Tuberculosis, HIV, malaria and neglected tropical diseases: strengthening collaboration to prevent and manage antimicrobial resistance

Tuberculosis, HIV, malaria and neglected tropical diseases Strengthening collaboration to prevent and manage antimicrobial resistance Tuberculosis, HIV, malaria and neglected tropical diseases Strengthening collaboration to prevent and manage antimicrobial resistance AMR_brochure.indd 1 27/03/19 10:12 am Tuberculosis, HIV, malaria and neglected tropical diseases: strengthening collaboration to prevent andmanage antimicrobial resistance ISBN 978-92-4-151545-0 ©World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, youmay copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion thatWHO endorses any specific organization, products or services. The use of theWHO logo is not permitted. If you adapt the work, then youmust license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by theWorld Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of theWorld Intellectual Property Organization. Suggested citation. Tuberculosis, HIV, malaria and neglected tropical diseases: strengthening collaboration to prevent andmanage antimicrobial resistance. Geneva:World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchaseWHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of thematerial in this publication do not imply the expression of any opinion whatsoever on the part ofWHO 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 and dashed lines onmaps represent approximate border lines for which there may not yet be full agreement. Themention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended byWHO 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 byWHO to verify the information contained in this publication. However, the publishedmaterial is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of thematerial lies with the reader. In no event shall WHO be liable for damages arising from its use. Printed in France AMR_brochure.indd 2 27/03/19 10:12 am iiiSTRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE Contents Abbreviations iv Foreword v Executive summary 1 1. Introduction 2 2. Background 3 2.1 Antimicrobial resistance 3 2.2 Sustainable Development Goals 3 2.3 How antimicrobial resistance aúects the achievement of the Sustainable Development Goals 3 2.4 Global Action Plan on Antimicrobial Resistance 4 2.5 Ad hoc United Nations Interagency Coordination Group on Antimicrobial Resistance 5 2.6 WHO 13th General Programme ofWork (2019–2023) 5 2.7 TB, HIV, malaria, neglected tropical diseases and antimicrobial resistance 6 3. Current antimicrobial resistance status: TB, HIV, malaria and relevant neglected tropical diseases 9 3.1 Factors driving antimicrobial resistance across disease areas 9 3.2 Tuberculosis 10 3.3 HIV 12 3.4 Malaria 13 3.5 Neglected tropical diseases 14 4. Preventing antimicrobial resistance related to TB, HIV, malaria and neglected tropical diseases and theWHO response 15 4.1 Preventing antimicrobial resistance 15 4.2 Surveillance of antimicrobial resistance 16 4.3 Laboratory networks 21 4.4 Communication, awareness-raising, education and training 23 5. Future directions 25 5.1 Identify research and development gaps and new tools and approaches 26 5.2 Clinical and programmatic indicators associated with and predicting the emergence of antimicrobial resistance 28 5.3 Joint support for countries 30 5.4 Identifying and optimizing synergy 31 5.5 Product pipelines 31 References 32 WHO antimicrobial resistance resources 34 Antimicrobial resistance – general 34 TB 34 HIV 35 Malaria 35 Neglected tropical diseases 36 AMR_brochure.indd 3 27/03/19 10:12 am iv TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES Abbreviations ACT artemisinin-based combination therapy AIDS acquired immunodeficiency syndrome AMR antimicrobial resistance BBINS Bangladesh, Bhutan, India, Nepal, Sri Lanka DNDi Drugs for Neglected Diseases initiative FAO Food and Agriculture Organization of the United Nations GAP Global Action Plan on Antimicrobial Resistance GLASS Global Antimicrobial Resistance Surveillance System HANMAT Horn of Africa Network for Monitoring Antimalarial Treatment HIV human immunodeficiency virus IACG Interagency Coordination Group on Antimicrobial Resistance MDR-TB multidrug-resistant tuberculosis MMV Medicines for Malaria Venture NTD neglected tropical disease OIE World Organisation for Animal Health PEPFAR United States President’s Emergency Plan for AIDS Relief PIAMNET Pakistan, Islamic Republic of Iran and Afghanistanmonitoring network RAVREDRA Red Amazónica para la Vigilancia de la Resistencia a las Drogas Antimaláricas network RR-TB rifampicin-resistant tuberculosis TB tuberculosis UNEP United Nations Environment Programme USAID United States Agency for International Development WHO World Health Organization XDR-TB extensively drug-resistant tuberculosis AMR_brochure.indd 4 27/03/19 10:12 am vSTRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE Foreword Antimicrobial resistance is one of the greatest health challenges of the 21st century, as recognized in the 2015World Health Assembly resolution on antimicrobial resistance and the 2016 Political Declaration of the High-level Meeting of the United Nations General Assembly on Antimicrobial Resistance. If antimicrobial resistance is not addressed, it may contribute to millions of deaths per year and cost the world economy US$ 1–3 trillion per year after 2030 (1). Drug-resistant TB, HIV, malaria and some neglected tropical diseases will make a substantial contribution to this burden. Antimicrobial resistance threatens to take us back to a time when common infections could not be treated and often led to sustained illness and death. To preserve the health gains of the past century, we will need to take eúective and coordinated action. WHO has recognized the importance of antimicrobial resistance in its 13th General Programme ofWork, which requires all programmes at all levels of the Organization to address antimicrobial resistance as a cross-cutting issue. Antimicrobial resistance will impact the achievement of the triple billion targets, especially universal health coverage. The three objectives of universal health coverage including equity, quality and protection from financial risk will not bemet without also eúectively addressing antimicrobial resistance. Equally, universal health coverage also oúers an excellent opportunity for preventing and managing antimicrobial resistance. WHO is leading the fight to prevent and contain antimicrobial resistance in human health and has been working in close collaboration with the Food and Agriculture Organization of the United Nations (FAO), theWorld Organization for Animal Health (OIE) (the FAO/OIE/WHO Tripartite Collaboration on Antimicrobial Resistance) and the United Nations Environment Programme (UNEP). The Tripartite organizations are working together through the Interagency Coordination Group on Antimicrobial Resistance (IACG) and reaûrmed their commitment to strengthen collaboration in amemorandum of understanding signed inMay 2018. The IACGwill issue a final report to the United Nations Secretary- General in 2019 that re-emphasizes the urgency and the need for a coordinated and stepped-up global response. The Tripartite and UNEP have developed a One Health approach tomanaging antimicrobial resistance, as proposed in the Global Action Plan on Antimicrobial Resistance (GAP), launched in 2015. This plan focuses on the importance of strengthening systems for preventing and managing infection, with more appropriate use of antimicrobial agents, as well as strengthening systems for surveillance. One of the core elements of the GAP is to support countries to develop and implement comprehensive, One Health-oriented antimicrobial resistance action plans. As of January 2019, 117 countries have developed national antimicrobial resistance action plans with support from partners. WHO has also developed GLASS, the Global Antimicrobial Surveillance System. Antimicrobial resistance is also a major challenge for TB, HIV andmalaria and has the potential to adversely aúect neglected tropical disease programmes. Sustainable Development Goal target 3.3 calls for ending the epidemics of these diseases by 2030.While antimicrobial resistance puts the achievement of many Sustainable Development Goals at risk, Sustainable Development Goal target 3.3 is especially aúected, with antimicrobial resistancemaking treating these diseases more diûcult and expensive. TB, HIV, malaria and neglected tropical disease programmes have been working to address the antimicrobial resistance challenge for many years by focusing on supporting national and global surveillance networks, strengthening laboratory networks, optimizing diagnostic testing and treatment, raising awareness of the dangers of antimicrobial resistance andworking with key stakeholders to drive product and service AMR_brochure.indd 5 27/03/19 10:12 am vi TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES delivery innovation. These same interventions are core components of strategies to prevent andmanage antimicrobial resistance across the human health spectrum. Lessons learned and good practices gained from experience in preventing andmanaging antimicrobial resistance in these diseases can be adapted and used to strengthen antimicrobial resistance approaches in other settings. Current opportunities exist to strengthen antimicrobial resistance collaboration at the country level by identifying and strengthening programmatic synergies that underpin strategies for preventing andmanaging antimicrobial resistance. This will require, for example, ensuring that countries develop and implement comprehensive, antimicrobial resistance action plans that include TB, HIV, malaria and neglected tropical diseases where relevant. Achieving this requires a coordinated eúort, working in partnership, involving all stakeholders at the global, regional, country and service delivery levels. Preventing and managing antimicrobial resistance will truly require sustained eúorts and global collaboration. RenMinghui Assistant Director-General for Communicable Diseases Raniero Guerra Assistant Director-General for Strategic Initiatives AMR_brochure.indd 6 27/03/19 10:12 am 1STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE Executive summary There is global commitment to address antimicrobial resistance through the Global Action Plan on Antimicrobial Resistance. High-impact communicable diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), malaria and neglected tropical diseases (NTDs), should be integrated into and aligned with global antimicrobial resistance eúorts. Antimicrobial resistance puts achievement of Sustainable Development Goal 3 and other Sustainable Development Goals at risk, making eúectively treating diseases more diûcult and costly and leading tomore illness and deaths. Lessons learned from addressing antimicrobial resistance in TB and the other diseases during the past 20 years provide useful guidance for other antimicrobial resistance programmes in earlier stages of development, including: ÿ recognizing at an early stage the antimicrobial resistance challenge and advocating and mobilizing global development partners to address it; ÿ establishing a global antimicrobial resistance surveillance system; ÿ establishing direct drug resistance testing for individual patients, providing data for population-based surveillance; ÿ expanding and strengthening national and regional laboratory networks; ÿ strengthening country capacity for managing antimicrobial resistance; ÿ reaching out to stakeholders at all levels through a public–private mix, including engaging pharmacies and health-care providers to provide training on testing and treatment protocols; and ÿ establishing product development partnerships and research consortiums to facilitate the introduction of new pipeline drugs, review new drug formulations and develop improved diagnostic tests to detect antimicrobial resistance. AMR_brochure.indd 1 27/03/19 10:12 am 2 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 1. Introduction The purpose of this report is to provide a brief overview of the status of antimicrobial resistance in high-impact communicable diseases (TB, HIV, malaria and some neglected tropical diseases) and to present some areas in which strengthened eúorts will be required in the future andmore collaborative programme designmay generate eûciency and strengthened systems for addressing antimicrobial resistancemore widely. This overview includes a summary of the current antimicrobial resistance situation by disease, current prevention and response eúorts in antimicrobial resistance and a future directions section examining opportunities for strengthening collaboration among disease and other antimicrobial resistance programmes. The report captures key messages in each area and is aimed at technical and funding partners, global and national policy-makers and other relevant stakeholders. AMR_brochure.indd 2 27/03/19 10:12 am 3STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 2. Background access to needed health-care services (including disease prevention, health promotion, treatment, rehabilitation and palliation) of suûcient quality to be eúective while also ensuring that the use of these services does not expose the user to financial hardship. 2.3 How antimicrobial resistance aþects the achievement of the Sustainable Development Goals Antimicrobial resistance is a substantial threat to several of the wider development goals, such as economic growth, poverty reduction and sustainable production and consumption (Fig. 1). Progress towards other goals, such as Sustainable Development Goal 6 on water and sanitation and Sustainable Development Goal 17 onworking in partnership will make important contributions to addressing antimicrobial resistance. However, the greatest threat will be to Sustainable Development Goal 3, human health. Antimicrobial resistance will make it harder to treat the diseases and lead to increased sickness, more protracted hospital stays andmore deaths. TheWorld Bank has estimated that health- care costs could increase by 25% in low-income countries in their worst-case scenario and reduce global gross domestic product (GDP) by 1–4% annually by 2050 (1). The spread of antimicrobial resistance could slow progress towards achieving Sustainable Development Goal 3.3 targets for TB, HIV, malaria and potentially some specific neglected tropical diseases if it is not managed or contained. Antimicrobial resistance will also dramatically increase the costs of providing health-care services. For example, the second- and third-line HIV treatments are 3 and 14 times more expensive, respectively, than first-line treatments (1) and lead tomore negative outcomes. Treating extensively drug-resistant TB (XDR-TB) takes up to two years, 2.1 Antimicrobial resistance Antimicrobial resistance (AMR) occurs when microorganisms such as bacteria, viruses, parasites and fungi develop resistance to antimicrobial agents. Although this is a natural phenomenon, the inappropriate and excessive use of antimicrobial agents can increase the pace and spread of antimicrobial resistance development. Diseases caused by resistant microorganisms are more diûcult to treat. Rising levels of drug resistance are a risk to the success of human immunodeficiency virus (HIV), tuberculosis (TB) andmalaria programmes. Microorganisms that are resistant to antimicrobial agents threaten the successful management of infections, safe surgery and cancer treatment. Coinfection with resistant microorganisms poses heightened risks for people with TB and HIV (2). 2.2 Sustainable Development Goals The United Nations adopted the Sustainable Development Goals (3) in September 2015. These reflect the growing complexity and interdependence of the global development agenda. The Sustainable Development Goals establish 17 global goals that have 169 specific targets, and if they are achieved by 2030 they will help to ensure the sustainability of economic and social development. Sustainable Development Goal 3 focuses on ensuring good health and well- being and covers infectious and noncommunicable diseases. Target 3.3 calls for ending by 2030 the epidemics of AIDS, TB, malaria and neglected tropical diseases and reducing the incidence of hepatitis, waterborne diseases and other communicable diseases. Sustainable Development Goal target 3.8 calls for universal health coverage (4), which is defined as ensuring that all people have AMR_brochure.indd 3 27/03/19 10:12 am 4 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES and the drugs and treatment required cost nearly six times more than treatments for non-resistant TB (5). Among extensively drug-resistant TB cases starting treatment globally in 2015, only 34% completed it or were cured (versus 82%with drug- sensitive strains), and in 45% the treatment failed or the person died (5). As noted in subsection 3.3 and Fig. 10, the emergence of HIV drug resistance threatens to reduce the gains in morbidity and mortality anticipated by a “treat all” approach and the scale-up of pre-exposure prophylaxis. 2.4 Global Action Plan on Antimicrobial Resistance TheWorld Health Assembly adopted the Global Action Plan on Antimicrobial Resistance (6) in May 2015, and the Food and Agriculture Organization of the United Nations (FAO) and theWorld Organization for Animal Health (OIE) endorsed it. The Global Action Plan on Antimicrobial Resistance covers antibiotic resistance in most detail but also refers, where appropriate, to existing action plans for viral, parasitic and bacterial diseases, including HIV, malaria and tuberculosis. The Global Action Plan on Antimicrobial Resistance provides the framework for developingmultisectoral national FIG. 1 Antimicrobial resistance and the Sustainable Development Goals AMR hits the poor hardest with higher treatment costs and lost income due to illness Untreatable infections in animals threatens sustainable food production Antimicrobial residues from hospitals, pharmaceutical companies and agriculture contaminate water, spread of resistant bacteria through inadequate provision of water, sanitation and hygiene AMR could increase health costs by 25% in low income countries and reduce global GDP by 1"4% annually by 2050 Need to balance access, innovation, conservation to protect antimicrobials to contain AMR Antimicrobials are essential for human health Addressing AMR requires multi" stakeholder approaches and one health partnerships Addressing A R requires ulti- a One Health partnerships AMRhits the p or hardest, with higher treatment costs and lost income due to illness treatable i fecti s i i l threaten sust inable food production Antimicrobial residues from ospitals, pharmaceutical companies and agriculture contaminatewater and spread of resistant bacteria through inadequate provision of water, sanitation and hygiene AMR could increase health costs by 25% in low-income countries and reduce global GDP by 1–4% annually by 2050Antimicrobial agents are essential for hum n ealth Need to balance access, innovation, conservation to protect antimicrobial agents to contain AMR AMR_brochure.indd 4 27/03/19 10:12 am 5STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE action plans to combat antimicrobial resistance. It sets out the key actions that the various actors involved should take to combat antimicrobial resistance, using an incremental approach over the next 5–10 years. The TB, HIV, malaria and neglected tropical diseases antimicrobial resistance work is aligned with the five objectives of the Global Action Plan: ÿ to improve awareness and understanding of antimicrobial resistance through eúective communication, education and training; ÿ to strengthen the knowledge and evidence base through surveillance and research; ÿ to reduce the incidence of infection through eúective sanitation, hygiene and infection preventionmeasures; ÿ to optimize the use of antimicrobial medicines in human and animal health; and ÿ to develop the economic case for sustainable investment that takes account of the needs of all countries and to increase investment in new medicines, diagnostic tools, vaccines and other interventions. 2.5 Ad hoc United Nations Interagency Coordination Group on Antimicrobial Resistance The United Nations Secretary-General has established the United Nations Interagency Coordination Group on Antimicrobial Resistance (IACG) (7) to improve coordination between international organizations and to ensure eúective global action against this threat to health security. The IACG is co-chaired by the United Nations Deputy Secretary-General and theWHODirector-General and comprises high- level representatives of relevant United Nations agencies, other international organizations and individual experts across diúerent sectors. The IACG’s mandate is to provide practical guidance for approaches needed to ensure sustained, eúective global action to address antimicrobial resistance; and to report back to the United Nations Secretary-General in 2019.WHO hosts the IACG Secretariat with contributions from the Food and Agriculture Organization of the United Nations (FAO) andWorld Organisation for Animal Health (OIE). WHO is responsible for addressing antimicrobial resistance in relation to human health including TB, HIV, malaria and relevant neglected tropical diseases. The longstanding FAO/OIE/WHO Tripartite Collaboration on Antimicrobial Resistance was further strengthened through the signature of a memorandum of understanding inMay 2018. The Tripartite agencies and the United Nations Environment Programme (UNEP) are actively working together to support a global multisectoral response to antimicrobial resistance, including implementing the IACG recommendations working withMember States, civil society and the private sector. 2.6 WHO 13th General Programme of Work (2019–2023) TheWHO 13th General Programme ofWork for 2019–2023 (8) is structured around three interconnected strategic priorities to ensure healthy lives and well-being for all at all ages. The goals are: ÿ 1 billion people benefiting from universal health coverage; ÿ 1 billion more people better protected from health emergencies; and ÿ 1 billion more people enjoying better health and well-being. Addressing antimicrobial resistance will contribute to all three goals. The 13th General Programme ofWork provides the framework for positioning communicable diseases eúorts in support of universal health coverage. Both ending the epidemics of high-impact communicable diseases (HIV, TB, malaria and neglected tropical diseases, Fig. 2–5) and preventing andmanaging antimicrobial resistance are priorities in the 13th General Programme ofWork and need to be addressed horizontally across all relevantWHO programmes at all levels of the Organization. The 13th General Programme ofWork Impact Framework has specific targets for TB, HIV, malaria and neglected tropical diseases; a target to increase the detection and treatment rates for rifampicin- resistant TB (includingmultidrug-resistant TB (MDR- TB) or combined resistance to at least rifampicin and isoniazid) to 80% by 2023, and targets to reduce the prevalence of resistant bloodstream infections and AMR_brochure.indd 5 27/03/19 10:12 am 6 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES improve the proportion of people with access to antibiotics. 2.7 TB, HIV, malaria, neglected tropical diseases and antimicrobial resistance Antimicrobial resistance has long posed challenges for managing TB, HIV, malaria and some neglected tropical diseases. Drug-resistant TB is a public health crisis and a health security threat; drug resistance in HIV is a growing challenge and threatens progress to end the epidemic as a public health threat by 2030. In the past, widespread resistance to chloroquine and other drugs led tomalaria resurgence and continuing epidemics in many countries and areas. As a consequence of having to address antimicrobial resistance challenges for many years, TB, HIV, malaria and neglected tropical disease programmes have refined their drug resistancemanagement and control strategies to reflect reality on the ground and lessons learned. Unfortunately, strategies for managing and controlling drug resistance related to these diseases have sometimes been implemented separately in the context of each individual disease programme and not under the overall umbrella of antimicrobial resistance. Elements that underpin many of the disease-specific interventions to prevent, detect and manage drug resistance also apply to non-disease- specific antimicrobial resistancemanagement programmes. Better integrating TB, HIV, malaria and neglected tropical disease drug resistance programmes into other antimicrobial resistance eúorts would help to strengthen the overall response to antimicrobial resistance andmaximize synergy in such areas as surveillance, laboratory strengthening, monitoring and evaluation, procurement and supply chain management, developing human resource capacity and the quality of health services delivered. FIG. 2 Estimated TB incidence rates by country, 2017 Source: Global tuberculosis report 2018 (5). Incidence per 100 000 population per year 0–24 25–99 100–199 200–299 ≥300 No data Not applicable AMR_brochure.indd 6 27/03/19 10:12 am 7STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE FIG. 3 HIV prevalence among people 15–49 years old by country, 2017 FIG. 4 Number of malaria cases by country, 2017 Source: World Health Organization, Global Malaria Programme, 2018. Estimated cases per 1000 population 0–0.1 0.2–1 2–10 11–50 51–100 >100 Non-endemic or no ongoing malaria transmission Not applicable Source: WHO Global Health Observatory data repository (http://apps.who.int/gho/data/node.main.622?lang=en), last updated 17 July 2018. <0.2% 0.2–0.5% 0.6–1.5% >1.5% No data Not applicable AMR_brochure.indd 7 27/03/19 10:12 am 8 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES FIG. 5 Number of people requiring treatment and care for neglected tropical diseases by country, 2017 Source: World Health Organization, Department of Control of Neglected Tropical Diseases, 2019. 