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Suggested Citation:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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.

Summary Malaria is a constant threat for nearly half of the world’s population, and people who travel to endemic areas for business, leisure, or military support opera- tions are also at risk. In 2018 the World Health Organization estimated that there were 228 million cases of malaria, with 405,000 resulting in death (WHO, 2019). While preventive measures like mosquito repellents, window screens and bed nets, repellent-impregnated clothing, and large-scale use of insecticides are available to reduce the risk of infection, these measures are not as effective as prophylactic drugs. Several drugs are widely used for malaria prophylaxis, and as of 2019 six are approved by the Food and Drug Administration (FDA) and are available by prescription: chloroquine, primaquine, mefloquine, doxycycline, atovaquone/ proguanil (A/P), and tafenoquine. Malaria has affected nearly every U.S. military deployment since the Civil War, and it remains an ongoing threat to those engaged in current conflicts in South- west 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. As is the case with any FDA-approved drug, each approved antimalarial drug has been tested for its safety and efficacy, so their risks of concurrent adverse events have been well characterized. However, the studies conducted to gain FDA approval are generally limited by small numbers of subjects and short follow-up periods, making it difficult to identify adverse events that are rare but potentially 1

2 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS serious or that occur or develop over long periods of concurrent use or events that may persist post-cessation. The spectrum of potential adverse events may thus not be fully appreciated until the drug has been on the market for many years. Concern with the potential for long-term or persistent adverse events has been raised by veterans, service members, and other users. This is especially true for antimalarial drugs that have neurologic- or psychiatric-based effects, particularly mefloquine. In response to these concerns, the Department of Veterans Affairs (VA) contracted with the National Academies of Sciences, Engineering, and Medicine (the National Academies) to convene an expert committee to assess the scientific evidence regarding the potential for long-term health effects resulting from the use of antimalarial drugs that have been approved by FDA and/or used by U.S. service members for malaria prophylaxis. CHARGE TO THE COMMITTEE At the committee’s first meeting on January 28, 2019, a VA representative charged it to examine and “assess long-term health effects that might result from the use [by adults] of antimalarial drugs” that have been approved by FDA for use as prophylaxis in adults or used by DoD or that are of special interest to VA. Mefloquine and tafenoquine were specified as the two drugs of highest interest and importance to VA. Other antimalarial drugs that have been used by DoD in the past 25 years were also deemed to be important. Antimalarials that were used more than 25 years ago but are no longer in use were considered to be of lesser importance and were not assessed. Although long-term health effects that might occur in any organ system were to be considered, VA specified that neurologic and psychiatric effects, including the potential development of posttraumatic stress disorder (PTSD), were particular areas of interest. VA stressed that long-term (which the committee interpreted to mean persistent, i.e., beginning during drug use and continuing after cessation, or latent, i.e., present only after cessation of drug use) health effects of antimalarial drugs should be the focus of the committee’s work because short-term (or concur- rent) adverse events are well recognized and indicated on a drug’s FDA-mandated package insert. The committee defined a health effect—and preferentially uses the term “adverse event”—as any generally recognized symptom, condition, or diag- nosis. As it was charged with addressing neurologic and psychiatric outcomes and because these outcomes were not assessed consistently across studies, the commit- tee adopted a rubric for categorizing different outcomes; that rubric is explained in Chapter 3. The committee was asked to offer conclusions based on available evidence regarding associations of persistent or latent adverse events and to offer observations concerning the best use of available data as well as considerations for future research on the short-term and also the persistent or latent health effects of antimalarial drugs. In conducting its work, the committee operated indepen- dently of VA and other government agencies. It was not asked to make, and it did

SUMMARY 3 not make, judgments regarding specific cases in which individuals have claimed injury from the use of an antimalarial drug or such issues as the potential costs of compensation for veterans or policies regarding such compensation. The commit- tee did not perform a cost–benefit analysis or a risk assessment regarding the use of these drugs. This report provides an evidence-based assessment of the scientific evidence regarding persistent and latent adverse events following the prophylactic use of the six antimalarial drugs of interest for the Secretary of Veterans Affairs to consider as VA exercises its responsibilities to veterans. COMMITTEE’S APPROACH TO ADDRESSING ITS CHARGE The committee’s principal source of information on the potential persistent and latent health effects associated with the use of the antimalarials of interest was epidemiologic studies (observational studies and clinical trials) that were identified from comprehensive searches of the published peer-reviewed literature. In total, the committee considered more than 12,000 abstracts and examined more than 3,000 full-text articles and book chapters. Other supplemental sources of informa- tion included U.S. and foreign government documents and reports; information supplied by VA, DoD, and FDA; invited presentations on particular topics (such as neurotoxicology, antimalarials policy practiced by other government agencies, and adverse events monitoring through postmarketing surveillance), and comments offered by veterans and others, such as spouses and advocates, who are concerned about health issues that may be related to antimalarial drug use. The information provided by the public at the open meetings and over the course of the study was used to identify gaps in the literature regarding specific health outcomes of concern. The committee did not collect original data or perform any secondary data analyses. A two-step process was used to screen the results of searches to identify poten- tially relevant literature for review. The first step entailed screening for relevance by title and abstract, and the second step was a full-text review to determine the final set of studies that the committee evaluated. For an epidemiologic analysis to be considered, it had to (1) have the drugs used in a prophylactic manner (not for treatment of active cases of malaria or for another disease or condition), (2) report on the presence or absence of adverse events or effects or other health outcome (such as blood counts), (3) have a comparison group, and (4) use adult populations (aged 16 years and older).1 Additionally, the most important criterion was that there had to be empirical information about the adverse event (or indicate a lack of such an event) that began or persisted at least 28 days after the cessation (final dose) of the drug of interest. As long as a study met these criteria, it was included, even if it had severe methodologic limitations. Ultimately, 21 epidemiologic studies that met the committee’s inclusion criteria were identified that addressed one or more of the six drugs of interest (Ackert et al., 2019; Andersen et al., 1998; DeSouza, 1  If some of the subjects were less than 16 years old, the study was included.

