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Letter to the Editor: G6PD Deficiency in the Tafenoquine Era

CDC/James Gathany This image shows a female Anopheles funestus mosquito that had landed on a human skin surface and was in the process of obtaining its blood meal. A. funestus is a known vector for the parasitic disease malaria. CDC/James Gathany
This image shows a female Anopheles funestus mosquito that had landed on a human skin surface and was in the process of obtaining its blood meal. A. funestus is a known vector for the parasitic disease malaria.

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Medical Surveillance Monthly Report

In the December 2019 issue of the MSMR, Lee and Poitras reported a 2.2% prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency among active duty U.S. service members between 2004 and 2018.1 Their study utilized Health Level 7-formatted chemistry data archived in the Composite Health Care System (CHCS), but it did not stratify by quantitative or qualitative testing.

When tafenoquine was approved by the U.S. Food and Drug Administration in 2018 for chemoprophylaxis and radical cure of Plasmodium vivax,2 the distinction between quantitative and qualitative testing became clinically significant. Formerly, primaquine was the only approved medication to treat hypnozoites, the dormant form of the parasite in the liver stage of malaria. Its use required a “normal” G6PD activity level, the threshold of which on qualitative tests was usually established at 30%–40%. Tafenoquine, with its longer half-life of 14 days (compared to 6 hours for primaquine), provides a far simpler dosing regimen for malaria chemoprophylaxis and radical cure, but it may precipitate hemolytic anemia at higher levels of G6PD activity. Consequently, the U.S. Centers for Disease Control and Prevention recommends a quantitative G6PD assessment before tafenoquine prescription2 to ensure activity exceeding 70%.3,4

An X-linked genetic disorder, G6PD deficiency in males is usually severe (enzyme activity < 30%), meaning that a “deficient” result on qualitative testing contraindicates the use of both primaquine and tafenoquine. The same is true for females who are homozygous or double heterozygous for mutant alleles—both of which are rare. However, single heterozygous females usually have milder deficiency (enzyme activity 30%–80%),3 meaning they would have a “normal” result on qualitative testing and could safely take primaquine but potentially not tafenoquine.

Univeral G6PD deficiency screening is required across the U.S. Armed Forces, but current policy does not mandate quantitative testing.5 Since tafenoquine may improve medication adherence and thus become a preferable antimalarial option, it is important to understand how many service members have only been qualitatively tested. In the U.S. Air Force, 167,945 active duty members had at least 1 G6PD test performed and recorded in the CHCS between 1 January 2015 and 31 December 2019. Of these, only 4,325 (2.6%), including 1,602 females, had a normal qualitative test with no quantitative result. This low percentage should continue to decrease since quantitative testing is standard protocol for all new recruits at U.S. Air Force basic military training as well as new officer accessions at the U.S. Air Force Academy and Officer Training School (email communication, Maj Dianne Frankel and Lt Col Kevin Baldovich, December 2019 and January 2020, respectively).

While the article by Lee and Poitras provides valuable information, G6PD deficiency surveillance in the tafenoquine era should incorporate quantitative values. These values should also be documented in service members’ deployment readiness records. For example, the Aeromedical Services Information Management System, the U.S. Air Force’s readiness platform, defines G6PD status as either “normal” or “deficient”—essentially as a qualitative test, even if a quantitative enzyme activity level is available in the electronic health record. This may lead to improper prescription of tafenoquine to airmen, particularly females, who are coded as having “normal” G6PD activity levels but whose levels are in fact intermediate.

Author affiliations: Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD (Maj Sayers; Lt Col Webber); Public Health and Preventive Medicine Department, U.S. Air Force School of Aerospace Medicine, Wright-Patterson Air Force Base, OH (Lt Col Webber).

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Air Force, the Department of Defense, or the U.S. Government.

REFERENCES

1. Lee J, Poitras BT. Prevalence of glucose-6-phosphate dehydrogenase deficiency, U.S. Armed Forces, May 2004–September 2018. MSMR. 2019;26(12):14–17.

2. Haston JC, Hwang J, Tan KR. Guidance for using tafenoquine for prevention and antirelapse therapy for malaria—United States, 2019. MMWR Morb Mortal Wkly Rep. 2019;68(46):1062–1068.

3. Commons RJ, McCarthy JS, Price RN. Tafenoquine for the radical cure and prevention of malaria: the importance of testing for G6PD deficiency. Med J Aust. 2020;212(4):152–153.e1.

4. Price RN, Commons RJ, Battle KE, Thriemer K, Mendis K. Plasmodium vivax in the era of the shrinking P. falciparum map. Trends Parasitol. 2020;36(6):560–570.

5. Defense Health Agency, Department of Defense. Procedural Instruction 6025.14. Active Duty Service Members (ADSM) Erythrocyte Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Sickle Cell Trait (SCT) Screening. 6 December 2018.

In reply:

We appreciate the response by Drs. Sayers and Webber to our article published in the December 2019 issue of the MSMR on the prevalence of G6PD deficiency among active duty service members. We are in agreement that quantitative as well as qualitative testing for the genetic condition is imperative to prevent the potentially harmful side effects from the use of the 8-aminoquinoline (8-AQ) class of antimalarial drugs (tafenoquine and primaquine) for malaria chemoprophylaxis and radical cure. We applaud the Air Force for the implementation of quantitative screening of G6PD deficiency among new recruits.

Our article highlights the need for leadership awareness of G6PD deficiency diagnoses to reduce the possibility of adverse events from the use of the 8-AQ class of antimalarial drugs. The inclusion of quantitative G6PD testing is an important tool to further identify at-risk service members.

Respectfully,

MAJ Jangwoo Lee, PhD; Beth Poitras, MPH

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