Addressing the Threat of Drug-Resistant Tuberculosis

A Realistic Assessment of the Challenge

WORKSHOP SUMMARY

Robert Giffin and Sally Robinson, Rapporteurs

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Addressing the Threat of Drug-Resistant Tuberculosis A Realistic Assessment of the Challenge WORKSHOP SUMMARY Robert Giffin and Sally Robinson, Rapporteurs

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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 project was supported by the American Diabetes Association; the Ameri- can Society for Microbiology; Amgen, Inc.; the Association of American Medical Colleges; AstraZeneca Pharmaceuticals; Blue Cross Blue Shield Association; the Burroughs Wellcome Fund; Celtic Therapeutics Management, LLLP; the Critical Path Institute; the Doris Duke Charitable Foundation; Eli Lilly and Company; Entelos Inc.; Genentech; GlaxoSmithKline; Johnson & Johnson; the March of Dimes Foundation; Merck & Co.; the National Institutes of Health—HHS Contract No. N01-OD-4-2139 (National Cancer Institute, National Center for Research Resources, National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Office of Rare Disease Research); Pfizer Inc.; UnitedHealth Group; and the U.S. Food and Drug Administration—HHS Contract No. 223-01-2460. Any opinions, findings, conclusions, or recommendations 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: 978-0-309-13044-8 International Standard Book Number-10: 0-309-13044-1 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 2009 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). 2009. Addressing the Threat of Drug-Resistant Tuberculosis: A Realistic Assessment of the Challenge: Workshop Summary. 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 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 ADDRESSING CHALLENGES IN DRuG DISCOvERy, DEvELOPMENT, AND DISTRIbuTION FOR MuLTIDRuG-RESISTANT TubERCuLOSIS: A WORkSHOP SERIES1 Donald M. berwick, Institute for Healthcare Improvement Enriqueta C. bond, Burroughs Wellcome Fund Gail H. Cassell, Eli Lilly and Company Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, National Institutes of Health Gerald H. Friedland, Yale University School of Medicine Elaine Gallin, Doris Duke Charitable Foundation Stephen Groft, Office of Rare Disease Research, National Institutes of Health Margaret A. Hamburg, Nuclear Threat Initiative Jim yong kim, Harvard Medical School Nancy Sung, Burroughs Wellcome Fund Roy Widdus, Global Forum for Health Research IOM Staff Robert b. Giffin, Director Rebecca A. English, Research Associate yeonwoo Lebovitz, Program Associate Sally Robinson, Program Officer Andrea knutsen, Senior Program Assistant Genea S. vincent, Senior Program Assistant Rona briere, Consulting Editor 1 IOM planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. 

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FORuM ON DRuG DISCOvERy, DEvELOPMENT, AND TRANSLATION1 Gail H. Cassell (Co-Chair), Eli Lilly and Company, Indiana Jeffrey M. Drazen (Co-Chair), New England Journal of Medicine, Massachusetts barbara Alving, National Center for Research Resources, Maryland Hal barron, Genentech, California Leslie Z. benet, University of California, San Francisco Catherine bonuccelli, AstraZeneca Pharmaceuticals, Delaware Linda brady, National Institute of Mental Health, Maryland Robert M. Califf, Duke University Medical Center, North Carolina Scott Campbell, American Diabetes Association, Virginia C. Thomas Caskey, University of Texas-Houston Health Science Center Peter b. Corr, Celtic Therapeutics, New York James H. Doroshow, National Cancer Institute, Maryland Paul R. Eisenberg, Amgen, Inc., California Gary L. Filerman, Atlas Research, Virginia Garret A. FitzGerald, University of Pennsylvania School of Medicine Elaine k. Gallin, The Doris Duke Charitable Foundation, New York Steven k. Galson, Office of the Surgeon General, U.S. Department of Health and Human Services, Maryland Mikhail Gishizky, Entelos, Inc., California Stephen Groft, National Institutes of Health, Maryland Edward W. Holmes, National University of Singapore Peter k. Honig, Merck & Co., Inc., Pennsylvania A. Jacqueline Hunter, GlaxoSmithKline, United Kingdom Michael katz, March of Dimes Foundation, New York Jack D. keene, Duke University Medical Center, North Carolina Ronald L. krall, GlaxoSmithKline, Pennsylvania Freda Lewis-Hall, Pfizer, Inc., New York William D. Matthew, National Institute of Neurological Disorders and Stroke, Maryland Musa Mayer, AdvancedBC.org, New York 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 1 IOM 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. i