4 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS 1983; Eick-Cost et al., 2017; Green et al., 2014; Laothavorn et al., 1992; Leary et al., 2009; Lee et al., 2013; Lege-Oguntoye et al., 1990; Meier et al., 2004; Miller et al., 2013; Nasveld et al., 2010; Rueangweerayut et al., 2017; Schlagenhauf et al., 1996; Schneider et al., 2013, 2014; Schneiderman et al., 2018; Schwartz and Regev-Yochay, 1999; Tan et al., 2017; Walsh et al., 2004; Wells et al., 2006). These formed the basis for the committee’s conclusions on the relationships between the use of antimalarial drugs and specific categories of persistent adverse health effects. Just over half of the identified studies (11) examined exposure to mefloquine; fewer examined the other drugs of interest: tafenoquine, 7; doxycycline, 7; A/P, 4; prima- quine, 4; and chloroquine, 3. Studies that did not follow their populations for at least 28 days after the final dose of a drug of interest was administered or that did not distinguish the timing of the adverse event (e.g., the follow-up time was more than 28 days after drug cessa- tion, but the authors did not distinguish which adverse events occurred inside and outside the 28-day window) are briefly mentioned in this report but are not evalu- ated in depth. For example, several studies included only a brief mention that “no serious adverse events were reported” without further explanation of what adverse events were examined, how “serious” was defined, or the timing of those events; these were not considered informative for the committee’s purposes. Likewise, studies that focused on derivatives of the drugs of interest (such as for drug dis- covery), drug-delivery systems (e.g., carriers, encapsulations), or the simultaneous administration of an antimalarial drug of interest in combination with any other antimalarial drug that is not an FDA-approved combination were considered to be outside of the committee’s scope of work and were excluded from consideration. The epidemiologic studies that met the inclusion criteria for primary evidence varied in their methods and quality. Each was assessed based on a common set of methodologic principles. The methods assessment included the selection of the study populations, study design, the length of follow-up, the sources of measure- ment for exposure and adverse events or health outcomes, the statistical analyses used, and control for confounding. A thorough evaluation was made of each study’s strengths, limitations, and potential biases and their implications for the study results and for the precision of reported results, and this informed the evalu- ation of the study’s contribution to the evidence base. If a study examined more than one drug or health outcome, it was considered separately for each drug and for each of those outcomes. It is important to note that a study could be well designed and well conducted but still have flaws, such as not distinguishing the timing of adverse events, that limited its information value to the committee. EVIDENCE REVIEWED BY THE COMMITTEE The committee reviewed epidemiologic studies that used different designs, populations, and analysis methods; examined disparate adverse events or out- comes; and used diverse methods to collect information. For assessment purposes,

