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Appendix B Invited Presentations The committee held two information-gathering sessions in the course of its work to help inform its deliberations. The first was held on January 28, 2019, in conjunction with its first meeting and included the formal charge of the commit- teeâs Statement of Task by representatives from the Department of Veterans Affairs (VA). The second information-gathering session was held March 27, 2019. The committee heard from presenters with knowledge of malaria chemoprophylaxis (hereafter referred to as prophylaxis) policies from the Department of Defense (DoD), Department of State, and the Peace Corps. In addition to presentations focused on antimalarial drug prophylaxis policies among different government agencies, representatives from the Food and Drug Administration (FDA) gave an overview of their postmarketing pharmacovigilance system of adverse events and how that information is used to monitor for signals of safety issues. A representa- tive of the Centers for Disease Control and Prevention (CDC) explained how the agency assembles and weights data for making country-specific recommendations for malaria prophylaxis for U.S. travelers. Because those recommendations are based largely on the published literature, the second part of the CDC presentation reviewed some of the common strengths and limitations of pertinent literature. The committee heard from an advocacy organization that presented a hypothesis for the existence of a neuropsychiatric disease they believe to be associated with the use of mefloquine prophylaxis in U.S. military service members. Finally, the committee heard a detailed presentation on the neurotoxic mechanisms of some antiÂ alarials, m particularly artemisinins. Each open session also included time for attendees to make statements for the committeeâs consideration. The themes of those state- ments are summarized in Chapter 3, under the heading of public comments. 383
384 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS COL Andrew Wiesen, M.D., M.P.H., provided a historical overview of malaria prophylaxis in the U.S. military from World War II to the present, describ- ing the toll of malaria that made efforts to provide effective prophylaxis a strategic imperative and the pharmacologic characteristics of the antimalarials used over the timeline of military engagements. He discussed the side effects of the antiÂ malarials and how they have affected and continue to affect compliance. Meflo- quine (LariamÂ®) was developed at the Walter Reed Army Institute of Research during the Vietnam War and approved for use as prophylaxis in 1989. It was used as a first-line prophylactic agent only for deployments to high-malaria-risk areas in sub-Saharan Africa, such as for the Liberian Task Force in 2003, and used as a second-line agent in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Doxycycline was used as the first-line agent in OIF and OEF, and continues to be used in deployments to Southwest Asia. COL Wiesen explained that geographic combatant commanders set the ârequirements for entryâ for forces serving in their areas; the commanders decide whether and what antimalarial prophylaxis is required based on DoD Health Affairs guidelines, and they may modify requirements as intelligence comes in. The use of a medical product that is not FDA approved requires approval from DoD Health Affairs and must be accomplished via an emergency use authorization process. COL Wiesen told the committee that there are challenges to establishing the causation of drug-related adverse events. For example, poor record-keeping, especially in a combat zone, can hamper the accurate assessment of service membersâ exposure to a drug. He stated that an objectively definable, measurable case definition would help to determine whether there are long-term effects related to the use of any of the antimalarials used for malaria prophylaxis. Kelley Cao, Pharm.D., provided an overview of the FDA Adverse Event Reporting System (FAERS), a computerized database used for postmarketing monitoring and pharmacovigilance of approved drugs. FDA defines pharmaco- vigilance as the science and activities relating to the detection, assessment, under- standing, and prevention of adverse effects or any other drug-related problems. Owing to the large numbers and broad populations of people who use a drug after it goes on the market, a wider array of adverse events can be detected and over longer periods of time than were observed during clinical trials. The FAERS database stores reports of adverse events for all U.S.