Evidence of a hard selective sweep for artemisinin resistant Plasmodium falciparum
Authors: Elizabeth Hemming-Schroeder, Eugenia Lo
Journal: The Lancet Infectious Diseases (2017)

Artemisinin combination therapies (ACTs) remain the gold standard for the treatment of uncomplicated Plasmodium falciparum malaria, 1WHOGuidelines for the Treatment of Malaria. 3rd ed. World Health Organization, Geneva2015Google Scholar although artemisinin resistant P falciparum has been detected in five countries in the Greater Mekong subregion (GMS).2WHOWorld malaria report 2016. World Health Organization, Geneva2016Google Scholar Artemisinin resistance is problematic, in that the associated slow parasite clearance leads to selection for partner drug resistance.3White NJ Can new treatment developments combat resistance in malaria?.Expert Opin Pharmocother. 2016; 17: 1303-1307Crossref PubMed Scopus (30) Google Scholar Malaria treatment failure to ACTs containing the partner drugs mefloquine and piperaquine has already reached alarming levels in areas of the GMS.4Takala–Harrison S Jacob CG Arze C et al.Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.J Infect Dis. 2015; 211: 670-679Crossref PubMed Scopus (303) Google Scholar The emergence of ACT resistant P falciparum in the GMS severely threatens worldwide malaria control. This threat is underscored by the previous spread of chloroquine and sulfadoxine-pyramethamine resistant P falciparum lineages from their origins in southeast Asia to India and sub-Saharan Africa.5Miotto O Amato R Ashley EA et al.Genetic architecture of artemisinin–resistant Plasmodium falciparum.Nat Genet. 2015; 47: 226-234Crossref PubMed Scopus (372) Google Scholar Previous evidence suggested that multiple lineages of artemisinin resistant P falciparum were circulating,4Takala–Harrison S Jacob CG Arze C et al.Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.J Infect Dis. 2015; 211: 670-679Crossref PubMed Scopus (303) Google Scholar, 5Miotto O Amato R Ashley EA et al.Genetic architecture of artemisinin–resistant Plasmodium falciparum.Nat Genet. 2015; 47: 226-234Crossref PubMed Scopus (372) Google Scholar which led to a focus shift away from a containment or firewall approach to elimination only.6World Health OrganizationStrategy for malaria elimination in the Greater Mekong Subregion: 2015–2030. WHO, Geneva2016Google Scholar However, as was the case with the emergence of chloroquine and sulfadoxine-pyrimethamine drug resistance in the past, a single parasite lineage probably ultimately dominated in the GMS, before spreading to India and Africa.7Mita T Tanabe K Kita K Spread and evolution of Plasmodium falciparum drug resistance.Parasitol Int. 2009; 58: 201-209Crossref PubMed Scopus (179) Google Scholar In The Lancet Infectious Diseases, Mallika Imwong and colleagues8Imwong M Suwannasin K Kunasol C et al.A molecular epidemiology observational study of the recent transnational spread of artemisinin resistant P falciparum in the Greater Mekong Subregion.Lancet Infect Dis. 2017; (published online Feb 1.)http://dx.doi.org/10.1016/S1473-3099(17)30048-8PubMed Google Scholar report the results of testing the hypothesis that a single dominant lineage of artemisinin resistant falciparum malaria parasites has spread through the GMS.8Imwong M Suwannasin K Kunasol C et al.A molecular epidemiology observational study of the recent transnational spread of artemisinin resistant P falciparum in the Greater Mekong Subregion.Lancet Infect Dis. 2017; (published online Feb 1.)http://dx.doi.org/10.1016/S1473-3099(17)30048-8PubMed Google Scholar 434 P falciparum isolates were collected from Myanmar, northeastern Thailand, southern Laos, and western Cambodia in 2008–15. Artemisinin resistance was examined through PfKelch13 mutations9Ariey 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 and microsatellite loci flanking PfKelch13.10Talundzic E Okoth SA Congpuong K et al.Selection and spread of artemisinin–resistant alleles in Thailand prior to the global artemisinin resistance containment campaign.PLoS Pathog. 2015; 11: e1004789Crossref PubMed Scopus (88) Google Scholar, 11Cheeseman IH Miller BA Nair S et al.A major genome region underlying artemisinin resistance in malaria.Science. 2012; 336: 79-82Crossref PubMed Scopus (308) Google Scholar Resistance to the partner drug piperaquine was also evaluated by amplification of Pfplasmepsin2 gene, a marker recently identified.12Witkowski 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 Imwong and colleagues provide evidence of a hard selective sweep of the PfKelch13 C580Y mutation, which has spread from western Cambodia to northeastern Thailand and southern Laos. This evidence of a shared origin of C580Y is supported by microsatellite data that revealed a common long haplotype flanking PfKelch13 in C580Y parasite isolates. The long C580Y haplotype was present at frequencies exceeding 73% in northeastern Thailand, southern Laos, and western Cambodia. Further, the authors found evidence of Pfplasmepsin2 amplification only in conjunction with the C580Y mutation in western Cambodia and northeastern Thailand, where Pfplasmepsin2 amplification was present in 71% and 100% of isolates, respectively. The finding of a dominant artemisinin resistant haplotype that is associated with partner drug resistance has implications for malaria control and ACT resistance containment strategies. Although the emergence of artemisinin and partner drug resistance in the GMS is well established,4Takala–Harrison S Jacob CG Arze C et al.Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.J Infect Dis. 2015; 211: 670-679Crossref PubMed Scopus (303) Google Scholar that a common dominant artemisinin resistant P falciparum lineage is spreading should give pause, even if it was to be expected. This observed pattern of ACT evolution in southeast Asia resembles that of both chloroquine and sulfadoxine-pyrimethamine resistance in the past, before the dominant resistant lineage spreading to India and Africa. ACT resistance spread would be especially devastating in sub-Saharan African which has approximately 90% of the global malaria burden.2WHOWorld malaria report 2016. World Health Organization, Geneva2016Google Scholar The findings of Imwong and colleagues' study suggest that a firewall approach of increased malaria control measures surrounding areas of antimalarial drug resistance should be reconsidered and could be effective at delaying the spread of artemisinin resistance. The GMS has been a persistent source of globally dominant antimalarial resistant P falciparum lineages. We think that these findings underscore the importance of containing and eliminating malaria in this region. Furthermore, the spread of this presumably selected artemisinin resistant lineage emphasises the urgency of finding a new antimalarial drug, or implementing alternative treatment regimens of the available antimalarial drugs.3White NJ Can new treatment developments combat resistance in malaria?.Expert Opin Pharmocother. 2016; 17: 1303-1307Crossref PubMed Scopus (30) Google Scholar Lastly, we recommend careful monitoring for the PfKelch13 C580Y haplotype in neighbouring countries, as well as India and west and east Africa to identify further spread of artemisinin resistance should it occur. In conclusion, this study fills an important knowledge gap about the evolution of ACT resistance in the GMS. Although the observed evolutionary pattern should not be surprising, we anticipate the findings to be highly impactful to malaria control policy. Imwong and colleagues provide substantial evidence that history is repeating itself with regard to antimalarial drug resistance in the case of ACT resistance. We declare no competing interests. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational studyOur results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective. Full-Text PDF Open Access