDS, 1999, 13:2489–2490. Van Cutsem G et al. TB/HIV co-infected patients on rifampicin containing treatment have equivalent ART treatment outcomes, and concurrent use of nevirapine is not associated with increased hepatotoxicity. 3rd IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, 24–27 July 2005 [Abstract Wepp 0303]. Dean GL et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS, 2002, 16:75–83.
47
48
49
50
51
52
53
54
55
56
References 57
151
Justesen US et al. Pharmacokinetic interaction between rifampicin and the combination of indinavir and low dose ritonavir in HIV infected patients. Clinical Infectious Diseases, 2004, 38: 426–429. WHO. Biregional strategy for harm reduction 2005–2009; HIV and injecting drug use. Manila, WHO South East Asia Region and Western Pacific Region, 2005.
58
59
International Harm Reduction Association (IHRA). Role of harm reduction networks in scaling up ARV to IDUs as part of the WHO ‘3 by 5’ Initiative. Project Report submitted by IHRA to WHO. Prepared by Edna Oppenheimer, May 2004. WHO. HIV/AIDS treatment and care for injecting drug users. Clinical protocols for the WHO European Region. Copenhagen, World Health Organization, Regional Office for Europe, 2007. Wood E et al. Rates of antiretroviral resistance among HIV-infected patients with and without a history of injecting drug use. AIDS, 2005, 19:1189–1195. Wood E et al. Adherence to antiretroviral therapy and CD4 T-cell count responses among HIV-infected injection drug users. Antiviral Therapy, 2004, 9: 229–235. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS, 1999, 13: 957–962. WHO. Management of common health problems of drug users. New Delhi: World Health Organization, Regional Office for South-East Asia (in press). British HIV Association. Guidelines for the treatment of HIV-infected adults with antiretroviral therapy. London, British HIV Association, 2005. WHO. HIV/AIDS treatment and care: WHO protocols for Commonwealth of Independent States (CIS) countries. Copenhagen, World Health Organization, Regional Office for Europe, 2004.
60
61
62
63
64
65
66
67
Bessesen M et al. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clinical Infectious Diseases, 1999, 28:1032–1035. Filippini P et al. Impact of occult hepatitis B virus infection in HIV patients naive for antiretroviral therapy AIDS, 2006, 20:1253–1260. Alberti A et al. Short statement on the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV coinfected patients. Journal of Hepatology, 2005, 42: 615–624.
68
69
152 70
Management of HIV infection and antiretroviral therapy in adults and adolescents
Ledergerber B et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet, 2004, 364: 51–62. Tomasoni LR et al. Predictors of long-term immunological outcome in rebounding patients on protease inhibitor-based HAART after initial successful virologic suppression: implications for timing to switch. HIV Clinical Trials, 2003, 4: 311–323. Kousignian I et al. Modeling the time course of CD4 T-lymphocyte counts according to the level of virologic rebound in HIV-1-infected patients on highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 2003, 34:50–57. Murri R et al. Is moderate HIV viremia associated with a higher risk of clinical progression in HIV-infected people treated with highly active antiretroviral therapy: evidence from the Italian cohort of antiretroviral-naive patients study. Journal of Acquired Immune Deficiency Syndromes, 2006, 41: 23–30.
71
72
73
74
Walmsley S et al., and the M98-863 Study Team. Lopinavir–ritonavir versus nelfinavir for initial treatment of HIV infection. New England Journal of Medicine, 2002, 346: 2039–2046. King MS, Brun AC, Kempf DJ. Relationship between adherence and the development of resistance in antiretroviral-naive, HIV-infected patients receiving lopinavir/ritonavir or nelfinavir. Journal of Infectious Diseases, 2005, 191:2046–2052. Molina JM et al.; AI454-176 JAGUAR Study Team. Didanosine in HIV1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial. Journal of Infectious Diseases, 2005, 191: 840–847. Leon EA et al. Early virological failure in treatment naïve HIV-infected adults receiving didanosine and tenofovir plus efavirenz and nevirapine. AIDS, 2005, 19: 213–215. Barrios A et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS, 2005, 19:569–575. Negredo E et al. Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS, 2004, 18:459–463. Ray AS, Olson L, Fridland A. Role of purine nucleoside phosphorylase in interactions between 2’,3’-dideoxyinosine and allopurinol, ganciclovir, or tenofovir. Antimicrobial Agents and Chemotherapy, 2004, 48:1089–1095.
