Origins and spread of novel genetic variants of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates in Indonesia

Abstract

Background: While malaria incidence in Indonesia has decreased threefold in the last decade, more than 200,000 cases were reported in 2016. Different endemicity of Plasmodium falciparum malaria among several islands in Indonesia has been recognized and two unique mutations of P. falciparum dihydropteroate synthase (pfdhps) affecting sulfadoxine-pyrimethamine (SP) resistance were detected from the research of SP efficiency and genotype analysis in South Kalimantan. In this study, geographical distribution and origin of these pfdhps K540T and I588F mutations were analysed. Methods: Malaria parasites DNA from several endemic areas in Indonesia; Sumatera, Java, Kalimantan, Lombok, Sumbawa, Timor, Sulawesi, and Papua islands; in two periods, 2004-2006 and 2009-2012 were subjected for pfdhfr and pfdhps sequence analysis. Results: Different genotype polymorphisms of pfdhfr and pfdhps were observed in the parasites from various regions in Indonesia and relatively more divergent genotypes were determined from Kalimantan isolates in both 2004-2006 and 2009-2012. The parasites containing K540T mutation were identified in 2004-2006 isolates from East Kalimantan, East Java and Sumbawa as an SGTGA haplotype. The other I588F mutation was also determined in 2004-2006 parasites, isolated from Lombok and Sumbawa islands as an SGEAA(588F) haplotype. The parasites with pfdhfr/pfdhps quintuple or sextuple mutation, a genotype marker of SP resistance, were determined mostly in Kalimantan in both 2004-2006 and 2009-2012. Conclusion: Analysis of the prevalence and pfdhfr/pfdhps combined genotypes of K540T or I588F mutations suggested that K540T might be origin in Kalimantan Island and I588F in Sumbawa Island and then these were spread to other areas along with people movement. This research indicates regular monitoring of drug efficacy and parasite genotype analysis is important to keep efficiency and prevent the spread of resistance. It is also essential for the latest anti-malarial drug artemisinin-based combination therapy.