-marketed human drugs and therapeutic biologics, and the data include both FDA-approved and off-label uses. Patients, consumers, and health care professionals can voluntarily submit reports of adverse events either to the manufacturer or to the FAERS database via MedWatch. Manufacturers are required to send adverse event reports to FDA, and these are channeled to FAERS. Dr. Cao observed that adverse event reporting trends can be affected by multiple factors, including media reports, the length of time on the market (reports tend to decline over time and rise after approval of new indications), and modifications to reporting requirements. FAERS reporting is especially strong for detecting rare adverse events and events that occur shortly
APPENDIX B 385 after drug exposure. FAERS data do have limitations. The incidence of adverse events cannot be estimated because of the under-reporting of events and the inabil- ity to determine the actual numbers of events and drug exposures. Case reports may lack detail, limiting their usefulness. Distinguishing a drug-related adverse event from a treated or pre-existing disease and detecting events with a long latency period are also challenges. FDA safety evaluators monitor the database for âsafety signalsââinformation that suggests a new potentially causal association, or a new aspect of a known associationâbetween an intervention and an event or set of related events, either adverse or beneficial. Data mining is used to identify higher-than-expected frequencies of productâadverse event combinations, to gen- erate hypotheses, and to evaluate the strength of a potential safety signal. After a safety signal is identified, safety evaluators follow a protocol to search the database and literature for cases, formulate a case definition, and evaluate for a drugâevent association. Detailed case reports, a consistency of effects within a drug class, ruling out alternative etiologies, and biologic plausibility can support causality. Depending on the severity of the safety signal, regulatory actions could include label changes, postmarketing requirements or epidemiologic studies, strategies to restrict use, and market withdrawal. Kathrine Tan, M.D., M.P.H., reviewed the activities that CDC pursues to monitor malaria in the United States, to inform guidelines for malaria prophy- laxis, and to review the strengths and limitations of current research. To develop malaria prophylaxis guidelines that are data driven and country specific, CDC monitors malaria transmission, parasite type, and the presence or emergence of drug resistance, and it performs systematic literature reviews and monitors litera- ture and drug labeling. CDC systemic literature reviews have yielded articles on primaquine (Hill et al., 2006), atovaquone/proguanil (Boggild et al., 2007), doxy- cycline (Tan et al., 2011), and the safety of atovaquone/proguanil in pregnancy (Andrejko et al., 2019). Dr. Tan pointed to two CDC-run observational studies of malaria prophylaxis with safety outcomes. Lobel et al. (1993) compared taking mefloquine and chloroquine for 1 year by Peace Corps volunteers; there were no serious adverse reactions, and the frequency of mild adverse events was the same across the two drugs. Dr. Tan also presented the results of a study (Tan et al., 2017) that examined long-term outcomes in returned Peace Corps volunteers, comparing the prevalence of more than 40 disease outcomes in those who used malaria pro- phylaxis drugs with those who did not. Dr. Tan noted that in this study psychiatric side effects were slightly more prevalent in those who took mefloquine than in all those who did not; after excluding those with a prior psychiatric diagnosis, there was no difference in prevalence. The authors concluded that malaria prophylaxis has few latent effects, but recommended that persons with prior psychiatric dis- ease avoid using mefloquine. Dr. Tan observed that there are several challenges to conducting studies of malaria prophylaxis and then used published articles to illustrate some of the challenges. For example, in studies based on self-report of exposure or outcome, a placebo effect or media attention to a drug may lead to an