SUMMARY 5 the committee categorized these studies by population, with studies of military and veterans presented first, followed by studies of other human populations (occu- pational groups, travelers, research volunteers, and residents of malaria-endemic areas). To supplement this information, other sources of adverse-event informa- tion, such as systematic reviews of concurrent adverse events, case reports, and studies of selected sub­ opulations, were also examined. The committee addition- p ally drew on the knowledge of the biologic underpinnings of the adverse event or outcome of interest generated through experimental animal and cell culture studies in order to evaluate the degree to which the effect of a specific drug on a specific adverse event is grounded in knowledge of the pathways by which such an impact could occur. Military and Veteran Populations Because active-duty military and veterans are the population of interest, s ­ tudies of these groups were accorded considerable weight in the committee’s deliberations. The committee reviewed all identified studies of U.S. and foreign service members and veterans who used any of the antimalarials of interest. Few of these studies included objective measures of drug concentrations in the blood or tissue; more typically, the use of a particular antimalarial and its dosage was based on prescription data, self-report, or specified as part of the study design. Full adher- ence with the drug regimen was generally assumed when estimating and quantify- ing the risk of specific adverse events and health outcomes related to the use of a particular drug, although research has shown this is not always the case. As with other studies of health outcomes in military populations, where there is seldom any measure of exposure to a specific agent, comparisons between deployed and nondeployed veterans are considered the next most relevant comparison. Since sending service members to known malaria-endemic areas without prevention measures would be unethical, several studies of military populations compare the effects of two or more antimalarials. Because of the many other factors and stresses associated with deployed environments like combat, specific effects attributable to the use of an antimalarial drug may be difficult to tease out. Studies of Non-Military and Non-Veteran Populations Although U.S. service members and veterans constitute the primary popula- tion of interest, the committee also considered other populations that use anti­ malarial drugs (occupationally exposed persons, travelers, research volunteers, and people living in malaria-endemic areas) in which there was the potential for more precise quantification and evaluation of the risks of adverse events. These populations use antimalarial drugs but do not have some of the potentially con- founding stressors, such as combat, typically found in military populations. Safety and tolerance studies performed in research volunteers from non-endemic areas

6 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS who were followed for at least 28 days post-drug-cessation provide additional lines of evidence, as do the results of studies conducted using endemic populations. Finally, studies of adverse events associated with the prophylactic use of a drug in a population with a specific underlying condition (such as pregnancy or comorbid conditions) or demographic trait are described when appropriate. Animal and Mechanistic Studies The most commonly used experimental animal models for testing the potential toxicity of antimalarial drugs are mice, rats, dogs, and rhesus monkeys. The committee used studies of laboratory animal models to determine whether there is evidence of a pathophysiologic process or biologic mechanism that could provide evidence bearing on the relationship between exposure to an antimalarial drug in humans and a persistent or latent health effect. Several factors must be considered when extrapolating these results to human disease and disease progression, including the magnitude and duration of exposure, the timing of exposure during development or differentiation, the route of exposure, model- specific factors (such as sex, genetic background, and stress), and differences in pharmacokinetics and pharmacodynamics across species. Insights about biologic processes inform whether an observed pattern of statistical association might be interpreted as the product of more than error, bias, confounding, or chance. Discussions about biologic plausibility are presented after the evidence in humans is presented as part of the comprehensive synthesis of all the pertinent evidence. WEIGHING THE EVIDENCE AND CONCLUSIONS The quantitative and qualitative procedures underlying the committee’s assessment of the evidence have been made as explicit and transparent as possible, as it focused its assessment on the potential for an association between the expo- sure to an antimalarial drug and health outcomes rather than a direct causal effect. A system of four categories of association for rating health outcomes based on the strength of the scientific evidence has gained wide acceptance by Congress, VA, researchers, and veterans groups, and has been used in the National Academies report series of assessments of veterans’ health as well as in several other stand- alone reports including evaluations of safety and the adverse health outcomes of vaccines. The four categories are sufficient, limited or suggestive, inadequate or insufficient, and no association. The criteria for each category express a degree of confidence based on the quality of the evidence, specifically the timing and dura- tion of the exposures, the nature of the specific adverse events or health outcomes, the populations exposed, and the quality, precision, and consistency of the studies examined. The conclusion does not take into account the benefit of the antimalarial to either population or individual health. Although both primary and supporting studies contributed to the committee’s conclusion regarding the evidence of pro-

SUMMARY 7 phylactic use of an antimalarial to be associated with adverse events in a particular body system, primary studies were given more weight. Conclusions were made independently of other reports or author conclusions. Several other groups have reviewed the available literature on a specific antimalarial drug, class, or a particular health outcome. However, they used different frameworks, inclusion criteria, or methods to judge association or causality, and therefore their conclusions may differ from those of the committee. For each of the six drugs of interest, adverse events were categorized by neu- rologic, psychiatric, gastrointestinal, eye, cardiovascular, and other disorders. The committee assembled and discussed the evidence to reach a consensus on the level of the evidence for persistent or latent health effects for each drug of interest; these conclusions are presented in the Synthesis and Conclusion sections. In making its assessments, the committee was careful to note that a lack of informative data does not mean that there is no increased risk of a specific adverse event, only that the available evidence does not provide support for an increased risk. Each conclu- sion consists of two parts: the first sentence assigns the level of association, and the second sentence offers additional detail regarding whether further research in a particular area is merited based on a consideration of all the available evidence and any signals that may be present. For those health outcomes in which the committee concluded there is not a clear justification for additional research, the intention was to distinguish those issues for which there is presently an empirical basis for look- ing more closely and those for which such a basis is not present. As more research accumulates, the outcomes that warrant further research may change. KEY FINDINGS AND GENERAL OBSERVATIONS Nine of the 21 epidemiologic studies examined multiple drugs of interest, and they contribute to the evidence described in multiple chapters. In many cases, even when there were multiple studies of the same drug and same outcome, the characteristics of the study populations and methods were so divergent as to be of questionable relevance to one another. Almost no studies collected data prospec- tively for the purpose of assessing persistent or latent adverse events months to years after the cessation of antimalarial use. The committee presents a total of 31 conclusions regarding the level of associa- tion between exposures to a drug of interest and persistent or latent adverse events (see Box S-1). For one association, there was determined to be a sufficient level of evidence to determine that an association exists. The committee concluded that there is sufficient evidence of an association between the use of tafenoquine and vortex keratopathy,2 which although it was found to persist beyond 28 days post-cessation, 2  Vortex keratopathy manifests as deposits in the inferior interpalpebal portion of the cornea. These deposits rarely result in reduction of visual acuity or ocular symptoms, and they typically resolve with discontinuation of the medication that caused them (AAO, 2019).

