Unraveling antimalarial resistance in Plasmodium vivax in Southeast Asia: from molecular markers to phenotypic and clinical evidence—A scoping review

Background Plasmodium vivax antimalarial resistance remains an important but understudied challenge in Southeast Asia. Although several molecular polymorphisms have been investigated as potential markers of antimalarial resistance, the available evidence remains scarce and fragmented, particularly regarding their associations with phenotypic drug susceptibility and clinical treatment outcomes. To date, molecular evidence of P. vivax antimalarial resistance has not been comprehensively synthesized across Southeast Asia. This scoping review therefore aimed to characterize the distribution of resistance-associated molecular polymorphisms and summarize available phenotypic and clinical evidence across the region. Methods PubMed, Google Scholar, and EBSCOHost were searched for studies published during the 10 years preceding September 2024. Studies reporting P. vivax resistance-associated point mutations in Southeast Asia were included. Data on study characteristics, geographic and temporal distribution, molecular polymorphisms, and available phenotypic or clinical evidence were extracted and synthesized descriptively in accordance with PRISMA-ScR. Geographic distributions of reported polymorphisms were visualized using Datawrapper, with sampling locations presented at the highest spatial resolution available from each study. Results Of 1,560 records identified, 25 studies met the inclusion criteria. Studies were concentrated in Cambodia, Lao PDR, Malaysia, Myanmar, Thailand, and the Philippines, with limited or no eligible molecular surveillance data from several other Southeast Asian countries. For chloroquine, pvcrt-o K10 insertion and pvmdr1 polymorphisms, particularly T958M, Y976F, and F1076L, were frequently reported but showed inconsistent associations with drug susceptibility and treatment outcomes. In contrast, antifolate resistance-associated polymorphisms were widespread, with the pvdhfr F57I/L+S58R+T61M+S117N/T quadruple genotype and pvdhps A383G+A553G double-mutant haplotype predominating across several malaria-endemic areas of Cambodia, Lao PDR, Malaysia, Myanmar, and Thailand. Accumulation of these multilocus genotypes was associated with increased antifolate resistance in functional studies and, in some populations, slower parasite clearance and higher SP treatment failure. pvK12 polymorphisms were uncommon, and no validated molecular marker of artemisinin resistance in P. vivax was identified. Evidence for ACT partner-drug resistance remained limited and heterogeneous. Conclusion pvdhfr/pvdhps mutations showed the strongest evidence of reduced antifolate susceptibility, whereas CQ and ACT partner-drug markers showed inconsistent associations with phenotypic and clinical resistance. No validated molecular marker of artemisinin resistance was identified. Integrated molecular, phenotypic, and therapeutic surveillance is needed to clarify resistance and its clinical relevance. Protocol Registration Not applicable. Clinical trial registry Not applicable.