The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa

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The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa Global and Local Challenges and Solutions SUMMARY OF A JOINT WORKSHOP by the Institute of Medicine and the Academy of Science of South Africa Steve Olson, Yeonwoo Lebovitz, and Anne Claiborne, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy and ACADEMY OF SCIENCE OF SOUTH AFRICA

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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 Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223001003T), the U.S. State Department (S-LMAQM- 08-GR-071), the American Diabetes Association, the American Society for Micro- biology, Amgen Inc., the Association of American Medical Colleges, Bristol-Myers Squibb, the Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, the Critical Path Institute, the Doris Duke Charitable Foundation, Eli Lilly & Co., GlaxoSmithKline, Howard Hughes Medical Institute, Johnson & Johnson, Novartis Pharmaceuticals Corporation, and Pfizer, Inc. Any opinions, findings, conclusions, or recommenda- tions expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-16024-7 International Standard Book Number-10: 0-309-16024-3 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2011 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). 2011. The Emerging Threat of Drug-Resistant Tuberculosis in Southern Africa: Global and Local Challenges and Solutions: Summary of a Joint Workshop. Washington, DC: The National Acad- emies 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 Sciences 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 Council 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 FOR THE WORKSHOP ON THE EMERGING THREAT OF DRUG-RESISTANT TUBERCULOSIS IN SOUTHERN AFRICA: GLOBAL AND LOCAL CHALLENGES AND SOLUTIONS1 GAIL H. CASSELL (Chair), Eli Lilly and Company (retired) DONALD M. BERWICK,2 Centers for Medicare and Medicaid Services BARRY R. BLOOM, Harvard School of Public Health ENRIQUETA C. BOND, QE Philanthropic Advisors RICHARD E. CHAISSON, Johns Hopkins University PAUL FARMER, Partners In Health, Harvard Medical School ANTHONY FAUCI, National Institute of Allergy and Infectious Diseases GARY FILERMAN, Atlas Research GERALD H. FRIEDLAND, Yale University School of Medicine ELAINE K. GALLIN,3 QE Philanthropic Advisors STEPHEN C. GROFT, Office of Rare Disease Research, National Institutes of Health VICTORIA McGOVERN, Burroughs Wellcome Fund NANCY SUNG, Burroughs Wellcome Fund ROY WIDDUS, Global Forum for Health Research IOM Staff ANNE B. CLAIBORNE, Director REBECCA A. ENGLISH, Research Associate YEONWOO LEBOVITZ, Program Associate GENEA S. VINCENT, Senior Program Assistant (until November 1, 2010) RONA BRIERE, Consulting Editor South Africa Liaison Planning Committee Members GAVIN J. CHURCHYARD, Aurum Institute for Health Research HOOSEN COOVADIA, Nelson Mandela School of Medicine, University of KwaZulu-Natal SALIM S. ABDOOL KARIM, University of KwaZulu-Natal, Centre for the AIDS Programme of Research in South Africa 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. 2 Donald Berwick was with the Institute for Healthcare Improvement during planning for the workshop. 3 Elaine Gallin was with the Doris Duke Charitable Foundation until December 2010. v

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A. WILLEM STURM, Nelson Mandela School of Medicine, University of KwaZulu-Natal MARTIE VAN DER WALT, Medical Research Council of South Africa PAUL VAN HELDEN, Stellenbosch University ROBIN WOOD, Desmond Tutu HIV Centre, University of Cape Town Academy of Science of South Africa Staff ROSEANNE D. DIAB, Executive Officer PHAKAMILE TRUTH MNGADI, Project Officer NTHABISENG TAOLE, Project Manager vi