8 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS BOX S -1 Summary of Conclusions Regarding Categories of Association Between Exposure to Antimalarial Drugs and Persistent or Latent Adverse Events by System Outcome Sufficient Evidence of an Association Epidemiologic evidence is sufficient to conclude that there is a posi- tive association between the prophylactic use of an antimalarial drug and the outcome in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. For example, if several small studies without known bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an as- sociation. Experimental data supporting biologic plausibility strengthen the evidence of an association but are not a prerequisite and are not enough to establish an association without corresponding epidemiologic findings. There is sufficient evidence of an association between the following anti- malarial drugs and health outcomes: • Tafenoquine and vortex keratopathy Limited or Suggestive Evidence of an Association Epidemiologic evidence suggests an association between prophy- lactic use of an antimalarial drug of interest and the outcome in studies of humans, but the evidence can be limited by an inability to confidently rule out chance, bias, or confounding. For example, a high-quality study with strong findings of a positive association in conjunction with less compelling or inconsistent results from studies of populations with similar exposures could constitute such evidence. None of the associations between anti- malarial drugs and health outcomes were determined to constitute limited or suggestive evidence. Inadequate or Insufficient Evidence of an Association The available epidemiologic studies are of insufficient quality, valid- ity, consistency, or statistical power to support a conclusion regarding the presence or absence of an association. For example, such studies may have failed to control for confounding factors or had inadequate assessment of exposure or outcomes. Because the committee could not possibly address every rare condition or disease, it does not draw explicit conclusions about outcomes that are not discussed, and instead it makes conclusions by body system. It also notes whether the existing evidence, including nonepidemiologic information, merits additional research in a specific area. There is inadequate or insufficient evidence of an asso- ciation between the following antimalarial drugs and health outcomes, grouped by whether the existing evidence supports additional research: Basis for additional research • Mefloquine and neurologic events • Mefloquine and psychiatric events, including PTSD

SUMMARY 9 • Mefloquine and eye disorders, including cataract • Tafenoquine and psychiatric events • Tafenoquine and eye disorders (other than vortex keratopathy) • Atovaquone/Proguanil and eye disorders • Doxycycline and gastrointestinal events No basis for additional research • Mefloquine and gastrointestinal events • Mefloquine and cardiovascular events • Tafenoquine and neurologic events • Tafenoquine and gastrointestinal events • Tafenoquine and cardiovascular events • Atovaquone/Proguanil and neurologic events • Atovaquone/Proguanil and psychiatric events • Atovaquone/Proguanil and gastrointestinal events • Atovaquone/Proguanil and cardiovascular events • Doxycycline and neurologic events • Doxycycline and psychiatric events • Doxycycline and eye disorders • Doxycycline and cardiovascular events • Primaquine and neurologic events • Primaquine and psychiatric events • Primaquine and gastrointestinal events • Primaquine and eye disorders • Primaquine and cardiovascular events • Chloroquine and neurologic events • Chloroquine and psychiatric events • Chloroquine and gastrointestinal events • Chloroquine and eye disorders • Chloroquine and cardiovascular events Limited or Suggestive Evidence of No Association Several adequate studies, which cover the full range of human expo­ sure, are consistent in showing no association or reduced risk (not dis- tinguished for the purposes of this evaluation, which was focused on the potential for adverse effects) with an exposure to an antimalarial of interest at any concentration and had relatively narrow confidence intervals. A conclu- sion of “no association” is inevitably limited to the conditions, exposures, and observation periods covered by the available studies, and the possibility of a small increase in risk related to the magnitude of exposure studied can never be excluded. However, a change in classification from inadequate or insufficient evidence of an association to limited or suggestive evidence of no association would require new studies that correct for the methodologic problems of previous studies and that have samples large enough to limit the possible study results attributable to chance. None of the associations between the antimalarial drugs and health outcomes were determined to constitute limited or suggestive evidence of no association.

