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Facing the Reality of Drug- Resistant Tuberculosis in India Challenges and Potential Solutions SUMMARY OF A JOINT WORKSHOP by the Institute of Medicine, the Indian National Science Academy, and the Indian Council of Medical Research Steve Olson, Rebecca A. English, Rita S. Guenther, and Anne B. Claiborne, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, and the Institute of Medicine. This study was supported by contracts between the National Academy of Sciences and Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223001003T), U.S. State Department (S-LMAQM-08-GR-071), American Society for Microbiology, Amgen Inc., Association of American Medical Colleges, Bristol-Myers Squibb, Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, Criti- cal Path Institute, Doris Duke Charitable Foundation, Eli Lilly & Co., FasterCures, Foundation for the NIH, Friends of Cancer Research, GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-21966-2 International Standard Book Number-10: 0-309-21966-3 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2012 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2012. Facing the Reality of Drug- Resistant Tuberculosis in India: Challenges and Potential Solutions: Summary of a Joint Workshop. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE ON FACING THE REALITY OF DRUG-RESISTANT TUBERCULOSIS IN INDIA: CHALLENGES AND POTENTIAL SOLUTIONS1 GAIL H. CASSELL (Chair), Harvard Medical School (visiting) BARRY R. BLOOM, Harvard School of Public Health ENRIQUETA C. BOND, QE Philanthropic Advisors RICHARD E. CHAISSON, Johns Hopkins University PAUL E. FARMER, Partners In Health, Harvard Medical School ANTHONY S. FAUCI, National Institute of Allergy and Infectious Diseases GARY L. FILERMAN, Atlas Health Foundation GERALD H. FRIEDLAND, Yale University School of Medicine ELAINE K. GALLIN, QE Philanthropic Advisors STEPHEN GROFT, National Center for Advancing Translational Sciences NANCY SUNG, Burroughs Wellcome Fund IOM Staff ANNE B. CLAIBORNE, Forum Director RITA S. GUENTHER, Program Officer REBECCA A. ENGLISH, Associate Program Officer ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ROBIN GUYSE, Senior Program Assistant RONA BRIERE, Consulting Editor Indian National Science Academy (INSA) Staff KRISHAN LAL, President PRAKASH N. TANDON, Past President A. K. JAIN, Inter Academy Officer 1 Institute of Medicine planning committees are solely responsible for organizing the work- shop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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Indian Council of Medical Research (ICMR) Staff VISHWA MOHAN KATOCH, Director General LALIT KANT, Head, Division of Epidemiology and Communicable Diseases MANJULA SINGH, Scientist C HARPREET SANDHU, Scientist D MUKESH KUMAR, Scientist E and Head vi

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 JEFFREY M. DRAZEN (Co-Chair), New England Journal of Medicine, Boston, Massachusetts STEVEN K. GALSON (Co-Chair), Amgen Inc., Thousand Oaks, California MARGARET ANDERSON, FasterCures, Washington, DC HUGH AUCHINCLOSS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland LESLIE Z. BENET, University of California, San Francisco ANN BONHAM, Association of American Medical Colleges, Washington, DC LINDA BRADY, National Institute of Mental Health, Bethesda, Maryland ROBERT CALIFF, Duke University Medical Center, Durham, North Carolina C. THOMAS CASKEY, Baylor College of Medicine, Houston, Texas GAIL H. CASSELL, Harvard Medical School (visiting), Carmel, Indiana PETER B. CORR, Celtic Therapeutics, LLLP, New York, New York ANDREW M. DAHLEM, Eli Lilly & Co., Indianapolis, Indiana TAMARA DARSOW, American Diabetes Association, Alexandria, Virginia JAMES H. DOROSHOW, National Cancer Institute, Bethesda, Maryland GARY L. FILERMAN, Atlas Health Foundation, McLean, Virginia GARRET A. FITZGERALD, University of Pennsylvania School of Medicine, Philadelphia MARK J. GOLDBERGER, Abbott Pharmaceuticals, Rockville, Maryland HARRY B. GREENBERG, Stanford University School of Medicine, California STEPHEN GROFT, National Center for Advancing Translational Sciences, Bethesda, Maryland LYNN HUDSON, Critical Path Institute, Tucson, Arizona THOMAS INSEL, National Center for Advancing Translational Sciences, Bethesda, Maryland MICHAEL KATZ, March of Dimes Foundation, White Plains, New York PETRA KAUFMANN, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 1 Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vii

