Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children

Abstract

ABSTRACTChanging treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterizedex vivodrug sensitivity and parasite polymorphisms associated with sensitivity in 459Plasmodium falciparumsamples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations betweenex vivodrug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity withpfcrt76T, as well as increased lumefantrine sensitivity withpfmdr186Y, Y184, and 1246Y. Over time,ex vivosensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences ofpfcrtK76 andpfmdr1N86 and D1246 increased, and the prevalences ofpfdhfrandpfdhpspolymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreasedex vivolumefantrine sensitivity and increased prevalence ofpfcrtK76 andpfmdr1N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence ofpfmdr186Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.