10 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS was also found to resolve within 3 to 12 months and did not have a clinical implica- tion, such as loss of vision. For the other 30 conclusions across all drugs and outcome categories con- sidered, the evidence between the drug of interest and persistent or latent adverse events was inadequate or insufficient. For all outcomes except for the potential of some eye disorders for A/P users, the occurrence of latent effects (those effects that did not manifest in individuals while taking the antimalarial and only emerged after drug cessation) was not supported. Based on information from the assessed epidemiologic studies and other studies of concurrent events, case reports, or biologic plausibility, the committee considers the existence of some persistent events for certain antimalarials to be highly plausible but not sufficiently studied. For this reason, in its conclusion for each outcome category the committee speci- fies whether the existing evidence warrants additional research in a specific area. The committee determined that there is a basis for further research for seven of the drug–outcome associations, and it views the most plausible persistent adverse events to be those that are the result of enduring concurrent events and thus gave additional weight to the evidence for concurrent events in determining whether there is a basis for further research. The interpretation of studies that did not find increased risk associated with a particular drug took into account the extent to which they would have been capable of detecting associations had they been present. The informativeness of such s ­ tudies depends in part on their statistical power, which is determined by factors that include the overall study size and frequency of the adverse events of interest. In a number of instances, studies that found no evidence of an association were of sufficient size and quality that it is unlikely that there are truly large increases in common adverse events, but this did not preclude smaller effects or effects on rarer outcomes. Even such modest increases in rare events may lead to substantial impairment for the individuals who are affected and result in a large absolute num- ber of adverse events, given the number of people who use the antimalarial drugs. Neurologic and Psychiatric Outcomes As noted above, VA asked the committee to specifically address the evidence for persistent neurologic and psychiatric outcomes and the potential development of PTSD. Of the six drugs of interest, these concerns were greatest for mefloquine. Concurrent adverse neurologic events associated with the use of mefloquine are well recognized and include dizziness, vertigo, loss of balance, headache, memory impairment, confusion, encephalopathy, sensory or motor neuropathies, convulsions, and tinnitus. However, the post-cessation studies did not find these concurrent adverse events to be present at statistically different rates among users of mefloquine than with those who used other antimalarial drugs or who did not use any prophylaxis. Similarly, the evidence supporting concurrent adverse psychiatric effects (anxiety, depression, mood swings, panic attacks, abnormal

SUMMARY 11 dreams, insomnia, hallucinations, aggression, psychotic or paranoid reactions, and suicidal thoughts) with the use of mefloquine is compelling, but the epidemiologic studies that examined these outcomes at least 28 days post-drug-cessation do not indicate an increase of persistent psychiatric events relative to other antimalarial drugs or no use of antimalarial drugs. Three high-quality studies—all conducted using active-duty U.S. military or veteran populations—reported PTSD diagnoses (based on International Classifi- cation of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes) or PTSD symptoms (based on validated instruments), taking into account deployment and combat exposure. In an analysis of active-duty service members, Eick-Cost et al. (2017) presented adjusted effect estimates of PTSD stratified by deployment s ­ tatus. Among the nondeployed, those who were prescribed mefloquine were found to have a statistically significant decrease in PTSD diagnoses relative to those prescribed doxycycline, but a statistically significantly increased risk rela- tive to individuals who were prescribed A/P. There was no difference in PTSD diagnoses for deployed service members prescribed mefloquine versus those prescribed doxycycline or A/P. When service members were stratified by prior psychiatric history, no statistically significant differences between mefloquine and d ­ oxycycline for PTSD diagnoses were found. In their analysis of the hospitaliza- tions of active-duty service members, Wells et al. (2006) reported no statistically significant differences for PTSD diagnoses for deployed service members who were prescribed mefloquine versus deployed service members who did not use an antimalarial drug or, separately, who were assigned to Europe or Japan. In their study of veterans who had responded to the 2009–2011 National Health Study for a New ­ eneration of U.S. Veterans, Schneiderman et al. (2018), using a standard- G ized instrument, also found no difference in PTSD symptoms between mefloquine users and nonusers of antimalarials after controlling for demographic character- istics and deployment. Therefore, based on the available evidence primarily from the epidemiologic ­ tudies, the committee concluded that there is insufficient or s inadequate evidence of an association between the use of mefloquine for malaria prophylaxis and persistent or latent neurologic events or psychiatric events, includ- ing PTSD. However, given the concurrent adverse events, case reports, public submissions, and experimental animal studies, the committee concluded that there is a basis for further study of such associations. Tafenoquine, like mefloquine, is contraindicated in persons with a history of psychotic disorders or current psychotic symptoms. None of the seven epidemiologic studies included data on psychiatric adverse events for which the timing post-tafenoquine-cessation was specified. In studies conducted pre- FDA approval, the most common concurrent psychiatric adverse reactions for tafenoquine were reported to be sleep disturbances, depression or depressed mood, and anxiety. Moreover, results from a combined set of studies submitted to FDA reported that psychiatric adverse events were similar between participants receiving tafenoquine and those receiving mefloquine and that the rates of adverse

