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

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ABSTRACT Background 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 of interest. Methods 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. Results Among 771 samples collected on the day IPTp was initiated, the prevalences of five 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. Conclusions IPTp-SP had poor preventive efficacy and selected for increased drug resistance, questioning the value of this intervention.

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