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
Pfdhfrand Pfdhpsgenes 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 kelch13gene ( Pfk13) linked to ACT-delayed parasite clearance was studied in the 2017/18 samples. Results
Among other changes, the point mutation of
PfdhpsS436 Hincreased in frequency from undetectable in 2005 to 28% in 2017/18. Triple Pfdhfrmutant allele (C IRNI) increased in frequency from 84% in 2005 to 95% in 2017/18, while the frequency of Pfdhfrdouble mutant alleles declined (allele C IC NI from 29% in 2005 to 6% in 2017/18, and CN RNI from 9% in 2005 to undetectable in 2010 and 2017/18). Thus, a multilocus Pfdhfr/ Pfdhpsgenotype with six mutations ( HGEAA/C IRNI), including PfdhpsS436 H, increased in frequency from 2010 to 2017/18. Although none of the mutations associated with ACT-delayed parasite clearance was observed, the Pfk13mutation A578S, the most widespread Pfk13SNP 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
PfdhpsS436 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/ Pfdhpsmutations in the context of SP efficacy studies for intermittent preventive treatment in pregnancy (IPTp).