Force Protection Risks in AFRICOM, INDOPACOM and SOUTHCOM Due to Rapid Diagnostic Test Failures for Falciparum Malaria, 2016-2022.

Malaria, caused by various species of the Plasmodium parasite, remains a significant health threat in most U.S. military regions-AFRICOM, CENT-COM, INDOPACOM, and SOUTHCOM-and although less prevalent, also poses periodic risks to military personnel in NORTHCOM through imported cases. Early diagnosis is crucial for effective malaria chemotherapy, and rapid diagnostic tests (RDTs) have proven valuable in resource-poor settings and operational environments. The BinaxNow Malaria RDT is currently the sole U.S. Food and Drug Administration (FDA)-approved test for use on U.S. military personnel. This simple RDT targets Plasmodium falciparum, the deadliest malaria species, by detecting the histidine-rich protein 2 (HRP2), as well as pan-Plasmodium species by detecting aldolase. The emergence of mutant P. falciparum parasites lacking pfhrp2/pfhrp3 genes and thus not expressing HRP2/HRP3 proteins poses a significant challenge in many malaria-endemic areas. This genetic variation has led to false-negative results in all HRP2-detecting RDTs including BinaxNow, undermining its utility. Current U.S. military force health protection (FHP) measures for preventing malaria, including chemoprophylaxis, permethrin-treated uniforms, and DEET application to exposed skin, are effective, but breakthrough infections still occur. The use of portable and user-friendly malaria diagnostics is necessary in remote locations that lack microscopy or nucleic acid-based diagnostic capabilities. The alarmingly high prevalence of mutant pfhrp2/3-deleted parasites poses a threat to malaria diagnosis in all Combatant Commands where point-of-care testing is vital. This review emphasizes the importance of ongoing monitoring to determine the frequency and distribution of mutant parasites. Urgent attention is needed to develop alternative RDTs that can effectively detect malaria infections caused by these mutant strains. These findings confirm that mutant pfhrp2/3-deleted parasites are highly prevalent in SOUTHCOM and parts of AFRICOM, rendering HRP2-based RDTs such as BinaxNow an unsuitable diagnostic tool for malaria in many of the SOUTHCOM and AFRICOM countries surveyed: Peru (14.3-62% between 2011-2018), Eritrea (62% in 2016 and 9.4% in 2020), Nigeria (13.3%), Sudan (11.2%), South Sudan (17.7%), and Uganda (3.3%). In INDOPACOM countries surveyed, no prevalence greater than 5% pfhrp2 deletions were observed. It is critical to continue surveillance on the frequency and distribution of these mutant parasites and develop alternative RDTs. WHO recommends that countries switch to non-HRP2-based RDTs when prevalence of pfhrp2/3 deletions that cause false-negative RDT results exceed 5%. Current prevalence of mutant pfhrp2/3-deleted parasites causing false-negative RDT results has exceeded this threshold in most parts of SOUTHCOM and several areas of AFRICOM. If alternative diagnostic tests are not utilized in areas affected, life-saving malaria treatment for U.S. military personnel could be delayed. Continuous mapping of the frequency and distribution of mutant parasites directly informs FHP protection policy decisions for alternative diagnostic tool utilization.