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Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis (2020)

Chapter: Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria

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Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×

Reference Design Population Study Groups‡ Body Systems Examined
Ackert et al., 2019* Randomized controlled trial Healthy male and female adult volunteers (ages 18–45) in the United States Tafenoquine (n = 306) Placebo (n = 161) Eye
Andersen et al., 1998 Randomized controlled trial Semi-immune male and female adult volunteers (ages 18–55) in Kenya Doxycycline (n = 55)
Azithromycin (n = 117)

250 mg daily (n = 59)
1,000 mg weekly (n = 58)

Placebo (n = 60)

Other
DeSouza, 1983 Clinical trial Healthy male adult volunteers (age range not reported) in Brazil Mefloquine
1,000 mg (n = 10)
Sulfadoxine (1,000 mg) and pyrimethamine (500 mg) (n = 10)
Gastrointestinal Cardiovascular
Eick-Cost et al., 2017* Retrospective observational study Male and female active-duty U.S. service members (ages ≥17) Deployed (n = 275,097)

Mefloquine (n = 25,691)
A/P (n = 2,620)
Doxycycline (n = 246,786)

Nondeployed (n = 92,743)

Mefloquine (n = 10,847)
A/P (n = 10,261)
Doxycycline (n = 71,635)

Neurologic Psychiatric
Green et al., 2014* Randomized controlled trial Healthy male and female adult volunteers (ages 18–65) in the United States Tafenoquine (n = 156)

Supratherapeutic dose of 1,200 mg (n = 52)
Therapeutic dose of 300 mg (n = 52)
Therapeutic dose of 600 mg (n = 52)

Moxifloxacin (400 mg) (n = 52)

Placebo (n = 52)

Cardiovascular
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Laothavorn et al., 1992 Prospective observational study Male patients with malaria and healthy male adult volunteers (ages 26–46) in Thailand Mefloquine (750 mg) (n = 18)
Patients with malaria (n = 102)
Cardiovascular
Leary et al., 2009* Randomized controlled trial Healthy male and female adult volunteers (ages 18–55) recruited from the United States and the United Kingdom Tafenoquine (n = 81)
Placebo (n = 39)
Eye Other
Lee et al., 2013 Cross-sectional survey Current and former male and female adult members of the Australian Federal Police Association (ages 35–45) Doxycycline (n = 189)
Deployed (n = 171)
Nondeployed (n = 18)
Gastrointestinal
Lege-Oguntoye et al., 1990 Randomized controlled trial Semi-immune male and female adult volunteers (ages 25–34) in Nigeria Chloroquine (n = 20)
Ascorbic acid (200 mg) (n = 10)
Other
Meier et al., 2004* Retrospective observational study Male and female adult travelers (ages 17–79) in the United Kingdom Mefloquine (n = 16,491)
Doxycycline (n = 4,574)
Proguanil and/or chloroquine (n = 16,129)
Neurologic
Psychiatric
Eye
Miller et al., 2013 Randomized controlled trial Healthy male and female adult volunteers (ages 18–55) in the United States Chloroquine (600 mg) and placebo for tafenoquine (n = 20)
Placebo for chloroquine and tafenoquine (450 mg) (n = 20)
Chloroquine (600 mg) and tafenoquine (450 mg) (n = 20)
Eye Other
Nasveld et al., 2010* Randomized controlled trial Healthy male and female Australian soldiers (ages 18–55) Mefloquine followed by primaquine (30 mg) (n = 162)
Tafenoquine followed by placebo (n = 492)
Psychiatric
Gastrointestinal
Eye
Cardiovascular
Other
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Reference Design Population Study Groups‡ Body Systems Examined
Rueangweerayut et al., 2017 Prospective observational study Healthy female adult volunteers (ages 18–45) in Thailand Tafenoquine (n = 51)

100 mg (n = 12)
200 mg (n = 19)
300 mg (n = 9)