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Lana Skirboll, National Institutes of Health, Maryland Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Irena Tartakovsky, Association of American Medical Colleges, Washington, DC Jorge A. Tavel, National Institute of Allergy and Infectious Diseases, Maryland Joanne Waldstreicher, Johnson & Johnson, New Jersey Janet Woodcock, U.S. Food and Drug Administration, Maryland Raymond L. Woosley, Critical Path Institute, Arizona ii

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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: Richard E. Chaisson, Center for Tuberculosis Research, Johns Hopkins School of Medicine Ann M. Ginsberg, Clinical Development, Global Alliance for TB Drug Development Ruth Levine, Center for Global Development Fuad Mirzayev, TB/HIV and Drug Resistance, Stop TB Department, World Health Organization Lee b. Reichman, Global Tuberculosis Institute, New Jersey Medical School Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was over- ix

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x REVIEWERS seen by barry R. bloom, Harvard School of Public Health. 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 xv SuMMARy 1 1 INTRODuCTION 15 Obstacles to Treatment, 16 Workshop Objectives, 17 Organization of This Report, 18 2 THE GLObAL SPREAD OF MuLTIDRuG-RESISTANT AND EXTENSIvELy DRuG-RESISTANT TubERCuLOSIS 19 Scope of the Problem, 19 Underreporting of MDR TB in Africa, 25 The Threat of Totally Drug-Resistant TB, 33 Importance of Better Data, 33 3 MDR Tb TRANSMISSION, HIv COINFECTION, AND TRANSMISSION CONTROL 35 Coinfection with HIV, 35 Treatment, 36 Transmission of XDR TB, 37 Perspective from Russia, 43 Mitigating Transmission, 43 Implications for Health Care Workers, 49 xi

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xii CONTENTS 4 DIAGNOSIS 51 Actual Need, 51 Diagnostic Quality, 53 Currently Available Diagnostics, 53 Point-of-Care (POC) Diagnostics, 54 5 INFRASTRuCTuRE AND HEALTH CARE DELIvERy SySTEMS 59 Vertical Versus Horizontal Programs, 59 Approaches to Addressing Infrastructure Problems, 62 Role of Information Technology, 63 6 GLObAL SySTEMS FOR THE PuRCHASE AND DELIvERy OF Tb DRuGS 67 Procurement Problems, 68 The Drug Quality Issue, 69 Need for Accurate Demand Forecasting, 73 7 RESEARCH ON THE GLObAL CONTROL OF Tb: uNDERSTANDING THE ROLE OF DRuGS, vACCINES, AND FuNDING 81 The Pipeline for New Drugs, 82 Probability of Success, 85 Economic Incentives for Drug Development, 93 8 STRATEGIES FOR CONFRONTING THE GLObAL MDR AND XDR Tb CRISIS 97 Recommendations Presented by Dr. Keshavjee, 97 Lessons Learned from the President’s Emergency Plan for AIDS Relief (PEPFAR), 102 Policy Focus on Drug-Resistant Versus Non-Drug-Resistant TB, 104 The Level of Response, 105 Summary of Key Points, 107 Closing Remarks, 108 REFERENCES 109 APPENDIXES A Agenda 113 B Participant Biographies 117 C Partners In Health White Paper—Stemming the Tide of Multidrug-Resistant Tuberculosis: Major Barriers to Addressing the Growing Epidemic 139

