Artemisinin partial resistance at a crossroads: evidence for continental variation in Plasmodium falciparumclearance phenotypes.

Abstract

Artemisinin-based combination therapies (ACTs) remain the cornerstone of global malaria treatment, yet their long-term efficacy is threatened by the emergence of artemisinin partial resistance (ART-R). Current surveillance definitions rely on Plasmodium falciparum parasite clearance half-life thresholds derived from southeast Asia, where mutant kelch13 (k13)-mediated resistance produces prolonged parasite clearance half-life values after ACT treatment. Whether these thresholds appropriately capture resistance phenotypes in Africa remains uncertain. We systematically reviewed 96 studies across southeast Asia and Africa, with 35 reporting genotype-linked parasite clearance half-life or ring-stage survival (RSA) data or both, to assess continental differences in clearance dynamics. In southeast Asia, parasites harbouring canonical k13 mutations consistently displayed prolonged parasite clearance half-life values compared with ART-sensitive infections, with a strong concordance between parasite clearance half-life and RSA survival. In east Africa and the Horn of Africa, however, independently emergent k13 mutations generally exhibited faster clearance kinetics despite elevated RSA survival rates. This discrepancy might reflect continental differences in host and epidemiological contexts and risks under-detecting emerging ART-R in Africa. Parasite clearance half-life thresholds, if unmodified, could continue to obscure early signals of spread and delay policy responses in African settings. Region-specific surveillance criteria integrating parasite clearance half-life, RSA, molecular markers, and partner-drug susceptibility are urgently needed to prevent resistant parasites from achieving genetic fixation, as earlier occurred in the Greater Mekong Subregion in Asia.