Primaquine (n = 11)

Other
Schlagenhauf et al., 1996 Prospective observational study Healthy male and female adult Swiss travelers (ages 18–65) Mefloquine (n = 394) Neurologic
Psychiatric
Schneider et al., 2013* Retrospective observational study Male and female travelers (ages ≥1) from the United Kingdom Mefloquine (n = 10,169)
A/P (n = 28,502) Chloroquine and/or proguanil (n = 2,904)
Unexposed (n = 41,573)
Neurologic
Psychiatric
Schneider et al., 2014* Retrospective observational study Male and female travelers (ages ≥1) from the United Kingdom Mefloquine (n = 10,169)
A/P (n = 28,502)
Chloroquine and/or proguanil (n = 2,904)
Unexposed (n = 41,573)
Eye
Schneiderman et al., 2018* Cross-sectional survey Post 9/11 male and female U.S. military veterans (ages ≥24) Deployed (n = 12,456)

No antimalarial use (n = 5,806)
Mefloquine (n = 307)
Doxycycline (n = 1,315)
Primaquine (n = 98)
Chloroquine (n = 274)
Mefloquine + other antimalarial (n = 425)
Other antimalarial (n = 525)
Type not specified (n = 3,706)

Nondeployed (n = 7,031)

No antimalarial use (n = 5,294)
Mefloquine (n = 39)

Psychiatric
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×

Chloroquine (n = 110)
Doxycycline (n = 141)
Primaquine (n = 35)
Mefloquine + other antimalarial (n = 52)
Other antimalarial (n = 114)
Type not specified (n = 1,246)

Schwartz and Regev-Yochay, 1999 Prospective observational study Non-immune adult Israeli travelers (ages 22–65) (sex distribution not reported) Mefloquine (n = 25)
Doxycycline (n = 19)
Primaquine (n = 106)

15 mg daily for individuals with a body weight of <70 kg
30 mg daily for individuals with a body weight of >70 kg

Hydroxychloroquine (200 mg) (n = 8)

Unknown
Tan et al., 2017 Cross-sectional survey Male and female returned U.S. Peace Corps volunteers (age range not reported) Mefloquine (n = 2,981)
A/P (n = 183)
Doxycycline (n = 831)
Chloroquine (n = 674)
Other prophylactic medication (n = 386)
No antimalarial use (n = 3,876)
Neurologic
Psychiatric
Gastrointestinal
Eye
Cardiovascular
Other
Walsh et al., 2004 Randomized controlled trial Thai soldiers (ages 18–55) (sex distribution not reported) Tafenoquine (n = 104)

400 mg for 3 consecutive days, followed by 400 mg once monthly

Placebo (n = 101)

Other
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Reference Design Population Study Groups‡ Body Systems Examined
Wells et al., 2006* Retrospective observational study Male and female U.S. active-duty service members (ages ≥17) Mefloquine (n = 8,858)

U.S. active-duty service members prescribed at least seven tablets of mefloquine and deployed to operational theater or combat zone

No antimalarial drug use

U.S. active-duty service members assigned to Europe or Japan (n = 156,203)
U.S. active-duty service members deployed for at least one month (n = 232,381)

Neurologic
Psychiatric
Gastrointestinal
Cardiovascular
Other

* Denotes epidemiologic studies considered to provide the most contributory evidence to address the committee’s charge.

Although study investigators did not make a traditional comparison between exposed and unexposed groups, they did compare individuals who experienced adverse events with those who did not experience adverse events in the data analysis; thus, the committee included this study in their evaluation of the available scientific evidence.

‡ For the six antimalarial drugs of interest the dosing regimen used follows standard FDA guidance unless otherwise noted.

Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Page 393
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Page 394
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Page 395
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Page 396
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Page 397
Suggested Citation:"Appendix C: Epidemiologic Studies That Met the Committee's Inclusion Criteria." 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.
×
Page 398
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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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