Dihydroartemisinin–piperaquine plus mefloquine in a mefloquine resistance context

Triple artemisinin-based combination therapies (TACTs) have been proposed to mitigate the risk of multidrug-resistant Plasmodium falciparum by combining two partner drugs with an artemisinin derivative. This strategy relies on the assumption that antagonistic resistance mechanisms will prevent parasites from simultaneously developing resistance to both partner drugs. Although promising, this hypothesis requires thorough validation. We investigated the in vitro activity of mefloquine-piperaquine (MQ-PPQ), a leading TACT candidate, against culture-adapted Cambodian field isolates. The risk of resistance selection was assessed through long-term in vitro drug pressure experiments followed by whole-genome sequencing and genome-wide association studies (GWAS).