Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Abstract

ABSTRACTSeasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP).Plasmodium falciparumsingle nucleotide polymorphisms (SNPs) inP. falciparumcrt(pfcrt),pfmdr1,pfdhfr, andpfdhpsare associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs inP. falciparumisolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment inP. falciparumPCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen forpfcrt76T (68.5% to 83.0%,P= 0.04),pfdhfr59R (54.8% to 83.3%,P= 0.0002), andpfdhfr108N (55.0% to 87.2%,P= 0.0001), with trends toward selection ofpfmdr186Y,pfdhfr51I, andpfdhps437G. After SMC with DP, only borderline selection of wild-typepfmdr1D1246 (mutant; 7.7% to 0%,P= 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT00941785.)