386 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS elevated baseline of reported adverse events. Also, malaria-prophylaxis studies do not typically use standardized screening tools or medical examination to verify neuropsychiatric outcomes, and thus it is difficult to compare findings among stud- ies. Dr. Tan noted that accounting for confounding factors can be a challenge; in addition to the normal stresses of travel, for example, service members experience the stressors of deployment or combat. Dr. Tan observed that while using admin- istrative data for public health studies is becoming more common, that approach also has limitations. For example, drug exposure cannot be validated, a drug may have been taken for a different indication, and diagnostic codes may have been used incorrectly. Finally, Dr. Tan observed that there is an evidence gap for studies of the long-term health effects of long-term malaria prophylaxis; of the available data, the Peace Corps and military data are the strongest. Literature on the safety of malaria prophylaxis in pregnant women and in children is also limited. Remington Nevin, M.D., M.P.H., Dr.P.H., chief executive officer and founder of The Quinism Foundation, presented an overview of a syndrome termed âquinism,â which the organization attributes to exposure to the quinoline class of drugs used for malaria prophylaxis. He described quinism as an âidiosyncratic chronic disabling syndrome of encephalopathy due to focal brainstem and limbic neurotoxicity injury caused by quinoline poisoning.â He further hypothesized that the onset of quinism is predicted by prodromal symptoms such as insomnia, night- mares, acute anxiety, and confusion. Although he focused on the drug mefloquine, he stated that evidence of quinoline toxicity dates to the early days of the U.S. mili- taryâs use of the drug class for malaria prophylaxis. He indicated that he believes that the National Academies of Sciences, Engineering, and Medicineâs literature review is âprematureâ because insufficient research has been performed on quino- line toxicity. Dr. Nevin proposed reframing the diagnostic paradigm that deems stressors such as combat trauma as the cause of a spectrum of neuropsychiatric symptoms; he identified mefloquine as the confounding factor in this paradigm and as the potential actual cause of symptoms that have been attributed to combat trauma. He noted that mefloquine use by military service members correlates with exposure to stressors as well as with symptoms the original drug manufacturer stated should prompt drug discontinuation. Dr. Nevin views retrospective studies as an inadequate approach to investigating mefloquine and quinism. He stated that failing to include quinoline toxicity as a possible confounder in diagnoses may have long compromised the assessment of posttraumatic stress disorder (PTSD), traumatic brain injury, and other conditions in veterans. He pointed specifically to exclusion Criterion H of the diagnosis of PTSD in the fifth edition of the Diag- nostic and Statistical Manual of Mental Disorders, which requires that symptoms not be attributable to medication, substance use, or other illness. He stated that in vitro and in vivo evidence of a pathophysiology for quinism exists, citing his publications as sources. He recommended that VA begin screening veterans for exposure to mefloquine and, if exposure has occurred, to assess specific side effects. He said that conflicts of interestâsuch as the role of antimalarial drugs
APPENDIX B 387 in maintaining national security and the potential for legal liability and disability claimsâconstrict VA and DoD and that these have likely have impeded the pursuit and publication of research on quinism. Kyle Petersen, D.O., FACP, FIDSA, provided an overview of Peace Corps malaria-prophylaxis policies. Volunteers serve 27-month tours in 61 countries, operating in rural villages with limited health care. The Peace Corps mandates malaria prophylaxis for volunteers in partially or highly malaria-endemic areas. Approximately 10% of malaria cases reported annually in U.S. citizens by CDC occur in Peace Corps volunteers; most cases originate in Africa and are due to P. falciparum. Two malaria deaths have occurred in the Peace Corps since 2000; both occurred in persons who were nonadherent with prophylaxis. Malaria pro- phylaxis is provided from the first day of service in country for volunteers in malaria-endemic countries; they are also issued a malaria rapid diagnostic test and malaria treatment medication. The Peace Corps does not monitor malarial chemo- prophylactic adherence in volunteers other than by confirming medication receipt and tracking malaria cases. Nonadherence to prophylaxis is investigated and can be grounds for dismissal. Dr. Petersen was unable to find Peace Corps policy on malaria prophylaxis prior to 2004, but he pointed to a 1993 article (Lobel et al.) stating that volunteers âare encouraged, but not obliged, to use mefloquineâ and that alternative agents were