75
76
77
78
79
80
References 81
153
Negredo E et al. Lopinavir/ritonavir plus nevirapine as a nucleoside sparing approach in antiretroviral experienced patients (NEKA Study). Journal of Acquired Immune Deficiency Syndromes, 2005, 38:47–52. Boyd M et al. Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96-week outcomes of HIV-NAT 009. HIV Medicine, 2005, 6:410–420. WHO. Palliative care: symptom management and end-of-life care. Integrated management of adolescent and adult illness. Interim guidelines for first-level facility health workers. Geneva, WHO, 2004. WHO. Post-exposure prophylaxis to prevent HIV infecton. Joint WHO/ILO guidelines and policies for the use of occupational and non-occupational post exposure prophylaxis (PEP) to prevention human immunodeficiency virus (HIV) infection. Geneva, WHO/ILO (in press). U.S. Department of Health and Human Services. Postexposure prophylaxis of persons with discrete identifiable exposures to hepatitis B virus (HBV). Recommendations and Reports. Morbidity and Mortality Weekly Report, December 23, 2005/54 (RR16);31. Available at http://www.cdc.gov/mmwr/ preview/mmwrhtml/rr5416a4.htm (accessed on 22 May 2007) U.S. Department of Health and Human Services. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States. Recommendations from the U.S. Department of Health and Human Services. Morbidity and Mortality Weekly Report, 2005, 54: 1–20. Wahn V et al. A horizontal transmission of HIV infection between two siblings. Lancet, 1986, 2:694. Drezett J. Post-exposure prophylaxis in raped women: IV International Conference on HIV infection in women and children. Rio de Janeiro: Livro de Resumos. Universidade, Federal do Rio De Janeiro e Institute of Virology of Maryland; 2002. Harrison LH et al. Post-sexual-exposure chemoprophylaxis (PEP) for HIV: a prospective cohort study of behavioral impact. 8th Conference on Retroviruses and Opportunistic Infections, Chicago, Illinois, 4–8 February 2001 [Abstract 225]. Harrison LH et al. Demand for post-sexual-exposure chemoprophylaxis for the prevention of HIV infection in Brazil. 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, California, 30th January–2nd February 2000.
82
83
84
85
86
87
88
89
90
154 91
Management of HIV infection and antiretroviral therapy in adults and adolescents
WHO. Sexually transmitted and other reproductive tract infections. Geneva, WHO, 2005:141–150. Cressey T et al. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1-infected patients weighing less than 60 kg on highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 2006, 42:386–388. Pruvost A et al. Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients. Antimicrobial Agents and Chemotherapy, 2005, 49:1907–1914. Cressey TR et al. Low-doses of indinavir boosted with ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and tolerability. Journal of Antimicrobial Chemotherapy, 2005, 55:1041–1044. Epub 9 May 2005.
92
93
94
95
Boyd M et al. Pharmacokinetics of reduced-dose indinavir/ritonavir 400/100 mg twice daily in HIV-1-infected Thai patients. Antiviral Therapy, 2005, 10:301–307.
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Ellis E, Scheinfeld N. Eosinophilic pustular folliculitis: a comprehensive review of treatment options. American Journal of Clinical Dermatology, 2004, 5:189–197. Chosidow O. Clinical practices. Scabies. New England Journal of Medicine, 2006, 354:1718–1727. Meinking TL et al. The treatment of scabies with ivermectin. New England Journal of Medicine, 1995, 333:26–30. Singh F, Rudikoff D. HIV-associated pruritus: etiology and management. American Journal of Clinical Dermatology, 2003, 4:177–188. Letko E et al. Stevens–Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Annals of Allergy, Asthma and Immunology, 2005, 94:419–436. Wheat LJ et al. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Seminars in Respiratory and Critical Care Medicine, 2004, 25:129–144.
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Index Adherence to treatment 28–31 assessment 19, 31 checklist 31 counselling 29–31 factors for poor adherence 28 and virological suppression 28 Antibodies to HIV 3, 102 Antiretroviral drugs combinations not recommended 24 dosages in adults and adolescents 117–18 for non-occupational exposure to HIV 107 for post-exposure prophylaxis 98 in pregnancy 43–4 interactions with buprenorphine 53, 126 interactions with methadone 51–2, 125 interactions with other drugs and opiates 125–6 storage 119–20 symptom-directed toxicity management 36–7; see also ARV drug toxicity toxicities 34–42; see also ARV drug toxicity Antiretroviral therapy 12–13 adherence; see Adherence to treatment CD4 count available 18–19 CD4 count not available 18 clinical and laboratory monitoring in first-line 32–3 clinical and laboratory monitoring in second-line 61–3 drug interactions 121–4 for injecting drug users; see Injecting drug users for pregnant women and those with childbearing potential 43–4 in tuberculosis/HIV coinfection 45–6 interactions with opiates 125–6; see also Opioid substitution therapy when to start 18–20 and active opportunistic infections 19–20 and hormonal contraceptives 44 ART failure 56–9 choice of second-line regimens 60 immunological/virological criteria 58–9 ARV drug toxicity 34–42 choice of NNRTIs 42 grading 34 individual drug substitutions 38