0–10 11–100 101–1 000 1 001–10 000 10 001–100 000 100 001–1 million 1 000 001–10 million 10 000 001–100 million >100 million AMR_brochure.indd 8 27/03/19 10:12 am 9STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 3. Current antimicrobial resistance status: TB, HIV, malaria and relevant neglected tropical diseases KEY MESSAGES ÿ TB drug resistance is a major cause of antimicrobial resistance mortality andmorbidity worldwide, and immediate action is required to prevent the further development and spread of resistance. ÿ Resistance of HIV to efavirenz and nevirapine, the most common first-line drugs, is a current global health threat leading to poor health outcomes such as treatment failure, mortality and increased programme costs and requires urgent action to be taken now to prevent the further development and spread of resistance. ÿ Malaria drug resistance constitutes a challenge particularly in the Greater Mekong subregion. Drug resistance has developed to artemisinin and some partner drugs used in artemisinin-based combination therapies, making treatment of people with Plasmodium falciparummalaria diûcult. The risk of importing or developing resistance in themalaria- endemic countries in the rest of the world is a concern, and surveillance of drug eûcacy is a high priority. ÿ Some drug resistance has been identified in neglected tropical diseases caused by bacteria (leprosy and yaws) and a parasite (visceral leishmaniasis). The resistance observed has been at low levels and does not apply to all available treatments. Drug resistance has not yet been observed in helminths that primarily infect humans. ÿ Antimicrobial resistance is also a phenomenon in other pathogens (such as non-specific bacteria and fungi) that may cause secondary infection in people with TB and HIV. Rising drug resistance levels in bacteria causing common acute infections in humans have been well documented, undermining the ability to treat these infections. 3.1 Factors driving antimicrobial resistance across disease areas Antimicrobial resistance occurs when drugs (antibiotics, antifungal agents, antiviral agents, antimalarial agents and anthelmintic agents) used to treat infections by microorganisms such as bacteria (TB, leprosy and non-specific bacteria), fungi, viruses (HIV) and parasites (malaria, soil- transmitted helminths and trematodes) kill most of the organisms, but sometimes not all, leaving a small subset of resistant microorganisms that survive. The surviving populations can then multiply, allowing infections to persist in the body, potentially leading to increasedmorbidity and mortality and increasing the risk of transmitting the resistant organisms to other people. Non-targeted organisms are also aúected and can be exposed to antimicrobial residues in the environment from hospitals, pharmaceutical production and agricultural activities. Genes for antimicrobial resistance can be transferred between bacteria in the environment (such as from non-pathogenic species to pathogenic species). Antimicrobial resistance in populations of microorganisms is selected over time based on exposure to specific drugs. Themisuse and overuse of antimicrobial AMR_brochure.indd 9 27/03/19 10:12 am 10 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES agents accelerate this process (2). Leading causes of antimicrobial resistance related to these diseases include: ÿ poor treatment practices, such as treatment interruption because of failure to adhere to prescribed treatment; stock-outs or interrupted access to key drugs; use of monotherapies or substandardmedicines; unregulated or informal use of drugs without prescriptions; lack of eúective drugs; use of inappropriate drugs to treat illnesses (such as artemisinin-based combination therapy to treat non-malarial febrile illnesses and antibiotics to treat viral infections); and non-optimal use of antibiotics (such as inadequate regimens or eúective monotherapy to treat TB); ÿ failure to identify drug-resistant pathogens, resulting in ineúective treatment and delayed switch tomore eúective drugs and the potential spread of the resistant pathogens; and ÿ inadequate disease prevention interventions, including poor infection control practices. 3.2 Tuberculosis The TB bacteria can develop resistance to one, two or more antimicrobial drugs used to cure the disease, leading to rifampicin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB). Extensively drug- resistant TB has been reported in 127 countries. MDR-TB is a public health crisis and global health security threat (5). In 2017, MDR-TB or RR-TB caused 558 000 new cases (3.5% of new cases and 18% of previously treated cases) and 230 000 deaths (Fig. 6). Only 25% of the estimatedMDR-TB cases (139 114) were treated, of which 55% that started treatment completed it or were cured (5) (Fig. 6). Three countries accounted for almost half of the world’s cases of multidrug-resistant or rifampicin- resistant TB: India (24%), China (13%) and the Russian Federation (10%). Globally, 3.5% of new TB cases and 18% of previously treated cases had multidrug-resistant or rifampicin-resistant TB (Fig. 7 and 8). The highest proportions (>50% in previously treated cases) are in countries of the former USSR. Among cases of multidrug-resistant TB in 2017, an estimated 8.5% had extensively drug-resistant TB (5). Multidrug-resistant TB is increasing as a proportion of all TB cases in some countries with a high burden of TB, with the burden either increasing faster or decreasingmore slowly than the overall TB burden (5). FIG. 6 Drug-resistant TB treatment cascade Source: Global tuberculosis report 2018 (5). 558 000 ssssssssssssssssssss ssssssssssssssssssss ssssssssssssssssssss ssssssssssssssssssss Estimated newmultidrug-resistant or rifampicin-resistant TB cases in 2017 161 000 ssssssssssssssss Newmultidrug-resistant or rifampicin- resistant TB cases detected in 2017 139 000 ssssssssssssss People starting treatment for multidrug-resistant TB in 2017 55% Treatment success for people starting treatment for multidrug-resistant or rifampicin-resistant TB in 2015 AMR_brochure.indd 10 27/03/19 10:12 am 11STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE FIG. 7 Percentage of new TB cases with multidrug-resistant or rifampicin-resistant TBa a Figures are based on the most recent year for which data have been reported, which varies among countries. Data cover the period 2002–2018. Source: Global tuberculosis report 2018 (5). a Figures are based on the most recent year for which data have been reported, which varies among countries. Data cover the period 2005–2018. The high percentages of previously treated TB cases with RR-TB in Belize, Guam and Sao Tome and Principe refer to only a small number of notified cases (range: 1–8 notified previously treated TB cases). Source: Global tuberculosis report 2018 (5). FIG. 8 Percentage of previously treated TB cases with multidrug-resistant or rifampicin-resistant TB Percentage of cases 0–5.9 6–11 12–29 30–49 ≥50 No data Not applicable Percentage of cases 0–2.9 3–5.9 6–11 12–17 ≥18 No data Not applicable AMR_brochure.indd 11 27/03/19 10:12 am 12 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 3.3 HIV HIV drug resistance is caused by a change (mutation) in the genetic structure of HIV that aúects the ability of a specific drug or combination of drugs to block the replication of the virus. All current antiretroviral drugs are at risk of becoming partly or fully inactive because of the emergence of resistant virus. HIV drug resistance jeopardizes the success of HIV treatment and endangers the attainment of the global targets to end the AIDS epidemic as a public health threat. The emergence of HIV drug resistance threatens the success of the “treat all” approach for HIV because resistance is more likely to lead to illness and potentially death (6). HIV drug resistance is increasing across all WHO regions, with the yearly increases greatest in eastern and southern Africa (Fig. 9). Pretreatment resistance to themost commonly used first-line drugs (efavirenz and nevirapine) has reached the level of 10%1 or greater among people initiating HIV treatment in many low- andmiddle-income countries assessed (6). Women are at great risk of carrying a virus with pretreatment resistance, posing a challenge to eliminating themother-to-child transmission of HIV and tomaternal and child health outcomes; about 50% of children newly diagnosed with HIV are infected with a virus resistant to commonly used first-line drugs (6). Modelling has predicted that, if resistance to the most common first-line drugs exceeds 10% among people starting HIV therapy in sub-Saharan Africa, in 15 years pretreatment drug resistance could be responsible for cumulatively 16% of deaths from AIDS-related causes (890 000 deaths), 9% of the 1 WHO guidelines on HIV drug resistance recommend that countries with levels of pretreatment resistance to efavirenz or nevirapine at or above 10% urgently consider using other HIV drugs in first-line regimens. FIG. 9 Increasing levels of pretreatment resistance to efavirenz and nevirapine, the most commonly used drugs in first-line HIV treatment Source: HIV drug resistance report 2017 (11). Southern Africa Western and central Africa Eastern Africa Asia Latin America 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 Studies: 60 Patients: 11 855 P-value for association: <0.00001 Studies: 51 Patients: 4 924 P-value for association: 0.002 Studies: 50 Patients: 7 169 P-value for association: <0.00001 Studies: 89 Patients: 16 088 P-value for association: 0.01 Studies: 83 Patients: 16 008 P-value for association: <0.00001 20 15 10 5 0 20 15 10 5 0 Pr ev al en ce of N N RT Ir es is ta nc e (% ) Pr ev al en ce of N N RT Ir es is ta nc e (% ) 20 15 10 5 0 20 15 10 5 0 Pr ev al en ce of N N RT Ir es is ta nc e (% ) Pr ev al en ce of N N RT Ir es is ta nc e (% ) 20 15 10 5 0 Pr ev al en ce of N N RT Ir es is ta nc e (% ) Fitted line AMR_brochure.indd 12 27/03/19 10:12 am 13STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE people acquiring HIV infection (450 000 people) and a programme cost of US$ 6.5 billion in sub- Saharan Africa (Fig. 10). Several low- andmiddle- income countries are currently transitioning to new regimens in first-line treatment to which resistance is expected to be low (6). Drug resistancemay also be a challenge in some of the opportunistic infections that aúect people with HIV, such as TB, cryptococcal meningitis (9), sexually transmitted infections and candidiasis (10). 3.4 Malaria Malaria is caused primarily by the Plasmodium falciparum and P. vivax parasites. Artemisinin- based combination therapy (ACT) is used to treat P. falciparum and chloroquine-resistant strains of P. vivax. Chloroquine- or ACTs, complemented with primaquine, are recommended for treating P. vivax in areas with chloroquine-susceptible infections (12). The scale-up of ACTs has been integral to the recent success of global malaria eúorts and protecting their eûcacy in treatingmalaria is a global health priority. The eûcacy of artemisinin- based combination therapy is threatened by the emergence of both artemisinin and partner drug resistance. Partner drug resistance can arise independently of artemisinin partial resistance. Partner drug resistance with or without artemisinin partial resistance increases the risk of treatment failure, and association of artemisinin resistance will worsen the treatment failure rate (12). Artemisinin partial resistance is currently limited to five countries of the Greater Mekong subregion: Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam (Fig. 11) and is suspected in Guyana, Papua NewGuinea and Rwanda. Artemisinin partial resistance has not been confirmed in Africa; multi-drug resistance2 is present in Cambodia, the Lao People’s Democratic Republic, Thailand and Viet Nam (12). P. vivax resistance is geographically widespread, but in many countries the parasite is still susceptible to chloroquine, especially when primaquine is taken concurrently. P. vivax resistance to 2 Multidrug-resistant malaria is defined as resistance to more than two antimalarial compounds of diúerent chemical classes. This term usually refers to P. falciparum resistance to chloroquine, sulfadoxine-pyrimethamine and a third antimalarial compound. FIG. 10 Predicted impact of HIV drug resistance in sub-Saharan Africa if levels of resistance to efavirenz and nevirapine, the most commonly used drugs in first-line HIV treatment, reach or exceed 10% Source: Global action plan on HIV drug resistance 2017–2021 (6). PROJECTED IMPACT IN SUB-SAHARAN AFRICAWHERE PPRETREATMENT HIV DRUG RESISTANCE ≥10% 2016–2021 2016–2030 2016–2021 2016–2030 2016–2021 2016–2030 FIRST LINE SECOND LINE THIRD LINE NEWHIV INFECTIONS AIDS DEATHS 148 000 TREATMENT COST IN US$ 450 000 150 000 890 000 $750million $6500 million $85 $1235$263 Cumulative cost Annual cost per person (2016) AMR_brochure.indd 13 27/03/19 10:12 am 14 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES artemisinin-based combination therapy has not been documented and thus artemisinin-based combination therapy can be used where there is extensive chloroquine resistance (12). WHO recommends that countries change their first-line treatments for P. falciparum and P. vivax when treatment failure rates exceed 10% (12). 3.5 Neglected tropical diseases Neglected tropical diseases (13) are a diverse group of 20 diúerent diseases that mostly aúect low- income andmarginalized populations. For many neglected tropical diseases, the risk of developing resistance to treatment is considered low because of the nature of the diseases (such as parasites with relatively long life cycles) or because no treatments are available to become resistant to (such as dengue, rabies, etc). Some drug resistance has been identified for neglected tropical diseases caused by bacteria – such as leprosy and yaws – and a parasite: visceral leishmaniasis. The resistance observed has been at low levels and does not apply to all available treatments. Drug resistance has not yet been observed for helminths that primarily infect humans. Antibiotic resistance to at least one of the three antibiotics used to treat leprosy has been detected in 19 countries. Eight per cent of the bacteria were resistant to at least one commonly used antibiotic. Resistance to two diúerent antibiotics was identified in 24 cases. Drug resistance was observed in 12 countries among 5.1% of relapses and 2.0% of new cases. Three countries (Brazil, Colombia and India) reportedmore than five resistant cases. The numbers of resistant cases are still low, and no bacterial strain has yet shown resistance to all three antibiotics simultaneously (14). Drug resistance has been reported to some first- line medicines used to treat yaws (15) and visceral leishmaniasis (16). The strategies for preventing and treating trachoma and yaws call for mass administration of the antibiotic azithromycin to populations at risk (17,18). This intervention can lead to increases in drug resistance related to non-targeted potentially pathogenic bacteria (such as Streptococcus pneumoniae). Care is therefore required to plan the mass drug administration tominimize the potential for increasing drug resistance related to non- targeted bacteria (19). Anthelmintic resistance is not yet a public health problem in human helminthiasis, where mass drug administration is a recommended intervention (schistosomiasis, onchocerciasis, lymphatic filariasis and soil-transmitted helminthiasis), but resistance is problematic in helminths of veterinary importance, indicating that resistance could develop (20). FIG. 11 Number of artemisinin-based combination therapies failing in the Greater Mekong Subregiona a Countries are classified by numbers of ACTs failing (>10% treatment failure) after 2010. Source: World malaria report 2018 (12). AMR_brochure.indd 14 27/03/19 10:12 am 15STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 4. Preventing antimicrobial resistance related to TB, HIV, malaria and neglected tropical diseases and theWHO response KEY MESSAGES ÿ Achieving universal health coverage and strengthening health systems are key factors for preventing antimicrobial resistance across all diseases and service delivery areas. ÿ For TB, HIV, malaria and neglected tropical diseases, antimicrobial resistance often can be predicted, prevented, managed and controlled bymaintaining focus on it and developing and implementing the right strategies. ÿ Drug resistance is often amarker of poor-quality treatment service delivery, and identifying and addressing quality gaps is important for preventing resistance. ÿ Surveillance, laboratory strengthening and expansion of laboratory services, enhanced data collection and use and better communication, awareness-raising, education and training are key components of all strategies for preventing andmanaging antimicrobial resistance and could be expanded to synergistically address antimicrobial resistance across all disease and service delivery areas. ÿ Addressing infectious diseases and antimicrobial resistance within the context of universal health coverage in amore integrated way oúers opportunities for eûciency and better outcomes. 4.1 Preventing antimicrobial resistance Preventing drug resistance is a critical component of any national communicable disease programme and is achieved by optimizing service delivery and eliminating programmatic gaps in disease prevention, treatment and care. WHO regularly updates its guidelines to optimize service delivery to prevent and treat TB, HIV, malaria and neglected tropical diseases. General disease prevention reduces both the overall disease burden and the transmission of sensitive and resistant pathogens – thus aúecting the spread of antimicrobial resistance. WHO also produces specific guidance for managing drug-resistant infections. These include: policy recommendations on the overall public health response required; clinical and programmatic guidance on selecting themost appropriate interventions and treatment regimens, including diagnostic and drug resistance testing; managing programmes and rationally usingmedicines; and possible recommendations on restricting access to drugs by prescription or using combination therapies. WHO policy and recommendations are informed by programmatic data on access to and use of preventive measures, resistance surveillance and eûcacy data and are routinely updated on the prevention, diagnosis and treatment of TB, HIV, malaria and neglected tropical diseases. WHO also produces guidance on other interventions and supporting programmes to better manage antimicrobial resistance in general, such as preventing and controlling infections in clinical settings, water, sanitation and hygiene in clinical settings, procurement and supply chain management, prequalification of drugs and other areas. Table 1 highlights examples ofWHO activities to identify, prevent andmanage antimicrobial resistance. AMR_brochure.indd 15 27/03/19 10:12 am 16 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES Preventing antimicrobial resistance also requires strengthening health systems to provide the needed products and services to people at the time they are required: for example, including critical, quality-assuredmedicines on lists of essential medicines; ensuring functioning supply chains that deliver the requiredmedicines to health-care facilities; preventing stock-outs and treatment disruption; and ensuring that clinical personnel have the necessary tools (such as treatment algorithms) to enable them to eúectively identify and treat a wide range of illnesses with the appropriate drugs. For example, expanded use of malaria rapid diagnostic tests does not always lead to the right treatment outcome. Artemisinin- based combination therapy is sometimes still given to patients with negative tests or antibiotics are provided to treat fever without confirmation that bacteria are the cause (21). This leads to potential misuse and overuse of artemisinin-based combination therapy or antibiotics and increased risk of drug-resistant malaria parasites or non- specific bacteria. For chronic diseases such as HIV, resistance can be prevented by national and clinic- based strategies that support optimal adherence to treatment and retention in care. 4.2 Surveillance of antimicrobial resistance Surveillance involves collecting, analysing and interpreting epidemiological data on antimicrobial resistance. Data can be collected from surveys that cover selected populations or at the individual level from routine data provided by health facilities and laboratories. Surveillance is critically important for monitoring trends and developing evidence- informed policies and interventions to prevent and manage antimicrobial resistance. In the past decades, WHO has helped to establish global, regional and country-level surveillance systems tomonitor drug resistance and therapeutic eûcacy trends in TB, HIV, malaria and neglected tropical diseases (Boxes 1–4). Overall, WHO supports drug resistance and therapeutic eûcacy surveillance activities in nearly all aúected countries: 160 countries for multidrug-resistant TB, 69 countries for HIV drug resistance and 64 countries for malaria, representingmost of the world’s population andmost of the burden of high- impact communicable diseases. Drug resistance status and trends for these diseases are routinely published in disease-specific reports and in peer- reviewed publications. To support the second strategic objective of the Global Action Plan on Antimicrobial Resistance to strengthen the knowledge and evidence base through surveillance and research, WHO launched the Global Antimicrobial Resistance Surveillance System (GLASS) in October 2015 and started country enrolment inMarch 2016. GLASS fosters the development of national antimicrobial resistance surveillance systems and provides a standardized approach to collecting, analysing and sharing antimicrobial resistance data for bacteria causing common acute infections. To date, 72 countries participate in GLASS (22). As a core function of disease-specific programmes, WHO surveillance activities include: ÿ developing standardizedmethods and tools for antimicrobial resistance surveillance, data collection and analysis; ÿ routinely collecting, quality assuring, analysing and disseminating surveillance data on drug resistance and therapeutic eûcacy and resistance trends at the global, regional and national levels; ÿ using surveillance data to informWHO guidelines and national treatment policies; ÿ providing guidance on appropriate programme indicators associated with and predictive of resistance to be included in health information systems; ÿ providing a framework for early detection and reporting of emerging antimicrobial resistance; ÿ building global data repositories, country databases and portals to support countries in storing, quality assuring and disseminating their data in a timely fashion; and ÿ providing technical support to countries in designing and conducting drug resistance and therapeutic eûcacy studies and surveys and in collecting, quality assuring, analysing, interpreting and disseminating their data. AMR_brochure.indd 16 27/03/19 10:12 am 17STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE TA BL E 1 Pa th og en re si st an ce ,r es is ta nc e m on it or in g an d W H O ac ti vi ti es Pa th og en St at us of re si st an ce a Re si st an ce m on ito rin g W H O ac tiv iti es to id en tif y, pr ev en ta nd m an ag e dr ug re si st an ce Ep id em io lo gi ca lm et ho ds fo rp op ul at io n- le ve lm on ito rin g an d su rv ei lla nc e of dr ug re si st an ce La bo ra to ry m et ho ds fo r re si st an ce de te ct io n Li te ra tu re re vi ew N at io na lly an d re gi on al ly re pr es en ta tiv e su rv ey s Co lle ct io n an d us e of ro ut in e dr ug re si st an ce da ta Th er ap eu tic eþ ca cy st ud ie sa t se nt in el si te s (p ar as ite cl ea ra nc e) Cu ltu re M ol ec ul ar m et ho ds (g en e pr ob es , se qu en ci ng ) G lo ba l m on ito rin g an d re po rt in g St an da rd iz ed pr ot oc ol sa nd to ol sf or dr ug re si st an ce su rv ei lla nc e, da ta co lle ct io n, an al ys is an d in te rp er ta tio n G lo ba l da ta ba se G lo ba l la