available. The 2004 Peace Corps technical guidelines identified mefloquine as the drug of choice in areas where chloroquine-resistant P. falciparum exists. The 2014 technical guidelines state that there is no first-line prophylactic malaria drug and that the Peace Corps medical officers who pro- vide primary care to volunteers should individualize prophylaxis selection to the volunteer. Dr. Petersen explained that volunteers are provided with information describing available prophylactic drugs, and each meets with a medical officer to discuss the drugsâ risks and benefits in order to make a choice. Peace Corps volunteers who use mefloquine are given a detailed description of side effects; in addition, they must sign that they received the information and that they will promptly report side effects to their medical officer. Dr. Petersen noted that it is common for people to underreport their psychiatric histories. A 2019 addendum to the 2014 technical guidelines included a medical officer checklist that requires a 3-week follow-up call to volunteers who take mefloquine. Therefore, in 2019 for volunteers who elect to take mefloquine, by policy they should receive information and have seven interactions with medical personnel before beginning their first dose. The Federal Employeesâ Compensation Act enables Peace Corps volunteers to file for compensation for illness or injury attributed to their service. The statute of limitations for a claim is 3 years from end of service or from the date of onset of symptoms believed to be associated with service. Because compensation is administered by the Department of Labor, Peace Corps medical records do not contain this claim information. The Peace Corps has not sought information on long-term disability claims related to malaria prophylaxis filed by its volunteers. While it receives an aggregated quarterly report of Federal Employeesâ Compensa-
388 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS tion Act claims, the diagnostic-coding methodology and limits to the searchability of the report make identifying claims related to malaria prophylaxis difficult. Dr. Petersen stated that the Peace Corps plans to discuss future research of long-term effects of antimalarials with CDC. Kimberly K. Ottwell, M.D., reviewed the malaria prevention strategies of the Department of State Bureau of Medical Services. Less than 5,000 employees and their family members are currently posted in high-risk malaria areas, and an esti- mated 2,000 travel to such areas for temporary duty assignments. Dr. Ottwell said that Department of State employees are not required to take malaria prophylaxis and that in 2018 there were 21 cases of malaria in the Department of State popula- tion; the majority of these patients acknowledged nonadherence to prophylaxis. Dr. Ottwell described a 0â5 ranking system for malaria risk and recommended prophylaxis at posts. According to a 2013 survey of Department of State employ- ees living in the high-risk posts, adherence with malaria prophylaxis was 78% for staff, 70% for children, and 66% for spouses. Mefloquine is the most commonly used drug, followed by atovaquone/proguanil and doxycycline; 50% of users reported that they never miss a dose, while 45% miss one out of four doses. The reasons given for not taking prophylaxis included fear of long-term side effects, colleaguesâ nonadherence, the belief that malaria is not serious and is curable, and neglecting to âfollow up.â Dr. Ottwell said that Department of State populations that live abroad and take prophylaxis for long periods are not monitored for health issues related to the long-term use of malaria prophylaxis. As multiple health care providers serve this population, it would be difficult to track. Dr. Ottwell stated that Department of State has no records of antimalarial-related disability claims. She said that a review of mental health medical evacuation and local hospitalization data did not turn up any diagnoses directly attributed to antimalarial prophylaxis or any anecdotal reports of related major mental health concerns. A review of general medical evacuation and local hospitalization data yielded the same results. She said that there have been anecdotal reports of minor antimalarial side effects, including mild depression, vivid dreams, sun sensitivity, pill esophagitis, and coli- tis but that these effects were managed effectively by health care providers. She stated that while tafenoquine has fewer psychiatric effects than mefloquine and has the ability to treat all stages of malaria infection, the drugâs contraindications (age <18 years, pregnancy, and