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Introduction

Despite the fact that malaria was eliminated in the United States in the 1950s, it continues to be a serious disease in many others countries around the world. The World Health Organization (WHO) estimated that in 2018 there were 228 million cases of malaria, and that an estimated 405,000 of these cases resulted in death (WHO, 2019). Malaria is a constant threat for nearly half of the world’s population, while among the other half, there are many people who travel to areas where malaria is endemic for business, leisure travel, or to assist with military support operations, and they are also at risk of contracting malaria. The use of malaria prevention methods such as dermal mosquito repellents, chemical-repellent-impregnated clothing, and bed nets can help reduce the risk, but they are not as effective as prophylactic drugs.

A variety of malaria-preventing drugs have been discovered since quinine was first isolated from the bark of the cinchona tree in the early 1800s, and several are in widespread use today. As of 2019, six drugs have been approved by the Food and Drug Administration (FDA) that are currently available by prescription for malaria prophylaxis. They are, by order of the year of FDA approval, chloroquine, primaquine, mefloquine, doxycycline, atovaquone/proguanil, and tafenoquine. As is the case with any FDA-approved drug, each of these antimalarial drugs was tested in several studies to examine its safety and efficacy, so their risks of adverse drug events have been well characterized, at least for short-term effects. These adverse events, which include nausea, upset stomach, and drowsiness, are actually quite common but usually do no permanent harm to the user; in a small number of cases, however, they can have serious or persistent consequences. Studies conducted to gain FDA approval are generally limited by their small numbers of subjects, strict inclusion and exclusion criteria, and short follow-up periods,

which makes it difficult during the approval process to identify adverse events that are rare but potentially serious or that occur or develop over long periods of time. As a result, some of the possible potential adverse events may be fully appreciated only after a drug has been on the market for many years.

Among the Americans most likely to be exposed to malaria are members of the military. Malaria has affected nearly every U.S. military deployment since the American Civil War and it remains an ongoing threat to service members involved in current conflicts in Southwest Asia and peacekeeping missions to Africa and Southeast Asia. Department of Defense (DoD) policy requires that service members deployed to malaria-endemic areas be issued antimalarial drugs and adhere to the drug-taking regimens. Policies concerning which should be used as first-line and as second-line agents have evolved over time in response to malaria parasite resistance to antimalarials and new data about the drugs’ adverse events and which precautions should be taken for specific underlying health conditions, areas of deployment, and other operational factors.

Service members, veterans, and other users have raised concerns about the use of these antimalarial drugs, particularly mefloquine, resulting in long-term or persistent effects, especially those that are neurologic or psychiatric based. Furthermore, the number of veterans seeking disability compensation for conditions attributed to mefloquine use while in service is increasing. The Department of Veterans Affairs (VA) has responsibility for the health care of veterans and, therefore, has an interest in knowing which symptoms and health effects might persist in veterans long after service. Given its mission and in response to these concerns, VA contracted with the National Academies of Sciences, Engineering, and Medicine (the National Academies) to convene an expert ad hoc committee to conduct an assessment of the scientific evidence regarding the potential for long-term health effects resulting from the use of any of the currently available antimalarial drugs that were approved by FDA and/or used by U.S. service members for malaria prophylaxis.

IDENTIFICATION AND SELECTION OF PROPHYLACTIC ANTIMALARIAL DRUGS TO BE REVIEWED

To determine the antimalarial drugs that would be included in this report, a senior research librarian at the National Academies compiled a list of all antimalarial drugs that have been approved by FDA. This list contained 25 potential drugs of interest. Staff members of the National Academies’ Health and Medicine Division then investigated each drug on the list to determine whether it was used for prophylaxis, treatment, or both prophylaxis and treatment of malaria. The drugs that are or have previously been used solely for the treatment of malaria were eliminated from further consideration; this included such agents as Artemisinins, Halofantrine, Fansidar, and Daraprim. The remaining drugs were cross-checked

with policies from DoD on the use of antimalarial drugs for the prophylaxis of malaria with no time limits (Woodson, 2013) and also with the Centers for Disease Control and Prevention timeline summarizing the history of antimalarial drugs (Arguin and Magill, 2017). The resulting list of antimalarial drugs was then sent to DoD for verification of each drug’s use as an antimalarial prophylactic in military populations. Representatives from DoD confirmed the drugs on the initial list and added two additional antimalarial agents, Dapsone (diaminodiphenyl sulfone) and combination chloroquine-primaquine (C-P pill) for the committee’s consideration.