bo ra to ry ne tw or ks w ith W H O de si gn at io n Te ch ni ca l as si st an ce fo rc ou nt rie s to im pl em en t dr ug re si st an ce su rv ey sa nd st ud ie s Ea rly w ar ni ng in di ca to rs fo rd ru g re si st an ce em er ge nc e HI V X X X X X X X X M yc ob ac te riu m tu be rc ul os is (T B) X X X X X X X X X X Pl as m od iu m (m al ar ia ) X X X X X X X X M yc ob ac te riu m le pr ae or le pr om at os is (le pr os y) X X X Tr ep on em a pa lli du m (y aw s) b X Le ish m an ia do no va ni (v is ce ra ll ei sh m an ia si s) X Ch la m yd ia tr ac ho m at is (tr ac ho m a) b X X X X He lm in th s( so il- tr an s- m itt ed he lm in th ia si s) c X X X X d X d He lm in th s (s ch is to so m es )c X X X d X d a G re en = n o d o cu m en te d re si st an ce ;o ra n g e = d ru g re si st an ce d o cu m en te d b u t n o t w id es p re ad o r re m ai n s re g io n al ly co n fi n ed ;r ed = d ru g re si st an ce as cu rr en t g lo b al h ea lt h th re at . b In te rv en ti o n s re q u ir e m as s d ru g ad m in is tr at io n w it h th e sa m e an ti b io ti c az it h ro m yc in ;m as s u se h as le d to d ru g re si st an ce in ya w s b ac te ri a an d o th er p at h o g en ic b ac te ri a b u t n o t tr ac h o m a b ac te ri a. c A n th el m in th ic d ru g re si st an ce h as b ee n o b se rv ed in h el m in th s th at in fe ct d o m es ti c an im al s b u t n o t ye t in st ra in s th at p ri m ar ily in fe ct h u m an s. d U n d er d ev el o p m en t. HIV AMR_brochure.indd 17 27/03/19 10:12 am 18 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES BOX 1 Surveillance of resistance to TB Established in 1994, the global surveillance system for TB drug resistance remains the oldest and largest initiative on antimicrobial resistance surveillance in the world (Fig. 12). TB Surveillance data are being collected either (1) through continuous surveillance systems based on routine testing of everyone with TB in countries with extensive laboratory capacity or (2) through periodic surveys, which are discrete studies measuring drug resistance among a selected sample of people who are representative of an entire population of people with TB in countries with insuûcient laboratory capacity for routine drug susceptibility testing of everyone with TB. Standardizedmethods allow comparability of data within countries over time and between countries. Surveillance data on TB drug resistance are collected annually through a web-based data collection tool that gathers notification data on everyone with TB worldwide. On average, 15 country surveys are conducted every year. Newmolecular technologies, including whole-genome sequencing technologies, have recently been incorporated into drug resistance surveys. Since 1994, data on drug resistance have been systematically collected and analysed from 165 countries (82% of the 194WHO Member States), which collectively represent more than 97% of the world’s population and TB cases (23,24). FIG. 12 Global coverage of surveillance data on TB drug resistance Source: Global tuberculosis report 2018 (5). Year of most recent data 1995–1999 2000–2004 2005–2009 2010–2014 2015–2018 Ongoing in 2018 Subnational data No data Not applicable AMR_brochure.indd 18 27/03/19 10:12 am 19STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE BOX 2 Surveillance of HIV drug resistance The emergence and transmission of some level of HIV drug resistance is inevitable, even when appropriate regimens are prescribed and adherence to treatment is optimal. To address this challenge, WHO developed a global strategy for the surveillance andmonitoring of HIV drug resistance in 2004 and updated it in 2015. The strategy includes four key activities: (1) annual monitoring of quality-of- care indicators of HIV drug resistance at all antiretroviral therapy clinics in a country; (2) surveillance of pretreatment HIV drug resistance among adults initiating first-line antiretroviral therapy; (3) surveillance of acquired HIV drug resistance in adults and children receiving treatment; and (4) surveillance of HIV drug resistance among children younger than 18months newly diagnosed with HIV. Survey data were generated from sentinel clinics from 2004 to 2014, but since 2014, nationally representative HIV drug resistancemethods have been recommended. The data generated from the HIV drug resistance surveys are representative of the entire population of individuals with HIV initiating HIV treatment or receiving HIV treatment, respectively. Since 2004, data from 271 surveys in 69 countries have been collected using standardized epidemiological and laboratory methods, allowing comparability of data within countries over time and across countries (Fig. 13). The survey results have been used to inform policies and treatment guidelines at the national and global levels. Quality assurance and dissemination of HIV drug resistance data are core activities ofWHO. Surveillance data for HIV drug resistance are entered and safely stored in theWHO global HIV drug resistance database, which has three main purposes: (1) supporting countries and genotyping laboratories in the quality assurance of epidemiological and sequence data for the purpose of generating high-quality country reports; (2) providing standardized resistance interpretations by linking to themost recent algorithm for interpreting HIV drug resistance; and (3) providing countries with a long-term secure repository for their HIV drug resistance data (25,26). A global network ofWHO-designated laboratories for HIV drug resistance supports the global eúort by producing reliable and quality-assured genotypic data. AMR_brochure.indd 19 27/03/19 10:12 am 20 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES BOX 3 Surveillance of antimalarial drug eÿcacy WHO set up surveillance of antimalarial drug eûcacy in 1996 with the development of a standard protocol to monitor antimalarial eûcacy through therapeutic eûcacy studies in collaboration with the United States Centers for Disease Control and Prevention. The protocol was first implemented in areas with highmalaria transmission rates, mainly in Africa. Later the standard protocol was updated twice to include countries with low tomoderate malaria transmission rates. WHO has developed a series of tools (including in vitro tests, molecular analysis andmeasuring drug concentrations) to better define and detect drug resistance among treatment failures. The use of these standardized procedures facilitates the comparison of results within and across regions over time.WHO organizes training at the regional and country levels on drug eûcacy monitoring and continually supports regional networks on drug eûcacy (27). WHO set up a global database in response to the challenges posed by the emergence of resistance to antimalarial drugs. The contents of the database are extracted from published and unpublished therapeutic eûcacy studies and surveys of molecular markers on antimalarial drug resistance conducted by partners at the country level. The database is the source forWHO’s onlineMalaria Threats Map, theWorld malaria report and update reports on antimalarial drug eûcacy and drug resistance. WHO has provided support in creating subregional networks for monitoring antimalarial resistance. TheMekong network, the Red Amazónica para la Vigilancia de la Resistencia a las Drogas Antimaláricas (RAVREDRA) network, the Pacific network, the BBINS (Bangladesh, Bhutan, India, þ FIG. 13 Global coverage of WHO-recommended surveillance surveys on HIV drug resistance Source: Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report (26). 2004–2013 2014–2017 2017–2018 Planned No data Not applicable Year of most recent survey AMR_brochure.indd 20 27/03/19 10:12 am 21STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE þ Nepal, Sri Lanka) network, the Horn of Africa Network for Monitoring Antimalarial Treatment (HANMAT) and PIAMNET (Pakistan, Islamic Republic of Iran and Afghanistanmonitoring network) have successfully increased drug eûcacy surveillance in the regions and generated the data needed for updating national treatment policies. Through these networks, WHO has oúered training for implementing protocols, microscopy, analysing and validating data and preparing reports and publications, which in turn improved the quality of the data. BOX 4 Therapeutic eÿcacy testing for selected neglected tropical diseases Threats of growing drug resistance related to some neglected tropical diseases has ledWHO to call for monitoring drug eûcacy and resistance at selected sentinel sites. TheWHO Strategic and Technical Advisory Group on Neglected Tropical Diseases has created a subgroup to support themonitoring of drug resistance in neglected tropical diseases. WHO has developed standard protocols for monitoring the eûcacy of the anthelminthic drugs used in preventive chemotherapy. Research is currently ongoing to develop appropriate combinations of anthelminthics to prevent or respond to the emergence of resistance. Countries have been encouraged to use theWHO-recommended protocols to monitor the local situation. TheWorking Group onMonitoring Neglected Tropical Diseases Drug Eûcacy is working to establish a network of laboratories with experience evaluating anthelminthic drug eûcacy and to developmore sensitive methods to measure anthelminthic eûcacy. 4.3 Laboratory networks For TB, HIV, malaria and neglected tropical diseases, drug resistance cannot yet be directly detected at the point of care. Samples (sputum, blood and faeces) are collected from patients and analysed in laboratories. In some cases, organisms are cultured and tested for resistance, or molecular methods (gene probes or sequencing) are used to detect resistance genes. For malaria and some neglected tropical diseases (soil-transmitted helminths and trematodes), therapeutic eûcacy tests are used to screen for treatment failure, which may be related to drug resistance. Support to strengthen and expand laboratory services is often needed to detect drug resistance (Box 5). WHO’s role has been to support the development and expansion of national, regional or specialized reference laboratories that monitor TB and HIV drug resistance (Fig. 14 and 15). WHO activities include: ÿ developing standardized drug resistance testing protocols, assay validation, standard operating procedures, tools and quality standards for internal and external quality assurance; ÿ undertaking quality assurance of resistance data and therapeutic eûcacy testing data to ensure accurate and reliable laboratory results and to facilitate the comparison of data over time and across countries; ÿ designating specialized, regional and national reference laboratories that support resistance testing for surveillance and diagnostic purposes from countries with limited or no testing capacity; ÿ identifying opportunities for eûciently integrating drug resistance and therapeutic eûcacy monitoring into broader national antimicrobial resistance and laboratory strengthening strategies and plans, including using shared health systems and laboratory platforms; and ÿ training laboratory workers, facilitating South– South collaboration across laboratories and strengthening laboratory capacity to detect and report on drug resistance at the country and regional levels. AMR_brochure.indd 21 27/03/19 10:12 am 22 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES FIG. 14 WHO TB Supranational Reference Laboratory Network Source: WHO TB Supranational Reference Laboratory Network [website] (24). Supranational Reference Laboratory – Coordinating Centre Supranational Reference Laboratory National Centre of Excellence Milan, Italy Rome, Italy Santiago, Chile Antwerp, Belgium Atlanta, USA Mexico City,Mexico Guadeloupe, France Buenos Aires, Argentina Adelaide, Australia Brisbane, Australia Bangkok, Thailand Hong Kong SAR, China Seoul, Republic of Korea Tokyo, Japan Chennai, India Karachi, Pakistan Delhi, India Cairo, Egypt Johannesburg, South Africa Kampala, Uganda Cotonou, Benin Le Hamma, Algeria Porto, Portugal Barcelona, Spain London, UK Gauting, Germany Borstel, Germany Copenhagen, Denmark Stockholm, Sweden Riga, Latvia Zagreb, Croatia Prague, Czech Republic Moscow, Russian Federation Yekaterinburg, Russian Federation Novosibirsk, Russian Federation FIG. 15 HIV Drug Resistance Laboratory Network as of July 2018 Source: Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report (26). WHO-designated national laboratory for HIV drug resistance testing WHO-designated regional laboratory for HIV drug resistance testing WHO-designated specialized laboratory for HIV drug resistance testing WHO-designated laboratory for HIV drug resistance testing using dried blood spot Laboratory with capacity for HIV drug resistance testing of integrase inhibitors Kampala Addis Ababa Dakar Johannesburg Kisumu Mexico City Atlanta Fort de France Ponce Rio de Janeiro (x2) Vancouver Winnipeg Bordeaux London Montpellier Utrecht Bangkok (x2) Chennai Pune Beijing Hanoi Ho Chi Minh City Shanghai Shenyang Sydney Abidjan Entebbe AMR_brochure.indd 22 27/03/19 10:12 am 23STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE BOX 5 Laboratory networks for TB, HIV and neglected tropical diseases WHO established a global TB drug resistance surveillance programme in 1994, supported by a network of global TB supranational reference laboratories. As of December 2018, 155 countries participated in the TB drug resistance surveillance programme, coveringmore than 95% of the world’s population and TB cases. The network of supranational reference laboratories includes 36 laboratories overseeing the drug resistance surveillance programme throughmore than 100 national TB reference laboratories (24). A global HIV drug resistance laboratory network was established in 2005 to support HIV drug resistance surveillance activities. As of July 2018,WHO had designated 30 laboratories in five of WHO’s six regions (Africa, the Americas, Europe, South-East Asia and theWestern Pacific) to conduct HIV drug resistance testing for public health surveillance (26). The first steps to establish a global neglected tropical disease drug resistance laboratory network were taken in February 2019: theWorking Group onMonitoring Neglected Tropical Diseases Drug Eûcacy met to define the terms of reference of the networks and the characteristics, capacity and geographical distribution of the laboratories that will be part of the network. 4.4 Communication, awareness-raising, education and training The first strategic objective of the Global Action Plan on Antimicrobial Resistance is to improve awareness and understanding of antimicrobial resistance through eúective communication, education and training. As highlighted in Section 3, antimicrobial resistance threatens sustainable development and is a major risk to ending the HIV, TB andmalaria epidemics. It is therefore critically important to maintain the issue of drug resistance on the global and national development agendas. WHO is working to improve awareness and understanding of drug resistance in countries, with diúerent audiences, as part of long-standing programmes in TB, HIV, malaria and neglected tropical diseases. Ongoing activities include: ÿ conveningMember States, civil society, researchers, implementing partners, donors, developers of drugs and diagnostics and other stakeholders to increase awareness and understanding around the status and impact of resistance; ÿ engaging and convening experts (through strategic and technical advisory groups, technical expert groups, global working groups etc.) to ensure timely and appropriate responses to elevated levels of resistance when they arise; ÿ compiling, interpreting and disseminating information and data on drug resistance to countries and development partners and supporting the strengthening of their situation analyses; ÿ using data generated by surveillance to inform policy and recommendations; ÿ providing regular updates about drug resistance trends toMember States throughmeetings of WHOGoverning Bodies and urging countries to take action; ÿ using international days mandated by theWorld Health Assembly (such asWorld Tuberculosis Day, WorldMalaria Day, World AIDS Day andWorld Antibiotic AwarenessWeek) to raise awareness about the challenge of drug resistance; ÿ supporting knowledge transfer, training and capacity development ofWHO regional and country oûces as well as national disease programmes on prevention and clinical and programmatic management of drug-resistant TB, HIV, malaria and neglected tropical diseases; AMR_brochure.indd 23 27/03/19 10:12 am 24 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES ÿ engagingmanufacturers of diagnostics, drugs andmedical devices in dialogue to ensure that key medicines are aúordable and that drugs that contribute to antimicrobial resistance are taken oú the market (such as malaria monotherapies); ÿ involving civil society and engaging communities in improving literacy on resistance and treatment adherence; ÿ engaging all relevant health-care providers in disease treatment, care and control through public–private mix approaches; and ÿ supporting countries in developing and implementing comprehensive national action plans to address antimicrobial resistance that include TB, HIV, malaria and neglected tropical diseases where relevant. AMR_brochure.indd 24 27/03/19 10:12 am 25STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 5. Future directions KEY MESSAGES ÿ Addressing antimicrobial resistance is part of the agendas of universal health coverage, patient safety and the quality of health-care services. ÿ Innovation and research in treatment and diagnostics will play key roles in reducing the development and spread of drug resistance related to TB, HIV, malaria and neglected tropical diseases and its risk to health. ÿ Product development partnerships have demonstrated eúectiveness in identifying and facilitating the development of new pipeline drugs for TB, malaria and neglected tropical diseases as drug resistance to current therapies spreads. ÿ Sets of clinical and programmatic quality-of-care indicators that predict and are associated with developing drug resistance have been identified andmonitored for HIV. Similar approaches might be explored to predict the emergence of resistance related to other diseases or at health-care delivery points, enabling early action to prevent andminimize the spread of antimicrobial resistance. ÿ Antimicrobial resistance related to bacteria, TB, HIV, malaria and neglected tropical diseases is a critical issue and needs to be kept high on the global, regional and national health development agendas. ÿ WHO has a key role to play in compiling and disseminating information on levels of resistance and trends as well as innovative practices to prevent, manage and control the development and spread of antimicrobial resistance related to TB, HIV, malaria, bacteria, fungi and neglected tropical diseases. ÿ WHO, working collaboratively with other development partners, will provide joint support to countries in developing, implementing and tracking progress against comprehensive, evidence-informed national antimicrobial resistance action plans that include TB, HIV, malaria and neglected tropical diseases where relevant. ÿ WHOwill work with countries to identify andmaximize synergy across programmes or service delivery areas and platforms to address TB, HIV, malaria and neglected tropical diseases antimicrobial resistance. AMR_brochure.indd 25 27/03/19 10:12 am 26 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 5.1 Identify research and development gaps and new tools and approaches New products, technologies and service delivery approaches will be needed to address antimicrobial resistance related to TB, HIV, malaria, neglected tropical diseases and across the whole spectrum of antimicrobial resistance. Research and development will play an important role in preventing and managing antimicrobial resistance. WHO has a clear leadership role to play in identifying prevention andmanagement gaps in antimicrobial resistance related to TB, HIV, malaria and neglected tropical diseases, which can include the need for new products and approaches to service delivery. WHO’s role includes: ÿ monitoring antimicrobial resistance prevalence and trends to assess needs and gaps; ÿ identifying and setting global, regional and national research agendas and priorities for antimicrobial resistance; ÿ convening institutions and expert networks to address antimicrobial resistance gaps, including collaborative eúorts to identify antimicrobial resistancemanagement needs in the animal health and agricultural sectors (such as through the FAO/OIE/WHO Tripartite Collaboration on Antimicrobial Resistance and UNEP) and how this aúects human health; ÿ compiling and disseminating good practices in preventing andmanaging antimicrobial resistance to facilitate changes in approaches to service delivery to address gaps in service quality and eúectiveness; ÿ supporting countries in conducting implementation research across a variety of settings and populations to improve approaches to service delivery (such as improving treatment adherence, preventing drug stock-outs, identifying drug resistance and optimizing treatment protocols in the face of increasing resistance) or address other factors that lead to the emergence and spread of antimicrobial resistance; ÿ assessing the burden of disease caused by antimicrobial resistance; and ÿ advocating for increased research and development investment to strengthen product pipelines that address aspects of antimicrobial resistance. To prevent andmanage drug resistance related to TB, HIV, malaria and neglected tropical disease, WHO can: ÿ identify and advocate for the development of better andmore aúordable tools, such as vaccines, eúective drugs with shorter or simplified treatment protocols, point-of-use diagnostic tests, gene sequencing andmolecular methods for surveillance of drug resistance; ÿ recommendmodels of service delivery that improve the quality and follow-up of key interventions that influence antimicrobial resistance, such as treatment adherence, diagnostic testing and appropriate response, algorithms to ensure eúective treatment and infection control to minimize disease transmission in hospital settings; ÿ collaborate to further address antimicrobial resistance in the animal husbandry and agricultural sectors; ÿ engage with product development partnerships, the private sector and other partners to advocate for developing new drug candidates (Box 6) or diagnostics and other products (Box 7); and ÿ support countries in rapidly adopting innovative practices or new products to prevent or manage antimicrobial resistance for maximum impact. AMR_brochure.indd 26 27/03/19 10:12 am 27STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE BOX 6 Product development partnerships to identify and develop new candidate drugs TheMedicines for Malaria Venture (MMV) and Drugs for Neglected Diseases initiative (DNDi) are product development partnerships that have identified and developed an innovative model to develop new pipeline drugs to treat malaria and neglected diseases. These partnerships provide a systematic way for partners to work together to identify and develop newmedicines and/or better formulations to increase the pipeline of available drugs to treat malaria and neglected tropical diseases. These partnerships facilitate the development of drugs that pharmaceutical companies may be reluctant to pursue by themselves because of economic considerations. Since it was created in 1999, MMV has built an extensive network of over 400 pharmaceutical, academic and endemic-country partners in more than 55 countries and has developed and brought forward 10 newmedicines to treat malaria (28). Increasing the pipeline of available malaria drugs will help to mitigate the impact if current resistance to artemisinin-based combination therapy becomes widespread. The product development partnership model has also been used to address drug resistance related to other diseases. The Global Antibiotic Research and Development Partnership was established inMay 2016 as a joint initiative byWHO and the DNDi. This not-for-profit research and development initiative addresses global public health needs by developing and delivering new or improved antibiotic treatments while endeavouring to ensure sustainable access. It also harnessesWHO’s mandate to drive the global response to antimicrobial resistance and set health priorities and DNDi’s expertise in maximizing partnerships to build a pipeline for neglected diseases and deliver not-for-profit, needs-driven research and development. Various partners and donors are contributing to this collaborative eúort. In 2010, theWHODepartment of Control of Neglected Tropical Diseases established theWorking Group onMonitoring Neglected Tropical Diseases Drug Eûcacy to promote the testing of new anthelminthic drugs or combinations of existing drugs. The group identified several potential drug candidates. ThreeWHO collaborating centres are participating in this working group. BOX 7 Role of development partners in the response to antimicrobial resistance In recent years, the work to respond to antimicrobial