glucose-6-phosphate dehydrogenase deficiency) and limited long-term safety data mean it cannot yet be used to completely replace mefloquine in the Department of State population. Thomas Brewer, Ph.D., described to the committee experimental work being done on the neurotoxicity of antimalarial drugs. Although the presentation focused on artemisinin, which is not one of the committeeâs drugs of interest because it is only approved for the treatment of malaria, the types of experiments used and the associated findings gave the committee a better foundation for its review of animal and other experimental studies related to the mechanisms of effect for the anti- malarials used for prophylaxis. The artemisinin family of antimalarial drugs was
APPENDIX B 389 long used in Chinese medicine because it was found that this compound (called Qinhaosu) was often lifesaving in malarial infections and it was reported to reverse malarial coma, show activity against resistant parasites, and not demonstrate tox- icity concerns when used for the treatment of malaria. After it was âdiscoveredâ by the Western nations, it was targeted for research and development by the U.S. Army and the World Health Organization. Two analogs of artemisinin were quickly developed: artemether and arteether. Techniques of modern pharmacology were applied to the development of all analogs, including drug quantification, measures of treatment sensitivity and specificity, and preclinical neuroscience methodologies applied to understand its mechanism of action and any toxicity. In vivo, each of these drugs is metabolized to dihydro-artemisinin. Research on artemisinin estab- lished its efficacy, and initial 14- and 28-day studies in animals and humans showed no evidence of toxicity. However, the artemether and arteether analogs showed an unexpected toxicity in high-dose studies, defined by a sudden death syndrome in a small proportion of the animals (dogs) studied. Additional, focused toxicity studies using dogs, rats, mice, and monkeys using lactate dehydrogenase as the marker of cell death were conducted to explain the deaths; the deaths were traced to central nervous system actions, which were identified as a circumscribed toxicity limited to the brainstem, with lesions in the auditory vestibular nucleus and in the reticular and the visceral autonomic brainstem nuclei. The artemisinin analogs showed an increase in lactate dehydrogenase in situ in some of the dogs, indicating selective neuronal damage in these brainstem neurons. In addition, evidence of cell death in neuronal cell cultures suggested a common neuronal target. Similar neurochemical outcomes were observed between glutamate-induced cell death and the kind of tox- icity observed with artemether and arteether, but no specific glutamatergic target has been found. These tests confirmed that the duration of drug administration and drug dose, as well as species specificity, were factors in the toxicity. The toxicity was specific for neurons and showed a particular structureâactivity relationship between this adverse lactate dehydrogenase outcome and the structure of the drug; specifi- cally, a ketone in the hydroxyl group site or an epoxide in the endoperoxide site both resulted in a loss of this cellular toxicity. It was clear that these small changes in structure resulted in dramatic changes in toxicity and translated into a poor therapeutic index. Mefloquine and halofantrine also showed some of this toxicity when tested in the same assay system, but whether these mechanisms are the same as those for the artemisinins was not determined. Although no clinical (human) evidence of neurotoxicity with artemisinin drugs has been reported, including any evidence of unusual damage to specific brainstem nuclei as seen in experimental animals receiving high doses of artemether and arteether, the animal data suggest relevance to mammalian systems that are potentially pertinent to human use. There- fore, the artemisinin drugs were further examined using audiometry in animals and humans because the brainstem auditory-evoked potential patterns have been clearly worked out. In an area in Vietnam with high malarial infectivity, 242 individuals who had previously received more than 21 courses of antimalarial treatment were
