Evolution and expansion of multidrug resistant malaria in Southeast Asia: a genomic epidemiology study

Abstract

Summary Background A multidrug resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia c.2008-2013, causing high treatment failure rates to the frontline combination therapy dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years. Methods We analysed whole genome sequencing data from 1,673 P. falciparum clinical samples collected in 2008-2018 from northeast Thailand, Laos, Cambodia and Vietnam. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population. Findings KEL1/PLA1 spread rapidly from 2015 into all of the surveyed countries and now exceeds 80% of the P. falciparum population in several regions. These parasites maintained a high level of genetic relatedness reflecting their common origin. However, several genetic subgroups have recently emerged within this co-lineage with diverse geographical distributions. Some of these emerging KEL1/PLA1 subgroups carry recent mutations in the chloroquine resistance transporter (crt) gene, which arise on a specific genetic background comprising multiple genomic regions. Interpretation After emerging and circulating for several years within Cambodia, the P. falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating elimination efforts. Funding Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, UK Department for International Development. Research in context Evidence before this study This study updates our previous work describing the emergence and spread of a multidrug resistant P. falciparum co-lineage (KEL1/PLA1) within Cambodia up to 2013. Since then, a regional genetic surveillance project, GenRe-Mekong, has reported that markers of dihydroartemisinin-piperaquine (DHA-PPQ) resistance have increased in frequency in neighbouring countries. A PubMed search (terms: “artemisinin”, “piperaquine”, “resistance”, “southeast asia”) for articles listed since our previous study (from 30/10/2017 to 05/01/2019) yielded 28 results, including reports of a recent sharp decline in DHA-PPQ clinical efficacy in Vietnam; the spread of genetic markers of DHA-PPQ resistance into neighbouring countries by Imwong and colleagues; and multiple reports associating mutations in the crt gene with piperaquine resistance, including newly emerging crt variants in Southeast Asia. Added value of this study We analysed P. falciparum whole genomes collected up to early 2018 from Eastern Southeast Asia (Cambodia and surrounding regions), describing the fine-scale epidemiology of multiple KEL1/PLA1 genetic subgroups that have spread out from Cambodia since 2015 and taken ...

Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China

“…However, long-term use of anti-malarial drugs particularly PPQ induced ADR [14]. Previous studies indicated that several mutations of pfcrt (93S, 97Y, 101F, 145I, 343L, 353 V, and 356 T) were related to reducing parasite sensitivity to PPQ [13,14,[36][37][38][39]. In this study, no mutations were detected at loci 93, 97, 101, 145, 343, 350, and 353.…”

“…Thus, the effect of PPQ cannot be ignored. However, long-term use of anti-malarial drugs particularly PPQ induced ADR [14]. Previous studies indicated that several mutations of pfcrt (93S, 97Y, 101F, 145I, 343L, 353 V, and 356 T) were related to reducing parasite sensitivity to PPQ [13,14,[36][37][38][39].…”

“…Unfortunately, ART resistance of P. falciparum isolates was reported in SEA [8][9][10]. Recently, dihydroartemisinin-piperaquine (DHA-PPQ) resistance has been detected in western Cambodia [11][12][13][14]. Although ACT remains effective in Africa and SEA, prolonged use of ART would lead to anti-malarial drug resistance.…”

A conserved metabolic signature associated with response to fast-acting antimalarial agents

“…At present, ART treatment failure has reached endemic status in SEA (1, 4, 5) and has seemingly emerged in Africa (6). More worryingly, parasites carrying both ART and partner drug piperaquine resistance mutations, have been reported in SEA threatening the current mainstay of ACTs (7,8).…”

Novel Endochin-Like Quinolones Exhibit Potent In Vitro Activity against Plasmodium knowlesi but Do Not Synergize with Proguanil

“…By using drugs in combination with different targets the intention is to delay the emergence of resistance to the individual components. However, recent evidence has emerged in the Greater Mekong subregion of resistance to both artemisinin (3,4) and current partner drugs (5,6). There is, therefore, an urgent need to develop new drugs and novel combination regimens before reduction in ACT efficacy occurs more widely.…”