Expanding Kelch13 artemisinin resistance markers are associated with higher malaria incidence in Uganda

Artemisinin partial resistance (ART-R)-associated Plasmodium falciparum Kelch13 mutations are expanding across Africa. However, their population-level consequences remain poorly understood, particularly in settings of moderate-to-high malaria transmission. We investigated associations between Kelch13 and partner drug mutation prevalence and monthly confirmed malaria incidence across 16 Ugandan districts from 2017 to 2022, using integrated molecular, epidemiological, climatic, malaria-control, and antimalarial resistance data and negative binomial regression. Combined prevalence of WHO-validated and candidate Kelch13 mutations increased over the study period. Each 10-percentage-point increase in Kelch13 prevalence was associated with a 13.1% higher incidence after multivariable adjustment (aIRR 1.131, 95% CI 1.090–1.174). Furthermore, each 10% increase in pfcrt K76T was associated with a 24% increase in malaria transmission. As expected, ITN distribution ≥80%, IRS coverage ≥90%, and higher altitude were associated with lower incidence, whereas temperatures of 25–30°C, relative humidity of 60–80%, and higher precipitation were associated with higher incidence. The persistence of the Kelch13 and pfcrt K76T association after adjustment suggests that expanding ART-R-associated parasite populations are independently associated with malaria incidence. The relationship may be bidirectional. These findings support interpreting ART-R within its ecological and intervention context and integrating molecular, epidemiological, and malaria-control surveillance to safeguard antimalarial efficacy.