resistance has benefited from investment by technical agencies, donor initiatives and the private sector. Unitaid, the United States Agency for International Development (USAID) and the Bill &Melinda Gates Foundation have supported trials and other studies of newmedicines and novel regimens for multidrug-resistant TB (such as the EndTB project coordinated by Partners in Health, Médecins Sans Frontières and Interactive Research and Development in Pakistan; the Global Alliance for TB Drug Development; and the STREAM trial of a shorter nine-monthmultidrug-resistant TB regimen). The initiatives of manufacturers of diagnostics (such as HAIN for line probe assay and CEPHEID for GeneXpert) andmedications (such as bedaquiline by Janssen and delamanid by Otsuka) have also been critical to improvemultidrug-resistant TB care. Unitaid has made critical contributions to support national TB laboratory networks to consolidate their work and implement new diagnostics for drug-resistant TB (EXPAND-TB project) and improve access to new TBmedicines. þ AMR_brochure.indd 27 27/03/19 10:12 am 28 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES þ For HIV, the Bill &Melinda Gates Foundation has supported the establishment of theWHOGlobal Strategy for the Surveillance andMonitoring of HIV Drug Resistance and the Global Action Plan on HIV Drug Resistance; the Global Fund to Fight AIDS, Tuberculosis andMalaria and the United States President’s Emergency Plan for AIDS Relief (PEPFAR) have supported countries in implementing national HIV drug resistance surveys and in strengthening laboratory capacity for HIV drug resistance testing. The United States Centers for Disease Control and Prevention has provided technical assistance to PEPFAR-supported countries in activities related to surveillance of HIV drug resistance. The United States National Institutes of Health provide in-kind support to the quality assurance of the global HIV drug resistance laboratory network. Over the years, some specializedWHO-designated HIV drug resistance laboratories (such as the University of British Columbia (Vancouver, Canada), Public Health Agency of Canada (Winnipeg, Canada); Center for Research in Infectious Diseases (CIENI, Mexico City, Mexico), United States Centers for Disease Control and Prevention/Global Action Plan on Antimicrobial Resistance (Atlanta, USA) have provided HIV drug resistance testing free of charge to support HIV drug resistance surveillance in several low- andmiddle-income countries with limited financial and technical capacity. Other partners, including the Public Health Agency of Canada, have contributed to diúerent aspects of HIV drug resistancemonitoring and surveillance eúorts. HIVResNet, a large network of institutions and experts, has provided strategic guidance to WHO over the years and contributed to the global eúorts to monitor, respond to and prevent HIV drug resistance. Unitaid is funding clinical trials for emerging antiretroviral medicines and supports treatment monitoring to facilitate treatment optimization, including for children. Partners have also played a key role in the work to develop newmalaria treatments, in supporting the surveillance of the eûcacy of existing antimalarial drugs, and in the eúorts to contain resistance and eliminate malaria in the Greater Mekong Subregion. The Bill &Melinda Gates Foundation, the Australian Department of Foreign Aúairs and Trade, the United KingdomDepartment for International Development, the Global Fund to Fight AIDS, Tuberculosis andMalaria and USAID provide essential support to the surveillance of eûcacy. The Global Fund to Fight AIDS, Tuberculosis andMalaria is the main funder of the work to eliminate P. falciparummalaria in the Greater Mekong subregion and thereby minimize the risk of future spread of drug-resistant parasites from this area. Unitaid is also fundingmalaria projects to improve diagnostics and prevention for pregnant women. The Bill &Melinda Gates Foundation and USAID have provided financial support for neglected tropical diseases, identifying alternative anthelminthics and establishing a network of laboratories while technical support was provided by three collaborating centres in Basel, Switzerland, Ghent, Belgium and Negrar, Italy and byMcGill University, the University of Texas, the University of London and Universidad de Valencia. 5.2 Clinical and programmatic indicators associated with and predicting the emergence of antimicrobial resistance Evidence from HIV programmes has shown that it is possible to identify andmonitor a set of programmatic quality-of-care indicators that provide an early warning for the emergence of drug resistance in certain populations or settings (see Box 8 and Table 2). Monitoring this set of indicators can help to predict where resistancemay emerge, enabling corrective actions to be taken to prevent the emergence and subsequent spread of drug resistance (29). For several diseases (such as TB, HIV and leprosy) drug resistance is more likely to arise among people who have been previously treated and stopped treatment or experienced treatment failure. This should prompt the use of a diúerent drug combination for subsequent treatment AMR_brochure.indd 28 27/03/19 10:12 am 29STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE regimens in accordance withWHO treatment guidelines. For neglected tropical diseases, the emergence of parasite resistance to some anthelminthics used to treat infections in livestock signals that human pathogenic helminth strains also need to bemonitored for resistance, especially given the scale of themass drug administration approaches used to treat these parasites in humans. Future work across disease areas might help to identify common sets of service delivery and/ or quality-of-care indicators that can be routinely monitored to prevent the emergence and spread of drug resistance. BOX 8 Quality-of-care indicators associated with and predicting the emergence of HIV drug resistance Monitoring a subset of quality of care indicators – also known as early warning indicators of HIV drug resistance – is a key component of theWHO public health strategy to prevent HIV drug resistance in countries scaling up antiretroviral therapy. These quality-of-care indicators specifically assess factors at individual antiretroviral therapy clinics associated with and predicting the emergence of HIV drug resistance. Monitoring these quality-of-care indicators is designed to provide countries with actionable information to improve clinical and programmatic performance to prevent HIV drug resistance from emerging. Many factors are associated with the emergence of HIV drug resistance. They include viral factors (such as subtype, replication capacity and pre-existing polymorphisms); drug-related factors (such as drug potency, pharmacokinetics, drug–drug interactions, drug tolerability and genetic barriers to selecting resistance) and programme factors (such as patient adherence, drug stock-outs and supply continuity and retention in treatment). Although viral and drug-related factors are often beyond the control of public health or programme action, monitoring the clinical or programmatic factors associated with HIV drug resistance can alert antiretroviral therapy programmes to situations that may favour the emergence of HIV drug resistance or failure to suppress viral load at the population level. This set of quality-of-care indicators monitors factors related to patient care (appropriate prescribing and viral load suppression at 12months); patient behaviour (adherence); and clinic-level and programmemanagement (follow-up, retention on antiretroviral therapy, procurement and supply management of antiretroviral drugs and appropriately switching regimen among people with failure to suppress viral load). Early warning indicators use internationally agreed standardized definitions and accompanying targets. Annual monitoring of early warning indicators enables the degrees of improvement or decline over time to bemeasured, both within and between clinics AMR_brochure.indd 29 27/03/19 10:12 am (29). 30 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 5.3 Joint support for countries The Global Action Plan on Antimicrobial Resistance outlines a framework for action on antimicrobial resistance with supporting countries to develop, implement andmonitor antimicrobial resistance national action plans as a priority. The One Health concept requires a perspective that covers antimicrobial resistance across all key components, including human health, animal health and agriculture because preventing andmanaging antimicrobial resistance requires activities across all relevant sectors. As of January 2019, 117 countries had national action plans, but the extent to which TB, HIV, malaria and neglected tropical disease programmes are involved varies. WHO and other TABLE 2 WHO-recommended early warning indicators of HIV drug resistance and their respective targets WHO-recommended early warning indicators of HIV drug resistance Target (green: good performance; amber: fair performance; red: poor performance) Retention on antiretroviral therapy at 12months (ART.5, antiretroviral therapy retention) % of patients retained on antiretroviral therapy 12months after initiating antiretroviral therapy Green: >85% Amber: 75–85% Red: <75% On-time pill pick-up (ART.7, antiretroviral therapy adherence proxy) % of people who pick up antiretroviral therapy nomore than two days late at the first drug pick-up after a defined baseline pick-up Green: >90% Amber: 80–90% Red: <80% Pharmacy stock-outa (not collectable through the HIV patient monitoring system) % of months with any days of stock-out of any routinely dispensed antiretroviral drug Green: 0% Red: >0% Viral load suppressionb (VLS.1, viral load suppression at 12months) % of people with viral load <1000 copies/mL 12months after initiating antiretroviral therapy Green: ≥90% Amber: 80–<90% Red: <80% Viral load completionc (VLS.2, viral load testing coverage) % of people with a 12-month viral load test result available Green: ≥70% Red: <70% a Stock-out refers to lack of availability of first-line antiretroviral drugs. b The denominator for the viral load suppression indicator is the number of people alive and receiving antiretroviral therapy 12 months after initiating treatment who have a viral load test result available. c The denominator for the viral load completion indicator is the number of people alive and receiving antiretroviral therapy 12 months after initiating treatment, who are therefore, consistent with the policy, expected to have a viral load test result available in the primary medical record. For all early warning indicators, a grey classification is applied in situations where a sampled antiretroviral therapy clinic is unable to report on a specific indicator because more than 30% of the data are missing. development partners need to collaborate better andmakemore eúort in providing joint support to countries to develop comprehensive national action plans that include interventions to address TB, HIV, malaria and neglected tropical diseases where relevant. Countries need coordinated support in collecting and using data on antimicrobial resistance (national and subnational) for evidence- informed decision-making. Technical support should also target drug regulatory authorities to ensure that new eúective medicines and other relevant products (such as diagnostic tests that detect drug resistance) are added to national lists of essential medicines and that treatment policies are changed as soon as possible if antimicrobial resistance is reducing the eúectiveness of existing treatment protocols. AMR_brochure.indd 30 27/03/19 10:12 am Source: WHO Consolidated guidelines on person-centred HIV patient monitoring and case surveillance (29). 31STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 5.4 Identifying and optimizing synergy As countries move to strengthen their primary health care systems and towards achieving universal health coverage in the context of reduced reliance on external funding resources, they will need to look for opportunities to increase the eûciency of health services and reachmore people with essential services. For antimicrobial resistance, this might mean using diagnostic platforms that can detect drug-resistant strains of pathogens for several diseases and strengthening and expanding the services oúered by laboratories to detect drug resistance. Synergy can also be found by training health-care providers to prevent andmanage antimicrobial resistance across multiple diseases and at various service delivery points, provide better treatment by using adapted treatment algorithms and undertake infection control and prevention interventions. Strengthening procurement and supply chain management systems to reduce drug stock-outs is also an important intervention for preventing antimicrobial resistance related to TB and HIV and to other diseases as well. Ensuring that health-care facilities have clean water and functioning sanitation facilities and that wastewater is adequately treated before being discharged into the environment from health-care facilities and drugmanufacturing facilities can strongly reduce antimicrobial resistance. 5.5 Product pipelines Collaboration is required to identify new drug candidates. New drugs take a long time to develop, are expensive andmust go through at least three phases of clinical trials before they can be approved for widespread use among humans. Pharmaceutical companies are often unwilling to invest the time andmoney required to bring new drugs to market unless they have a high probability of achieving adequate returns on investment. This is often a challenge for such diseases as TB, HIV, malaria and neglected tropical diseases, which have their greatest impact in low- andmiddle- income countries. As highlighted in Box 6, product development partnerships and other research consortiums can facilitate and fundwork to identify new pipeline drugs. Further research is also needed to develop formulations for children, shorter duration treatments, treatments with reduced side-eúects, more eúective combinations of existing drugs, lower cost treatments, medicines with greater stability and long-acting formulations. Point-of-care diagnostic tests that directly measure drug resistance are not currently available. Research and funding are also needed to develop new technologies and products and common diagnostic platforms that can detect drug resistance across multiple diseases. AMR_brochure.indd 31 27/03/19 10:12 am 32 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES References 1. Adeyi OO, Baris E, Jonas OB, Irwin A, Berthe FCJ, Le Gall FG et al. Drug-resistant infections: a threat to our economic future (Vol. 2). Washington (DC): World Bank; 2017 (http://documents.worldbank.org/curated/en/323311493396993758/final-report, accessed 4 February 2019). 2. Antimicrobial resistance. Geneva: World Health Organization; 2018 (https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance, accessed 4 February 2019). 3. Sustainable Development Goals [website]. New York: United Nations; 2019 (https://sustainabledevelopment.un.org/sdgs, accessed 4 February 2019). 4. What is health financing for universal health coverage? [website]. Geneva: World Health Organization; 2019 (https://www.who.int/health_financing/universal_coverage_definition/en, accessed 4 February 2019). 5. Global tuberculosis report 2018. Geneva: World Health Organization; 2018 (https://www.who.int/tb/publications/global_report/en, accessed 4 February 2019). 6. Global action plan on HIV drug resistance 2017–2021. Geneva: World Health Organization; 2017 (http://apps.who.int/iris/bitstream/handle/10665/255883/9789241512848-eng.pdf, accessed 4 February 2019). 7. United Nations Interagency Coordination Group on Antimicrobial Resistance (IACG) [website]. Geneva: World Health Organization; 2019 (https://www.who.int/antimicrobial-resistance/interagency-coordination-group/en, accessed 4 February 2019). 8. Thirteenth General Programme ofWork 2019–2023. Geneva: World Health Organization; 2018 (https://www.who.int/about/what-we-do/gpw-thirteen-consultation/en, accessed 4 February 2019). 9. Mpoza E, Rhein J, Abassi M. Emerging fluconazole resistance: implications for themanagement of cryptococcal meningitis. MedMycol Case Rep. 2017;19:30–2. 10. Pankhurst CL. Candidiasis (oropharyngeal). BMJ Clin Evid. 2009;2009:1304. 11. HIV drug resistance report 2017. Geneva: World Health Organization; 2017 (http://www.who.int/hiv/pub/drugresistance/hivdr-report-2017/en, accessed 4 February 2019). 12. World malaria report 2018. Geneva: World Health Organization; 2018 (https://www.who.int/malaria/publications/world-malaria-report-2018/en, accessed 4 February 2019). 13. Neglected tropical diseases [website]. Geneva: World Health Organization; 2019 (https://www.who.int/neglected_diseases/diseases/en, accessed 4 February 2019). 14. Cambau E, Saunderson P, MatsuokaM, Cole ST, Kai M, Suúys P et al. Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by aWHO surveillance network for the period 2009–15. Clin Microbiol Infect. 2018;24:1305–10. 15. Mitjà O, Godornes C, Houinei W, Kapa A, Paru R, Abel H et al. Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study. Lancet. 2018;391:1599– 1607. AMR_brochure.indd 32 27/03/19 10:12 am 33STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 16. Ponte-Sucre A, Gamarro F, Dujardin J-C, Barrett MP, Lopez-Vélez R, Garcia-Hernandez R et al. Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoS Negl Trop Dis. 2017;11:e0006052. 17. Trachoma fact sheet. Geneva: World Health Organization; 2018 (https://www.who.int/en/news-room/fact-sheets/detail/trachoma, accessed 4 February 2019). 18. Yaws fact sheet. Geneva: World Health Organization; 2018 (https://www.who.int/news-room/fact-sheets/detail/yaws, accessed 4 February 2019). 19. O’Brien KS, Emerson P, Hooper PJ, Reingold AL, Dennis EG, Keenan JD et al. Antimicrobial resistance followingmass azithromycin distribution for trachoma: a systematic review. Lancet Infect Dis. 2019;19:e14–e25. 20. Seventhmeeting of theWorking Group onMonitoring of Neglected Tropical Diseases Drug Eûcacy. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/bitstream/handle/10665/273620/WHO-CDS-neglected tropical disease-PCT-2018.06-eng.pdf, accessed 4 February 2019). 21. Bruxvoort KJ, Leurent B, Chandler CIR, Ansah EK, Baiden F, Björkman A et al. The impact of introducing malaria rapid diagnostic tests on fever case management: a synthesis of ten studies from the ACT Consortium. Am J TropMed Hyg. 2017;97:1170–9. 22. Global Antimicrobial Resistance Surveillance System (GLASS) [website]. Geneva: World Health Organization; 2019 (https://www.who.int/glass/en, accessed 4 February 2019). 23. Tuberculosis: surveillance of drug-resistant TB [website]. Geneva: World Health Organization; 2019 (https://www.who.int/tb/areas-of-work/monitoring-evaluation/mdr-tb-surveillance/en, accessed 4 February 2019). 24. WHO TB Supranational Reference Laboratory Network [website]. Geneva: World Health Organization; 2010 (available at https://www.who.int/tb/areas-of-work/laboratory/srl-network/en, accessed 4 February 2019). 25. HIV drug resistance surveillance guidance: 2015 update. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/bitstream/handle/10665/204471/9789241510097_eng.pdf, accessed 4 February 2019). 26. Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report. Geneva: World Health Organization; 2018 (https://www.who.int/hiv/pub/drugresistance/gap-hivdr-progress2018/en, accessed 4 February 2019. 27. Malaria: drug resistance and response [website]. Geneva: World Health Organization; 2019 (https://www.who.int/malaria/areas/drug_resistance/en, accessed 4 February 2019). 28. An overview of our work. Geneva: Medicines for Malaria Venture; 2019 (https://www.mmv.org/about-us/about-mmv, accessed 4 February 2019). 29. Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. Geneva: World Health Organization; 2017 (https://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en, accessed 4 February 2019). AMR_brochure.indd 33 27/03/19 10:12 am 34 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES WHO antimicrobial resistance resources Antimicrobial resistance – general WHO antimicrobial resistance website http://www.who.int/topics/antimicrobial_resistance/en Global Action Plan on Antimicrobial Resistance http://www.who.int/antimicrobial-resistance/publications/global-action-plan/en Global Framework for Development & Stewardship to Combat Antimicrobial Resistance – Draft roadmap http://www.who.int/entity/antimicrobial-resistance/global-action-plan/UpdatedRoadmap-Global- Framework-for-Development-Stewardship-to-combatantimicrobial resistance_2017_11_03.pdf Global Antimicrobial Resistance Surveillance System: Manual for Early Implementation http://www.who.int/antimicrobial-resistance/publications/surveillance-system-manual/en Worldwide country situation analysis: response to antimicrobial resistance http://www.who.int/antimicrobial-resistance/publications/situationanalysis/en Antimicrobial resistance: global report on surveillance 2014 http://www.who.int/antimicrobial-resistance/publications/surveillancereport/en Global Antimicrobial Resistance Surveillance System –manual for early implementation https://www.who.int/antimicrobial-resistance/publications/surveillance-system-manual/en Global Antimicrobial Resistance Surveillance System (GLASS) report – early implementation 2016–2017 https://www.who.int/glass/resources/publications/early-implementation-report/en TB Drug-resistant TB:WHOwebsite http://www.who.int/tb/areas-of-work/drug-resistant-tb/en The End TB Strategy http://www.who.int/tb/strategy/en Global tuberculosis report 2018 http://www.who.int/tb/publications/global_report/en WHO treatment guidelines for drug-resistant tuberculosis http://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639-eng.pdf Companion handbook to theWHO guidelines for the programmatic management of drug-resistant tuberculosis http://www.who.int/tb/publications/pmdt_companionhandbook/en Guidelines for surveillance of drug resistance in tuberculosis – 5th edition http://www.who.int/tb/publications/2015/drs_guidelines/en Compendium ofWHO guidelines and associated standards: ensuring optimum delivery of the cascade of care for patients with tuberculosis http://apps.who.int/iris/bitstream/10665/259180/1/9789241512572-eng.pdf AMR_brochure.indd 34 27/03/19 10:12 am 35STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE HIV Global Health Sector Strategy on HIV, 2016–2021 http://apps.who.int/iris/bitstream/handle/10665/246178/WHO-HIV-2016.05-eng.pdf HIV drug resistance: WHOwebsite http://www.who.int/hiv/topics/drugresistance/en/ Global Action Plan on HIV Drug Resistance 2017–2021 http://apps.who.int/iris/bitstream/handle/10665/255883/9789241512848-eng.pdf Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report https://www.who.int/hiv/pub/drugresistance/gap-hivdr-progress2018/en/ HIV drug resistance surveillance guidance http://apps.who.int/iris/bitstream/handle/10665/204471/9789241510097_eng.pdf Guidelines on the public health response to pretreatment HIV drug resistance http://www.who.int/hiv/pub/guidelines/hivdr-guidelines-2017/en HIV drug resistance report 2017 http://www.who.int/hiv/pub/drugresistance/hivdr-report-2017/en Consolidated guidelines on person-centred HIV patient monitoring and case surveillance http://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en Tackling HIV drug resistance: trends, guidelines and global action. http://apps.who.int/iris/bitstream/handle/10665/255881/WHO-HIV-2017.21-eng.pdf Malaria Global technical strategy for malaria 2016–2030 http://www.who.int/malaria/publications/atoz/9789241564991/en Malaria drug resistance: WHOwebsite http://www.who.int/malaria/areas/drug_resistance/en World malaria report 2018 https://www.who.int/malaria/publications/world-malaria-report-2018/report/en WHO status reports on Plasmodium falciparum drug eûcacy and resistance http://www.who.int/entity/malaria/areas/drug_resistance/updates/en/index.html Eliminatingmalaria in the Greater Mekong Subregion: united to end a deadly disease http://www.who.int/entity/malaria/publications/atoz/eliminating-malaria-greater-mekong/en/ index.html Methods for surveillance of antimalarial drug eûcacy http://www.who.int/entity/malaria/publications/atoz/9789241597531/en/index.html Q&A on artemisinin resistance http://www.who.int/entity/malaria/publications/atoz/9789241597531/en/index.html Guidelines for the treatment of malaria. Third edition http://www.who.int/malaria/publications/atoz/9789241549127/en AMR_brochure.indd 35 27/03/19 10:12 am 36 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES Neglected tropical diseases Neglected tropical diseases: WHOwebsite http://www.who.int/neglected_diseases/en Seventhmeeting of theWorking Group onMonitoring of Neglected Tropical Diseases Drug Eûcacy http://apps.who.int/iris/bitstream/handle/10665/273620/WHO-CDS-neglected tropical disease-PCT- 2018.06-eng.pdf AMR_brochure.indd 36 27/03/19 10:12 am

World Health Organization 20 Avenue Appia 1211 Geneva 27 Switzerland www.who.int ISBN 978-92-4-151545-0