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JACK D. KEENE, Duke University Medical Center, Durham, North Carolina RONALD L. KRALL, University of Pennsylvania, Center for Bioethics, Steamboat Springs, Colorado FREDA LEWIS-HALL, Pfizer Inc., New York, New York MARK B. McCLELLAN, The Brookings Institution, Washington, DC CAROL MIMURA, University of California, Berkeley ELIZABETH (BETSY) MYERS, Doris Duke Charitable Foundation, New York, New York JOHN ORLOFF, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey AMY PATTERSON, National Institutes of Health, Bethesda, Maryland MICHAEL ROSENBLATT, Merck & Co., Inc., Whitehouse Station, New Jersey JANET SHOEMAKER, American Society for Microbiology, Washington, DC ELLEN SIGAL, Friends of Cancer Research, Washington, DC ELLIOTT SIGAL, Bristol-Myers Squibb, Princeton, New Jersey ELLEN R. STRAHLMAN, GlaxoSmithKline, Research Triangle Park, North Carolina NANCY SUNG, Burroughs Wellcome Fund, Research Triangle Park, North Carolina JANET TOBIAS, Ikana Media and Mount Sinai School of Medicine, New York, New York JOANNE WALDSTREICHER, Janssen Research & Development, LLC, Raritan, New Jersey JANET WOODCOCK, Food and Drug Administration, White Oak, Maryland IOM Staff ANNE B. CLAIBORNE, Forum Director RITA S. GUENTHER, Program Officer REBECCA A. ENGLISH, Associate Program Officer ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ROBIN GUYSE, Senior Program Assistant viii

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for clarity, objectivity and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: Digambar Behera, Lala Ram Sarup Institute of TB and Respiratory Diseases Vishwa Mohan Katoch, Indian Council of Medical Research P. R. Narayanan, National Institute for Research in Tuberculosis, Chennai K. Srinath Reddy, Public Health Foundation of India Christine F. Sizemore, National Institute of Allergy and Infectious Diseases Soumya Swaminathan, National Institute for Research in Tuberculosis, Chennai Prakash N. Tandon, Indian National Science Academy Kristina Wallengren, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal ix

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x REVIEWERS Although the reviewers listed above provided many constructive com- ments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Melvin Worth. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authors and the institution.

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Contents ACRONYMS xvii 1 INTRODUCTION 1 History and Dimensions of the Problem, 6 The Burden of Drug-Resistant TB, 7 Treating TB in Context, 8 Overview of TB and MDR TB in India, 10 Setting the Stage, 14 Organization of the Report, 16 2 DRUG-RESISTANT TB IN INDIA 17 The Burden of TB and MDR TB in India, 18 Plans of the Revised National TB Control Program, 20 Involvement of the Private Sector, 27 Challenges to the Revised National TB Control Program, 28 Treatment of Drug-Resistant TB, 30 Improving Health System Performance to Address the Challenge of Drug-Resistant TB, 33 Potential Innovations and Action Items, 35 3 THE GLOBAL BURDEN OF DRUG-RESISTANT TB 37 Overview of the Global Burden of TB and MDR TB, 38 MDR TB Prevention and Control in China, 40 Historical Perspective on TB and MDR TB Control Efforts, 41 xi

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xii CONTENTS Global Challenges and Potential Solutions, 43 Potential Innovations and Action Items, 46 4 PREVENTING TRANSMISSION OF DRUG-RESISTANT TB 49 India’s Program Efforts to Prevent Transmission of Drug-Resistant TB, 50 The Impact of Treatment on MDR TB Transmission, 52 The Genetic Evolution of M.tb., 54 The Molecular Epidemiology of M.tb., 56 Potential Innovations and Action Items, 57 5 DETECTING DRUG RESISTANCE AND STRENGTHENING LABORATORY CAPACITY 59 Diagnosis of Drug-Resistant TB, 60 Quality Assurance Considerations in the Development of New Diagnostics, 63 The Supranational Reference Laboratory Network, 64 Expanding Laboratory Capacity in India for the Diagnosis of Drug-Resistant TB, 67 Potential Innovations and Action Items, 69 6 ADDRESSING TB AND DRUG-RESISTANT TB IN VULNERABLE POPULATIONS 71 Drug-Resistant TB in Pediatric Populations, 72 The Burden of Pediatric TB in Households of Patients with MDR TB, 75 Drug Resistance in HIV-Infected Populations, 78 Drug-Resistant TB in Migrant and Refugee Populations, 80 Case Studies in Cambodia and Ethiopia, 84 Potential Innovations and Action Items, 88 7 COMBATING DRUG-RESISTANT TB THROUGH PUBLIC–PRIVATE COLLABORATION AND INNOVATIVE APPROACHES 89 Operation ASHA: “Going the Last Mile,” 90 Engaging the Private Sector in India, 93 Technological Innovations in TB Control, 95 Potential Innovations and Action Items, 98