390 LONG-TERM HEALTH EFFECTS OF ANTIMALARIAL DRUGS compared with 108 never-treated controls to determine whether there was clinical or electrophysiologic evidence of brainstem neurotoxicity in humans previously exposed to artemisinin compounds. No evidence of brainstem toxicity or adverse effects of brainstem function was found with episodic use of artemisinins for treat- ment of malaria in humans. In summary, the evidence thus far shows that in laboratory animals the route of administration, oil/water solubility, and concentration-duration of drug level are critical determinants of the animal toxicity and should be given appropriate consideration in the clinical decisions regarding route, choice of drug used, and drug regimens. Based on the experimental evidence, an oral, water-soluble drug with moderately rapid clearance may be the most attractive choice in the absence of significant differences in efficacy. However, the specific reports of this remark- able animal brain pathology in some animal species persists. In one study, rats treated with arteether (not artemisinin or artemether) showed a progressive and severe decline in performance on auditory discrimination. The deficit was char- acterized by decreases in accuracy, increases in response time, and, eventually, response suppression in the rodents. When auditory performance was suppressed, rats also showed gross behavioral signs of toxicity that included tremor, gait dis- turbances, and lethargy with arteether treatment. Subsequent histologic assessment of arteether-treated rats revealed marked damage in the brainstem nuclei, ruber, superior olive, trapezoideus, and inferior vestibular. The damage included chro- matolysis, necrosis, and gliosis. These results demonstrate distinct differences in the ability of artemisinins to produce neurotoxicity in animals. No human toxicity has been described to date. Studies have not yet focused on testing the brainstem neurotoxicity of chronic artemisinin (and analogs and metabolites) administration for prophylactic use in animals or in humans. However, with evidence of this mag- nitude and consequence for mammalian brain toxicity with these drugs, human toxicity testing in all paradigms of administration is indicated. It is also important to consider testing with extended duration of action and in the relevant dose range pertinent to prophylactic usage. REFERENCES Andrejko, K. L., R. C. Mayer, S. Kovacs, E. Slutsker, E. Bartlett, K. R. Tan, and J. R. Gutman. 2019. The safety of atovaquoneâproguanil for the prevention and treatment of malaria in pregnancy: A systematic review. Travel Med Infect Dis 27:20-26. Boggild, A. K., M. E. Parise, L. S. Lewis, and K. C. Kain. 2007. Atovaquoneâproguanil: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis. Am J Trop Med Hyg 76(2):208-223. Brewer, T. G. 2019. Overview of artemisinin neurotoxity: Research and development findings to policy impacts. Presentation to the Committee to Review Long-Term Health Effects of Anti- malarialDrugs. March 27. Cao, K. 2019. Introduction to postmarketing drug safety surveillance: Pharmacovigilance in FDA/ CDER. Presentation to the Committee to Review Long-Term Health Effects of Antimalarial Drugs. January 28.
APPENDIX B 391 Hill, D. R., J. K. Baird, M. E. Parise, L. S. Lewis, E. T. Ryan, and A. J. Magill. 2006. Primaquine: Report from CDC Expert Meeting on Malaria Chemoprophylaxis I. Am J Trop Med Hyg 75(3):402-415. Lobel, H. O., M. Miani, T. Eng, K. W. Bernard, A. W. Hightower, and C. C. Campbell. 1993. Long- term malaria prophylaxis with weekly mefloquine. Lancet 341(8849):848-851. Nevin, R. 2019. Identifying and evaluating sources of evidence of quinism: A novel disease affecting U.S. veterans. Presentation to the Committee to Review Long-Term Health Effects of Antima- larial Drugs. January 28. Ottwell, K. K. 2019. Department of State Bureau of Medical Services malaria prevention strategies. Presentation to the Committee to Review Long-Term Health Effects of Antimalarial Drugs. March 27. Petersen, K. 2019. Malaria in the Peace Corps. Presentation to the Committee to Review Long-Term Health Effects of Antimalarial Drugs. March 27. Tan, K. R. 2019. CDCâs activities in examining adverse events of antimalarials. Presentation to the Committee to Review Long-Term Health Effects of Antimalarial Drugs. January 28. Tan, K. R., A. J. Magill, M. E. Parise, and P. M. Arguin. 2011. Doxycycline for malaria chemopro- phylaxis and treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis. Am J Trop Med Hyg 84(4):517-531. Tan, K. R. S. J. Henderson, J. Williamson, R. W. Ferguson, T. M. Wilkinson, P. Jung, and P. M. Ar- guin. 2017. Long-term health outcomes among returned Peace Corps volunteers after malaria prophylaxis, 1995-2014. Travel Med Infect Dis 17:50-55. Wiesen, A. 2019. Overview of DoD antimalarial use policies. Presentation to the Committee to Re- view Long-Term Health Effects of Antimalarial Drugs. January 28.