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 Gail H. Cassell (Co-Chair), Eli Lilly and Company (retired), Indiana Jeffrey M. Drazen (Co-Chair), New England Journal of Medicine, Massachusetts Barbara Alving, National Center for Research Resources, 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, Maryland Robert M. Califf, Duke University Medical Center, North Carolina Scott Campbell, Foundation for the National Institutes of Health, Maryland C. Thomas Caskey, University of Texas-Houston Health Science Center Peter B. Corr, Celtic Therapeutics, LLLP, New York James H. Doroshow, National Cancer Institute, Maryland Gary L. Filerman, Atlas Research, Washington, DC Garret A. FitzGerald, University of Pennsylvania School of Medicine Elaine K. Gallin,2 QE Philanthropic Advisors, Maryland Steven K. Galson, Amgen Inc., California Harry B. Greenberg, Stanford University School of Medicine, California Stephen Groft, National Institutes of Health, Maryland Annalisa Jenkins, Bristol-Myers Squibb, New Jersey Michael Katz, March of Dimes Foundation, New York Jack D. Keene, Duke University Medical Center, North Carolina Ronald L. Krall, University of Pennsylvania Freda Lewis-Hall, Pfizer, Inc., New York William D. Matthew, National Institute of Neurological Disorders and Stroke, Maryland Mark B. McClellan, Brookings Institution, Washington, DC Carol Mimura, University of California-Berkeley John Orloff, Novartis Pharmaceuticals Corporation, New Jersey Amy P. Patterson, National Institutes of Health, Maryland Janet Shoemaker, American Society for Microbiology, Washington, DC Ellen V. Sigal, Friends of Cancer Research, Virginia Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Jorge A. Tavel, National Institute of Allergy and Infectious Diseases, 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. 2 Elaine Gallin was with the Doris Duke Charitable Foundation until December 2010. vii

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Janet Tobias, Ikana Media, New York Joanne Waldstreicher, Johnson & Johnson, New Jersey Janet Woodcock, U.S. Food and Drug Administration, Maryland Raymond L. Woosley, The Critical Path Institute, Arizona 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 objectivity, evidence, and responsiveness to the study 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: Enriqueta C. Bond, QE Philanthropic Advisors Jerrold J. Ellner, Boston University School of Medicine, Boston Medical Center Gerald Friedland, Yale School of Medicine Salim S. Abdool Karim, University of KwaZulu-Natal, Center for the AIDS Programme of Research in South Africa (CAPRISA) Salmaan Keshavjee, Harvard Medical School, Partners In Health Although the reviewers listed above have provided many constructive comments and suggestions, they did not endorse 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 ix

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x REVIEWERS 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 xv 1 INTRODUCTION 1 The Burden of Drug-Resistant TB, 3 Workshop Objectives, 4 The Problem and Priorities, 4 Organization of This Report, 6 2 THE INCIDENCE OF DRUG-RESISTANT TB IN SOUTHERN AFRICA 9 Relationship Between Reported Incidence and Diagnostic Tools, 10 MDR and XDR TB in South Africa, 12 Outbreak of MDR and XDR TB in KwaZulu-Natal Province, 14 TB and HIV Coinfection in Southern Africa, 19 3 SURVEILLANCE AND TRACKING OF DRUG-RESISTANT TB 21 Genetic Analysis of Drug-Resistant Strains, 22 Intensified TB Case Finding, 24 Information Systems to Enhance Laboratory Capacity, 27 4 TRANSMISSION AND INFECTION CONTROL 31 Transmissibility of TB, 32 Infection Control in Hospital and Other Health Care Settings, 33 Contact Tracing and Community-Based Infection Control Practices, 38 xi

