The Global Crisis of Drug-Resistant
Tuberculosis and Leadership of China
and the BRICS

Challenges and Opportunities

SUMMARY OF A JOINT WORKSHOP

by the Institute of Medicine and
the Institute of Microbiology, Chinese Academy of Sciences

Steve Olson, Rebecca A. English, and Anne B. Claiborne, Rapporteurs

Forum on Drug Discovery, Development, and Translation

Board on Health Sciences Policy

INSTITUTE OF MEDICINE
              OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

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Steve Olson, Rebecca A. English, 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 workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose mem- bers are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This activity was supported by contracts between the National Academy of Sci- ences and Department of Health and Human Services (HHSN26300023 [Under Base #HHSN263201200074I] and Contract No. N01-OD-4-2139 TO #276; HHSF22301026T [Under Base #HHSF223200810020I]), AbbVie Inc., American Diabetes Association, American Society for Microbiology, Amgen Inc., Association of American Medical Colleges, AstraZeneca, Bristol-Myers Squibb, Burroughs Wellcome Fund, CDC Foundation, Celtic Therapeutics, LLLP, Critical Path Institute, Doris Duke Charitable Foundation, Eli Lilly & Co. Foundation, Eli Lilly and Company, FasterCures, Fondation Mérieux, Friends of Cancer Research, ­ laxoSmithKline, G Johnson & Johnson, March of Dimes Foundation, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., and Sanofi. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity. International Standard Book Number-13:  978-0-309-28596-4 International Standard Book Number-10:  0-309-28596-8 Additional copies of this workshop summary are available for sale 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 2014 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). 2014. The Global Crisis of Drug- Resistant Tuberculosis and Leadership of China and the BRICS: Challenges and Opportunities: 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. C. D. Mote, Jr., 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. C. D. Mote, Jr., 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 Global Crisis of Drug-Resistant Tuberculosis and the Leadership of the BRICS Countries: Challenges and Opportunities1 U.S. Planning Committee 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 NANCY SUNG, Burroughs Wellcome Fund2 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 China Liaison Committee Appointed by the Institute of Microbiology, Chinese Academy of Sciences GUOPING ZHAO (Co-Chair), Institute for Biological Sciences, Chinese Academy of Sciences LIXIN ZHANG (Co-Chair), Institute of Microbiology, Chinese Academy of Sciences 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  Nancy Sung was with the Burroughs Wellcome Fund during the planning of the workshop. v

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Secretaries-in-General BABAK JAVID, Tsinghua University YANLIN ZHAO, Chinese Center for Disease Control and Prevention Members LIJUN BI, Institute of Biophysics, Chinese Academy of Sciences JILONG CHEN, Institute of Microbiology, Chinese Academy of Sciences XIAOXING CHENG, Division of Research, Institute of Tuberculosis, Beijing 309 Hospital MIN FANG, Institute of Microbiology, Chinese Academy of Sciences GEORGE FU GAO, Institute of Microbiology, Chinese Academy of Sciences QIAN GAO, Shanghai Medical College, Fudan University BAOXUE GE, Clinical and Translational Research Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University HUI GUO, Institute of Microbiology, Chinese Academy of Sciences QI JIN, Institute of Pathogen Biology, Peking Union Medical College, Chinese Academy of Medical Sciences MINYONG LI, School of Pharmacy, Shandong University CUIHUA LIU, Institute of Microbiology, Chinese Academy of Sciences GANG LIU, School of Medicine, Tsinghua University MIAOMIAO LIU, Institute of Microbiology, Chinese Academy of Sciences XUETING LIU, Institute of Microbiology, Chinese Academy of Sciences KAIXIA MI, Institute of Microbiology, Chinese Academy of Sciences YUEMAO SHEN, Institute of Medicine, Shandong University SHUYI SI, Institute of Medicinal Biotechnology, Peking Union Medical College, and Chinese Academy of Medical Sciences FUHANG SONG, Institute of Microbiology, Chinese Academy of Sciences KANGLIN WAN, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention BEINAN WANG, Institute of Microbiology, Chinese Academy of Sciences HONGHAI WANG, Institute of Genetics, Fudan University XUEQIONG WU, Institute of Tuberculosis, Beijing 309 Hospital JIANPING XIE, School of Life Sciences, Southwest University WANLI XING, School of Life Sciences, Tsinghua University LAN XU, International Affairs Office, Institute of Microbiology, Chinese Academy of Sciences FUPING ZHANG, Institute of Microbiology, Chinese Academy of Sciences vi

