Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis (2020) / Chapter Skim
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10 Improving the Quality of Research on the Long-Term Health Effects of Antimalarial Drugs
10 Improving the Quality of Research on the Long-Term Health Effects of Antimalarial Drugs
Pages 355-378
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From page 355... ...
, and those specific assessments will not be repeated here. In this chapter the committee reflects more broadly on the current overall state of scientific knowledge regarding persistent and latent adverse events of the antimalarial drugs of interest when used for malaria prophylaxis and how to best advance the understanding of possible persistent events of antimalarial drugs.
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From page 356... ...
ATTRIBUTES OF AVAILABLE RESEARCH The currently available body of high-quality research addressing the use of antimalarial drugs for malaria prophylaxis (some of which have been in use for more than 70 years) and persistent or latent adverse effects is quite limited, even when combined across all the drugs of interest and all organ systems and types of possible adverse events.
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From page 357... ...
, and presenting data on adverse events that occurred or persisted 28 days or more post-drug-cessation. Each of these studies has its own limitations, but they were determined to be the most informative for addressing the question of whether there is evidence of persistent or latent adverse health outcomes associated with the prophylactic use of antimalarial drugs.
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From page 358... ...
While these reports cannot contribute to causal inference in part because of a lack of comparison groups, they can direct attention to and inform areas or health outcomes that merit more methodologically rigorous evaluation for specific drugs. The biologic effects of the various antimalarial drugs are relatively well understood with regard to their effectiveness in preventing clinical malaria and aspects of acute toxicity, but there is a very limited body of research that directly addresses the pathways by which these drugs might result in persistent changes that produce adverse events that may or may not be reversible.
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From page 359... ...
military service members and veterans. However, antimalarial prophylaxis is not limited to these two groups, and it is reasonable to assume that research conducted in other populations may provide relevant information regarding the persistence of adverse events following the prophylactic use of antimalarial drugs, and thus, studies of non-military populations were included in the committee's assessment.
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From page 360... ...
Comparison Groups The committee was asked to focus its assessment on the potential association between the use of any of the six FDA-approved antimalarial drugs for prophylaxis and persistent or latent adverse events. It was not asked to assess the efficacy of the antimalarials of interest, nor was it asked to compare the antimalarial drugs on the basis of toxicity.
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From page 361... ...
. In studies of people who are employed by or participate in organizations in which the use of antimalarial drugs for prophylaxis is required (e.g., military, Peace Corps, Department of State)
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From page 362... ...
The first step, however, is to specify and define the outcomes of interest, preferably using standardized diagnoses or definitions of outcomes. Given the dearth of available and informative literature on the persistent or latent adverse events associated with the use of antimalarial drugs, this area of research is in its infancy, and often the specific outcome is not defined, but instead broad classes of outcomes are included, such as "gastrointestinal effects" or "neuropsychiatric disorders." In the research that forms the basis of this report, even with broad classes of outcomes, definitions vary considerably.
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From page 363... ...
, the potentially traumatic events experienced previous to drug exposure and concurrently with drug exposure were not systematically assessed. Therefore, any associations between use of an antimalarial drug and PTSD symptoms were generally insufficiently ascertained.
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From page 364... ...
Drug-Associated Neurologic and Psychiatric Adverse Effects The committee was charged with assessing the evidence for persistent adverse events, with an emphasis on neurologic or psychiatric events, that are associated with the use of antimalarial drugs when used for prophylaxis. The concurrent use of many prescription drugs has been associated with neuropsychiatric adverse events, and therefore the manifestations associated with antimalarials are not unique.
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From page 365... ...
that may place individuals at a higher risk of experiencing adverse events. In military populations, there is a particular concern with the many other challenges associated with deployment in addition to any impact of antimalarial drug use.
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From page 366... ...
From the perspective of biologic plausibility, the mechanistic links between antimalarial drugs and persistent or latent adverse outcomes have yet to be systematically and definitively explored through experimental studies, and the current literature in that area is not strong. In general, five outcome categories emerged as the areas of greatest interest in the literature: neurologic, psychiatric, gastrointestinal, eye, and cardiovascular.
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From page 367... ...
This is concerning because the use of antimalarial drugs in malaria-endemic areas is recommended, and a user's choice of drug may be informed by the frequency and type of adverse events reported. Of the 31 conclusions that the committee considered across all drugs and outcome categories, in all but one case the evidence of an association between the drug of interest and persistent or latent adverse events was deemed inadequate or insufficient.
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From page 368... ...
A key limitation of the existing literature is that very few studies were designed specifically to examine latent or persistent adverse events. However, more recently there has been more interest in assessing potential persistent or latent adverse events of antimalarial drugs, as compared with when the first of these drugs were approved in the 1940s and 1950s.
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From page 369... ...
Administrative Databases Some of the most informative studies thus far have used health care databases or other data sources that cover large populations. Therefore, a logical place to look for additional opportunities is in other large databases that include a sufficiently large number of individuals who used antimalarial drugs and provide documentation of their subsequent health experience, or else by obtaining data needed for both exposure and outcome assessment by linking several large databases.
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From page 370... ...
and/or observational studies into routine practice. While there are an array of logistic and ethical considerations -- especially because the people using and served by these systems may be considered populations with limited decision-making autonomy -- the potential value of addressing possible health consequences of antimalarial prophylaxis in the population of interest using DoD and VA health information systems offers tremendous potential to advance knowledge and should be considered for future studies.
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From page 371... ...
These data sources -- which are intended only to be illustrative of potential data sources and not exhaustive or directive -- along with advanced statistical methods, are increasingly being used to study medication-related adverse events, and those methods could be applied to the question of persistent or latent health effects associated with the use of antimalarial drugs. However, an examination of psychiatric disorders, and the associated measurement difficulties, bring particular challenges that will need to be carefully considered, as discussed earlier in this chapter.
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From page 372... ...
Among those gaps is the lack of information on the possible persistent effects of antimalarials. Collaborations In its evaluation of the available evidence to address persistent adverse events, the committee identified studies that clearly had collected data that could be informative, but the analyses were either not conducted or not presented in a way that was informative for the committee's purposes.
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From page 373... ...
Approaches to Research That Are Unlikely to Contribute to the Evidence Base Based on the questions of concern and past experience, there are a number of approaches that are unlikely to provide much insight regarding persistent or latent adverse events of antimalarial drugs. Cross-sectional studies that attempt to correlate drug use and symptoms or diagnoses without the ability to explicitly consider the temporal course of events will not make it possible to separate acute from persistent or latent adverse events.
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From page 374... ...
is clearly applicable to the assessment of persistent adverse events of antimalarial drugs. Beyond the continued exploitation of large administrative databases, some other designs warrant consideration for complementing such studies.
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From page 375... ...
Am J Trop Med Hyg 96(1)
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From page 376... ...
2007. Self-reported adverse events associated with antimalarial chemoprophylaxis in Peace Corps volunteers.
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From page 377... ...
Presentation to the Committee to R eview Long-Term Health Effects of Antimalarial Drugs, January 28, 2019.
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