Multidrug-resistant Plasmodium falciparum malaria in the Greater Mekong subregion
Authors: Didier Ménard, Jérôme Clain, Frédéric Ariey
Journal: The Lancet Infectious Diseases (2018)

Over the past decade, the burden of malaria has been greatly reduced in the Greater Mekong subregion, although artemisinin-resistant parasites have emerged,1Ariey F Witkowski B Amaratunga C et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature. 2014; 505: 50-55Crossref PubMed Scopus (1283) Google Scholar, 2WHOStatus report on artemisinin and ACT resistance.http://www.who.int/malaria/publications/atoz/artemisinin-resistance-april2017/enDate: April 2017Google Scholar and high rates of treatment failure on dihydroartemisinin–piperaquine have been reported in Cambodia since 2012.3Amato R Lim P Miotto O et al.Genetic markers associated with dihydroartemisinin–piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype–phenotype association study.Lancet Infect Dis. 2017; 17: 164-173Summary Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 4Duru V Khim N Leang R et al.Plasmodium falciparum dihydroartemisinin–piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations.BMC Med. 2015; 13: 305Crossref PubMed Scopus (111) Google Scholar, 5Leang R Taylor WR Bouth DM et al.Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western Cambodia: dihydroartemisinin–piperaquine open-label multicenter clinical assessment.Antimicrob Agents Chemother. 2015; 59: 4719-4726Crossref PubMed Scopus (217) Google Scholar, 6Witkowski B Duru V Khim N et al.A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study.Lancet Infect Dis. 2017; 17: 174-183Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 7WHOWorld malaria report.http://www.who.int/malaria/publications/world-malaria-report-2017/enDate: 2017Google Scholar Unsurprisingly, this situation is linked to the aggressive strategies implemented in this region to eliminate malaria and the inevitable massive reduction in the Plasmodium falciparum parasite population, leading to selection of best-adapted, multidrug-resistant parasites. In this context, identifying and circumventing survival strategies used by multidrug-resistant P falciparum populations is a major public health issue.8Roberts L Drug-resistant malaria advances in Mekong.Science. 2017; 358: 155-156Crossref PubMed Scopus (11) Google Scholar In The Lancet Infectious Diseases, Roberto Amato and colleagues9Amato R Pearson RD Almagro-Garcia J et al.Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study.Lancet Infect Dis. 2018; (published online Feb 1.)http://dx.doi.org/10.1016/S1473-3099(18)30068-9Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar present a timely, original, and in-depth genetic analysis of the origins of P falciparum parasites resistant to dihydroartemisinin–piperaquine using genome sequence data of samples collected in Cambodia from 2007 to 2013. First, they confirmed the multiple origins of artemisinin-resistant parasites (24 distinct kelch13 mutations) in western Cambodia, and then the selection of a predominant kelch13 580Tyr mutant over a period of 7 years. Six different origins of the 580Tyr mutant were detected, but one lineage named KEL1 largely predominated. Consistent with reports from Imwong and colleagues,10Imwong M Hien TT Thuy-Nhien NT Dondorp AM White NJ Spread of a single multidrug resistant malaria parasite lineage (PfPailin) to Vietnam.Lancet Infect Dis. 2017; 17: 1022-1023Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 11Imwong M Suwannasin K Kunasol C et al.The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study.Lancet Infect Dis. 2017; 17: 491-497Summary Full Text Full Text PDF PubMed Scopus (281) Google Scholar Amato and colleagues showed that this lineage had outcompeted lineages with other 580Tyr alleles and had spread eastward through the parasite population via recombination. Second, the authors observed a single major origin of plasmepsin 2–3 amplifications, indicating that piperaquine-resistant P falciparum parasites were probably derived from the same epidemiological origin (named the PLA1 lineage by the authors). Third, they showed that dihydroartemisinin–piperaquine resistance rapidly spread via diffusion of the KEL1/PLA1 co-lineage from western to northeastern Cambodia. Confined to western Cambodia until 2011, in 2012–13, the KEL1/PLA1 co-lineage was observed in northern Cambodia (close to the Cambodian–Laos border) in isolates sharing much higher levels of co-ancestry with western Cambodian parasites than the rest of the local parasite population. Taken together, the results of the study suggest that antimalarial drugs exerted strong selection on the parasite genomes in this endemic area, recognised as the epicentre of emergence of multidrug resistance. The authors provided answers to pressing questions regarding the nature of parasites spreading across the Greater Mekong subregion and their susceptibility to alternative drug combinations, and discussed the major risks and uncertainties in the longer term. The results of this study are reminiscent of the evolution of chloroquine resistance, wherein multiple P falciparum chloroquine resistance transporter (Pfcrt) alleles emerged in southeast Asia before one allele (the CVIET allele) eventually spread to Africa, leading to millions of deaths. Obviously, this scenario should be avoided for artemisinin combination therapy. For chloroquine, the molecular signatures of resistance were only detected in early 2000, long after resistant parasites had spread outside their original focus. The spread of strains resistant to artemisinin combination therapy in western Cambodia is underway; however, it is reassuring to learn from this study that genomic tools are available to monitor the onset of this spread and, by contrast with chloroquine resistance, to track resistant parasites in real time. We must take advantage of this situation. One way is to improve understanding of the causes of emergence and selection of resistance to artemisinin combination therapy by progressing analyses of parasite population genetics. For example, the early events associated with dihydroartemisinin–piperaquine resistance should be identified through analysis of samples collected before 2007. Moreover, studies could investigate additional mutations, genetic determinants, and specific genetic backgrounds conferring selective advantage to the KEL1/PLA1 co-lineage (eg, increased drug resistance, improved fitness of the asexual stages in the human host, increased transmissibility by increasing gametocyte numbers, favouring transmission to Anopheles spp mosquitoes). Additionally, we need to implement vigilant surveillance of drug resistance to closely follow the effect of using artesunate–mefloquine as first-line treatment on P falciparum populations in Cambodia and to track emergence of the double amplification of pfmdr1 and pfplasmepsin2, already observed among 580Tyr mutants.12Rossi G De Smet M Khim N Kindermans JM Menard D Emergence of Plasmodium falciparum triple mutant in Cambodia.Lancet Infect Dis. 2017; 17: 1233Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar Finally, the opportunity exists to improve basic knowledge through studying parasites from areas of low endemicity where drug pressure is high but resistance to artemisinin combination therapy has not developed. This strategy would help to identify what makes parasites from western Cambodia unique regarding the emergence of antimalarial resistance. We are confident that genomic studies will help to streamline the use of antimalarial drugs and improve local anti-malaria strategies through identification of weak points in the parasite populations. We declare no competing interests. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic studyThe KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin–piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. Full-Text PDF Open Access