Tuberculosis, HIV, malaria and neglected tropical diseases Strengthening collaboration to prevent and manage antimicrobial resistance Tuberculosis, HIV, malaria and neglected tropical diseases Strengthening collaboration to prevent and manage antimicrobial resistance AMR_brochure.indd 1 27/03/19 10:12 am Tuberculosis, HIV, malaria and neglected tropical diseases: strengthening collaboration to prevent andmanage antimicrobial resistance ISBN 978-92-4-151545-0 ©World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, youmay copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion thatWHO endorses any specific organization, products or services. The use of theWHO logo is not permitted. If you adapt the work, then youmust license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by theWorld Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of theWorld Intellectual Property Organization. Suggested citation. Tuberculosis, HIV, malaria and neglected tropical diseases: strengthening collaboration to prevent andmanage antimicrobial resistance. Geneva:World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchaseWHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of thematerial in this publication do not imply the expression of any opinion whatsoever on the part ofWHO 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 and dashed lines onmaps represent approximate border lines for which there may not yet be full agreement. Themention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended byWHO 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 byWHO to verify the information contained in this publication. However, the publishedmaterial is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of thematerial lies with the reader. In no event shall WHO be liable for damages arising from its use. Printed in France AMR_brochure.indd 2 27/03/19 10:12 am iiiSTRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE Contents Abbreviations iv Foreword v Executive summary 1 1. Introduction 2 2. Background 3 2.1 Antimicrobial resistance 3 2.2 Sustainable Development Goals 3 2.3 How antimicrobial resistance aúects the achievement of the Sustainable Development Goals 3 2.4 Global Action Plan on Antimicrobial Resistance 4 2.5 Ad hoc United Nations Interagency Coordination Group on Antimicrobial Resistance 5 2.6 WHO 13th General Programme ofWork (2019–2023) 5 2.7 TB, HIV, malaria, neglected tropical diseases and antimicrobial resistance 6 3. Current antimicrobial resistance status: TB, HIV, malaria and relevant neglected tropical diseases 9 3.1 Factors driving antimicrobial resistance across disease areas 9 3.2 Tuberculosis 10 3.3 HIV 12 3.4 Malaria 13 3.5 Neglected tropical diseases 14 4. Preventing antimicrobial resistance related to TB, HIV, malaria and neglected tropical diseases and theWHO response 15 4.1 Preventing antimicrobial resistance 15 4.2 Surveillance of antimicrobial resistance 16 4.3 Laboratory networks 21 4.4 Communication, awareness-raising, education and training 23 5. Future directions 25 5.1 Identify research and development gaps and new tools and approaches 26 5.2 Clinical and programmatic indicators associated with and predicting the emergence of antimicrobial resistance 28 5.3 Joint support for countries 30 5.4 Identifying and optimizing synergy 31 5.5 Product pipelines 31 References 32 WHO antimicrobial resistance resources 34 Antimicrobial resistance – general 34 TB 34 HIV 35 Malaria 35 Neglected tropical diseases 36 AMR_brochure.indd 3 27/03/19 10:12 am iv TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES Abbreviations ACT artemisinin-based combination therapy AIDS acquired immunodeficiency syndrome AMR antimicrobial resistance BBINS Bangladesh, Bhutan, India, Nepal, Sri Lanka DNDi Drugs for Neglected Diseases initiative FAO Food and Agriculture Organization of the United Nations GAP Global Action Plan on Antimicrobial Resistance GLASS Global Antimicrobial Resistance Surveillance System HANMAT Horn of Africa Network for Monitoring Antimalarial Treatment HIV human immunodeficiency virus IACG Interagency Coordination Group on Antimicrobial Resistance MDR-TB multidrug-resistant tuberculosis MMV Medicines for Malaria Venture NTD neglected tropical disease OIE World Organisation for Animal Health PEPFAR United States President’s Emergency Plan for AIDS Relief PIAMNET Pakistan, Islamic Republic of Iran and Afghanistanmonitoring network RAVREDRA Red Amazónica para la Vigilancia de la Resistencia a las Drogas Antimaláricas network RR-TB rifampicin-resistant tuberculosis TB tuberculosis UNEP United Nations Environment Programme USAID United States Agency for International Development WHO World Health Organization XDR-TB extensively drug-resistant tuberculosis AMR_brochure.indd 4 27/03/19 10:12 am vSTRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE Foreword Antimicrobial resistance is one of the greatest health challenges of the 21st century, as recognized in the 2015World Health Assembly resolution on antimicrobial resistance and the 2016 Political Declaration of the High-level Meeting of the United Nations General Assembly on Antimicrobial Resistance. If antimicrobial resistance is not addressed, it may contribute to millions of deaths per year and cost the world economy US$ 1–3 trillion per year after 2030 (1). Drug-resistant TB, HIV, malaria and some neglected tropical diseases will make a substantial contribution to this burden. Antimicrobial resistance threatens to take us back to a time when common infections could not be treated and often led to sustained illness and death. To preserve the health gains of the past century, we will need to take eúective and coordinated action. WHO has recognized the importance of antimicrobial resistance in its 13th General Programme ofWork, which requires all programmes at all levels of the Organization to address antimicrobial resistance as a cross-cutting issue. Antimicrobial resistance will impact the achievement of the triple billion targets, especially universal health coverage. The three objectives of universal health coverage including equity, quality and protection from financial risk will not bemet without also eúectively addressing antimicrobial resistance. Equally, universal health coverage also oúers an excellent opportunity for preventing and managing antimicrobial resistance. WHO is leading the fight to prevent and contain antimicrobial resistance in human health and has been working in close collaboration with the Food and Agriculture Organization of the United Nations (FAO), theWorld Organization for Animal Health (OIE) (the FAO/OIE/WHO Tripartite Collaboration on Antimicrobial Resistance) and the United Nations Environment Programme (UNEP). The Tripartite organizations are working together through the Interagency Coordination Group on Antimicrobial Resistance (IACG) and reaûrmed their commitment to strengthen collaboration in amemorandum of understanding signed inMay 2018. The IACGwill issue a final report to the United Nations Secretary- General in 2019 that re-emphasizes the urgency and the need for a coordinated and stepped-up global response. The Tripartite and UNEP have developed a One Health approach tomanaging antimicrobial resistance, as proposed in the Global Action Plan on Antimicrobial Resistance (GAP), launched in 2015. This plan focuses on the importance of strengthening systems for preventing and managing infection, with more appropriate use of antimicrobial agents, as well as strengthening systems for surveillance. One of the core elements of the GAP is to support countries to develop and implement comprehensive, One Health-oriented antimicrobial resistance action plans. As of January 2019, 117 countries have developed national antimicrobial resistance action plans with support from partners. WHO has also developed GLASS, the Global Antimicrobial Surveillance System. Antimicrobial resistance is also a major challenge for TB, HIV andmalaria and has the potential to adversely aúect neglected tropical disease programmes. Sustainable Development Goal target 3.3 calls for ending the epidemics of these diseases by 2030.While antimicrobial resistance puts the achievement of many Sustainable Development Goals at risk, Sustainable Development Goal target 3.3 is especially aúected, with antimicrobial resistancemaking treating these diseases more diûcult and expensive. TB, HIV, malaria and neglected tropical disease programmes have been working to address the antimicrobial resistance challenge for many years by focusing on supporting national and global surveillance networks, strengthening laboratory networks, optimizing diagnostic testing and treatment, raising awareness of the dangers of antimicrobial resistance andworking with key stakeholders to drive product and service AMR_brochure.indd 5 27/03/19 10:12 am vi TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES delivery innovation. These same interventions are core components of strategies to prevent andmanage antimicrobial resistance across the human health spectrum. Lessons learned and good practices gained from experience in preventing andmanaging antimicrobial resistance in these diseases can be adapted and used to strengthen antimicrobial resistance approaches in other settings. Current opportunities exist to strengthen antimicrobial resistance collaboration at the country level by identifying and strengthening programmatic synergies that underpin strategies for preventing andmanaging antimicrobial resistance. This will require, for example, ensuring that countries develop and implement comprehensive, antimicrobial resistance action plans that include TB, HIV, malaria and neglected tropical diseases where relevant. Achieving this requires a coordinated eúort, working in partnership, involving all stakeholders at the global, regional, country and service delivery levels. Preventing and managing antimicrobial resistance will truly require sustained eúorts and global collaboration. RenMinghui Assistant Director-General for Communicable Diseases Raniero Guerra Assistant Director-General for Strategic Initiatives AMR_brochure.indd 6 27/03/19 10:12 am 1STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE Executive summary There is global commitment to address antimicrobial resistance through the Global Action Plan on Antimicrobial Resistance. High-impact communicable diseases, including tuberculosis (TB), human immunodeficiency virus (HIV), malaria and neglected tropical diseases (NTDs), should be integrated into and aligned with global antimicrobial resistance eúorts. Antimicrobial resistance puts achievement of Sustainable Development Goal 3 and other Sustainable Development Goals at risk, making eúectively treating diseases more diûcult and costly and leading tomore illness and deaths. Lessons learned from addressing antimicrobial resistance in TB and the other diseases during the past 20 years provide useful guidance for other antimicrobial resistance programmes in earlier stages of development, including: ÿ recognizing at an early stage the antimicrobial resistance challenge and advocating and mobilizing global development partners to address it; ÿ establishing a global antimicrobial resistance surveillance system; ÿ establishing direct drug resistance testing for individual patients, providing data for population-based surveillance; ÿ expanding and strengthening national and regional laboratory networks; ÿ strengthening country capacity for managing antimicrobial resistance; ÿ reaching out to stakeholders at all levels through a public–private mix, including engaging pharmacies and health-care providers to provide training on testing and treatment protocols; and ÿ establishing product development partnerships and research consortiums to facilitate the introduction of new pipeline drugs, review new drug formulations and develop improved diagnostic tests to detect antimicrobial resistance. AMR_brochure.indd 1 27/03/19 10:12 am 2 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 1. Introduction The purpose of this report is to provide a brief overview of the status of antimicrobial resistance in high-impact communicable diseases (TB, HIV, malaria and some neglected tropical diseases) and to present some areas in which strengthened eúorts will be required in the future andmore collaborative programme designmay generate eûciency and strengthened systems for addressing antimicrobial resistancemore widely. This overview includes a summary of the current antimicrobial resistance situation by disease, current prevention and response eúorts in antimicrobial resistance and a future directions section examining opportunities for strengthening collaboration among disease and other antimicrobial resistance programmes. The report captures key messages in each area and is aimed at technical and funding partners, global and national policy-makers and other relevant stakeholders. AMR_brochure.indd 2 27/03/19 10:12 am 3STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 2. Background access to needed health-care services (including disease prevention, health promotion, treatment, rehabilitation and palliation) of suûcient quality to be eúective while also ensuring that the use of these services does not expose the user to financial hardship. 2.3 How antimicrobial resistance aþects the achievement of the Sustainable Development Goals Antimicrobial resistance is a substantial threat to several of the wider development goals, such as economic growth, poverty reduction and sustainable production and consumption (Fig. 1). Progress towards other goals, such as Sustainable Development Goal 6 on water and sanitation and Sustainable Development Goal 17 onworking in partnership will make important contributions to addressing antimicrobial resistance. However, the greatest threat will be to Sustainable Development Goal 3, human health. Antimicrobial resistance will make it harder to treat the diseases and lead to increased sickness, more protracted hospital stays andmore deaths. TheWorld Bank has estimated that health- care costs could increase by 25% in low-income countries in their worst-case scenario and reduce global gross domestic product (GDP) by 1–4% annually by 2050 (1). The spread of antimicrobial resistance could slow progress towards achieving Sustainable Development Goal 3.3 targets for TB, HIV, malaria and potentially some specific neglected tropical diseases if it is not managed or contained. Antimicrobial resistance will also dramatically increase the costs of providing health-care services. For example, the second- and third-line HIV treatments are 3 and 14 times more expensive, respectively, than first-line treatments (1) and lead tomore negative outcomes. Treating extensively drug-resistant TB (XDR-TB) takes up to two years, 2.1 Antimicrobial resistance Antimicrobial resistance (AMR) occurs when microorganisms such as bacteria, viruses, parasites and fungi develop resistance to antimicrobial agents. Although this is a natural phenomenon, the inappropriate and excessive use of antimicrobial agents can increase the pace and spread of antimicrobial resistance development. Diseases caused by resistant microorganisms are more diûcult to treat. Rising levels of drug resistance are a risk to the success of human immunodeficiency virus (HIV), tuberculosis (TB) andmalaria programmes. Microorganisms that are resistant to antimicrobial agents threaten the successful management of infections, safe surgery and cancer treatment. Coinfection with resistant microorganisms poses heightened risks for people with TB and HIV (2). 2.2 Sustainable Development Goals The United Nations adopted the Sustainable Development Goals (3) in September 2015. These reflect the growing complexity and interdependence of the global development agenda. The Sustainable Development Goals establish 17 global goals that have 169 specific targets, and if they are achieved by 2030 they will help to ensure the sustainability of economic and social development. Sustainable Development Goal 3 focuses on ensuring good health and well- being and covers infectious and noncommunicable diseases. Target 3.3 calls for ending by 2030 the epidemics of AIDS, TB, malaria and neglected tropical diseases and reducing the incidence of hepatitis, waterborne diseases and other communicable diseases. Sustainable Development Goal target 3.8 calls for universal health coverage (4), which is defined as ensuring that all people have AMR_brochure.indd 3 27/03/19 10:12 am 4 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES and the drugs and treatment required cost nearly six times more than treatments for non-resistant TB (5). Among extensively drug-resistant TB cases starting treatment globally in 2015, only 34% completed it or were cured (versus 82%with drug- sensitive strains), and in 45% the treatment failed or the person died (5). As noted in subsection 3.3 and Fig. 10, the emergence of HIV drug resistance threatens to reduce the gains in morbidity and mortality anticipated by a “treat all” approach and the scale-up of pre-exposure prophylaxis. 2.4 Global Action Plan on Antimicrobial Resistance TheWorld Health Assembly adopted the Global Action Plan on Antimicrobial Resistance (6) in May 2015, and the Food and Agriculture Organization of the United Nations (FAO) and theWorld Organization for Animal Health (OIE) endorsed it. The Global Action Plan on Antimicrobial Resistance covers antibiotic resistance in most detail but also refers, where appropriate, to existing action plans for viral, parasitic and bacterial diseases, including HIV, malaria and tuberculosis. The Global Action Plan on Antimicrobial Resistance provides the framework for developingmultisectoral national FIG. 1 Antimicrobial resistance and the Sustainable Development Goals AMR hits the poor hardest with higher treatment costs and lost income due to illness Untreatable infections in animals threatens sustainable food production Antimicrobial residues from hospitals, pharmaceutical companies and agriculture contaminate water, spread of resistant bacteria through inadequate provision of water, sanitation and hygiene AMR could increase health costs by 25% in low income countries and reduce global GDP by 1"4% annually by 2050 Need to balance access, innovation, conservation to protect antimicrobials to contain AMR Antimicrobials are essential for human health Addressing AMR requires multi" stakeholder approaches and one health partnerships Addressing A R requires ulti- a One Health partnerships AMRhits the p or hardest, with higher treatment costs and lost income due to illness treatable i fecti s i i l threaten sust inable food production Antimicrobial residues from ospitals, pharmaceutical companies and agriculture contaminatewater and spread of resistant bacteria through inadequate provision of water, sanitation and hygiene AMR could increase health costs by 25% in low-income countries and reduce global GDP by 1–4% annually by 2050Antimicrobial agents are essential for hum n ealth Need to balance access, innovation, conservation to protect antimicrobial agents to contain AMR AMR_brochure.indd 4 27/03/19 10:12 am 5STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE action plans to combat antimicrobial resistance. It sets out the key actions that the various actors involved should take to combat antimicrobial resistance, using an incremental approach over the next 5–10 years. The TB, HIV, malaria and neglected tropical diseases antimicrobial resistance work is aligned with the five objectives of the Global Action Plan: ÿ to improve awareness and understanding of antimicrobial resistance through eúective communication, education and training; ÿ to strengthen the knowledge and evidence base through surveillance and research; ÿ to reduce the incidence of infection through eúective sanitation, hygiene and infection preventionmeasures; ÿ to optimize the use of antimicrobial medicines in human and animal health; and ÿ to develop the economic case for sustainable investment that takes account of the needs of all countries and to increase investment in new medicines, diagnostic tools, vaccines and other interventions. 2.5 Ad hoc United Nations Interagency Coordination Group on Antimicrobial Resistance The United Nations Secretary-General has established the United Nations Interagency Coordination Group on Antimicrobial Resistance (IACG) (7) to improve coordination between international organizations and to ensure eúective global action against this threat to health security. The IACG is co-chaired by the United Nations Deputy Secretary-General and theWHODirector-General and comprises high- level representatives of relevant United Nations agencies, other international organizations and individual experts across diúerent sectors. The IACG’s mandate is to provide practical guidance for approaches needed to ensure sustained, eúective global action to address antimicrobial resistance; and to report back to the United Nations Secretary-General in 2019.WHO hosts the IACG Secretariat with contributions from the Food and Agriculture Organization of the United Nations (FAO) andWorld Organisation for Animal Health (OIE). WHO is responsible for addressing antimicrobial resistance in relation to human health including TB, HIV, malaria and relevant neglected tropical diseases. The longstanding FAO/OIE/WHO Tripartite Collaboration on Antimicrobial Resistance was further strengthened through the signature of a memorandum of understanding inMay 2018. The Tripartite agencies and the United Nations Environment Programme (UNEP) are actively working together to support a global multisectoral response to antimicrobial resistance, including implementing the IACG recommendations working withMember States, civil society and the private sector. 2.6 WHO 13th General Programme of Work (2019–2023) TheWHO 13th General Programme ofWork for 2019–2023 (8) is structured around three interconnected strategic priorities to ensure healthy lives and well-being for all at all ages. The goals are: ÿ 1 billion people benefiting from universal health coverage; ÿ 1 billion more people better protected from health emergencies; and ÿ 1 billion more people enjoying better health and well-being. Addressing antimicrobial resistance will contribute to all three goals. The 13th General Programme ofWork provides the framework for positioning communicable diseases eúorts in support of universal health coverage. Both ending the epidemics of high-impact communicable diseases (HIV, TB, malaria and neglected tropical diseases, Fig. 2–5) and preventing andmanaging antimicrobial resistance are priorities in the 13th General Programme ofWork and need to be addressed horizontally across all relevantWHO programmes at all levels of the Organization. The 13th General Programme ofWork Impact Framework has specific targets for TB, HIV, malaria and neglected tropical diseases; a target to increase the detection and treatment rates for rifampicin- resistant TB (includingmultidrug-resistant TB (MDR- TB) or combined resistance to at least rifampicin and isoniazid) to 80% by 2023, and targets to reduce the prevalence of resistant bloodstream infections and AMR_brochure.indd 5 27/03/19 10:12 am 6 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES improve the proportion of people with access to antibiotics. 2.7 TB, HIV, malaria, neglected tropical diseases and antimicrobial resistance Antimicrobial resistance has long posed challenges for managing TB, HIV, malaria and some neglected tropical diseases. Drug-resistant TB is a public health crisis and a health security threat; drug resistance in HIV is a growing challenge and threatens progress to end the epidemic as a public health threat by 2030. In the past, widespread resistance to chloroquine and other drugs led tomalaria resurgence and continuing epidemics in many countries and areas. As a consequence of having to address antimicrobial resistance challenges for many years, TB, HIV, malaria and neglected tropical disease programmes have refined their drug resistancemanagement and control strategies to reflect reality on the ground and lessons learned. Unfortunately, strategies for managing and controlling drug resistance related to these diseases have sometimes been implemented separately in the context of each individual disease programme and not under the overall umbrella of antimicrobial resistance. Elements that underpin many of the disease-specific interventions to prevent, detect and manage drug resistance also apply to non-disease- specific antimicrobial resistancemanagement programmes. Better integrating TB, HIV, malaria and neglected tropical disease drug resistance programmes into other antimicrobial resistance eúorts would help to strengthen the overall response to antimicrobial resistance andmaximize synergy in such areas as surveillance, laboratory strengthening, monitoring and evaluation, procurement and supply chain management, developing human resource capacity and the quality of health services delivered. FIG. 2 Estimated TB incidence rates by country, 2017 Source: Global tuberculosis report 2018 (5). Incidence per 100 000 population per year 0–24 25–99 100–199 200–299 ≥300 No data Not applicable AMR_brochure.indd 6 27/03/19 10:12 am 7STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE FIG. 3 HIV prevalence among people 15–49 years old by country, 2017 FIG. 4 Number of malaria cases by country, 2017 Source: World Health Organization, Global Malaria Programme, 2018. Estimated cases per 1000 population 0–0.1 0.2–1 2–10 11–50 51–100 >100 Non-endemic or no ongoing malaria transmission Not applicable Source: WHO Global Health Observatory data repository (http://apps.who.int/gho/data/node.main.622?lang=en), last updated 17 July 2018. <0.2% 0.2–0.5% 0.6–1.5% >1.5% No data Not applicable AMR_brochure.indd 7 27/03/19 10:12 am 8 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES FIG. 5 Number of people requiring treatment and care for neglected tropical diseases by country, 2017 Source: World Health Organization, Department of Control of Neglected Tropical Diseases, 2019. 