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xii CONTENTS Particular Challenges for Health Care Workers, 39 Transmission and Infection Control Among Miners and Migrant Workers in Lesotho, 41 5 DIAGNOSIS OF DRUG-RESISTANT TB 43 Need for Rapid Diagnostics, 44 Progress on Point-of-Care Diagnostics, 47 Challenges of Laboratory Capacity, 48 Use of Biomarkers to Diagnose TB, 50 6 TREATMENT OF DRUG-RESISTANT TB 55 Treatment of Drug-Resistant TB, 56 Community-Based Care, 68 Limitations of Health Care Systems and Cost Issues, 70 7 DRUG-RESISTANT TB IN CHILDREN 73 Epidemiology of Pediatric Drug-Resistant TB, 73 Prophylaxis and Diagnosis of Pediatric Drug-Resistant TB, 77 Drug Treatment Regimens for Pediatric Drug-Resistant TB, 77 Management of Pediatric Drug-Resistant TB, 79 Outcomes of Pediatric Drug-Resistant TB, 80 8 CONVERGENCE OF SCIENCE AND POLICY TO CREATE A BLUEPRINT FOR ACTION 81 Epidemiology, 81 Infection Control, 82 Diagnostics, 83 Treatment, 83 Pediatric TB, 86 Research Needs, 87 The Need for Partnerships, 87 REFERENCES 89 APPENDIXES A AGENDA 95 B REPORT FROM THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) WORKSHOP 103 C PARTICIPANT BIOGRAPHIES 109

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Table, Figure, and Boxes TABLE 4-1 Percentage of Health Care Workers Reporting Various Infection Control Measures, 35 FIGURE 2-1 More than 75,000 new cases of MDR TB are estimated to have occurred in Africa in 2010, 11 BOXES 1-1 The Nature of the Threat, 2 2-1 Problems of Dealing with Drug-Resistant TB in Mozambique, 13 2-2 Estimating the Contribution of TB to Mortality in South Africa, 15 5-1 Some Diagnostic Methods Currently in Use for TB, 46 6-1 CD4 Count as a Predictor of Mortality Among MDR and XDR TB Patients, 66 7-1 A Family Case Study Illustrating Issues in Pediatric MDR TB, 74 xiii

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Acronyms ACME Automated Classification of Medical Entities ACR adult clinical record AIDS acquired immune deficiency syndrome AIR Airborne Infection Research ANRS Agency for AIDS Research (France) ARASA AIDS and Rights Alliance for Southern Africa ART antiretroviral treatment ARV antiretroviral ASADI African Science Academy Development Initiative ASSAf Academy of Science of South Africa BCG Bacillus Calmette-Guérin vaccine C-DOTS Community-based Directly Observed Treatment Short Course CAPRISA Center for the AIDS Programme of Research in South Africa CD4 Cluster of Differentiation 4 CDC Centers for Disease Control and Prevention CoSH Church of Scotland Hospital CSIR Council for Scientific and Industrial Research DNA deoxyribonucleic acid DOTS Directly Observed Treatment Short Course FIND Foundation for Innovative New Diagnostics xv

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xvi ACRONYMS GFP green fluorescent proteins GLC Green Light Committee GLI Global Laboratory Initiative GPS global positioning system HIV human immunodeficiency virus ICD-10 International Classification of Diseases, 10th revision IFNg interferon-gamma IOM Institute of Medicine IRIS immune reconstitution inflammatory syndrome ISTC International Standards for Tuberculosis Care LAM lipoarabinomannan LIPHE Laboratory Information for Public Health Excellence LPA line probe assay LRP luciferase reporter phage M.tb. Mycobacterium tuberculosis MDR TB multidrug-resistant tuberculosis MGIT mycobacteria growth indicator tube MRC Medical Research Council NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health PCR polymerase chain reaction PETTS Preserving Effective Tuberculosis Treatment with Second-line drugs study QFT-GIT QuantiFERON-TB Gold In-Tube test RNA ribonucleic acid SAPiT Starting Antiretroviral therapy at three Points in Tuberculosis therapy study TB tuberculosis TCR T cell receptor TDR TB totally drug-resistant tuberculosis TF CARES Tugela Ferry Care and Research Collaboration

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xvii ACRONYMS UN United Nations UV ultraviolet WHO World Health Organization WP work package XDR TB extensively drug-resistant tuberculosis

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