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Tables, Figures, and Boxes TAbLES S-1 Estimated Number of TB Cases and Number of Deaths, by Type, 2006, 3 2-1 Estimated Number of TB Cases and Number of Deaths, by Type, 2006, 21 2-2 Performance of National TB Programs, 27 4-1 Laboratory Capacity in High-Burden Countries, 2006, 52 aboratory 6-1 Green Light Committee Projects and Patients, 2006–2009, 68 7-1 Four of the Eight TB Vaccine Candidates in Clinical Trials That Have Moved into Phase II Studies, 91 FIGuRES S-1 MDR TB burden and patients in treatment, 7 2-1 Global incidence of TB, 20 2-2 Per capita incidence of TB, 21 2-3 Two-thirds of the MDR TB burden is located in just three countries, 22 2-4 Percentage of MDR TB among new TB cases (1994–2007), 26 2-5 African countries with a known MDR TB rate, 28 xiii

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xi TAblES, FIguRES, AND bOxES 2-6 Numbers of MDR TB and XDR TB patients in Tugela Ferry, 2005–2007, 30 2-7 A representation of the limited knowledge of the extent of MDR TB in KwaZulu-Natal Province, 2006, 31 2-8 High mortality due to MDR and XDR TB in Tugela Ferry (2005–2007), 32 3-1 MDR TB burden and patients in treatment, 37 3-2 Facilities in KwaZulu-Natal Province where at least one XDR TB case was described or diagnosed from June 2005 to March 2007, 39 3-3 Genotypes of 17 patients with MDR and XDR TB relapse, 41 3-4 Four TB strains in a single patient, 42 3-5 Partners In Health’s community-based TB treatment triage strategy in Haiti, 47 6-1 Commodity logistics system in Kenya (as of April 2004), 74 6-2 Artemisinin combination therapy (ACT) supply chain risk map, 77 6-3 Artemisinin combination therapy (ACT) supply chain incentives map, 78 7-1 Discovery timeline of currently available TB drugs, 83 7-2 Distribution of TB drug targets, 84 7-3 Global clinical portfolio of TB drugs in development, 86 7-4 Federal funding for HIV/AIDS, 1982–2008, 89 7-5 Funding for TB from the National Institute of Allergy and Infectious Diseases in fiscal year 2007, 90 8-1 A patient being carried by a family member to a clinic, 100 bOXES 3-1 Transmission of MDR and XDR TB in Shanghai, 44 5-1 Universal Access for MDR Care: The Cambodian and Ethiopian Perspectives, 60 7-1 Examples of Push and Pull Mechanisms for Stimulating Drug and Vaccine Development, 94 8-1 Specific Recommendations from the Report Stemming the Tide of Multidrug-Resistant Tuberculosis: Major barriers to Addressing the growing Epidemic, 98

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Acronyms ACH air changes per hour ACT artemisinin combination therapy ACTG AIDS Clinical Trial Group AFRO African regional office AIDS acquired immune deficiency syndrome ANRS French National Agency for AIDS Research ATP adenosine triphosphate CDC U.S. Centers for Disease Control and Prevention CGD Center for Global Development DOTS directly observed treatment, short course DST drug susceptibility testing EMEA European Medicines Agency FDA U.S. Food and Drug Administration FIND Foundation for Innovative New Diagnostics GDF Global Drug Facility GLC Green Light Committee GLI Global Laboratory Initiative HIV human immunodeficiency virus x

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xi ACRONyMS IDA International Dispensary Association IHR International Health Regulations IOM Institute of Medicine IT information technology IUATLD International Union Against Tuberculosis and Lung Disease LIMS laboratory information management system MDR TB multidrug-resistant tuberculosis MEND Medicine in Need MIRU mycobacterial interspersed repetitive unit MRSA methicillin-resistant Staphylococcus aureus MSH Management Sciences for Health NGO nongovernmental organization NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health PCR polymerase chain reaction PEPFAR U.S. President’s Emergency Plan for AIDS Relief PETT CDC’s Preserving Effectiveness of TB Treatment study PHLIP Public Health Laboratory Interoperability Project POC point of care PRV priority review voucher R&D research and development RFLP restriction fragment length polymorphism SA Staphylococcus aureus SRL Global Supranational Reference Laboratory TB tuberculosis UNICEF United Nations Children’s Fund USAID U.S. Agency for International Development UV ultraviolet WHO World Health Organization XDR TB extensively drug-resistant tuberculosis