0–10 11–100 101–1 000 1 001–10 000 10 001–100 000 100 001–1 million 1 000 001–10 million 10 000 001–100 million >100 million AMR_brochure.indd 8 27/03/19 10:12 am 9STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 3. Current antimicrobial resistance status: TB, HIV, malaria and relevant neglected tropical diseases KEY MESSAGES ÿ TB drug resistance is a major cause of antimicrobial resistance mortality andmorbidity worldwide, and immediate action is required to prevent the further development and spread of resistance. ÿ Resistance of HIV to efavirenz and nevirapine, the most common first-line drugs, is a current global health threat leading to poor health outcomes such as treatment failure, mortality and increased programme costs and requires urgent action to be taken now to prevent the further development and spread of resistance. ÿ Malaria drug resistance constitutes a challenge particularly in the Greater Mekong subregion. Drug resistance has developed to artemisinin and some partner drugs used in artemisinin-based combination therapies, making treatment of people with Plasmodium falciparummalaria diûcult. The risk of importing or developing resistance in themalaria- endemic countries in the rest of the world is a concern, and surveillance of drug eûcacy is a high priority. ÿ Some drug resistance has been identified in neglected tropical diseases caused by bacteria (leprosy and yaws) and a parasite (visceral leishmaniasis). The resistance observed has been at low levels and does not apply to all available treatments. Drug resistance has not yet been observed in helminths that primarily infect humans. ÿ Antimicrobial resistance is also a phenomenon in other pathogens (such as non-specific bacteria and fungi) that may cause secondary infection in people with TB and HIV. Rising drug resistance levels in bacteria causing common acute infections in humans have been well documented, undermining the ability to treat these infections. 3.1 Factors driving antimicrobial resistance across disease areas Antimicrobial resistance occurs when drugs (antibiotics, antifungal agents, antiviral agents, antimalarial agents and anthelmintic agents) used to treat infections by microorganisms such as bacteria (TB, leprosy and non-specific bacteria), fungi, viruses (HIV) and parasites (malaria, soil- transmitted helminths and trematodes) kill most of the organisms, but sometimes not all, leaving a small subset of resistant microorganisms that survive. The surviving populations can then multiply, allowing infections to persist in the body, potentially leading to increasedmorbidity and mortality and increasing the risk of transmitting the resistant organisms to other people. Non-targeted organisms are also aúected and can be exposed to antimicrobial residues in the environment from hospitals, pharmaceutical production and agricultural activities. Genes for antimicrobial resistance can be transferred between bacteria in the environment (such as from non-pathogenic species to pathogenic species). Antimicrobial resistance in populations of microorganisms is selected over time based on exposure to specific drugs. Themisuse and overuse of antimicrobial AMR_brochure.indd 9 27/03/19 10:12 am 10 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES agents accelerate this process (2). Leading causes of antimicrobial resistance related to these diseases include: ÿ poor treatment practices, such as treatment interruption because of failure to adhere to prescribed treatment; stock-outs or interrupted access to key drugs; use of monotherapies or substandardmedicines; unregulated or informal use of drugs without prescriptions; lack of eúective drugs; use of inappropriate drugs to treat illnesses (such as artemisinin-based combination therapy to treat non-malarial febrile illnesses and antibiotics to treat viral infections); and non-optimal use of antibiotics (such as inadequate regimens or eúective monotherapy to treat TB); ÿ failure to identify drug-resistant pathogens, resulting in ineúective treatment and delayed switch tomore eúective drugs and the potential spread of the resistant pathogens; and ÿ inadequate disease prevention interventions, including poor infection control practices. 3.2 Tuberculosis The TB bacteria can develop resistance to one, two or more antimicrobial drugs used to cure the disease, leading to rifampicin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB). Extensively drug- resistant TB has been reported in 127 countries. MDR-TB is a public health crisis and global health security threat (5). In 2017, MDR-TB or RR-TB caused 558 000 new cases (3.5% of new cases and 18% of previously treated cases) and 230 000 deaths (Fig. 6). Only 25% of the estimatedMDR-TB cases (139 114) were treated, of which 55% that started treatment completed it or were cured (5) (Fig. 6). Three countries accounted for almost half of the world’s cases of multidrug-resistant or rifampicin- resistant TB: India (24%), China (13%) and the Russian Federation (10%). Globally, 3.5% of new TB cases and 18% of previously treated cases had multidrug-resistant or rifampicin-resistant TB (Fig. 7 and 8). The highest proportions (>50% in previously treated cases) are in countries of the former USSR. Among cases of multidrug-resistant TB in 2017, an estimated 8.5% had extensively drug-resistant TB (5). Multidrug-resistant TB is increasing as a proportion of all TB cases in some countries with a high burden of TB, with the burden either increasing faster or decreasingmore slowly than the overall TB burden (5). FIG. 6 Drug-resistant TB treatment cascade Source: Global tuberculosis report 2018 (5). 558 000 ssssssssssssssssssss ssssssssssssssssssss ssssssssssssssssssss ssssssssssssssssssss Estimated newmultidrug-resistant or rifampicin-resistant TB cases in 2017 161 000 ssssssssssssssss Newmultidrug-resistant or rifampicin- resistant TB cases detected in 2017 139 000 ssssssssssssss People starting treatment for multidrug-resistant TB in 2017 55% Treatment success for people starting treatment for multidrug-resistant or rifampicin-resistant TB in 2015 AMR_brochure.indd 10 27/03/19 10:12 am 11STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE FIG. 7 Percentage of new TB cases with multidrug-resistant or rifampicin-resistant TBa a Figures are based on the most recent year for which data have been reported, which varies among countries. Data cover the period 2002–2018. Source: Global tuberculosis report 2018 (5). a Figures are based on the most recent year for which data have been reported, which varies among countries. Data cover the period 2005–2018. The high percentages of previously treated TB cases with RR-TB in Belize, Guam and Sao Tome and Principe refer to only a small number of notified cases (range: 1–8 notified previously treated TB cases). Source: Global tuberculosis report 2018 (5). FIG. 8 Percentage of previously treated TB cases with multidrug-resistant or rifampicin-resistant TB Percentage of cases 0–5.9 6–11 12–29 30–49 ≥50 No data Not applicable Percentage of cases 0–2.9 3–5.9 6–11 12–17 ≥18 No data Not applicable AMR_brochure.indd 11 27/03/19 10:12 am 12 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 3.3 HIV HIV drug resistance is caused by a change (mutation) in the genetic structure of HIV that aúects the ability of a specific drug or combination of drugs to block the replication of the virus. All current antiretroviral drugs are at risk of becoming partly or fully inactive because of the emergence of resistant virus. HIV drug resistance jeopardizes the success of HIV treatment and endangers the attainment of the global targets to end the AIDS epidemic as a public health threat. The emergence of HIV drug resistance threatens the success of the “treat all” approach for HIV because resistance is more likely to lead to illness and potentially death (6). HIV drug resistance is increasing across all WHO regions, with the yearly increases greatest in eastern and southern Africa (Fig. 9). Pretreatment resistance to themost commonly used first-line drugs (efavirenz and nevirapine) has reached the level of 10%1 or greater among people initiating HIV treatment in many low- andmiddle-income countries assessed (6). Women are at great risk of carrying a virus with pretreatment resistance, posing a challenge to eliminating themother-to-child transmission of HIV and tomaternal and child health outcomes; about 50% of children newly diagnosed with HIV are infected with a virus resistant to commonly used first-line drugs (6). Modelling has predicted that, if resistance to the most common first-line drugs exceeds 10% among people starting HIV therapy in sub-Saharan Africa, in 15 years pretreatment drug resistance could be responsible for cumulatively 16% of deaths from AIDS-related causes (890 000 deaths), 9% of the 1 WHO guidelines on HIV drug resistance recommend that countries with levels of pretreatment resistance to efavirenz or nevirapine at or above 10% urgently consider using other HIV drugs in first-line regimens. FIG. 9 Increasing levels of pretreatment resistance to efavirenz and nevirapine, the most commonly used drugs in first-line HIV treatment Source: HIV drug resistance report 2017 (11). Southern Africa Western and central Africa Eastern Africa Asia Latin America 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 1996 2000 2004 2008 2012 2016 Studies: 60 Patients: 11 855 P-value for association: <0.00001 Studies: 51 Patients: 4 924 P-value for association: 0.002 Studies: 50 Patients: 7 169 P-value for association: <0.00001 Studies: 89 Patients: 16 088 P-value for association: 0.01 Studies: 83 Patients: 16 008 P-value for association: <0.00001 20 15 10 5 0 20 15 10 5 0 Pr ev al en ce of N N RT Ir es is ta nc e (% ) Pr ev al en ce of N N RT Ir es is ta nc e (% ) 20 15 10 5 0 20 15 10 5 0 Pr ev al en ce of N N RT Ir es is ta nc e (% ) Pr ev al en ce of N N RT Ir es is ta nc e (% ) 20 15 10 5 0 Pr ev al en ce of N N RT Ir es is ta nc e (% ) Fitted line AMR_brochure.indd 12 27/03/19 10:12 am 13STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE people acquiring HIV infection (450 000 people) and a programme cost of US$ 6.5 billion in sub- Saharan Africa (Fig. 10). Several low- andmiddle- income countries are currently transitioning to new regimens in first-line treatment to which resistance is expected to be low (6). Drug resistancemay also be a challenge in some of the opportunistic infections that aúect people with HIV, such as TB, cryptococcal meningitis (9), sexually transmitted infections and candidiasis (10). 3.4 Malaria Malaria is caused primarily by the Plasmodium falciparum and P. vivax parasites. Artemisinin- based combination therapy (ACT) is used to treat P. falciparum and chloroquine-resistant strains of P. vivax. Chloroquine- or ACTs, complemented with primaquine, are recommended for treating P. vivax in areas with chloroquine-susceptible infections (12). The scale-up of ACTs has been integral to the recent success of global malaria eúorts and protecting their eûcacy in treatingmalaria is a global health priority. The eûcacy of artemisinin- based combination therapy is threatened by the emergence of both artemisinin and partner drug resistance. Partner drug resistance can arise independently of artemisinin partial resistance. Partner drug resistance with or without artemisinin partial resistance increases the risk of treatment failure, and association of artemisinin resistance will worsen the treatment failure rate (12). Artemisinin partial resistance is currently limited to five countries of the Greater Mekong subregion: Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam (Fig. 11) and is suspected in Guyana, Papua NewGuinea and Rwanda. Artemisinin partial resistance has not been confirmed in Africa; multi-drug resistance2 is present in Cambodia, the Lao People’s Democratic Republic, Thailand and Viet Nam (12). P. vivax resistance is geographically widespread, but in many countries the parasite is still susceptible to chloroquine, especially when primaquine is taken concurrently. P. vivax resistance to 2 Multidrug-resistant malaria is defined as resistance to more than two antimalarial compounds of diúerent chemical classes. This term usually refers to P. falciparum resistance to chloroquine, sulfadoxine-pyrimethamine and a third antimalarial compound. FIG. 10 Predicted impact of HIV drug resistance in sub-Saharan Africa if levels of resistance to efavirenz and nevirapine, the most commonly used drugs in first-line HIV treatment, reach or exceed 10% Source: Global action plan on HIV drug resistance 2017–2021 (6). PROJECTED IMPACT IN SUB-SAHARAN AFRICAWHERE PPRETREATMENT HIV DRUG RESISTANCE ≥10% 2016–2021 2016–2030 2016–2021 2016–2030 2016–2021 2016–2030 FIRST LINE SECOND LINE THIRD LINE NEWHIV INFECTIONS AIDS DEATHS 148 000 TREATMENT COST IN US$ 450 000 150 000 890 000 $750million $6500 million $85 $1235$263 Cumulative cost Annual cost per person (2016) AMR_brochure.indd 13 27/03/19 10:12 am 14 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES artemisinin-based combination therapy has not been documented and thus artemisinin-based combination therapy can be used where there is extensive chloroquine resistance (12). WHO recommends that countries change their first-line treatments for P. falciparum and P. vivax when treatment failure rates exceed 10% (12). 3.5 Neglected tropical diseases Neglected tropical diseases (13) are a diverse group of 20 diúerent diseases that mostly aúect low- income andmarginalized populations. For many neglected tropical diseases, the risk of developing resistance to treatment is considered low because of the nature of the diseases (such as parasites with relatively long life cycles) or because no treatments are available to become resistant to (such as dengue, rabies, etc). Some drug resistance has been identified for neglected tropical diseases caused by bacteria – such as leprosy and yaws – and a parasite: visceral leishmaniasis. The resistance observed has been at low levels and does not apply to all available treatments. Drug resistance has not yet been observed for helminths that primarily infect humans. Antibiotic resistance to at least one of the three antibiotics used to treat leprosy has been detected in 19 countries. Eight per cent of the bacteria were resistant to at least one commonly used antibiotic. Resistance to two diúerent antibiotics was identified in 24 cases. Drug resistance was observed in 12 countries among 5.1% of relapses and 2.0% of new cases. Three countries (Brazil, Colombia and India) reportedmore than five resistant cases. The numbers of resistant cases are still low, and no bacterial strain has yet shown resistance to all three antibiotics simultaneously (14). Drug resistance has been reported to some first- line medicines used to treat yaws (15) and visceral leishmaniasis (16). The strategies for preventing and treating trachoma and yaws call for mass administration of the antibiotic azithromycin to populations at risk (17,18). This intervention can lead to increases in drug resistance related to non-targeted potentially pathogenic bacteria (such as Streptococcus pneumoniae). Care is therefore required to plan the mass drug administration tominimize the potential for increasing drug resistance related to non- targeted bacteria (19). Anthelmintic resistance is not yet a public health problem in human helminthiasis, where mass drug administration is a recommended intervention (schistosomiasis, onchocerciasis, lymphatic filariasis and soil-transmitted helminthiasis), but resistance is problematic in helminths of veterinary importance, indicating that resistance could develop (20). FIG. 11 Number of artemisinin-based combination therapies failing in the Greater Mekong Subregiona a Countries are classified by numbers of ACTs failing (>10% treatment failure) after 2010. Source: World malaria report 2018 (12). AMR_brochure.indd 14 27/03/19 10:12 am 15STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 4. Preventing antimicrobial resistance related to TB, HIV, malaria and neglected tropical diseases and theWHO response KEY MESSAGES ÿ Achieving universal health coverage and strengthening health systems are key factors for preventing antimicrobial resistance across all diseases and service delivery areas. ÿ For TB, HIV, malaria and neglected tropical diseases, antimicrobial resistance often can be predicted, prevented, managed and controlled bymaintaining focus on it and developing and implementing the right strategies. ÿ Drug resistance is often amarker of poor-quality treatment service delivery, and identifying and addressing quality gaps is important for preventing resistance. ÿ Surveillance, laboratory strengthening and expansion of laboratory services, enhanced data collection and use and better communication, awareness-raising, education and training are key components of all strategies for preventing andmanaging antimicrobial resistance and could be expanded to synergistically address antimicrobial resistance across all disease and service delivery areas. ÿ Addressing infectious diseases and antimicrobial resistance within the context of universal health coverage in amore integrated way oúers opportunities for eûciency and better outcomes. 4.1 Preventing antimicrobial resistance Preventing drug resistance is a critical component of any national communicable disease programme and is achieved by optimizing service delivery and eliminating programmatic gaps in disease prevention, treatment and care. WHO regularly updates its guidelines to optimize service delivery to prevent and treat TB, HIV, malaria and neglected tropical diseases. General disease prevention reduces both the overall disease burden and the transmission of sensitive and resistant pathogens – thus aúecting the spread of antimicrobial resistance. WHO also produces specific guidance for managing drug-resistant infections. These include: policy recommendations on the overall public health response required; clinical and programmatic guidance on selecting themost appropriate interventions and treatment regimens, including diagnostic and drug resistance testing; managing programmes and rationally usingmedicines; and possible recommendations on restricting access to drugs by prescription or using combination therapies. WHO policy and recommendations are informed by programmatic data on access to and use of preventive measures, resistance surveillance and eûcacy data and are routinely updated on the prevention, diagnosis and treatment of TB, HIV, malaria and neglected tropical diseases. WHO also produces guidance on other interventions and supporting programmes to better manage antimicrobial resistance in general, such as preventing and controlling infections in clinical settings, water, sanitation and hygiene in clinical settings, procurement and supply chain management, prequalification of drugs and other areas. Table 1 highlights examples ofWHO activities to identify, prevent andmanage antimicrobial resistance. AMR_brochure.indd 15 27/03/19 10:12 am 16 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES Preventing antimicrobial resistance also requires strengthening health systems to provide the needed products and services to people at the time they are required: for example, including critical, quality-assuredmedicines on lists of essential medicines; ensuring functioning supply chains that deliver the requiredmedicines to health-care facilities; preventing stock-outs and treatment disruption; and ensuring that clinical personnel have the necessary tools (such as treatment algorithms) to enable them to eúectively identify and treat a wide range of illnesses with the appropriate drugs. For example, expanded use of malaria rapid diagnostic tests does not always lead to the right treatment outcome. Artemisinin- based combination therapy is sometimes still given to patients with negative tests or antibiotics are provided to treat fever without confirmation that bacteria are the cause (21). This leads to potential misuse and overuse of artemisinin-based combination therapy or antibiotics and increased risk of drug-resistant malaria parasites or non- specific bacteria. For chronic diseases such as HIV, resistance can be prevented by national and clinic- based strategies that support optimal adherence to treatment and retention in care. 4.2 Surveillance of antimicrobial resistance Surveillance involves collecting, analysing and interpreting epidemiological data on antimicrobial resistance. Data can be collected from surveys that cover selected populations or at the individual level from routine data provided by health facilities and laboratories. Surveillance is critically important for monitoring trends and developing evidence- informed policies and interventions to prevent and manage antimicrobial resistance. In the past decades, WHO has helped to establish global, regional and country-level surveillance systems tomonitor drug resistance and therapeutic eûcacy trends in TB, HIV, malaria and neglected tropical diseases (Boxes 1–4). Overall, WHO supports drug resistance and therapeutic eûcacy surveillance activities in nearly all aúected countries: 160 countries for multidrug-resistant TB, 69 countries for HIV drug resistance and 64 countries for malaria, representingmost of the world’s population andmost of the burden of high- impact communicable diseases. Drug resistance status and trends for these diseases are routinely published in disease-specific reports and in peer- reviewed publications. To support the second strategic objective of the Global Action Plan on Antimicrobial Resistance to strengthen the knowledge and evidence base through surveillance and research, WHO launched the Global Antimicrobial Resistance Surveillance System (GLASS) in October 2015 and started country enrolment inMarch 2016. GLASS fosters the development of national antimicrobial resistance surveillance systems and provides a standardized approach to collecting, analysing and sharing antimicrobial resistance data for bacteria causing common acute infections. To date, 72 countries participate in GLASS (22). As a core function of disease-specific programmes, WHO surveillance activities include: ÿ developing standardizedmethods and tools for antimicrobial resistance surveillance, data collection and analysis; ÿ routinely collecting, quality assuring, analysing and disseminating surveillance data on drug resistance and therapeutic eûcacy and resistance trends at the global, regional and national levels; ÿ using surveillance data to informWHO guidelines and national treatment policies; ÿ providing guidance on appropriate programme indicators associated with and predictive of resistance to be included in health information systems; ÿ providing a framework for early detection and reporting of emerging antimicrobial resistance; ÿ building global data repositories, country databases and portals to support countries in storing, quality assuring and disseminating their data in a timely fashion; and ÿ providing technical support to countries in designing and conducting drug resistance and therapeutic eûcacy studies and surveys and in collecting, quality assuring, analysing, interpreting and disseminating their data. AMR_brochure.indd 16 27/03/19 10:12 am 17STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE TA BL E 1 Pa th og en re si st an ce ,r es is ta nc e m on it or in g an d W H O ac ti vi ti es Pa th og en St at us of re si st an ce a Re si st an ce m on ito rin g W H O ac tiv iti es to id en tif y, pr ev en ta nd m an ag e dr ug re si st an ce Ep id em io lo gi ca lm et ho ds fo rp op ul at io n- le ve lm on ito rin g an d su rv ei lla nc e of dr ug re si st an ce La bo ra to ry m et ho ds fo r re si st an ce de te ct io n Li te ra tu re re vi ew N at io na lly an d re gi on al ly re pr es en ta tiv e su rv ey s Co lle ct io n an d us e of ro ut in e dr ug re si st an ce da ta Th er ap eu tic eþ ca cy st ud ie sa t se nt in el si te s (p ar as ite cl ea ra nc e) Cu ltu re M ol ec ul ar m et ho ds (g en e pr ob es , se qu en ci ng ) G lo ba l m on ito rin g an d re po rt in g St an da rd iz ed pr ot oc ol sa nd to ol sf or dr ug re si st an ce su rv ei lla nc e, da ta co lle ct io n, an al ys is an d in te rp er ta tio n G lo ba l da ta ba se G lo ba l la bo ra to ry ne tw or ks w ith W H O de si gn at io n Te ch ni ca l as si st an ce fo rc ou nt rie s to im pl em en