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WENHONG, ZHANG, Institute of Infectious Diseases, Huashan Hospital, Fudan University ZONGDE ZHANG, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital XUYU ZHOU, Institute of Microbiology, Chinese Academy of Sciences Institute of Microbiology, Chinese Academy of Sciences, Staff ABIODUN ADEBAYO, Postdoctoral Researcher CAIXIA CHEN, Postdoctoral Researcher HUANQIN DAI, Associate Professor SHAOFENG LI, Lab Secretary FUHANG SONG, Associate Professor LAN XU, Deputy Director, International Affairs Office Workshop Implementation Staff: Students of Professor Lixin Zhang’s Lab, Institute of Microbiology, Chinese Academy of Sciences Abiodun Adebayo, Elizabeth Ashforth, Chaoxian Bai, Caixia Chen, Jinsong Chen, Xiangyin Chen, Huanqin Dai, Hui Guo, Jianying Han, Wei He, Wenni He, Pei Huang, Xiaopeng Jia, Shaofeng Li, Mei Liu, Miaomiao Liu, Ye Liu, Hanyi Lv, Biao Ren, Fuhang Song, Mengyi Su, Yaojun Tong, Hongfei Wang, Jian Wang, Luoqiang Wang, Qi Wang, Qian Wang, Quanxin Wang, Feng Xie, Na Yang, Jingyu Zhang, Li Zhang, Yuhan Zhang, Ying Zhuo vii

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 JEFFREY M. DRAZEN (Co-Chair), New England Journal of Medicine, Boston, MA STEVEN K. GALSON (Co-Chair), Amgen Inc., Thousand Oaks, CA RUSS BIAGIO ALTMAN, Stanford University, CA MARGARET ANDERSON, FasterCures, Washington, DC HUGH AUCHINCLOSS, National Institute of Allergy and Infectious Diseases, Bethesda, MD CHRISTOPHER P. AUSTIN, National Center for Advancing Translational Sciences, Bethesda, MD ANN C. BONHAM, Association of American Medical Colleges, Washington, DC LINDA BRADY, National Institute of Mental Health, Bethesda, MD GAIL H. CASSELL, Harvard Medical School (Visiting), Carmel, IN PETER B. CORR, Celtic Therapeutics, LLLP, New York, NY ANDREW M. DAHLEM, Eli Lilly and Company, Indianapolis, IN JAMES H. DOROSHOW, National Cancer Institute, Bethesda, MD GARY L. FILERMAN, Atlas Health Foundation, McLean, VA MARK J. GOLDBERGER, Abbott Pharmaceuticals, Rockville, MD HARRY B. GREENBERG, Stanford University School of Medicine, CA PETER HONIG, AstraZeneca, Wilmington, PA KATHY L. HUDSON, National Institutes of Health, Bethesda, MD LYNN D. HUDSON, Critical Path Institute, Tucson, AZ S. CLAIBORNE JOHNSTON, University of California, San Francisco MICHAEL KATZ, March of Dimes Foundation, White Plains, NY PETRA KAUFMANN, National Institute of Neurological Disorders and Stroke, Bethesda, MD JACK D. KEENE, Duke University Medical Center, Durham, NC RUSTY KELLEY, Burroughs Wellcome Fund, Research Triangle Park, NC RONALD L. KRALL, University of Pennsylvania Center for Bioethics, Steamboat Springs, CO FREDA C. LEWIS-HALL, Pfizer Inc., New York, NY CAROL MIMURA, University of California, Berkeley BERNARD H. MUNOS, InnoThink Center for Research in Biomedical Innovation, Indianapolis, IN ELIZABETH (BETSY) MYERS, Doris Duke Charitable Foundation, New York, NY JOHN J. ORLOFF, Novartis Pharmaceuticals Corporation, East Hanover, NJ 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. ix

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ROBERT E. RATNER, American Diabetes Association, Alexandria, VA MICHAEL ROSENBLATT, Merck & Co., Inc., Whitehouse Station, NJ JAMES S. SHANNON, GlaxoSmithKline, Brentford, Middlesex, UK JANET SHOEMAKER, American Society for Microbiology, Washington, DC ELLEN V. SIGAL, Friends of Cancer Research, Washington, DC LANA R. SKIRBOLL, Sanofi, Washington, DC BRIAN L. STROM, University of Pennsylvania Perelman School of Medicine, Philadelphia JANET TOBIAS, Ikana Media and Mount Sinai School of Medicine, New York, NY JOANNE WALDSTREICHER, Johnson & Johnson, New Brunswick, NJ JANET WOODCOCK, Food and Drug Administration, Rockville, MD IOM Staff ANNE B. CLAIBORNE, Forum Director 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 x

