Increasing prevalence of a novel triple-mutant dihydropteroate synthase genotype in Plasmodium falciparum in western Kenya.

Lucchi NW1, Okoth SA2, Komino F3, Onyona P3, Goldman IF4, Ljolje D2, Shi YP4, Barnwell JW4, Udhayakumar V4, Kariuki S3.

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Abstract

The molecular basis of sulfadoxine-pyrimethamine (SP) resistance lies in a combination of single-nucleotide polymorphisms (SNPs) in two genes coding for Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps), targeted by pyrimethamine and sulfadoxine, respectively. The continued use of SP for intermittent preventive treatment in pregnant women in many African countries, despite SP's discontinuation as a first-line antimalarial treatment option, due to high levels of drug resistance, may further increase the prevalence of SP-resistant parasites and/or lead to selection of new mutations. An antimalarial drug resistance surveillance study was conducted in western Kenya between 2010 and 2013. A total of 203 clinical samples from children with uncomplicated malaria were genotyped for SNPs associated with SP resistance. The prevalence of the triple mutant Pfdhfr C50 I51R59N: 108I164 and the double mutant Pfdhps S436 G437E540: A581A613 genotypes was high. Two triple mutant Pfdhps genotypes were found: S436 G437E540G: 581A613 and H: 436 G437E540: A581A613, with the latter, thus far, uniquely found in western Kenya. The prevalence of the S436 G: 437 E: 540 G: 581A613 genotype was low. However, a steady increase in the triple Pfdhps H:436 G: 437 E: 540A581A613 genotype was observed since its appearance in early 2000. These isolates shared substantial microsatellite haplotypes with the most common double mutant allele suggesting that this triple mutant allele may have evolved locally. Overall, these findings show that the triple H: 436 G437E540: A581A613 mutant may be increasing in this population and could compromise the efficacy of SP for IPTp if it increases the resistant threshold further.