Changing treatment practices may be selecting for changes in the drug sensitivity of
malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples 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 between ex vivo drug sensitivity and parasite polymorphisms included decreased
chloroquine and
monodesethylamodiaquine sensitivity and increased
lumefantrine and
piperaquine sensitivity with pfcrt 76T, as well as increased
lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for
lumefantrine and
piperaquine and increased for
chloroquine, the prevalences of pfcrt
K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with
antifolate resistance were unchanged. In
recurrent infections, recent prior treatment with
artemether-lumefantrine was associated with decreased ex vivo
lumefantrine sensitivity and increased prevalence of pfcrt
K76 and pfmdr1 N86, 184F, and D1246. In children assigned
chemoprevention with monthly
dihydroartemisinin-
piperaquine with documented circulating
piperaquine,
breakthrough infections had increased the prevalence of pfmdr1 86Y 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.