t dr ug re si st an ce su rv ey sa nd st ud ie s Ea rly w ar ni ng in di ca to rs fo rd ru g re si st an ce em er ge nc e HI V X X X X X X X X M yc ob ac te riu m tu be rc ul os is (T B) X X X X X X X X X X Pl as m od iu m (m al ar ia ) X X X X X X X X M yc ob ac te riu m le pr ae or le pr om at os is (le pr os y) X X X Tr ep on em a pa lli du m (y aw s) b X Le ish m an ia do no va ni (v is ce ra ll ei sh m an ia si s) X Ch la m yd ia tr ac ho m at is (tr ac ho m a) b X X X X He lm in th s( so il- tr an s- m itt ed he lm in th ia si s) c X X X X d X d He lm in th s (s ch is to so m es )c X X X d X d a G re en = n o d o cu m en te d re si st an ce ;o ra n g e = d ru g re si st an ce d o cu m en te d b u t n o t w id es p re ad o r re m ai n s re g io n al ly co n fi n ed ;r ed = d ru g re si st an ce as cu rr en t g lo b al h ea lt h th re at . b In te rv en ti o n s re q u ir e m as s d ru g ad m in is tr at io n w it h th e sa m e an ti b io ti c az it h ro m yc in ;m as s u se h as le d to d ru g re si st an ce in ya w s b ac te ri a an d o th er p at h o g en ic b ac te ri a b u t n o t tr ac h o m a b ac te ri a. c A n th el m in th ic d ru g re si st an ce h as b ee n o b se rv ed in h el m in th s th at in fe ct d o m es ti c an im al s b u t n o t ye t in st ra in s th at p ri m ar ily in fe ct h u m an s. d U n d er d ev el o p m en t. HIV AMR_brochure.indd 17 27/03/19 10:12 am 18 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES BOX 1 Surveillance of resistance to TB Established in 1994, the global surveillance system for TB drug resistance remains the oldest and largest initiative on antimicrobial resistance surveillance in the world (Fig. 12). TB Surveillance data are being collected either (1) through continuous surveillance systems based on routine testing of everyone with TB in countries with extensive laboratory capacity or (2) through periodic surveys, which are discrete studies measuring drug resistance among a selected sample of people who are representative of an entire population of people with TB in countries with insuûcient laboratory capacity for routine drug susceptibility testing of everyone with TB. Standardizedmethods allow comparability of data within countries over time and between countries. Surveillance data on TB drug resistance are collected annually through a web-based data collection tool that gathers notification data on everyone with TB worldwide. On average, 15 country surveys are conducted every year. Newmolecular technologies, including whole-genome sequencing technologies, have recently been incorporated into drug resistance surveys. Since 1994, data on drug resistance have been systematically collected and analysed from 165 countries (82% of the 194WHO Member States), which collectively represent more than 97% of the world’s population and TB cases (23,24). FIG. 12 Global coverage of surveillance data on TB drug resistance Source: Global tuberculosis report 2018 (5). Year of most recent data 1995–1999 2000–2004 2005–2009 2010–2014 2015–2018 Ongoing in 2018 Subnational data No data Not applicable AMR_brochure.indd 18 27/03/19 10:12 am 19STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE BOX 2 Surveillance of HIV drug resistance The emergence and transmission of some level of HIV drug resistance is inevitable, even when appropriate regimens are prescribed and adherence to treatment is optimal. To address this challenge, WHO developed a global strategy for the surveillance andmonitoring of HIV drug resistance in 2004 and updated it in 2015. The strategy includes four key activities: (1) annual monitoring of quality-of- care indicators of HIV drug resistance at all antiretroviral therapy clinics in a country; (2) surveillance of pretreatment HIV drug resistance among adults initiating first-line antiretroviral therapy; (3) surveillance of acquired HIV drug resistance in adults and children receiving treatment; and (4) surveillance of HIV drug resistance among children younger than 18months newly diagnosed with HIV. Survey data were generated from sentinel clinics from 2004 to 2014, but since 2014, nationally representative HIV drug resistancemethods have been recommended. The data generated from the HIV drug resistance surveys are representative of the entire population of individuals with HIV initiating HIV treatment or receiving HIV treatment, respectively. Since 2004, data from 271 surveys in 69 countries have been collected using standardized epidemiological and laboratory methods, allowing comparability of data within countries over time and across countries (Fig. 13). The survey results have been used to inform policies and treatment guidelines at the national and global levels. Quality assurance and dissemination of HIV drug resistance data are core activities ofWHO. Surveillance data for HIV drug resistance are entered and safely stored in theWHO global HIV drug resistance database, which has three main purposes: (1) supporting countries and genotyping laboratories in the quality assurance of epidemiological and sequence data for the purpose of generating high-quality country reports; (2) providing standardized resistance interpretations by linking to themost recent algorithm for interpreting HIV drug resistance; and (3) providing countries with a long-term secure repository for their HIV drug resistance data (25,26). A global network ofWHO-designated laboratories for HIV drug resistance supports the global eúort by producing reliable and quality-assured genotypic data. AMR_brochure.indd 19 27/03/19 10:12 am 20 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES BOX 3 Surveillance of antimalarial drug eÿcacy WHO set up surveillance of antimalarial drug eûcacy in 1996 with the development of a standard protocol to monitor antimalarial eûcacy through therapeutic eûcacy studies in collaboration with the United States Centers for Disease Control and Prevention. The protocol was first implemented in areas with highmalaria transmission rates, mainly in Africa. Later the standard protocol was updated twice to include countries with low tomoderate malaria transmission rates. WHO has developed a series of tools (including in vitro tests, molecular analysis andmeasuring drug concentrations) to better define and detect drug resistance among treatment failures. The use of these standardized procedures facilitates the comparison of results within and across regions over time.WHO organizes training at the regional and country levels on drug eûcacy monitoring and continually supports regional networks on drug eûcacy (27). WHO set up a global database in response to the challenges posed by the emergence of resistance to antimalarial drugs. The contents of the database are extracted from published and unpublished therapeutic eûcacy studies and surveys of molecular markers on antimalarial drug resistance conducted by partners at the country level. The database is the source forWHO’s onlineMalaria Threats Map, theWorld malaria report and update reports on antimalarial drug eûcacy and drug resistance. WHO has provided support in creating subregional networks for monitoring antimalarial resistance. TheMekong network, the Red Amazónica para la Vigilancia de la Resistencia a las Drogas Antimaláricas (RAVREDRA) network, the Pacific network, the BBINS (Bangladesh, Bhutan, India, þ FIG. 13 Global coverage of WHO-recommended surveillance surveys on HIV drug resistance Source: Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report (26). 2004–2013 2014–2017 2017–2018 Planned No data Not applicable Year of most recent survey AMR_brochure.indd 20 27/03/19 10:12 am 21STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE þ Nepal, Sri Lanka) network, the Horn of Africa Network for Monitoring Antimalarial Treatment (HANMAT) and PIAMNET (Pakistan, Islamic Republic of Iran and Afghanistanmonitoring network) have successfully increased drug eûcacy surveillance in the regions and generated the data needed for updating national treatment policies. Through these networks, WHO has oúered training for implementing protocols, microscopy, analysing and validating data and preparing reports and publications, which in turn improved the quality of the data. BOX 4 Therapeutic eÿcacy testing for selected neglected tropical diseases Threats of growing drug resistance related to some neglected tropical diseases has ledWHO to call for monitoring drug eûcacy and resistance at selected sentinel sites. TheWHO Strategic and Technical Advisory Group on Neglected Tropical Diseases has created a subgroup to support themonitoring of drug resistance in neglected tropical diseases. WHO has developed standard protocols for monitoring the eûcacy of the anthelminthic drugs used in preventive chemotherapy. Research is currently ongoing to develop appropriate combinations of anthelminthics to prevent or respond to the emergence of resistance. Countries have been encouraged to use theWHO-recommended protocols to monitor the local situation. TheWorking Group onMonitoring Neglected Tropical Diseases Drug Eûcacy is working to establish a network of laboratories with experience evaluating anthelminthic drug eûcacy and to developmore sensitive methods to measure anthelminthic eûcacy. 4.3 Laboratory networks For TB, HIV, malaria and neglected tropical diseases, drug resistance cannot yet be directly detected at the point of care. Samples (sputum, blood and faeces) are collected from patients and analysed in laboratories. In some cases, organisms are cultured and tested for resistance, or molecular methods (gene probes or sequencing) are used to detect resistance genes. For malaria and some neglected tropical diseases (soil-transmitted helminths and trematodes), therapeutic eûcacy tests are used to screen for treatment failure, which may be related to drug resistance. Support to strengthen and expand laboratory services is often needed to detect drug resistance (Box 5). WHO’s role has been to support the development and expansion of national, regional or specialized reference laboratories that monitor TB and HIV drug resistance (Fig. 14 and 15). WHO activities include: ÿ developing standardized drug resistance testing protocols, assay validation, standard operating procedures, tools and quality standards for internal and external quality assurance; ÿ undertaking quality assurance of resistance data and therapeutic eûcacy testing data to ensure accurate and reliable laboratory results and to facilitate the comparison of data over time and across countries; ÿ designating specialized, regional and national reference laboratories that support resistance testing for surveillance and diagnostic purposes from countries with limited or no testing capacity; ÿ identifying opportunities for eûciently integrating drug resistance and therapeutic eûcacy monitoring into broader national antimicrobial resistance and laboratory strengthening strategies and plans, including using shared health systems and laboratory platforms; and ÿ training laboratory workers, facilitating South– South collaboration across laboratories and strengthening laboratory capacity to detect and report on drug resistance at the country and regional levels. AMR_brochure.indd 21 27/03/19 10:12 am 22 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES FIG. 14 WHO TB Supranational Reference Laboratory Network Source: WHO TB Supranational Reference Laboratory Network [website] (24). Supranational Reference Laboratory – Coordinating Centre Supranational Reference Laboratory National Centre of Excellence Milan, Italy Rome, Italy Santiago, Chile Antwerp, Belgium Atlanta, USA Mexico City,Mexico Guadeloupe, France Buenos Aires, Argentina Adelaide, Australia Brisbane, Australia Bangkok, Thailand Hong Kong SAR, China Seoul, Republic of Korea Tokyo, Japan Chennai, India Karachi, Pakistan Delhi, India Cairo, Egypt Johannesburg, South Africa Kampala, Uganda Cotonou, Benin Le Hamma, Algeria Porto, Portugal Barcelona, Spain London, UK Gauting, Germany Borstel, Germany Copenhagen, Denmark Stockholm, Sweden Riga, Latvia Zagreb, Croatia Prague, Czech Republic Moscow, Russian Federation Yekaterinburg, Russian Federation Novosibirsk, Russian Federation FIG. 15 HIV Drug Resistance Laboratory Network as of July 2018 Source: Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report (26). WHO-designated national laboratory for HIV drug resistance testing WHO-designated regional laboratory for HIV drug resistance testing WHO-designated specialized laboratory for HIV drug resistance testing WHO-designated laboratory for HIV drug resistance testing using dried blood spot Laboratory with capacity for HIV drug resistance testing of integrase inhibitors Kampala Addis Ababa Dakar Johannesburg Kisumu Mexico City Atlanta Fort de France Ponce Rio de Janeiro (x2) Vancouver Winnipeg Bordeaux London Montpellier Utrecht Bangkok (x2) Chennai Pune Beijing Hanoi Ho Chi Minh City Shanghai Shenyang Sydney Abidjan Entebbe AMR_brochure.indd 22 27/03/19 10:12 am 23STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE BOX 5 Laboratory networks for TB, HIV and neglected tropical diseases WHO established a global TB drug resistance surveillance programme in 1994, supported by a network of global TB supranational reference laboratories. As of December 2018, 155 countries participated in the TB drug resistance surveillance programme, coveringmore than 95% of the world’s population and TB cases. The network of supranational reference laboratories includes 36 laboratories overseeing the drug resistance surveillance programme throughmore than 100 national TB reference laboratories (24). A global HIV drug resistance laboratory network was established in 2005 to support HIV drug resistance surveillance activities. As of July 2018,WHO had designated 30 laboratories in five of WHO’s six regions (Africa, the Americas, Europe, South-East Asia and theWestern Pacific) to conduct HIV drug resistance testing for public health surveillance (26). The first steps to establish a global neglected tropical disease drug resistance laboratory network were taken in February 2019: theWorking Group onMonitoring Neglected Tropical Diseases Drug Eûcacy met to define the terms of reference of the networks and the characteristics, capacity and geographical distribution of the laboratories that will be part of the network. 4.4 Communication, awareness-raising, education and training The first strategic objective of the Global Action Plan on Antimicrobial Resistance is to improve awareness and understanding of antimicrobial resistance through eúective communication, education and training. As highlighted in Section 3, antimicrobial resistance threatens sustainable development and is a major risk to ending the HIV, TB andmalaria epidemics. It is therefore critically important to maintain the issue of drug resistance on the global and national development agendas. WHO is working to improve awareness and understanding of drug resistance in countries, with diúerent audiences, as part of long-standing programmes in TB, HIV, malaria and neglected tropical diseases. Ongoing activities include: ÿ conveningMember States, civil society, researchers, implementing partners, donors, developers of drugs and diagnostics and other stakeholders to increase awareness and understanding around the status and impact of resistance; ÿ engaging and convening experts (through strategic and technical advisory groups, technical expert groups, global working groups etc.) to ensure timely and appropriate responses to elevated levels of resistance when they arise; ÿ compiling, interpreting and disseminating information and data on drug resistance to countries and development partners and supporting the strengthening of their situation analyses; ÿ using data generated by surveillance to inform policy and recommendations; ÿ providing regular updates about drug resistance trends toMember States throughmeetings of WHOGoverning Bodies and urging countries to take action; ÿ using international days mandated by theWorld Health Assembly (such asWorld Tuberculosis Day, WorldMalaria Day, World AIDS Day andWorld Antibiotic AwarenessWeek) to raise awareness about the challenge of drug resistance; ÿ supporting knowledge transfer, training and capacity development ofWHO regional and country oûces as well as national disease programmes on prevention and clinical and programmatic management of drug-resistant TB, HIV, malaria and neglected tropical diseases; AMR_brochure.indd 23 27/03/19 10:12 am 24 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES ÿ engagingmanufacturers of diagnostics, drugs andmedical devices in dialogue to ensure that key medicines are aúordable and that drugs that contribute to antimicrobial resistance are taken oú the market (such as malaria monotherapies); ÿ involving civil society and engaging communities in improving literacy on resistance and treatment adherence; ÿ engaging all relevant health-care providers in disease treatment, care and control through public–private mix approaches; and ÿ supporting countries in developing and implementing comprehensive national action plans to address antimicrobial resistance that include TB, HIV, malaria and neglected tropical diseases where relevant. AMR_brochure.indd 24 27/03/19 10:12 am 25STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 5. Future directions KEY MESSAGES ÿ Addressing antimicrobial resistance is part of the agendas of universal health coverage, patient safety and the quality of health-care services. ÿ Innovation and research in treatment and diagnostics will play key roles in reducing the development and spread of drug resistance related to TB, HIV, malaria and neglected tropical diseases and its risk to health. ÿ Product development partnerships have demonstrated eúectiveness in identifying and facilitating the development of new pipeline drugs for TB, malaria and neglected tropical diseases as drug resistance to current therapies spreads. ÿ Sets of clinical and programmatic quality-of-care indicators that predict and are associated with developing drug resistance have been identified andmonitored for HIV. Similar approaches might be explored to predict the emergence of resistance related to other diseases or at health-care delivery points, enabling early action to prevent andminimize the spread of antimicrobial resistance. ÿ Antimicrobial resistance related to bacteria, TB, HIV, malaria and neglected tropical diseases is a critical issue and needs to be kept high on the global, regional and national health development agendas. ÿ WHO has a key role to play in compiling and disseminating information on levels of resistance and trends as well as innovative practices to prevent, manage and control the development and spread of antimicrobial resistance related to TB, HIV, malaria, bacteria, fungi and neglected tropical diseases. ÿ WHO, working collaboratively with other development partners, will provide joint support to countries in developing, implementing and tracking progress against comprehensive, evidence-informed national antimicrobial resistance action plans that include TB, HIV, malaria and neglected tropical diseases where relevant. ÿ WHOwill work with countries to identify andmaximize synergy across programmes or service delivery areas and platforms to address TB, HIV, malaria and neglected tropical diseases antimicrobial resistance. AMR_brochure.indd 25 27/03/19 10:12 am 26 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 5.1 Identify research and development gaps and new tools and approaches New products, technologies and service delivery approaches will be needed to address antimicrobial resistance related to TB, HIV, malaria, neglected tropical diseases and across the whole spectrum of antimicrobial resistance. Research and development will play an important role in preventing and managing antimicrobial resistance. WHO has a clear leadership role to play in identifying prevention andmanagement gaps in antimicrobial resistance related to TB, HIV, malaria and neglected tropical diseases, which can include the need for new products and approaches to service delivery. WHO’s role includes: ÿ monitoring antimicrobial resistance prevalence and trends to assess needs and gaps; ÿ identifying and setting global, regional and national research agendas and priorities for antimicrobial resistance; ÿ convening institutions and expert networks to address antimicrobial resistance gaps, including collaborative eúorts to identify antimicrobial resistancemanagement needs in the animal health and agricultural sectors (such as through the FAO/OIE/WHO Tripartite Collaboration on Antimicrobial Resistance and UNEP) and how this aúects human health; ÿ compiling and disseminating good practices in preventing andmanaging antimicrobial resistance to facilitate changes in approaches to service delivery to address gaps in service quality and eúectiveness; ÿ supporting countries in conducting implementation research across a variety of settings and populations to improve approaches to service delivery (such as improving treatment adherence, preventing drug stock-outs, identifying drug resistance and optimizing treatment protocols in the face of increasing resistance) or address other factors that lead to the emergence and spread of antimicrobial resistance; ÿ assessing the burden of disease caused by antimicrobial resistance; and ÿ advocating for increased research and development investment to strengthen product pipelines that address aspects of antimicrobial resistance. To prevent andmanage drug resistance related to TB, HIV, malaria and neglected tropical disease, WHO can: ÿ identify and advocate for the development of better andmore aúordable tools, such as vaccines, eúective drugs with shorter or simplified treatment protocols, point-of-use diagnostic tests, gene sequencing andmolecular methods for surveillance of drug resistance; ÿ recommendmodels of service delivery that improve the quality and follow-up of key interventions that influence antimicrobial resistance, such as treatment adherence, diagnostic testing and appropriate response, algorithms to ensure eúective treatment and infection control to minimize disease transmission in hospital settings; ÿ collaborate to further address antimicrobial resistance in the animal husbandry and agricultural sectors; ÿ engage with product development partnerships, the private sector and other partners to advocate for developing new drug candidates (Box 6) or diagnostics and other products (Box 7); and ÿ support countries in rapidly adopting innovative practices or new products to prevent or manage antimicrobial resistance for maximum impact. AMR_brochure.indd 26 27/03/19 10:12 am 27STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE BOX 6 Product development partnerships to identify and develop new candidate drugs TheMedicines for Malaria Venture (MMV) and Drugs for Neglected Diseases initiative (DNDi) are product development partnerships that have identified and developed an innovative model to develop new pipeline drugs to treat malaria and neglected diseases. These partnerships provide a systematic way for partners to work together to identify and develop newmedicines and/or better formulations to increase the pipeline of available drugs to treat malaria and neglected tropical diseases. These partnerships facilitate the development of drugs that pharmaceutical companies may be reluctant to pursue by themselves because of economic considerations. Since it was created in 1999, MMV has built an extensive network of over 400 pharmaceutical, academic and endemic-country partners in more than 55 countries and has developed and brought forward 10 newmedicines to treat malaria (28). Increasing the pipeline of available malaria drugs will help to mitigate the impact if current resistance to artemisinin-based combination therapy becomes widespread. The product development partnership model has also been used to address drug resistance related to other diseases. The Global Antibiotic Research and Development Partnership was established inMay 2016 as a joint initiative byWHO and the DNDi. This not-for-profit research and development initiative addresses global public health needs by developing and delivering new or improved antibiotic treatments while endeavouring to ensure sustainable access. It also harnessesWHO’s mandate to drive the global response to antimicrobial resistance and set health priorities and DNDi’s expertise in maximizing partnerships to build a pipeline for neglected diseases and deliver not-for-profit, needs-driven research and development. Various partners and donors are contributing to this collaborative eúort. In 2010, theWHODepartment of Control of Neglected Tropical Diseases established theWorking Group onMonitoring Neglected Tropical Diseases Drug Eûcacy to promote the testing of new anthelminthic drugs or combinations of existing drugs. The group identified several potential drug candidates. ThreeWHO collaborating centres are participating in this working group. BOX 7 Role of development partners in the response to antimicrobial resistance In recent years, the work to respond to antimicrobial resistance has benefited from investment by technical agencies, donor initiatives and the private sector. Unitaid, the