Association between malaria preventive treatment regimens in pregnancy and plasmodium falciparum drug resistance mediating polymorphisms in Busia district, Eastern Uganda

Abstract

Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance and, in recent trials, dihydroartemesinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with dihydroartemesinin-piperaquine or sulfadoxine-pyrimethamine of Plasmodium falciparum genetic polymorphisms that alter sensitivity to these drugs. The prevalence of known genetic polymorphisms associated with altered drug sensitivity was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving sulfadoxine-pyrimethamine, and 80 from those receiving dihydroartemesinin-piperaquine. For women receiving dihydroartemesinin-piperaquine, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp compared to that in samples collected prior to the intervention for PfMDR1 N86Y (19.7% vs. 4.1%, p<0.001),PfMDR1 Y184F (73.7% vs. 53.6%, p=0.002), and PfCRT K76T (45.6% vs. 24.4%, p=0.002).Considering sulfadoxine-pyrimethamine, prior to IPTp the prevalence of all five common antifolate mutations was over 92%, and this prevalence increased following exposure to sulfadoxine-pyrimethamine, although none of these changes were statistically significant. The prevalence of two additional mutations associated with high-level sulfadoxine-pyrimethamine resistance was greater, but not significantly so, in samples collected during IPTp compared to those collected before the intervention (PfDHFR 164L: 9.3% vs.3.9%, p=0.07; PfDHPS 581G: 3.4% vs. 2.9%, p=0.73). Use of IPTp in Uganda selected for parasites with mutations associated with decreased sensitivity to IPTp regimens. Principal component analysis suggested that gravidity, parasite density, gestational age, participant age and treatment regimen contributed to the differences in prevalence of polymorphisms before and after IPTp.