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Reviewers This workshop summary has been reviewed in draft form by indi­ viduals 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 workshop summary as sound as possible and to ensure that the workshop summary 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 workshop summary: William Bishai, KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine Jarbas Barbosa da Silva, Jr., Ministry of Health, Federative Republic of Brazil Martie van der Walt, South African Medical Research Council Peter Yablonskii, Ministry of Health and Social Development, Russian Federation Wenhong Zhang, Shanghai Huashan Hospital, Fudan University Yaping Zhang, Chinese Academy of Sciences Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was xi

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xii REVIEWERS overseen by Melvin Worth. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institutional proce- dures and that all review comments were carefully considered. Responsibil- ity for the final content of this workshop summary rests entirely with the rapporteurs and the institution.

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Contents ACRONYMS xix 1 INTRODUCTION AND OVERVIEW OF THE WORKSHOP 1 Workshop Chair’s Key Messages, 2 The Beijing Workshop, 2 Organization of the Report, 7 2 THE CHALLENGES AND OPPORTUNITIES FOR THE BRICS COUNTRIES TO LEAD 11 Overall Role of the BRICS Countries, 12 Brazil, 14 South Africa, 15 India, 18 Russia, 19 China, 20 3 CATCHING UP WITH THE MICROBE 23 MDR TB in New York City, 24 Community-Based Care, 27 The Need for Resources, 29 4 DRUG-RESISTANT TB IN CHINA 31 Management of MDR TB in China, 32 2007 National Survey of Drug Resistance in China, 35 xiii

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xiv CONTENTS The Diagnosis and Treatment of MDR TB in Hospitals, 38 MDR and XDR TB Chemotherapy in China, 39 Drug-Resistant TB and HIV in China, 41 MDR TB and Diabetes, 42 5 EXPERIENCES WITH MDR TB IN OTHER COUNTRIES 45 MDR TB in the Russian Federation, 46 Community-Based Care in South Africa, 49 Direct Collaboration in Cambodia and Ethiopia, 53 6 DRUG-RESISTANT TUBERCULOSIS IN PEDIATRIC POPULATIONS 55 Children as Sentinels for Transmission and Policy Response, 56 Pediatric Drug-Resistant TB in China, 58 Drug-Resistant TB Meningitis in Children, 59 Pediatric MDR and XDR TB in the Russian Federation and Other Countries of the Former Soviet Union, 60 7 GLOBAL PERSPECTIVES ON TRANSMISSION AND INFECTION CONTROL 63 The Value of Genotype Mapping, 64 Infection Control Challenges for Health Care Workers in China, 67 Infection Control Challenges for Health Care Workers in South Africa, 69 Institutional Infection Control in Russia, 71 Stopping Transmission in Institutional and Community Settings, 76 8 RAPID DIAGNOSTIC TECHNOLOGIES: STATUS AND LIMITATIONS 79 Gaps in Drug Susceptibility Testing in South Africa, 80 Diagnostic Tests in China, 84 The Genetic Diversity of Drug-Resistant TB, 88 9 ADDRESSING DIAGNOSIS AND TREATMENT ACROSS THE SPECTRUM OF DRUG RESISTANCE 91 The Spectrum of MDR and XDR TB, 92 The Need for a Paradigm Shift in the Treatment of the Spectrum of Drug-Resistant TB, 94 MDR, XDR, and Untreatable TB in Africa, 96 MDR, XDR, and Untreatable TB from a Laboratory Perspective, 98

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CONTENTS xv Totally Drug-Resistant TB in India: Lessons and Opportunities from a Clinical Perspective, 102 TB Terminology and Advocacy Needs, 106 10  DEVELOPING AND STRENGTHENING THE DRUG SUPPLY CHAIN FOR DRUG-RESISTANT TB 109 Overcoming Barriers in the Global Supply Chain, 110 A Systems Perspective on the Global Supply Chain, 113 Information in the Global Supply Chain, 115 Launching New Anti-TB Drugs, 116 11 EMBRACING A NEW VISION FOR RESEARCH 119 Creating a Synergy of Discovery and Delivery of Care, 120 New Tools to Facilitate TB Research, 122 TBResist: A Global Consortium for Whole-Genome Sequencing of Drug-Resistant TB, 123 Meta-Analysis, 125 12  WHAT WILL BE REQUIRED TO ACHIEVE ZERO DEATHS FROM TB? 129 Why Has Controlling TB Been So Difficult?, 130 How Can Progress Be Radically Improved?, 131 The Role of the BRICS Countries, 134 13  CREATING AN EVIDENCE-BASED BLUEPRINT FOR ACTION 137 Addressing Drug-Resistant TB in Children, 137 Adopting Genomic Tools to Map the Epidemic of Drug-Resistant TB and Address Diagnostic Challenges, 139 Blocking Transmission of Drug-Resistant TB, 140 Reforming Drug Distribution and Assuring Drug Quality, 141 Increasing the Visibility of Drug-Resistant TB, 142 REFERENCES 143 APPENDIXES A Workshop Agenda 151 B Participant Biographies 171