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xiii CONTENTS 8 CONFRONTING CHALLENGES TO THE SUPPLY CHAIN FOR SECOND-LINE DRUGS 99 Challenges in Drug Supply Chain Logistics, 100 India’s Second-Line Drug Supply Chain, 103 Improving the Availability and Reducing the Cost of MDR TB Drugs, 107 Moving Toward a Functional Market for Second-Line TB Drugs, 108 Discussion, 110 Potential Innovations and Action Items, 111 9 CREATING A BLUEPRINT FOR ACTION 113 Drug-Resistant TB in India, 113 Preventing Transmission of Drug-Resistant TB, 114 Strengthening Laboratory Capacity, 115 Addressing TB and Drug-Resistant TB in Vulnerable Populations, 116 Combating Drug-Resistant TB Through Public–Private Collaboration and Innovative Approaches, 117 Strengthening the Second-Line Drug Supply Chain, 119 REFERENCES 121 APPENDIXES A Workshop Agenda 129 B Summary of a Joint Meeting of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Indian Biomedical Research Agencies, Held April 20-21, 2011, New Delhi, India 141 C Participant Biographies 145

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Tables, Figures, and Boxes TABLES 2-1 Drug Resistance Surveillance in Three Indian States, 20 3-1 Estimated Versus Reported MDR TB Cases in 2009, 39 3-2 Reduced Prices of Second-Line TB Drugs (1997–2000), 44 3-3 Prices for Green Light Committee-Approved Drugs, 45 6-1 Profile of XDR TB in India, 81 FIGURES 1-1 Of the estimated 5 million MDR TB cases that occurred between 2000 and 2009, only 0.5 percent were treated in programs approved by the Green Light Committee, 15 2-1 India has the highest TB burden of any country in the world, 19 2-2 Distribution of Revised National TB Control Program (RNTCP) cul- ture and drug susceptibility testing (DST) laboratories across India as of March 2011, 25 6-1 TB incidence rates are highest in young adults in the African and Southeast Asian regions, 73 xv

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xvi TABLES, FIGURES, AND BOXES 6-2 The TB epidemic in India is being driven primarily by the approxi- mately 400 million people infected with TB who are not coinfected with HIV, 82 7-1 The DOTS model in India includes a network of three types of facili- ties: TB hospitals, diagnostic centers, and treatment centers, 91 7-2 A map of part of Karachi pinpoints TB patients (small figures), pri- vate health care providers (small red squares), and hospitals (boxes containing a capital H), 96 8-1 A schematic of the typical drug supply chain structure, which may not hold for all countries, 101 8-2 The Revised National TB Control Program (RNTCP) goals for MDR TB diagnosis call for increasing the number of sputum-positive retreatment patients to be tested and treated in future years, 104 8-3 Second-line drugs move from state drug stores to DOTS-Plus provid- ers through a series of steps, 105 BOXES 1-1 Key Viewpoints from Previous Workshops, 2 1-2 The Nature of the Threat, 8

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Acronyms AIDS acquired immune deficiency syndrome AIIMS All India Institute of Medical Sciences API active pharmaceutical ingredient CAS Central Asian CDC U.S. Centers for Disease Control and Prevention CHW community health worker CPC cetyl-pyridinium chloride CRI colorimetric redox indicator DOT directly observed treatment DOTS Directly Observed Treatment-Short course DST drug susceptibility testing EAI East African-Indian EXPAND-TB Expanding Access to New Diagnostics for TB FIND Foundation for Innovative New Diagnostics GDF Global Drug Facility GLC Green Light Committee GLI Global Laboratory Initiative GMP Good Manufacturing Practice GP general practitioner xvii

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xviii ACRONYMS HIV human immunodeficiency virus ICMR Indian Council of Medical Research INSA Indian National Science Academy IOM Institute of Medicine IRD Interactive Research and Development IRIS immune reconstitution inflammatory syndrome ISO International Organisation for Standardization IUATLD International Union Against Tuberculosis and Lung Disease (“the Union”) K-RITH KwaZulu-Natal Research Institute for Tuberculosis and HIV LAM lipoarabinomannan LED light-emitting diode LMIS logistics management information systems LPA line probe assay LRS Lala Ram Sarup MDR TB multidrug-resistant tuberculosis MGIT mycobacteria growth indicator tube MIRU mycobacterial interspersed repetitive units MODS microscopic observation drug susceptibility M.tb. Mycobacterium tuberculosis NAAT nucleic acid amplification testing NGO nongovernmental organization NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NRA nitrate reductase assay PAS P-aminosalicylic acid PCR polymerase chain reaction PEPFAR U.S. President’s Emergency Plan for AIDS Relief PETTS Preserving Effective TB Treatment Study PKR Pakistan rupees PPM public–private mix RCC Rolling Continuation Channel RNTCP Revised National Tuberculosis Control Program SSCP single-strand conformational polymorphism

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xix ACRONYMS TB tuberculosis TDR TB totally drug-resistant tuberculosis TLA thin layer agar Tuberculosis Research Centre (India)1 TRC TST tuberculin skin test USAID U.S. Agency for International Development VNTR variable number of tandem repeats WHO World Health Organization XDR TB extensively drug-resistant tuberculosis 1 Since the workshop, the Tuberculosis Research Centre (TRC) in Chennai, India, was renamed the National Institute for Research in Tuberculosis.

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