Similar trends of pyrimethamine resistance-associated mutations in Plasmodium vivax and P. falciparum

Abstract

The antifolate drugs sulfadoxine and pyrimethamine are commonly used to treat Plasmodium falciparum malaria. However, they can also affect the Plasmodium vivax parasite if it coexists with P. falciparum, as both species have common drug targets. Resistance to the antifolate drugs arises due to point mutations in the target enzymes of the respective parasite. To assess the cross-species impact of antifolate drug treatment, we describe here the dihydrofolate reductase (DHFR) mutations among field isolates of P. vivax and P. falciparum. The overall DHFR mutation rate for P. vivax was lower than that for P. falciparum. However, both species of Plasmodium followed similar trends of DHFR mutations. Similar to P. falciparum, the DHFR mutation rate of P. vivax also varied from region to region. It was lower in P. vivax-dominant regions but higher in the P. falciparum-dominated areas and highest where antifolates are used as the first line of antimalarial treatment. In conclusion, the antifolate treatment of falciparum malaria is proportionately affecting the DHFR mutations of P. vivax, suggesting that the drug should be used with caution to minimize the development of cross-species resistance in the field.

FIG. 1.

Map of India showing study sites.

FIG. 2.

Mutation rates in the P. vivax DHFR enzyme. (A) Mutation rate in individual PVDHFR codons. (B) Prevalence rate of the total number of mutations in PVDHFR. (C) Prevalence rates of the PVDHFR genotypes. The amino acid sequence (mutated amino acids are in boldface type) shown in the lower panel corresponds to PVDHFR codons 57, 58, 61, 93, and 117.

FIG. 3.

Mutation patterns of P. vivax and P. falciparum DHFR enzyme sequences among total Indian isolates. The chi-square test was applied to assess the DHFR mutation trends across the species.

FIG. 4.

Mutation patterns of P. vivax and P. falciparum DHFR enzyme sequences among the regional isolates. The PFDHFR data for UP, Assam, and A&N are derived from our previous studies (2). The chi-square test was applied to assess DHFR mutation rates among the groups.