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Tables, Figures, and Boxes TABLES 4-1 Projected Future TB Laboratory Network in China, 34 9-1 Drugs Used to Treat MDR TB, 93 FIGURES 2-1 The BRICS countries provide the majority of funding for TB control in the 104 countries that account for 94 percent of global cases, 13 3-1 Funding for TB through block grants from the U.S. Public Health Service dropped to zero in 1972 but rose substantially after the epidemic of DR TB in New York City in the late 1980s and early 1990s, 25 3-2 TB rates in New York City rose to a peak in 1992 and then fell rapidly as new interventions were implemented, 26 4-1 The majority of MDR TB patients who completed treatment did so at China CDC facilities, 36 5-1 Comparison of TB mortality in the Russian Federation, Siberia, and Tomsk Oblast (per 100,000 population), 48 5-2 Many factors have compromised MDR TB treatment for a typical patient in KwaZulu-Natal province, 52 xvii

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xviii tableS, figures, and boxes 7-1 The incidence of occupational TB infection among health care workers providing TB services in the Vladimir region of Russia fell to zero after an infection control program was implemented, 73 BOXES 1-1 Themes of the Workshop Series, 3 1-2 The Nature of the Threat, 5 1-3 Statement of Task for the Workshop, 6 1-4 The Delhi Ministerial Communiqué, 8 7-1 The Hospital System in China, 67 9-1 A New Approach to Diagnosis of TBM, 100 9-2 Surgical Treatment of Endobronchial TB, 102 10-1 The Challenge for Manufacturers, 112 11-1 Investing in TB Sequencing, 125

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Acronyms AFB acid-fast bacilli AIDS acquired immune deficiency syndrome AMFm Affordable Medicines Facility for Malaria API active pharmaceutical ingredient ART antiretroviral treatment BLF bronchoalveolar lavage fluid BMGF Bill & Melinda Gates Foundation BMI body mass index BRICS Brazil, Russia, India, China, and South Africa CAMELIA Cambodian Early versus Late Introduction of Antiretrovirals China CDC Chinese Center for Disease Control and Prevention CIPRA Comprehensive International Program for Research on AIDS DNA deoxyribonucleic acid DOT directly observed treatment DOTS Directly Observed Treatment-Short course DR TB drug-resistant tuberculosis DST drug susceptibility testing EMR electronic medical record FLD first-line anti-tuberculosis drug xix

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xx acronyms GDF Global Drug Facility GHC Global Health Committee GLC Green Light Committee H3 Africa Human Heredity and Health in Africa HBC high tuberculosis burden country HIV human immunodeficiency virus IMCAS Institute of Microbiology, Chinese Academy of Sciences IOM Institute of Medicine IUATLD International Union Against Tuberculosis and Lung Disease (“The Union”) K-RITH KwaZulu-Natal Research Institute for Tuberculosis and HIV LAMP loop-mediated isothermal amplification LED light-emitting diode LPA line probe assay MDR TB multidrug-resistant tuberculosis MHC major histocompatibility complex M.tb. Mycobacterium tuberculosis NGO nongovernmental organization NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NTM nontuberculous mycobacteria PAS para-aminosalicylic acid PATRIC Pathosystems Resource Integration Center PCR polymerase chain reaction PEPFAR U.S. President’s Emergency Plan for AIDS Relief PMDRT programmatic treatment and management of MDR and XDR TB patients PQR Price and Quality Reporting QFT QuantiFERON-TB test RIF rifampicin RNA ribonucleic acid RNTCP Revised National TB Control Program rRNA ribosomal ribonucleic acid

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acronyms xxi SAT simultaneous amplification test SLD second-line anti-tuberculosis drug TB tuberculosis TBM tuberculous meningitis TDR TB totally drug-resistant tuberculosis THINK Tuberculosis and HIV Investigative Network of KwaZulu-Natal TST tuberculin skin test UNICEF United Nations Children’s Fund U.S. CDC U.S. Centers for Disease Control and Prevention UV ultraviolet UVGI ultraviolet germicidal irradiation VNTR variable-number tandem-repeat WHO World Health Organization XDR TB extensively drug-resistant tuberculosis

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