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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. Washington, DC: The National Academies Press. doi: 10.17226/25688.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

David A. Savitz and Anne N. Styka, Editors Committee to Review Long-Term Health Effects of Antimalarial Drugs Board on Population Health and Public Health Practice Health and Medicine Division A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by Contract Order No. VA 36C24E18C0067 between the National Academy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13:  978-0-309-67210-8 International Standard Book Number-10:  0-309-67210-4 Digital Object Identifier:  https://doi.org/10.17226/25688 Additional copies of this publication 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. Copyright 2020 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. Assessment of long-term health effects of antimalarial drugs when used for prophylaxis. Washington, DC: The National Academies Press. https://doi.org/10.17226/25688.

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

COMMITTEE TO REVIEW LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS David A. Savitz (Chair), Professor, Brown University Sara L. Dolan, Associate Professor of Psychology and Neuroscience and Graduate Program Director, Clinical Psychology Program, Baylor University Marie R. Griffin, Professor, Health Policy and Medicine, Director, Vanderbilt Master of Public Health Program, Vanderbilt University James P. Herman, Flor van Maanen Professor and Chair Department of Pharmacology and Systems Physiology, Director, University of Cincinnati Neurobiology Research Center; Director, Stress Neurobiology Laboratory, College of Medicine, University of Cincinnati Yuval Neria, Professor of Medical Psychology, Director of PTSD Treatment and Research Program, Director of Columbia–NewYork Presbyterian Military Family Wellness Center, Columbia University Medical Center Andy Stergachis, Professor of Pharmacy and Global Health, Associate Dean, School of Pharmacy, Director, Global Medicines Program, University of Washington Elizabeth A. Stuart, Professor of Mental Health, Biostatistics, and Health Policy and Management, Associate Dean for Education, Bloomberg School of Public Health, Johns Hopkins University  Carol Tamminga, Professor, University of Texas Southwestern Medical Center Jonathan L. Vennerstrom, Professor, Department of Pharmaceutical Sciences, University of Nebraska Medical Center Christina M. Wolfson, Director of the Neuroepidemiology Research Unit and Professor, McGill University Study Staff Anne N. Styka, Study Director Kristin E. White, Associate Program Officer Stephanie J. Hanson, Research Associate Rebecca F. Chevat, Senior Program Assistant Rose Marie Martinez, Senior Board Director, Board on Population Health and Public Health v

vi

Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: Paul Ahlquist, University of Wisconsin–Madison Lesley H. Curtis, Duke University Susan Ellenberg, University of Pennsylvania School of Medicine Joshua J. Gagne, Brigham and Women’s Hospital Tobias Gerhard, Rutgers, The State University of New Jersey K. Malcom Maclure, University of British Columbia Ann Mckee, Boston University School of Medicine William P. Nash, Veterans Affairs Greater Los Angeles Healthcare System Laurence Slutsker, PATH Malaria and NTD Program David Sullivan, Johns Hopkins Bloomberg School of Public Health Carol S. Wood, Oak Ridge National Laboratory Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or vii

viii REVIEWERS recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by Tracy Lieu, Kaiser Permanente, Northern California, and Brian L. Strom, Rutgers, The State University of New Jersey. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

Preface The men and women who serve in the U.S. Armed Forces and who are deployed to distant locations around the world encounter myriad health threats. In addition to those associated with the potential for combat, exposure to harmful agents, and disruption of their family life, they may face disease threats that are specific to the locations to which they are sent. Prominent among these is malaria, a parasitic disease that is endemic to several locations where U.S. forces have been posted over the years, including in parts of Afghanistan and Iraq. The threat of malaria—a debilitating and potentially deadly illness—can be significantly mitigated through the use of antimalarial drugs for prevention. Such drugs have known side effects, however, and concerns over whether adverse events related to taking the drugs persist after administration is stopped are well justified. This is a challenging issue, given the diversity of antimalarial drugs used, the wide range of potential adverse events, and the numerous other health concerns that service members encounter following deployment. While there are many questions that could be asked regarding the use of anti- malarial drugs for deployed personnel, the committee’s charge was very specific: assemble, examine, and assess the research that contributes to an understanding of whether the use of antimalarial drugs may cause persistent or latent health prob- lems. The committee was not asked to review patient reports or to make recom- mendations regarding the use of such drugs (as the Food and Drug Administration does) nor to provide guidelines for those traveling to malaria-endemic areas (as the Centers for Disease Control and Prevention does). Instead, the committee was charged with evaluating the available scientific and medical information, and it did not speculate or conjecture beyond that body of knowledge. It is thus important to note that a determination that the evidence was not sufficient to draw a conclusion ix