The initial list was also sent to VA for confirmation of the antimalarial drugs of interest to be assessed. When VA formally presented the Statement of Task to the committee, it added tafenoquine to the list of drugs for consideration. VA also stressed that those antimalarial prophylactic agents that are currently available or that have been used within the past 25 years were of highest interest. Based on the contract between VA and the National Academies and as specified in the committee’s Statement of Task, this report includes the following antimalarial drugs that are used as prophylaxis, have been approved by FDA or used by U.S. military personnel, and are currently available or have been used in the recent past: mefloquine (Lariam®), tafenoquine (Arakoda™), atovaquone-proguanil (Malarone®), doxycycline (Acticlate®, Vibramycin®, Doryx®, Vibra-Tabs®, Doryx® MPC, doxycycline hyclate), chloroquine (Aralen®), and primaquine. Literature on other antimalarials, such as studies related to quinine’s mechanisms of action, were also considered in order to inform the understanding of the mechanisms and the potential persistent or latent biologic effects of similar drugs. Although quinine, tetracycline, hydroxychloroquine, dapsone (diaminodiphenyl sulfone), and quinacrine (mepacrine, Atabrine) were used for prophylaxis of malaria by U.S. service members, these agents were all used more than 25 years ago and before the 1990–1991 Persian Gulf War and were not considered further.

CHARGE TO THE COMMITTEE

Box 1-1 shows the committee’s Statement of Task. A VA representative delivered the charge to the committee during the open session of the committee’s first meeting on January 28, 2019. As described above, the antimalarial drugs to be considered by the committee were approved by FDA for use as prophylaxis in adults or used by DoD or were of special interest to VA. Mefloquine (also sold under the trade name Lariam®) and tafenoquine (Arakoda™) were specified as the two drugs of highest interest and importance to VA, with other antimalarial drugs that are currently in use by DoD or that have been used by DoD in the past 25 years also to be considered important. Antimalarials that were used more than 25 years ago but that are no longer in use were considered to be of lesser importance. VA stressed that the focus of the committee’s work should be the long-term health effects of antimalarial drugs that are used for prophylaxis because the short-term adverse events of the

antimalarial drugs of interest are well recognized and are clearly indicated on the package inserts issued by FDA. Although the committee was asked to examine neurologic and psychiatric effects of the drugs—and the potential development of posttraumatic stress disorder (PTSD) in particular—the committee was to consider effects that might occur in any organ system. Instead of recommendations, the committee was asked to offer conclusions based on available evidence regarding the long-term effects and to provide observations on the best use of available data as well as considerations for future research in examining the persistent or latent health effects of antimalarial drugs.

Given the difficulty of conducting strict causality assessments, the committee chose instead to base its assessment on measures of association between exposure to an antimalarial drug and health outcomes. Assessing evidence for associations rather than causation means that the rigor of the evidence required to support a finding of statistical association is weaker than what is required to support causality, although some of the criteria that would contribute to determining causality may be met.

THE STUDY PROCESS AND INFORMATION GATHERING

The National Academies convened a 10-member interdisciplinary committee that included experts in epidemiology, biostatistics, pharmacology, drug safety, psychology, psychiatry, neurology, biochemistry, medicinal chemistry, toxicology,

malaria, and military and veteran’s health. The committee met in person for five 2-day meetings over 10 months. Between the in-person meetings, small groups of committee members held conference calls to review specific studies or to discuss the evidence base on a particular health outcome or topic.

In conducting its work, the committee operated independently of VA and any other government agency. It was not asked to make—and it did not make—judgments regarding specific cases in which individual people have claimed injury from the use of an antimalarial drug or regarding such broader issues as the potential costs of compensation for veterans or policies about such compensation. Several other groups have reviewed the available literature on specific antimalarial drugs, classes, or particular health outcomes. However, they used different frameworks, inclusion criteria, or methods to judge association or causality, and therefore the conclusions presented may differ from those of this committee. This report is intended to provide an evidence-based assessment of the scientific information available on long-term health effects following the prophylactic use of the antimalarial drugs which the Secretary of Veterans Affairs can consider as VA exercises its responsibilities to veterans. The committee did not perform a cost–benefit analysis or a risk assessment regarding the use of these drugs. This report, as with all National Academies’ reports, is freely accessible online at the National Academies Press’s website (www.nap.edu).