12 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS events for both groups were higher than those for participants receiving a placebo. Despite the issues with these studies—the timing of the events was not specified, the studies did not conduct systematic monitoring for the outcomes, and for several of the studies people with a history of psychiatric disorders were excluded—still these findings enhance the plausibility of psychiatric events being associated with use of tafenoquine. As such, although the committee concluded that there was insufficient or inadequate evidence of an association between the use of tafenoquine for malaria prophylaxis and persistent or latent psychiatric events, it also concluded that there was a basis for further study of persistent or latent psychiatric events. Other Outcomes for Which There Is a Basis for Additional Research The committee also identified several other indications of associations for specific outcomes in its review of post-cessation epidemiologic studies and sup- porting evidence (such as case reports of persistent adverse events, concurrent adverse events, or biologic plausibility) that would merit further study. For three of the drugs—mefloquine, tafenoquine, and atovaquone/proguanil—the com- mittee believes there is a basis for additional research on persistent or latent eye disorders. For doxycycline there is a basis for additional research into persistent gastrointestinal events. ADVANCING RESEARCH ON ANTIMALARIAL DRUGS Given the seriousness of malaria and the billions of people at risk for it, there will be a continued need for antimalarial drugs. Studying the persistent and latent effects of exposures is challenging, and therefore it is important to recognize that a perfect or complete understanding is likely unrealistic. A key limitation of the existing literature is that very few studies were designed specifically to examine latent or persistent adverse events. To establish causal links between antimalarial exposure and persistent adverse events, it will be important to have a series of randomized trials and multiple well-designed observational studies of varying types that are designed to examine potential persistent outcomes and overcome the considerable weaknesses noted in past research. Ideally these studies would have explicit documentation of the timing of antimalarial drug use and symptom occurrence (with clear temporal ordering), an extended follow-up that includes assessments at multiple time points, and a validated collection of information regarding potential confounders, antimalarial exposure (dose and timing), and the outcomes of potential interest, including a careful collection of neurologic and psychiatric outcomes using validated instruments. Because some of the outcomes of concern are or may be rare, the samples will need to be of sufficient size to detect associations if they do exist. While it may not be realistic to carry out a large set of studies that have all of these components, there are strong designs that take

SUMMARY 13 advantage of existing data sets that would be feasible. In addition, a series of well- designed studies that each have a number of (but perhaps not all) these components could be quite informative, and they could be used to triangulate the evidence so as to develop an understanding of the potential mechanisms and persistent adverse events. Using standardized definitions and making exposure, outcome, and covari- ates as compatible as possible would better allow for a synthesis of the evidence across studies. There has recently been more interest in assessing the potential persistent or latent adverse events of antimalarial drugs than there was when the first of the drugs were approved in the 1940s. For example, two required Phase IV trials are now being conducted to evaluate long-term tafenoquine safety. With regard to mefloquine specifically, several factors may influence whether additional studies of its use for malaria prophylaxis are conducted and how informative those results will be. Although mefloquine is still recommended for civilian use, the numbers of prescriptions for it have declined substantially, likely in part due to the 2013 FDA boxed warning regarding concurrent psychiatric symptoms (see Chapter 4), to media reports of adverse events, and to the availability of similarly efficacious drugs with comparatively fewer adverse events or different adverse event profiles. Since 2009, DoD policy has severely restricted the use of mefloquine for service members. Therefore, any prospective or retrospective studies conducted using service members since these policies went into effect will lack generalizability and will include people who have previously tolerated mefloquine, which may account for some of the findings of no difference in risk of most outcomes compared with other antimalarials. Some of the most informative studies have used health care databases or other data sources that cover large populations. Therefore, a logical place to look for additional opportunities would be in other large databases that include a suf- ficiently large number of individuals who used antimalarial drugs and that provide documentation of their subsequent health experience; another option would be to link several large databases to obtain the data needed for both exposure and out- come assessment. Such data sources might include general VA and DoD health care databases, existing DoD and VA registries, cohorts of service members or veterans assembled previously, Medicare, FDA Sentinel, commercially available claims databases, and health care data from other countries with national health care systems. Other avenues of investigation that would likely be informative about persistent or latent adverse events are re-analyses of some of the existing studies to clarify the temporal course of drug use and health experience to enable inferences regarding concomitant versus persistent adverse events. It was clear to the committee that data on post-drug-cessation events had been collected for several epidemiologic studies, but the data were not reported in a manner that allowed the committee to distinguish the timing of the adverse events. A pooled data analysis effort using a standardized approach may also move this area of scientific inquiry forward.