x PREFACE regarding a particular drug–outcome association should not be interpreted as a determination that the drug does not cause adverse health effects: the lack of evi- dence of adverse effects is not evidence of a lack of adverse effects. The commit- tee looked carefully and exhaustively at the evidence and in this report describes the process by which the information it considered was gathered and presents its summary and assessment of what that research can tell us. The committee hopes that its work will help the Department of Veterans Affairs, the Department of Defense, and other agencies, such as the Peace Corps and the Department of State, that send teams and workers to serve in malaria- endemic areas to provide guidance to its health care providers—in particular, regarding specific questions and symptoms in persons who have used the drugs of interest for prophylaxis and who may have concerns about their long-term health. It is clear that some proportion of those who were deployed and prescribed antimalarial drugs became ill. The committee received accounts from a number of those who had experienced such illnesses, some quite severe, and there can be no doubt that their health problems are real and that they followed their use of antimalarial drugs. We very much appreciate the courage and commitment of those who took the time to educate the committee based on their personal experience. The committee also wishes to acknowledge the Department of Veterans Affairs, Department of Defense, Food and Drug Administration, Peace Corps, Centers for Disease Control and Prevention, and Department of State who made presentations to the committee and responded to follow-up questions. We are extremely appreciative of the outstanding efforts of the staff of the National Acad- emies of Sciences, Engineering, and Medicine’s Health and Medicine Division; Anne Styka, who served as study director; Stephanie Hanson and Kristin White, who had a daunting task of identifying and culling the large and complex literature and more generally guiding and assisting the committee in its mission. We also are grateful to Rebecca Chevat who generously and capably provided logistical sup- port to the committee. Finally, the committee would like to acknowledge a number of other individuals who helped make this work possible: Daniel Bearss, a senior research librarian who helped design and perform the initial literature searches and who sadly passed away during the course of this work; Jorge Mendoza, a senior research librarian who conducted the second set of literature searches; Audrey Thevenon, a program officer on the Board on Life Sciences, who provided expertise in malaria; Andy Koltun, a summer intern through Georgetown Univer- sity School of Medicine’s Population Health Scholars Track, who helped screen several thousand abstracts; Robert Pool for his editorial assistance; and Misrak Dabi, finance business partner who managed and led the financial and budgeting activities for the project. David A. Savitz, Chair Committee to Review Long-Term Health Effects of Antimalarial Drugs

Contents ACRONYMS AND ABBREVIATIONS xv SUMMARY 1 1 INTRODUCTION 17 Identification and Selection of Prophylactic Antimalarial Drugs to Be Reviewed, 18 Charge to the Committee, 19 The Study Process and Information Gathering, 20 Organization of the Report, 22 References, 23 2 BACKGROUND 25 Malaria in Humans, 25 Prophylactic Antimalarial Drugs, 28 Military Use of Antimalarials, 38 References, 49 3 IDENTIFICATION AND EVALUATION OF THE EVIDENCE BASE 57 Identification of the Evidence, 57 Evaluation of the Evidence, 64 Approach to Assessing the Body of Evidence, 84 References, 87 xi

xii CONTENTS 4 MEFLOQUINE 91 Food and Drug Administration Package Insert for Mefloquine, 92 Policies and Inquiries Related to the Use of Mefloquine by Military Forces, 100 Pharmacokinetics, 106 Adverse Events, 107 Other Identified Studies of Mefloquine Prophylaxis in Human Populations, 128 Biologic Plausibility, 140 Synthesis and Conclusions, 143 References, 162 5 TAFENOQUINE  177 Food and Drug Administration Package Insert for Tafenoquine, 179 Policies and Inquiries Related to the Use of Tafenoquine by Military Forces, 182 Pharmacokinetics, 184 Adverse Events, 184 Other Identified Studies of Tafenoquine in Human Populations, 198 Biologic Plausibility, 201 Synthesis and Conclusions, 202 References, 212 6 ATOVAQUONE/PROGUANIL 217 Food and Drug Administration Package Insert for Atovaquone/Proguanil, 218 Pharmacokinetics, 221 Adverse Events, 222 Other Identified Studies of A/P Prophylaxis in Human Populations, 232 Biologic Plausibility, 234 Synthesis and Conclusions, 235 References, 242 7 DOXYCYCLINE 247 Food and Drug Administration Package Insert for Doxycycline, 250 Pharmacokinetics, 253 Adverse Events, 254 Other Identified Studies of Doxycycline Prophylaxis in Human Populations, 267 Biologic Plausibility, 270 Synthesis and Conclusions, 272 References, 284

