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Background  Sulfadoxine-pyrimethamine (SP) is the only anti-malarial drug formulation approved for intermittent preventive treatment in pregnancy (IPTp). However, mutations in the  Plasmodium falciparum dhfr  ( Pfdhfr ) and  dhps  ( Pfdhps ) genes confer resistance to pyrimethamine and sulfadoxine, respectively. Here, the frequencies of SP resistance-associated mutations from 2005 to 2018 were compared in samples from Kenyan children with malaria residing in a holoendemic transmission region.    Methods  Partial sequences of the  Pfdhfr  and  Pfdhps  genes were amplified and sequenced from samples collected in 2005 (n = 81), 2010 (n = 95), 2017 (n = 43), and 2018 (n = 55). The frequency of known mutations conferring resistance to pyrimethamine and sulfadoxine were estimated and compared. Since artemisinin-based combination therapy (ACT) is the current first-line treatment for malaria, the presence of mutations in the propeller domain of  P. falciparum kelch13  gene ( Pfk13 ) linked to ACT-delayed parasite clearance was studied in the 2017/18 samples.    Results  Among other changes, the point mutation of  Pfdhps  S436 H  increased in frequency from undetectable in 2005 to 28% in 2017/18. Triple  Pfdhfr  mutant allele (C IRN I) increased in frequency from 84% in 2005 to 95% in 2017/18, while the frequency of  Pfdhfr  double mutant alleles declined (allele C I C N I from 29% in 2005 to 6% in 2017/18, and CN RN I from 9% in 2005 to undetectable in 2010 and 2017/18). Thus, a multilocus  Pfdhfr / Pfdhps  genotype with six mutations ( HGE AA/C IRN I), including  Pfdhps  S436 H , increased in frequency from 2010 to 2017/18. Although none of the mutations associated with ACT-delayed parasite clearance was observed, the  Pfk13  mutation A578S, the most widespread  Pfk13  SNP found in Africa, was detected in low frequency (2.04%).    Conclusions  There were changes in SP resistance mutant allele frequencies, including an increase in the  Pfdhps  S436 H . Although these patterns seem consistent with directional selection due to drug pressure, there is a lack of information to determine the actual cause of such changes. These results suggest incorporating molecular surveillance of  Pfdhfr / Pfdhps  mutations in the context of SP efficacy studies for intermittent preventive treatment in pregnancy (IPTp).

malaria journal

Changes in the frequencies of Plasmodium falciparum dhps and dhfr drug-resistant mutations in children from Western Kenya from 2005 to 2018: the rise of Pfdhps S436H