Selection of Parasites with Diminished Drug Susceptibility by Amodiaquine-Containing Antimalarial Regimens in Uganda

Background. Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy. Methods. We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized for treatment with AQ-SP, AS-AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro susceptibility to monodesethylamodiaquine (MDAQ) was measured with a histidine-rich protein 2-based enzyme-linked immunosorbent assay, and potential resistance-mediating polymorphisms in pfmdr1 were evaluated. Results. Parasites collected from patients treated with AQ-SP or AS-AQ within the prior 12 weeks were less susceptible to MDAQ (n = 18; mean of the median inhibitory concentration [IC50], 62.9 nmol/L; range, 12.7-158.3 nmol/L) than were parasites from those not treated within 12 weeks (; mean IC50, 37.5 nmol/L; range, 6.3-184.7 nmol/L;) or only from those patients in the treatment arm that did not receive AQ (n = 20; mean IC50, 28.8 nmol/L; range, 6.3-121.8 nmol/L; P = .004). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr1 86Y and 1246Y) increased after AQ therapy, although differences were not statistically significant. Conclusions. Prior therapy selected for diminished response to MDAQ, which suggests that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr1.