CONTENTS xiii 8 PRIMAQUINE 291 Food and Drug Administration Package Insert for Primaquine, 293 Policies and Inquiries Related to the Use of Primaquine by Military Forces, 295 Pharmacokinetics, 298 Adverse Events, 299 Other Identified Studies of Primaquine Prophylaxis in Human Populations, 306 Biologic Plausibility, 308 Synthesis and Conclusions, 309 References, 315 9 CHLOROQUINE 323 Food and Drug Administration Package Insert for Chloroquine, 325 Pharmacokinetics, 329 Adverse Events, 329 Other Identified Studies of Chloroquine Prophylaxis in Human Populations, 336 Biologic Plausibility, 339 Synthesis and Conclusions, 340 References, 347 10 IMPROVING THE QUALITY OF RESEARCH ON THE LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS  355 Attributes of Available Research, 356 Quality of Methods of Reviewed Studies, 358 Comparisons of Findings Across All Antimalarial Drugs of Interest, 366 Advancing Research on Antimalarial Drugs, 367 References, 375 APPENDIXES A Public Meeting Agendas 379 B Invited Presentations 383 C Epidemiologic Studies That Met the Committee’s Inclusion Criteria 393 D Committee Member and Staff Biographies 399

Acronyms and Abbreviations AFP Australian Federal Police Association AIDS acquired immunodeficiency syndrome A/P atovaquone/proguanil BMI body mass index CAS Chemical Abstract Service CDC Centers for Disease Control and Prevention CI confidence interval CNS central nervous system DEET N,N-diethyl-3-metatoluamide DNA deoxyribonucleic acid DoD Department of Defense DSM Diagnostic and Statistical Manual of Mental Disorders DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ECG electrocardiogram FAERS FDA Adverse Event Reporting System FAF fundus autofluorescence FDA Food and Drug Administration FST fluorescent spot test xv

xvi ACRONYMS AND ABBREVIATIONS G6PD glucose-6-phosphate dehydrogenase GFR glomerular filtration rate GPRD General Practice Research Database HIV human immunodeficiency virus HR hazard ratio IBD irritable bowel disease IBS irritable bowel syndrome ICD International Classification of Diseases ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification IPTp intermittent preventive treatment in pregnancy IR incidence rate IRR incidence rate ratio n sample size NewGen Study National Health Study for a New Generation of U.S. Veterans OEF Operation Enduring Freedom OIF Operation Iraqi Freedom OND Operation New Dawn OR odds ratio p p value PART presumptive anti-relapse therapy PCL-C PTSD Checklist–Civilian version PHQ Patient Health Questionnaire PICO Participants, Inventions, Comparisons and Outcomes PTSD posttraumatic stress disorder QTc corrected QT interval (on an ECG) RR relative risk SCID Structured Clinical Interview for DSM-5 SD-OCT spectral domain optical coherence tomography SF-12 Medical Outcomes Study 12-item Short Form SNP single nucleotide polymorphism UK United Kingdom UV-A ultraviolet A UV-B ultraviolet B

ACRONYMS AND ABBREVIATIONS xvii VA Department of Veterans Affairs WHO World Health Organization

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Among the many who serve in the United States Armed Forces and who are deployed to distant locations around the world, myriad health threats are encountered. In addition to those associated with the disruption of their home life and potential for combat, they may face distinctive disease threats that are specific to the locations to which they are deployed. U.S. forces have been deployed many times over the years to areas in which malaria is endemic, including in parts of Afghanistan and Iraq. Department of Defense (DoD) policy requires that antimalarial drugs be issued and regimens adhered to for deployments to malaria-endemic areas. Policies directing which should be used as first and as second-line agents have evolved over time based on new data regarding adverse events or precautions for specific underlying health conditions, areas of deployment, and other operational factors

At the request of the Veterans Administration, Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis assesses the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that were approved by FDA or used by U.S. service members for malaria prophylaxis, with a focus on mefloquine, tafenoquine, and other antimalarial drugs that have been used by DoD in the past 25 years. This report offers conclusions based on available evidence regarding associations of persistent or latent adverse events.

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