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management of first-line 35–7 management of second-line 62–3 stavudine 39, 42
Clinical diagnosis and management of skin conditions 135–41 Criteria for HIV-related clinical events in adults and adolescents 111–16 Hepatic flares; see IRIS HIV infection in adults and adolescents 4–13 clinical assessment 4–10 immunological assessment 11 laboratory diagnosis 2–3 management 12–13 medical history checklist 5–6 physical examination checklist 7–8 revised WHO clinical staging 8–9 risk factors for 5 signs and symptoms suggestive of 10 and hepatitis B/C coinfection 54–5 and nutritional support; see Nutritional support and palliative care; see Palliative care and total lymphocyte count 11 HIV testing 2–3 after occupational exposure 103 Immune reconstitution inflammatory syndrome (IRIS) 25–7 and hepatic flares 55 Injecting drug users 47–53 antiretroviral therapy for 48–9 and harm-reduction programmes 47 and opioid substitution therapy 50–1 and viral hepatitis and chronic liver disease 49–50 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 23 dosages 117 in drug toxicity 42 in hepatitis B/HIV coinfection 54 in IDUs 48–9 in pregnancy 44 in TB/HIV coinfection 45 storage 119–20 Non-occupational exposure to HIV 105–10 counselling 107–8 emergency contraception 108 risk of acquiring 105 status of source 106–7 Nucleoside reverse transcriptase inhibitors (NRTIs) 22–3
Index
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dosages 117 in hepatitis B/HIV coinfection 54 in pregnancy 44 in TB/HIV coinfection 45 storage 119–20 triple regimens 24 Nutritional support 74–6 Occupational exposure 88–104 assessment 94–6 laboratory evaluation 101 measures against hepatitis B and C 100–1 practices that influence/reduce risk 89 prevention 90–1 risk of acquiring infection 88–9 steps for management 92–104 universal standard precautions 91 and infectious body fluids 88 and risk of acquiring HIV, HBV, HCV 89 see also Post-exposure prophylaxis Opioid substitution therapy 50–1 buprenorphine 53 methadone 51–3 Opportunistic infections 127–31 bacterial meningitis 73 bacterial pneumonia 71, 114 candidiasis 16, 64, 76, 83, 128 cerebral toxoplasmosis 16, 73, 115, 129 chronic diarrhoea 68–9 cryptococcosis 17–19, 73, 115, 128 cryptosporidiosis 69, 115, 131 dysphagia 64–5 extrapulmonary TB 67, 114, 130 herpes simplex virus (HSV) 114, 129, 137 herpes zoster 82, 111, 130, 137 lymphadenopathy 7, 66–7, 111 management before starting ART 20 Mycobacterium avium complex (MAC) disease 69, 131, 139 neurological signs and symptoms 72–3 penicilliosis 129, 138 Pneumocystis jiroveci pneumonia (PCP) 20, 71, 114, 127 prophylaxis with co-trimoxazole 14–16 prophylaxis with fluconazole 16–17 respiratory symptoms 70–1 skin conditions 135–41 syndromic management; see Syndromic approach to the management of opportunistic infections
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toxoplasmosis 73, 115, 129 tuberculosis 69, 113, 114, 130, 140; see also Tuberculosis
Palliative care in HIV infection 77–85 components 78 end-of-life care 84–5 management of pain 78–82 management of symptoms 83–4 Post-exposure prophylaxis 93–104 ARVs for; see Antiretroviral drugs counselling 95, 107 definitions 86–7, 105 eligibility criteria 93–4 follow up 103–4 for hepatitis B and C 90, 100–1 for sexually transmitted infections 108–10 in pregnancy 99 non-occupational (nPEP); see Non-occupational exposure to HIV principles 87 side-effects and adherence 99–100 treatment regimens 97–101 Protease inhibitors 24 dosages 117 interactions with methadone 125 interactions with buprenorphine 126 storage 119 Severity grading of selected clinical and laboratory toxicities 142–5 Syndromic approach to the management of opportunistic infections 64–73; see also Opportunistic infections Tuberculosis case definitions and treatment 132–4; see also Opportunistic infections
Successful scaling-up of antiretroviral therapy requires the rational use of antiretroviral drugs. This manual provides guidance and information in a practical and user-friendly format, using tables and figures, accompanied by limited text and provides recommendations based on evidence from clinical trials, observational cohort data and expert opinion. It comprises eight main sections:
Laboratory diagnosis of HIV infection in adults and adolescents; Assessment of adults and adolescents with HIV infection; Prevention of opportunistic infections; Management of antiretroviral therapy; Management of opportunistic infections; Management of nutrition and palliative care; Management of post-exposure prophylaxis, and related Annexes.
The full set of WHO guidelines is available at www.searo.who.int/hiv-aids publications and http://www.who.int/hiv/pub/guidelines/en/index.html.
ISBN
978 92 9002 289 7
978 92 9022 289 7
Mahatma Gandhi Marg Indraprastha Estate, New Delhi - 110002 Tel : 91 - 11 - 23370804, Fax : 91 - 11 - 23370197 www.searo.who.int