Plasmodium falciparum Isolates Carrying pf k13 Polymorphisms Harbor the SVMNT Allele of pfcrt in Northwestern Indonesia

Abstract

Artemisinin-based combination therapy is the first-line antimalarial regimen in Indonesia. Susceptibility of Plasmodium falciparum to artemisinin is falling in the Greater Mekong sub-Region, but it is not known whether the efficacy of current combinations is also threatened in nearby Sumatera. We evaluated the genetic loci pfcrt, pfmdr1 and pfk13, considered to be under selection by artemisinin combination therapy, among 404 P. falciparum infections identified by PCR detection in a cross-sectional survey of 3,731 residents of three Regencies. The pfcrt haplotype SVMNT (codons 72-76) was the most prevalent and displayed significant linkage disequilibrium with the pfmdr1 haplotype YY (codons 86, 184) (OR 26.7, 95% CI 5.96 - 239.4; Ppfcrt predominates. Among 231 evaluable isolates, only nine (3.9%) showed any evidence of non-synonymous gene variants in the propeller domain of pfk13. The Thr474Ala variant was seen in six individuals, and Cys580Tyr identified with low confidence in only a single isolate from an asymptomatic individual. Among a subset of 117 symptomatic P. falciparum-infected individuals randomized to receive either dihydroartemisinin-piperaquine or artemether-lumefantrine, treatment outcome was not associated with pre-treatment genotype. However, sub-microscopic persistent parasites at day 28 or day 42 of follow-up were significantly more likely to harbor the pfmdr1 haplotype NF (codons 86, 184) than were pre-treatment isolates (P<0.001 for both treatment groups). Current ACT regimens appear to be effective in Sumatera, but evidence of persistent sub-microscopic infection in some patients suggests further detailed studies of drug susceptibility should be undertaken.