StemCell Therapy

Feb. 25, 2020

WASHINGTON Although the immediate side effects of antimalarial drugs are widely recognized, few studies were designed specifically to examine health problems that might occur or persist months or years after people stopped taking them. For this reason, a new report from the National Academies of Sciences, Engineering, and Medicine finds there is currently insufficient evidence to determine whether there is an association between antimalarial use and neurologic and psychiatric outcomes, including anxiety, depression, and the development of symptoms that mimic post-traumatic stress disorder (PTSD). Further research is warranted because existing studies are limited in their design.

As of 2019, six drugs have been approved by the U.S. Food and Drug Administration (FDA) for prevention of malaria and are available by prescription: tafenoquine, atovaquone/proguanil (A/P), doxycycline, mefloquine, primaquine, and chloroquine. The report examines the possible long-term health effects of these six drugs, with a particular focus on the neurologic and psychiatric effects of mefloquine, which was widely prescribed to U.S. troops until 2009; and tafenoquine, a newly approved drug. It contains 31 conclusions regarding the level of association between the antimalarial use and persistent or latent adverse events.

The committee that wrote the report defined persistent events as those that start while the drug is being taken and continue at least 28 days after the drug is stopped. Latent events are not apparent while the drug is being taken, but present any time at least 28 days after cessation.

The report also presents strategies for designing and conducting studies that would advance the understanding of possible persistent and latent events associated with antimalarial drugs.

The committee recognized that adverse events while taking some antimalarial drugs are quite common, but the pressing, well-justified question of whether health problems continue after use has simply not generated the rigorous research needed to answer it, said committee chair David Savitz, professor of epidemiology at the Brown University School of Public Health. The absence of evidence on long-term health effects of these drugs does not mean the link doesnt exist, only that there is a critical need for well-designed studies to answer important safety questions.

In 2018, there were 228 million cases of malaria worldwide, with 405,000 resulting in death. Malaria has affected nearly every U.S. military deployment since the Civil War, and it remains an ongoing threat to those involved in the current conflicts in the Middle East. In addition to U.S. service members and veterans, the report also examines the adverse events and health outcomes experienced by populations including Peace Corps volunteers, travelers, people living in malaria-endemic areas, and research volunteers. While travelers are encouraged to take an antimalarial drug as a preventative treatment, military personnel are required to do so under proper medical supervision.

Limitations of Existing Research Some of the currently available antimalarials have been in use since the 1940s, but after an extensive literature review, the committee found only 21 epidemiological studies that examined adverse events occurring at least 28 days after the final dose. The studies conducted to gain FDA approval are generally limited by small sample sizes and short follow-up periods, making it difficult to identify persistent or latent effects. In other studies, adherence rates may be inflated, as people are often reluctant to report when they modify a dose or stop taking a medication altogether.

Furthermore, because of the many other factors and stresses associated with deployed environments, like combat, it is challenging to attribute specific health effects to the use of an antimalarial drug. For a diagnosis of PTSD, the person should have directly experienced a traumatic event; the medication itself is not the traumatic event, as the diagnostic criteria explicitly state, the report says.

Conclusions on Association Between Antimalarial Use and Health Outcomes For each of the six approved drugs, the committee examined adverse events categorized by body system: neurologic, psychiatric, gastrointestinal, eye, cardiovascular, and other disorders.

There is a sufficient level of evidence of an association between tafenoquine and vortex keratopathy, a condition that involves asymptomatic deposits in the cornea, the committee found. While it was found to persist beyond 28 days, it was also found to resolve within 3 to 12 months and not result in clinical outcomes, such as loss of vision.

While the committee found little evidence for associations between the drugs and most outcome categories, it also found the evidence provides a basis for additional research into an association between the following antimalarial drugs and health outcomes:

Advancing Research on Antimalarials Given the billions of people at risk for malaria and the severity of the disease, there will be a continuing need for people to take antimalarials, the report emphasizes. The threat of drug-resistant parasites also necessitates research into new preventatives.

To establish causal links between taking antimalarial drugs and persistent or latent adverse health effects, the committee recognized the need for a series of randomized trials and multiple well-designed observational studies of varying types. Ideally, these studies would:

Researchers could also conduct studies using health care databases that cover a large number of individuals who used antimalarial drugs and reported their subsequent health experiences. Such data sources might include Department of Veterans Affairs (VA) and Department of Defense (DOD) health care databases, existing DOD and VA registries, Medicare, FDA Sentinel, commercially available claims databases, and national health care data from other countries. Adverse event registries, such as that used by FDA, would not be informative, since they do not provide comparative data, the committee concluded.

The study undertaken by the Committee to Review Long-Term Health Effects of Antimalarial Drugs was sponsored by the U.S. Department of Veterans Affairs. The National Academies are private, nonprofit institutions that provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. They operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visitnationalacademies.org.

Follow us:Twitter@theNASEMInstagram@thenasemFacebook@NationalAcademies Contact:Stephanie Miceli, Media Relations Officer Office of News and Public Information202-334-2138; e-mailnews@nas.edu

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Determining Whether There Is a Link Between Antimalarial Drugs and Persistent Health Effects Requires More Rigorous Studies - National Academies of...

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