14 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Several other strategies and approaches were considered for advancing the evidence base on persistent adverse events associated with the use of antimalarial drugs. Conducting studies of adverse events up to 3–6 months post-cessation would be informative if focused and validated assessments of health status were performed over the subsequent weeks or months. This might involve extending clinical trials or systematically following returning travelers using clinical evalu- ations or even questionnaires that are sufficiently sensitive to discern even sub- clinical health status. To the extent that there are hypotheses regarding individuals with selected risk factors, smaller, more intensive evaluations could be used to target adverse events in these populations. Large case–control studies of specific adverse events could potentially generate additional evidence on associations of antimalarial drugs. Finally, well-conceived in vitro or in vivo studies could provide meaningful information to help in interpreting the evidence from human popula- tions. Mechanistic links between antimalarial drugs and persistent or latent adverse outcomes have yet to be systematically and definitively explored through experi- mental studies, and the current literature in that area is relatively weak. Examples of research that would be required for suitable rigor include testing the impacts of prolonged exposure to biologically relevant antimalarial dosing across several behavioral tests with validity for persistent or latent psychiatric, neurologic, or other disorders and in vivo testing of lasting antimalarial-induced cell loss and toxicity using contemporary standards of assessment. A number of approaches are unlikely to provide much additional insight regarding the persistent adverse events of antimalarial drugs. These include cross- sectional studies that do not allow for distinguishing between the use of a drug and correlates of symptoms or diagnoses; small clinical trials without sufficiently long post-cessation follow-up periods or sufficient numbers of participants to provide the needed statistical precision to address clinically significant outcomes; and studies of reports submitted to adverse event registries, such as that used by FDA. FINAL OBSERVATIONS There is a sharp contrast between the extensive evidence pertaining to con- current adverse events that are experienced while a drug is being used or shortly following its cessation and the dearth of high-quality information pertaining to adverse experiences that are present after the use of that drug has ended. This remains true after combining the available studies across all the drugs of interest (some of which have been in use for more than 70 years) and types of possible adverse events. There appears to be a disconnect between the level of concern raised—millions of people have used the drugs, and there are recognized con- current adverse events and case reports of adverse events—and the systematic research on persistent adverse events, particularly in areas such as the use of meflo- quine and persistent neurologic or psychiatric outcomes. The available epidemio- logic studies are highly variable in their methodologic quality and relevance and

SUMMARY 15 rarely can be considered replications, given the diversity of study populations and designs. Although conducting high-quality research on the persistent and latent effects of exposures is challenging, this should not prevent it from being done. REFERENCES AAO (American Academy of Ophthalmology). 2019. Corneal verticillata. https://www.aao.org/­ bcscsnippetdetail.aspx?id=27980840-6807-4c45-aaae-b8652b087987 (accessed October 30, 2019). Ackert, J., K. Mohamed, J. S. Slakter, S. El-Harazi, A. Berni, H. Gevorkyan, E. Hardaker, A. ­ ussaini, H S. W. Jones, G. C. K. W. Koh, J. Patel, S. Rasmussen, D. S. Kelly, D. E. Baranano, J. T. T ­ hompson, K. A. Warren, R. C. Sergott, J. Tonkyn, A. Wolstenholme, H. Coleman, A. Yuan, S. Duparc, and J. A. Green. 2019. Randomized placebo-controlled trial evaluating the ophthalmic safety of single-dose tafenoquine in healthy volunteers. Drug Saf 42(9):1103-1114. Andersen, S. L., A. J. Oloo, D. M. Gordon, O. B. Ragama, G. M. Aleman, J. D. Berman, D. B. Tang, M. W. Dunne, and G. D. Shanks. 1998. Successful double-blinded, randomized, placebo- controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis 26(1):146-150. DeSouza, J. M. 1983. Phase I clinical trial of mefloquine in Brazilian male subjects. Bull World Health Organ 61(5):809-814. Eick-Cost, A. A., Z. Hu, P. Rohrbeck, and L. L. Clark. 2017. Neuropsychiatric outcomes after ­ efloquine exposure among U.S. military service members. Am J Trop Med Hyg 96(1):159-166. m Green, J. A., A. K. Patel, B. R. Patel, A. Hussaini, E. J. Harrell, M. J. McDonald, N. Carter, K. M ­ ohamed, S. Duparc, and A. K. Miller. 2014. Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects. J Clin Pharmacol 54:995-1005. Laothavorn, P., J. Karbwang, K. Na Bangchang, D. Bunnag, and T. Harinasuta. 1992. Effect of m ­ efloquine on electrocardiographic changes in uncomplicated falciparum malaria patients. Southeast Asian J Trop Med Public Health 23(1):51-54. Leary, K. J., M. A. Riel, M. J. Roy, L. R. Cantilena, D. Bi, D. C. Brater, C. van de Pol, K. Pruett, C. Kerr, J. M. Veazey, Jr., R. Beboso, and C. Ohrt. 2009. A randomized, double-blind, safety and tolerability study to assess the ophthalmic and renal effects of tafenoquine 200 mg weekly versus placebo for 6 months in healthy volunteers. Am J Trop Med Hyg 81:356-362. Lee, T. W., L. Russell, M. Deng, and P. R. Gibson. 2013. Association of doxycycline use with the development of gastroenteritis, irritable bowel syndrome and inflammatory bowel disease in Australians deployed abroad. Intern Med J 43(8):919-926. Lege-Oguntoye, L., G. C. Onyemelukwe, B. B. Maiha, E. O. Udezue, and S. Eckerbom. 1990. The effect of short-term malaria chemoprophylaxis on the immune response of semi-immune adult volunteers. East Afr Med J 67(11):770-778. Meier, C. R., K. Wilcock, and S. S. Jick. 2004. The risk of severe depression, psychosis or panic attacks with prophylactic antimalarials. Drug Saf 27(3):203-213. Miller, A. K., E. Harrell, L. Ye, S. Baptiste-Brown, J. P. Kleim, C. Ohrt, S. Duparc, J. J. Möhrle, A. Webster, S. Stinnett, A. Hughes, S. Griffith, and A. P. Beelen. 2013. Pharmacokinetic interac- tions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects. Br J Clin Pharmacol 76:858-867. Nasveld, P. E., M. D. Edstein, M. Reid, L. Brennan, I. E. Harris, S. J. Kitchener, P. A. Leggat, P. Pickford, C. Kerr, C. Ohrt, W. Prescott, and the Tafenoquine Study Team. 2010. Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. Antimicrob Agents Chemother 54:792-798.

