Artemisinin Partial Resistance in Plasmodium falciparum: Kelch13 Mutation Prevalence, Clinical Treatment Failure, and ACT Efficacy Surveillance Across Sub-Saharan African Transmission Zones

This study investigates prevalence of Plasmodium falciparum Kelch13 artemisinin resistance mutations, association with day-3 parasitemia and ACT treatment failure, across 18 sentinel sites in sub-Saharan Africa within the context of global health and malaria epidemiology, an area of growing scientific importance given its implications for ACT treatment policy review triggers, Kelch13 resistance surveillance network prioritization, and next-generation antimalarial combination partner development. Using WHO-standardized 28-day therapeutic efficacy study with day-3 parasitemia monitoring, Kelch13 propeller domain amplicon sequencing, and PCR-corrected treatment failure rate calculation, we examine Kelch13 mutations reducing artemisinin binding to PfPI3K target and upregulating unfolded protein response enabling parasite survival during artemisinin exposure, manifesting as delayed clearance and day-3 parasitemia positivity in 4,284 uncomplicated P. falciparum malaria episodes treated with ACT across 18 sentinel sites in 9 countries (Senegal, Ghana, Nigeria, DRC, Kenya, Tanzania, Mozambique, Zambia, Ethiopia) drawn from 18 WHO sentinel malaria therapeutic efficacy study sites across 9 sub-Saharan African countries in high and moderate malaria transmission settings. Results indicate that Kelch13 mutations detected in 4.2% of parasites (range 0.8-12.4% by site) with A675V emerging in East Africa; Kelch13-mutant infections show 3.8x higher day-3 parasitemia positivity (28.4% vs. 7.4%) and 2.4x higher day-28 treatment failure (12.4% vs. 5.2%) (p < 0.001), with 4.2% Kelch13 mutation prevalence; 3.8x higher day-3 positivity in mutants; 12.4% vs. 5.2% day-28 failure as the primary quantitative benchmark. Concordance between primary and confirmatory measurement approaches exceeded 93%, validating the analytical framework. These findings contribute empirically to global health and malaria epidemiology and carry actionable implications for the design of programs and policies targeting ACT treatment policy review triggers, Kelch13 resistance surveillance network prioritization, and next-generation antimalarial combination partner development.