Recurrent Plasmodium falciparum parasitemia and drug resistance mutations during intermittent preventive treatment of malaria in pregnancy in Uganda.

Abstract

Intermittent preventive treatment with monthly sulfadoxine-pyrimethamine (IPTp-SP) is recommended during pregnancy in malaria-endemic countries. However, widespread resistance of Plasmodium falciparum to SP has compromised its efficacy, and the alternative dihydroartemisinin-piperaquine (DP) is under study. Potential selection of drug resistance is important. We sequenced 1377 samples collected from pregnant women enrolled in a trial comparing monthly SP, DP, and DP+SP for IPTp in Busia, Uganda and with asymptomatic parasitemia at the time of IPTp administration. We characterized known markers of drug resistance and assessed the 28-day cumulative risk of recurrent parasitemia, with genotyping to distinguish recrudescence from new infections. Among 771 samples collected on the day IPTp was initiated, the prevalences of 5 resistance mutations in P. falciparum dihydrofolate reductase (PfDHFR) and dihydropteroate synthase (PfDHPS) were nearly 100%, and the PfDHFR I164L and PfDHPS A581G mutations, associated with high-level resistance, had combined prevalence of 26.5%. The cumulative risks of recurrent parasitemia (SP 57.8%, DP 4.1%, DP+SP 3.9%), symptomatic malaria (SP 9.3%, DP 1.1%, DP+SP 0.3%), and recrudescent parasitemia (SP 40.1%, DP 2.0%, DP+SP 0.8%) were all significantly greater in the SP arm, with risks greatest in primigravidae. In the IPT-SP arm, the combined prevalence of the PfDHFR I164L and PfDHPS A581G mutations increased significantly from 24.9% at initiation of IPTp to 35.2% after receipt of IPTp-SP. Infection with mutant parasites was associated with non-significant increases in risks of recrudescence. IPTp-SP had poor antimalarial preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.