Association of Genetic Mutations in Plasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates
Imwong M., Pukrittakayamee S., Looareesuwan S., Pasvol G., Poirreiz J., White NJ., Snounou G.
ABSTRACT Mutations in the Plasmodium falciparum gene ( dhfr ) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax , the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfr gene of P. vivax ( pvdhfr ) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand ( n = 100), India ( n = 16), and Madagascar and the Comoros Islands ( n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr ( pvdhfr ), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands ( P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations ( P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax . These mutations presumably arose from selection pressure.