16 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS Rueangweerayut, R., G. Bancone, E. J. Harrell, A. P. Beelen, S. Kongpatanakul, J. J. Möhrle, V. Rousell, K. Mohamed, A. Qureshi, S. Narayan, N. Yubon, A. Miller, F. H. Nosten, L. Luzzatto, S. Duparc, J.-P. Kleim, and J. A. Green. 2017. Hemolytic potential of tafenoquine in female volunteers heterozygous for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PD Mahidol variant) versus G6PD normal volunteers. Am J Trop Med Hyg 97(3):702-711. Schlagenhauf, P., R. Steffen, H. Lobel, R. Johnson, R. Letz, A. Tschopp, N. Vranjes, Y. Bergqvist, O. Ericsson, U. Hellgren, L. Rombo, S. Mannino, J. Handschin, and D. Sturchler. 1996. Mefloquine tolerability during chemoprophylaxis: Focus on adverse event assessments, stereochemistry and compliance. Trop Med Int Health 1(4):485-494. Schneider, C., M. Adamcova, S. S. Jick, P. Schlagenhauf, M. K. Miller, H. G. Rhein, and C. R. Meier. 2013. Antimalarial chemoprophylaxis and the risk of neuropsychiatric disorders. Travel Med Infect Dis 11(2):71-80. Schneider, C., M. Adamcova, S. S. Jick, P. Schlagenhauf, M. K. Miller, H. G. Rhein, and C. R. Meier. 2014. Use of anti-malarial drugs and the risk of developing eye disorders. Travel Med Infect Dis 12(1):40-47. Schneiderman, A. I., Y. S. Cypel, E. K. Dursa, and R. Bossarte. 2018. Associations between use of antimalarial medications and health among U.S. veterans of the wars in Iraq and Afghanistan. Am J Trop Med Hyg 99(3):638-648. Schwartz, E., and G. Regev-Yochay. 1999. Primaquine as prophylaxis for malaria for nonimmune travelers: A comparison with mefloquine and doxycycline. Clin Infect Dis 29(6):1502-1506. Tan, K. R., S. J. Henderson, J. Williamson, R. W. Ferguson, T. M. Wilkinson, P. Jung, and P. M. Arguin. 2017. Long term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995–2014. Travel Med Infect Dis 17:50-55. Walsh, D. S., C. Eamsila, T. Sasiprapha, S. Sangkharomya, P. Khaewsathien, P. Supakalin, D. B. Tang, P. Jarasrumgsichol, C. Cherdchu, M. D. Edstein, K. H. Rieckmann, and T. G. Brewer. 2004. Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P. falciparum malaria. J Infect Dis 190(8):1456-1463. Wells, T. S., T. C. Smith, B. Smith, L. Z. Wang, C. J. Hansen, R. J. Reed, W. E. Goldfinger, T. E. Corbeil, C. N. Spooner, and M. A. Ryan. 2006. Mefloquine use and hospitalizations among US service members, 2002-2004. Am J Trop Med Hyg 74(5):744-749. WHO (World Health Organization). 2019. World Malaria Report, 2019. https://www.who.int/­ publications-detail/world-malaria-report-2019 (accessed December 10, 2019).

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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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