United States Agency for International Development (USAID) and the Bill &Melinda Gates Foundation have supported trials and other studies of newmedicines and novel regimens for multidrug-resistant TB (such as the EndTB project coordinated by Partners in Health, Médecins Sans Frontières and Interactive Research and Development in Pakistan; the Global Alliance for TB Drug Development; and the STREAM trial of a shorter nine-monthmultidrug-resistant TB regimen). The initiatives of manufacturers of diagnostics (such as HAIN for line probe assay and CEPHEID for GeneXpert) andmedications (such as bedaquiline by Janssen and delamanid by Otsuka) have also been critical to improvemultidrug-resistant TB care. Unitaid has made critical contributions to support national TB laboratory networks to consolidate their work and implement new diagnostics for drug-resistant TB (EXPAND-TB project) and improve access to new TBmedicines. þ AMR_brochure.indd 27 27/03/19 10:12 am 28 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES þ For HIV, the Bill &Melinda Gates Foundation has supported the establishment of theWHOGlobal Strategy for the Surveillance andMonitoring of HIV Drug Resistance and the Global Action Plan on HIV Drug Resistance; the Global Fund to Fight AIDS, Tuberculosis andMalaria and the United States President’s Emergency Plan for AIDS Relief (PEPFAR) have supported countries in implementing national HIV drug resistance surveys and in strengthening laboratory capacity for HIV drug resistance testing. The United States Centers for Disease Control and Prevention has provided technical assistance to PEPFAR-supported countries in activities related to surveillance of HIV drug resistance. The United States National Institutes of Health provide in-kind support to the quality assurance of the global HIV drug resistance laboratory network. Over the years, some specializedWHO-designated HIV drug resistance laboratories (such as the University of British Columbia (Vancouver, Canada), Public Health Agency of Canada (Winnipeg, Canada); Center for Research in Infectious Diseases (CIENI, Mexico City, Mexico), United States Centers for Disease Control and Prevention/Global Action Plan on Antimicrobial Resistance (Atlanta, USA) have provided HIV drug resistance testing free of charge to support HIV drug resistance surveillance in several low- andmiddle-income countries with limited financial and technical capacity. Other partners, including the Public Health Agency of Canada, have contributed to diúerent aspects of HIV drug resistancemonitoring and surveillance eúorts. HIVResNet, a large network of institutions and experts, has provided strategic guidance to WHO over the years and contributed to the global eúorts to monitor, respond to and prevent HIV drug resistance. Unitaid is funding clinical trials for emerging antiretroviral medicines and supports treatment monitoring to facilitate treatment optimization, including for children. Partners have also played a key role in the work to develop newmalaria treatments, in supporting the surveillance of the eûcacy of existing antimalarial drugs, and in the eúorts to contain resistance and eliminate malaria in the Greater Mekong Subregion. The Bill &Melinda Gates Foundation, the Australian Department of Foreign Aúairs and Trade, the United KingdomDepartment for International Development, the Global Fund to Fight AIDS, Tuberculosis andMalaria and USAID provide essential support to the surveillance of eûcacy. The Global Fund to Fight AIDS, Tuberculosis andMalaria is the main funder of the work to eliminate P. falciparummalaria in the Greater Mekong subregion and thereby minimize the risk of future spread of drug-resistant parasites from this area. Unitaid is also fundingmalaria projects to improve diagnostics and prevention for pregnant women. The Bill &Melinda Gates Foundation and USAID have provided financial support for neglected tropical diseases, identifying alternative anthelminthics and establishing a network of laboratories while technical support was provided by three collaborating centres in Basel, Switzerland, Ghent, Belgium and Negrar, Italy and byMcGill University, the University of Texas, the University of London and Universidad de Valencia. 5.2 Clinical and programmatic indicators associated with and predicting the emergence of antimicrobial resistance Evidence from HIV programmes has shown that it is possible to identify andmonitor a set of programmatic quality-of-care indicators that provide an early warning for the emergence of drug resistance in certain populations or settings (see Box 8 and Table 2). Monitoring this set of indicators can help to predict where resistancemay emerge, enabling corrective actions to be taken to prevent the emergence and subsequent spread of drug resistance (29). For several diseases (such as TB, HIV and leprosy) drug resistance is more likely to arise among people who have been previously treated and stopped treatment or experienced treatment failure. This should prompt the use of a diúerent drug combination for subsequent treatment AMR_brochure.indd 28 27/03/19 10:12 am 29STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE regimens in accordance withWHO treatment guidelines. For neglected tropical diseases, the emergence of parasite resistance to some anthelminthics used to treat infections in livestock signals that human pathogenic helminth strains also need to bemonitored for resistance, especially given the scale of themass drug administration approaches used to treat these parasites in humans. Future work across disease areas might help to identify common sets of service delivery and/ or quality-of-care indicators that can be routinely monitored to prevent the emergence and spread of drug resistance. BOX 8 Quality-of-care indicators associated with and predicting the emergence of HIV drug resistance Monitoring a subset of quality of care indicators – also known as early warning indicators of HIV drug resistance – is a key component of theWHO public health strategy to prevent HIV drug resistance in countries scaling up antiretroviral therapy. These quality-of-care indicators specifically assess factors at individual antiretroviral therapy clinics associated with and predicting the emergence of HIV drug resistance. Monitoring these quality-of-care indicators is designed to provide countries with actionable information to improve clinical and programmatic performance to prevent HIV drug resistance from emerging. Many factors are associated with the emergence of HIV drug resistance. They include viral factors (such as subtype, replication capacity and pre-existing polymorphisms); drug-related factors (such as drug potency, pharmacokinetics, drug–drug interactions, drug tolerability and genetic barriers to selecting resistance) and programme factors (such as patient adherence, drug stock-outs and supply continuity and retention in treatment). Although viral and drug-related factors are often beyond the control of public health or programme action, monitoring the clinical or programmatic factors associated with HIV drug resistance can alert antiretroviral therapy programmes to situations that may favour the emergence of HIV drug resistance or failure to suppress viral load at the population level. This set of quality-of-care indicators monitors factors related to patient care (appropriate prescribing and viral load suppression at 12months); patient behaviour (adherence); and clinic-level and programmemanagement (follow-up, retention on antiretroviral therapy, procurement and supply management of antiretroviral drugs and appropriately switching regimen among people with failure to suppress viral load). Early warning indicators use internationally agreed standardized definitions and accompanying targets. Annual monitoring of early warning indicators enables the degrees of improvement or decline over time to bemeasured, both within and between clinics AMR_brochure.indd 29 27/03/19 10:12 am (29). 30 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES 5.3 Joint support for countries The Global Action Plan on Antimicrobial Resistance outlines a framework for action on antimicrobial resistance with supporting countries to develop, implement andmonitor antimicrobial resistance national action plans as a priority. The One Health concept requires a perspective that covers antimicrobial resistance across all key components, including human health, animal health and agriculture because preventing andmanaging antimicrobial resistance requires activities across all relevant sectors. As of January 2019, 117 countries had national action plans, but the extent to which TB, HIV, malaria and neglected tropical disease programmes are involved varies. WHO and other TABLE 2 WHO-recommended early warning indicators of HIV drug resistance and their respective targets WHO-recommended early warning indicators of HIV drug resistance Target (green: good performance; amber: fair performance; red: poor performance) Retention on antiretroviral therapy at 12months (ART.5, antiretroviral therapy retention) % of patients retained on antiretroviral therapy 12months after initiating antiretroviral therapy Green: >85% Amber: 75–85% Red: <75% On-time pill pick-up (ART.7, antiretroviral therapy adherence proxy) % of people who pick up antiretroviral therapy nomore than two days late at the first drug pick-up after a defined baseline pick-up Green: >90% Amber: 80–90% Red: <80% Pharmacy stock-outa (not collectable through the HIV patient monitoring system) % of months with any days of stock-out of any routinely dispensed antiretroviral drug Green: 0% Red: >0% Viral load suppressionb (VLS.1, viral load suppression at 12months) % of people with viral load <1000 copies/mL 12months after initiating antiretroviral therapy Green: ≥90% Amber: 80–<90% Red: <80% Viral load completionc (VLS.2, viral load testing coverage) % of people with a 12-month viral load test result available Green: ≥70% Red: <70% a Stock-out refers to lack of availability of first-line antiretroviral drugs. b The denominator for the viral load suppression indicator is the number of people alive and receiving antiretroviral therapy 12 months after initiating treatment who have a viral load test result available. c The denominator for the viral load completion indicator is the number of people alive and receiving antiretroviral therapy 12 months after initiating treatment, who are therefore, consistent with the policy, expected to have a viral load test result available in the primary medical record. For all early warning indicators, a grey classification is applied in situations where a sampled antiretroviral therapy clinic is unable to report on a specific indicator because more than 30% of the data are missing. development partners need to collaborate better andmakemore eúort in providing joint support to countries to develop comprehensive national action plans that include interventions to address TB, HIV, malaria and neglected tropical diseases where relevant. Countries need coordinated support in collecting and using data on antimicrobial resistance (national and subnational) for evidence- informed decision-making. Technical support should also target drug regulatory authorities to ensure that new eúective medicines and other relevant products (such as diagnostic tests that detect drug resistance) are added to national lists of essential medicines and that treatment policies are changed as soon as possible if antimicrobial resistance is reducing the eúectiveness of existing treatment protocols. AMR_brochure.indd 30 27/03/19 10:12 am Source: WHO Consolidated guidelines on person-centred HIV patient monitoring and case surveillance (29). 31STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 5.4 Identifying and optimizing synergy As countries move to strengthen their primary health care systems and towards achieving universal health coverage in the context of reduced reliance on external funding resources, they will need to look for opportunities to increase the eûciency of health services and reachmore people with essential services. For antimicrobial resistance, this might mean using diagnostic platforms that can detect drug-resistant strains of pathogens for several diseases and strengthening and expanding the services oúered by laboratories to detect drug resistance. Synergy can also be found by training health-care providers to prevent andmanage antimicrobial resistance across multiple diseases and at various service delivery points, provide better treatment by using adapted treatment algorithms and undertake infection control and prevention interventions. Strengthening procurement and supply chain management systems to reduce drug stock-outs is also an important intervention for preventing antimicrobial resistance related to TB and HIV and to other diseases as well. Ensuring that health-care facilities have clean water and functioning sanitation facilities and that wastewater is adequately treated before being discharged into the environment from health-care facilities and drugmanufacturing facilities can strongly reduce antimicrobial resistance. 5.5 Product pipelines Collaboration is required to identify new drug candidates. New drugs take a long time to develop, are expensive andmust go through at least three phases of clinical trials before they can be approved for widespread use among humans. Pharmaceutical companies are often unwilling to invest the time andmoney required to bring new drugs to market unless they have a high probability of achieving adequate returns on investment. This is often a challenge for such diseases as TB, HIV, malaria and neglected tropical diseases, which have their greatest impact in low- andmiddle- income countries. As highlighted in Box 6, product development partnerships and other research consortiums can facilitate and fundwork to identify new pipeline drugs. Further research is also needed to develop formulations for children, shorter duration treatments, treatments with reduced side-eúects, more eúective combinations of existing drugs, lower cost treatments, medicines with greater stability and long-acting formulations. Point-of-care diagnostic tests that directly measure drug resistance are not currently available. Research and funding are also needed to develop new technologies and products and common diagnostic platforms that can detect drug resistance across multiple diseases. AMR_brochure.indd 31 27/03/19 10:12 am 32 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES References 1. Adeyi OO, Baris E, Jonas OB, Irwin A, Berthe FCJ, Le Gall FG et al. Drug-resistant infections: a threat to our economic future (Vol. 2). Washington (DC): World Bank; 2017 (http://documents.worldbank.org/curated/en/323311493396993758/final-report, accessed 4 February 2019). 2. Antimicrobial resistance. Geneva: World Health Organization; 2018 (https://www.who.int/en/news-room/fact-sheets/detail/antimicrobial-resistance, accessed 4 February 2019). 3. Sustainable Development Goals [website]. New York: United Nations; 2019 (https://sustainabledevelopment.un.org/sdgs, accessed 4 February 2019). 4. What is health financing for universal health coverage? [website]. Geneva: World Health Organization; 2019 (https://www.who.int/health_financing/universal_coverage_definition/en, accessed 4 February 2019). 5. Global tuberculosis report 2018. Geneva: World Health Organization; 2018 (https://www.who.int/tb/publications/global_report/en, accessed 4 February 2019). 6. Global action plan on HIV drug resistance 2017–2021. Geneva: World Health Organization; 2017 (http://apps.who.int/iris/bitstream/handle/10665/255883/9789241512848-eng.pdf, accessed 4 February 2019). 7. United Nations Interagency Coordination Group on Antimicrobial Resistance (IACG) [website]. Geneva: World Health Organization; 2019 (https://www.who.int/antimicrobial-resistance/interagency-coordination-group/en, accessed 4 February 2019). 8. Thirteenth General Programme ofWork 2019–2023. Geneva: World Health Organization; 2018 (https://www.who.int/about/what-we-do/gpw-thirteen-consultation/en, accessed 4 February 2019). 9. Mpoza E, Rhein J, Abassi M. Emerging fluconazole resistance: implications for themanagement of cryptococcal meningitis. MedMycol Case Rep. 2017;19:30–2. 10. Pankhurst CL. Candidiasis (oropharyngeal). BMJ Clin Evid. 2009;2009:1304. 11. HIV drug resistance report 2017. Geneva: World Health Organization; 2017 (http://www.who.int/hiv/pub/drugresistance/hivdr-report-2017/en, accessed 4 February 2019). 12. World malaria report 2018. Geneva: World Health Organization; 2018 (https://www.who.int/malaria/publications/world-malaria-report-2018/en, accessed 4 February 2019). 13. Neglected tropical diseases [website]. Geneva: World Health Organization; 2019 (https://www.who.int/neglected_diseases/diseases/en, accessed 4 February 2019). 14. Cambau E, Saunderson P, MatsuokaM, Cole ST, Kai M, Suúys P et al. Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by aWHO surveillance network for the period 2009–15. Clin Microbiol Infect. 2018;24:1305–10. 15. Mitjà O, Godornes C, Houinei W, Kapa A, Paru R, Abel H et al. Re-emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study. Lancet. 2018;391:1599– 1607. AMR_brochure.indd 32 27/03/19 10:12 am 33STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE 16. Ponte-Sucre A, Gamarro F, Dujardin J-C, Barrett MP, Lopez-Vélez R, Garcia-Hernandez R et al. Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoS Negl Trop Dis. 2017;11:e0006052. 17. Trachoma fact sheet. Geneva: World Health Organization; 2018 (https://www.who.int/en/news-room/fact-sheets/detail/trachoma, accessed 4 February 2019). 18. Yaws fact sheet. Geneva: World Health Organization; 2018 (https://www.who.int/news-room/fact-sheets/detail/yaws, accessed 4 February 2019). 19. O’Brien KS, Emerson P, Hooper PJ, Reingold AL, Dennis EG, Keenan JD et al. Antimicrobial resistance followingmass azithromycin distribution for trachoma: a systematic review. Lancet Infect Dis. 2019;19:e14–e25. 20. Seventhmeeting of theWorking Group onMonitoring of Neglected Tropical Diseases Drug Eûcacy. Geneva: World Health Organization; 2018 (https://apps.who.int/iris/bitstream/handle/10665/273620/WHO-CDS-neglected tropical disease-PCT-2018.06-eng.pdf, accessed 4 February 2019). 21. Bruxvoort KJ, Leurent B, Chandler CIR, Ansah EK, Baiden F, Björkman A et al. The impact of introducing malaria rapid diagnostic tests on fever case management: a synthesis of ten studies from the ACT Consortium. Am J TropMed Hyg. 2017;97:1170–9. 22. Global Antimicrobial Resistance Surveillance System (GLASS) [website]. Geneva: World Health Organization; 2019 (https://www.who.int/glass/en, accessed 4 February 2019). 23. Tuberculosis: surveillance of drug-resistant TB [website]. Geneva: World Health Organization; 2019 (https://www.who.int/tb/areas-of-work/monitoring-evaluation/mdr-tb-surveillance/en, accessed 4 February 2019). 24. WHO TB Supranational Reference Laboratory Network [website]. Geneva: World Health Organization; 2010 (available at https://www.who.int/tb/areas-of-work/laboratory/srl-network/en, accessed 4 February 2019). 25. HIV drug resistance surveillance guidance: 2015 update. Geneva: World Health Organization; 2015 (https://apps.who.int/iris/bitstream/handle/10665/204471/9789241510097_eng.pdf, accessed 4 February 2019). 26. Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report. Geneva: World Health Organization; 2018 (https://www.who.int/hiv/pub/drugresistance/gap-hivdr-progress2018/en, accessed 4 February 2019. 27. Malaria: drug resistance and response [website]. Geneva: World Health Organization; 2019 (https://www.who.int/malaria/areas/drug_resistance/en, accessed 4 February 2019). 28. An overview of our work. Geneva: Medicines for Malaria Venture; 2019 (https://www.mmv.org/about-us/about-mmv, accessed 4 February 2019). 29. Consolidated guidelines on person-centred HIV patient monitoring and case surveillance. Geneva: World Health Organization; 2017 (https://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en, accessed 4 February 2019). AMR_brochure.indd 33 27/03/19 10:12 am 34 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES WHO antimicrobial resistance resources Antimicrobial resistance – general WHO antimicrobial resistance website http://www.who.int/topics/antimicrobial_resistance/en Global Action Plan on Antimicrobial Resistance http://www.who.int/antimicrobial-resistance/publications/global-action-plan/en Global Framework for Development & Stewardship to Combat Antimicrobial Resistance – Draft roadmap http://www.who.int/entity/antimicrobial-resistance/global-action-plan/UpdatedRoadmap-Global- Framework-for-Development-Stewardship-to-combatantimicrobial resistance_2017_11_03.pdf Global Antimicrobial Resistance Surveillance System: Manual for Early Implementation http://www.who.int/antimicrobial-resistance/publications/surveillance-system-manual/en Worldwide country situation analysis: response to antimicrobial resistance http://www.who.int/antimicrobial-resistance/publications/situationanalysis/en Antimicrobial resistance: global report on surveillance 2014 http://www.who.int/antimicrobial-resistance/publications/surveillancereport/en Global Antimicrobial Resistance Surveillance System –manual for early implementation https://www.who.int/antimicrobial-resistance/publications/surveillance-system-manual/en Global Antimicrobial Resistance Surveillance System (GLASS) report – early implementation 2016–2017 https://www.who.int/glass/resources/publications/early-implementation-report/en TB Drug-resistant TB:WHOwebsite http://www.who.int/tb/areas-of-work/drug-resistant-tb/en The End TB Strategy http://www.who.int/tb/strategy/en Global tuberculosis report 2018 http://www.who.int/tb/publications/global_report/en WHO treatment guidelines for drug-resistant tuberculosis http://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639-eng.pdf Companion handbook to theWHO guidelines for the programmatic management of drug-resistant tuberculosis http://www.who.int/tb/publications/pmdt_companionhandbook/en Guidelines for surveillance of drug resistance in tuberculosis – 5th edition http://www.who.int/tb/publications/2015/drs_guidelines/en Compendium ofWHO guidelines and associated standards: ensuring optimum delivery of the cascade of care for patients with tuberculosis http://apps.who.int/iris/bitstream/10665/259180/1/9789241512572-eng.pdf AMR_brochure.indd 34 27/03/19 10:12 am 35STRENGTHENING COLLABORATION TO PREVENT AND MANAGE ANTIMICROBIAL RESISTANCE HIV Global Health Sector Strategy on HIV, 2016–2021 http://apps.who.int/iris/bitstream/handle/10665/246178/WHO-HIV-2016.05-eng.pdf HIV drug resistance: WHOwebsite http://www.who.int/hiv/topics/drugresistance/en/ Global Action Plan on HIV Drug Resistance 2017–2021 http://apps.who.int/iris/bitstream/handle/10665/255883/9789241512848-eng.pdf Global Action Plan on HIV Drug Resistance 2017–2021: 2018 progress report https://www.who.int/hiv/pub/drugresistance/gap-hivdr-progress2018/en/ HIV drug resistance surveillance guidance http://apps.who.int/iris/bitstream/handle/10665/204471/9789241510097_eng.pdf Guidelines on the public health response to pretreatment HIV drug resistance http://www.who.int/hiv/pub/guidelines/hivdr-guidelines-2017/en HIV drug resistance report 2017 http://www.who.int/hiv/pub/drugresistance/hivdr-report-2017/en Consolidated guidelines on person-centred HIV patient monitoring and case surveillance http://www.who.int/hiv/pub/guidelines/person-centred-hiv-monitoring-guidelines/en Tackling HIV drug resistance: trends, guidelines and global action. http://apps.who.int/iris/bitstream/handle/10665/255881/WHO-HIV-2017.21-eng.pdf Malaria Global technical strategy for malaria 2016–2030 http://www.who.int/malaria/publications/atoz/9789241564991/en Malaria drug resistance: WHOwebsite http://www.who.int/malaria/areas/drug_resistance/en World malaria report 2018 https://www.who.int/malaria/publications/world-malaria-report-2018/report/en WHO status reports on Plasmodium falciparum drug eûcacy and resistance http://www.who.int/entity/malaria/areas/drug_resistance/updates/en/index.html Eliminatingmalaria in the Greater Mekong Subregion: united to end a deadly disease http://www.who.int/entity/malaria/publications/atoz/eliminating-malaria-greater-mekong/en/ index.html Methods for surveillance of antimalarial drug eûcacy http://www.who.int/entity/malaria/publications/atoz/9789241597531/en/index.html Q&A on artemisinin resistance http://www.who.int/entity/malaria/publications/atoz/9789241597531/en/index.html Guidelines for the treatment of malaria. Third edition http://www.who.int/malaria/publications/atoz/9789241549127/en AMR_brochure.indd 35 27/03/19 10:12 am 36 TUBERCULOSIS , HIV, MALARIA AND NEGLECTED TROPICAL DISEASES Neglected tropical diseases Neglected tropical diseases: WHOwebsite http://www.who.int/neglected_diseases/en Seventhmeeting of theWorking Group onMonitoring of Neglected Tropical Diseases Drug Eûcacy http://apps.who.int/iris/bitstream/handle/10665/273620/WHO-CDS-neglected tropical disease-PCT- 2018.06-eng.pdf AMR_brochure.indd 36 27/03/19 10:12 am

World Health Organization 20 Avenue Appia 1211 Geneva 27 Switzerland www.who.int ISBN 978-92-4-151545-0