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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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Assessment of
Long-Term
Health Effects of
Antimalarial Drugs
When Used for
Prophylaxis

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

images

THE NATIONAL ACADEMIES PRESS
Washington, DC
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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.
×

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
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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.

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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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.

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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.

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.
×

Image

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.

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.
×

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

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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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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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:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or

Page viii Cite
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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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.

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.
×

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 antimalarial 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 problems. The committee was not asked to review patient reports or to make recommendations 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

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.
×

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 evidence of adverse effects is not evidence of a lack of adverse effects. The committee 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 Academies 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 support 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 University 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

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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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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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
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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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
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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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VA Department of Veterans Affairs
WHO World Health Organization
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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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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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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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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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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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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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