Molecular epidemiology of Plasmodium spp. in North Sumatera, Indonesia, and the efficacy of dihydroartemisinin-piperaquine and artemetherlumefantrine for treatment of clinical malaria

Abstract

Intensive efforts to control malaria in the past two decades have resulted in substantially decreased morbidity and mortality in Indonesia, as in malaria endemic countries elsewhere. At present, 70% of malaria endemic regions in Indonesia have achieved low transmission status. However, stronger measures are needed to accomplish the national target of elimination by 2030. Scaling up on active surveillance using highly sensitive diagnostic tests is crucial to allow identification of low-density, asymptomatic infections, strengthened by effective treatment with artemisinin-based combination therapy (ACT) to reduce cases and halt transmission. Resistance to this drug combination, therefore, poses the greatest threat for both malaria control and the elimination goal. The aims of this research project are: (1) to investigate the distribution of Plasmodium spp. in three rural areas of North Sumatera province, Indonesia, to provide information on malaria risk in the province; (2) to identify drug resistance-associated genetic polymorphisms carried by local Plasmodium falciparum parasites; (3) to evaluate the efficacy of two ACTs, dihydroartemisinin-piperaquine and artemetherlumefantrine for treatment of uncomplicated falciparum malaria. In this study, molecular diagnostics identified four Plasmodium species (P. vivax 33.9%, P. knowlesi 32.0%, P. falciparum 24.8%, and P. malariae 9.3%) among 16.5% of participants (614/3731). P. falciparum populations were dominated by amodiaquine-resistant parasites, indicated by a high proportion of pfcrt-SVMNT and pfmdr1 86Y/184Y haplotypes. This study is the first to our knowledge to test for the presence of mutations in the pfk13-propeller domain in western Indonesia, and evidence of polymorphisms in pfk13 was found in a small number of individuals. A Thr to Ala mutation at codon 474, was observed in six individuals, and the C580Y mutation, previously associated with reduced susceptibility to artemisinin in the Greater Mekong subregion , was seen in a single asymptomatic individual that was not part of the clinical study. Baseline marker carriage was then tested for association with treatment outcomes in the treated cohort study. Dihydroartemisinin-piperaquine and artemetherlumefantrine were both shown to be highly effective for treatment of P. falciparum malaria, irrespective of the pfk13 genotypes. Nevertheless, recurrent parasitaemia of all four species was observed in both groups at day 42, implying lack of sterilising protection from lumefantrine and piperaquine. Further studies are warranted to explore the phenotypic impact of pfk13 mutant alleles in this region and regular monitoring of drug efficacy against all species present is required.