Significant Divergence in Sensitivity to Antimalarial Drugs between Neighboring Plasmodium falciparum Populations along the Eastern Border of Myanmar [PublishAheadOfPrint]

Malaria parasites in different endemic areas display different levels of resistance to antimalarial drugs as the result of varied drug use histories. To provide updated knowledge of drug sensitivities during the malaria elimination phase in Southeast Asia, an epicenter of multidrug resistance, we determined in vitro susceptibilities of culture-adapted Plasmodium falciparum isolates from two eastern border regions (Wa and Kachin) of Myanmar to ten drugs. Despite their close proximity, the Kachin parasites displayed higher IC₅₀ values than the Wa parasites to chloroquine, piperaquine, naphthoquine, mefloquine, quinine, pyrimethamine, pyronaridine, lumefantrine and dihydroartemisinin. Genotyping of genes associated with drug resistance also showed significant differences in the prevalence of mutant alleles between the two regions. Particularly, major pfdhfr mutations mediating pyrimethamine resistance and the pfdhps A437G mutation had significantly higher frequencies in the Kachin parasites (P<0.005). Moreover, when pfdhfr and pfdhps were considered together, the wild-type allele was found only in the Wa samples (22.6%). In addition, the pfmdr1 Y184F mutation reached 38.7% in the Kachin parasites as compared to 9.7% in the Wa parasites, whereas N86Y was only detected in the Wa parasites at 22.6%. Furthermore, the F446I mutation and all mutations in the propeller domain of PfK13 gene were significantly more frequent in the Kachin parasites. Collectively, this work demonstrated that even in spatially closely separated regions, parasites could exhibit drastic differences in drug sensitivities and genetic make-ups underlying drug resistance, which may reflect regionally different drug histories and genetic drift of these isolated parasite populations.

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