Several activities were undertaken to develop the scientific foundation for the report’s findings and conclusions. The principal sources of information on potential long-term health effects associated with the use of the antimalarials of interest to the committee came from detailed searches of the published peer-reviewed literature which were not subject to time constraints. The committee did not collect original data, conduct original studies, or perform any secondary data analyses. In total the committee considered more than 12,000 abstracts of scientific and medical studies and read more than 3,000 full-text articles and book chapters. The literature search strategy and process for reviewing all results is discussed in detail in Chapter 3, Identification and Evaluation of the Evidence Base. This process was supplemented by examining other pertinent published literature, government documents and reports, and testimony and by consulting relevant National Academies reports.

As is the practice of nearly all National Academies consensus committees, the committee held two open sessions not only to gather additional information from people who have particular expertise on topics and subjects that arise during deliberations (such as experts in toxicology, agency representatives who are familiar with antimalarials policy and changes to it, and those who monitor reports of adverse events through postmarketing surveillance), but also especially to listen to individual veterans and others, such as spouses and advocates, who are concerned about aspects of health that may be related to use of these antimalarial drugs. Open sessions were held during the committee’s first two meetings; the agendas and presentation topics are presented in Appendix A, and brief summaries

of the presentations are found in Appendix B. The comments and information provided by the public at the open meetings and over the course of the study were used to identify information gaps in the literature regarding specific health outcomes of concern.

In addition to information provided by invited speakers and members of the public, the committee obtained information from VA and DoD via information requests that followed up on issues raised during presentations and on sources of data on policy. The committee also made two information requests to FDA to request the data or an explanation of the data that were used to support changes to the package insert or label associated with the adverse events of mefloquine. All presentations, responses to information requests, and written comments are available in the public access file for the project.¹

ORGANIZATION OF THE REPORT

The remainder of this report is organized into nine chapters and four appendixes. Chapter 2 presents background information about the antimalarial drugs of interest as well as the military use of them and deployment factors that may exacerbate certain effects of some antimalarial drugs. Chapter 3 describes the considerations that guided the committee’s identification, review, and evaluation of the scientific evidence.

The committee’s evaluation of the epidemiologic literature and other supplemental information and its conclusions regarding the evidence are presented by drug in Chapters 4–9: Chapter 4, Mefloquine; Chapter 5, Tafenoquine; Chapter 6, Atovaquone/Proguanil; Chapter 7, Doxycycline; Chapter 8, Primaquine; and Chapter 9, Chloroquine. Because most of the attention concerning the adverse effects of antimalarials has been associated with the use of mefloquine, this drug is presented first. The other five drugs of interest are ordered by the FDA date of approval for use as a prophylactic for malaria, from most recent to earliest. Each drug-specific chapter begins with a brief history of the drug’s development and use followed by a summary of the changes that have been made to the drug package insert or label since its approval as a prophylactic drug for malaria and then its pharmacokinetic properties. Known short-term adverse events associated with the use of the drug are then reported, followed by a summary and assessment of each of the identified epidemiologic studies that met the committee’s inclusion criteria and were able to contribute some information on long-term health outcomes following cessation of the drug. Because neurologic and psychiatric outcomes, including PTSD, were specified in the committee’s charge, results related to these outcomes are presented whenever they have been reported. Supplemental supporting evidence is then presented, including other identified studies of health

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¹ Public access materials can be requested from paro@nas.edu.

outcomes in populations that used the drug of interest for prophylaxis but that did not meet the committee’s inclusion criteria regarding the timing of follow-up; case reports of persistent adverse events; and information on adverse events of the drug when used in specific groups, such as women who are pregnant or those who have chronic health conditions. After the primary and supplemental evidence in humans is presented, supporting literature from experimental animal and in vitro studies is then summarized. Each chapter ends with a synthesis of all of the evidence presented and the inferences and conclusions that can be made from the available evidence, organized by body system category (neurologic disorders, psychiatric disorders, gastrointestinal disorders, eye disorders, cardiovascular disorders, and other disorders).

Chapter 10 contains a summary of the inferences from the available literature along with the methodologic challenges and limitations to investigating the persistent or latent effects of antimalarial drugs for prophylaxis. The committee discusses research considerations or approaches that can be implemented to improve the quality of data collected as well as the overall evidence base. Appendix A provides a list of open meeting agendas and invited presentation topics and Appendix B summarizes the invited presentations to the committee. A table that gives a high-level overview of each of the 21 epidemiologic studies that met the committee’s inclusion criteria is presented in Appendix C. Committee and staff biographies can be found in Appendix D.

REFERENCES

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