Knowing the enemy: genetics to track antimalarial resistance
Authors: Didier Ménard, Alfredo Mayor
Journal: The Lancet Infectious Diseases (2020)

In the absence of an effective vaccine, the efficacy of antimalarial chemotherapies underpins the success of malaria control programmes. Artemisinin-based combination therapies (ACTs), which combine fast-acting artemisinin derivatives and longer-acting partner drugs, are the mainstay of treatment of uncomplicated falciparum malaria in endemic regions.1WHOWorld malaria report. World Health Organization, Geneva2019Google Scholar However, as reported for almost all antimalarial drugs used worldwide, Plasmodium falciparum resistance to artemisinin is emerging.2Menard D Dondorp A Antimalarial drug resistance: a threat to malaria elimination.Cold Spring Harb Perspect Med. 2017; 7a025619Crossref PubMed Scopus (181) Google Scholar, 3White NJ Pukrittayakamee S Hien TT Faiz MA Mokuolu OA Dondorp AM Malaria.Lancet. 2014; 383: 723-735Summary Full Text Full Text PDF PubMed Scopus (717) Google Scholar First detected in Cambodia in 2008,4Dondorp AM Nosten F Yi P et al.Artemisinin resistance in Plasmodium falciparum malaria.New Engl J Med. 2009; 361: 455-467Crossref PubMed Scopus (2401) Google Scholar, 5Noedl H Se Y Schaecher K et al.Evidence of artemisinin-resistant malaria in western Cambodia.New Engl J Med. 2008; 359: 2619-2620Crossref PubMed Scopus (1226) Google Scholar partial artemisinin resistance is now widespread in the Greater Mekong subregion.6Amato 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; 18: 337-345Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 7Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 8Imwong 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 (258) Google Scholar, 9Menard D Khim N Beghain J et al.A worldwide map of Plasmodium falciparum K13-propeller polymorphisms.N Engl J Med. 2016; 374: 2453-2464Crossref PubMed Scopus (330) Google Scholar Moreover, resistance to ACT partner drugs has become common in Cambodia, where high rates of dihydroartemisinin–piperaquine treatment failure have been observed.10van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (152) Google Scholar The risk of spreading ACT-resistant parasites from the Greater Mekong subregion to Africa, as happened in the 1980s with chloroquine and pyrimethamine resistance, is a major concern.11Blasco B Leroy D Fidock DA et al.Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.Nat Med. 2017; 23: 917-928Crossref PubMed Scopus (249) Google Scholar The close surveillance of antimalarial resistance, predicted from the genetic variation contained in the DNA of malaria parasites, is therefore essential. Although there are some caveats (eg, the association between the molecular markers and in-vivo resistance is not always linear), this genetic information can be used to guide policy decissions.12Nsanzabana C Djalle D Guerin PJ Menard D Gonzalez IJ Tools for surveillance of anti-malarial drug resistance: an assessment of the current landscape.Malar J. 2018; 17: 75Crossref PubMed Scopus (29) Google Scholar In The Lancet Infectious Diseases, Mallika Imwong and colleagues15Imwong M Dhorda M Tun KM et al.Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study.Lancet Infect Dis. 2020; (published online July 14.)https://doi.org/10.1016/S1473-3099(20)30228-0Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar present a comprehensive description of the geographical and temporal changes in P falciparum molecular markers of resistance to antimalarial drugs used in the Greater Mekong subregionin the past decade. The team investigated point mutations and amplifications in genes associated with artemisinin (pfkelch13), piperaquine (pfcrt, plasmepsin-2), and mefloquine–lumefantrine (pfmdr1) resistance in more than 10 000 blood samples collected from 2007 to 2018 in Myanmar, Thailand, Laos, and Cambodia. They also explored microsatellites and single nucleotide polymorphisms in the flanking regions each side of the mutations to estimate the genetic relatedness of the predominant mutants. Their results show the effect molecular data can have in informing public health interventions. Different evolutionary dynamics of antimalarial drug resistance were found in the eastern and western Greater Mekong subregion, without evidence of P falciparum resistance spreading. In the western Greater Mekong subregion, an almost fixed pfkelch13 Cys580Tyr lineage (called PfPailin), resistant to both artemisinin and piperaquine (defined by plasmepsin-2 gene amplification and specific mutations in the pfcrt gene) and associated with high rates of dihydroartemisinin–piperaquine treatment failure, has outcompeted other pfkelch13 mutants. By contrast, a single artemisinin-resistant pfkelch13 Phe446Ile haplotype predominates in the eastern Greater Mekong subregion, which spread from the northwest to the east of Myanmar without acquiring additional resistance to piperaquine. The intensive deployment of dihydroartemisinin–piperaquine for treatment and elimination purposes in Kayin state (eastern Myanmar) was not associated with further selection of artemisinin and piperaquine resistance, supporting its mass use for elimination. This study has implications for the proactive development of interventions that can reduce the spread and impact of antimalarial drug resistance. First, the local emergence of pfkelch13 mutants (Cys580Tyr and Phe446Ile) and their reduced regional spread contrast with the previous expansions of choloroquine-resistant and pyrimethamine-resistant parasites from the Greater Mekong subregion to Africa. However, single point mutations in the pfkech13 gene that confer resistance to artemisinin seem to arise more frequently than the complex sets of genetic mutations associated with chloroquine (pfcrt gene) and sulfadoxine–pyrimethamine (dhfr and dhps genes) resistance. Therefore, the risk of local emergence of artemisinin-resistant pfkelch13 mutants in malaria-endemic settings other than the Greater Mekong subregion might be more likely to occur than the spread of artemisinin-resistant parasites, as observed in Guyana13Mathieu LC Cox H Early AM et al.Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance.eLife. 2020; 9e51015Crossref PubMed Scopus (44) Google Scholar and Papua New Guinea.14Miotto O Sekihara M Tachibana SI et al.Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea.bioRxiv. 2019; (published online July 17.) (preprint).DOI: 10.1101/621813Google Scholar Second, mass drug administrations used for malaria elimination do not seem to drive the selection of antimalarial drug resistance, although adequate sample sizes are essential to achieve more robust conclusions. Further studies are required to provide insights into the factors that determine drug resistance, such as the fitness cost of the mutations conferring resistance, the competition between resistant and sensitive parasite strains, and the immune status of the host population, among others. How all these factors interact in the Greater Mekong subregion to make this area a hotspot for the emergence of antimalarial resistance is still an open question. A better understanding of how resistance emerges and the factors that drive parasite gene flow across geographic regions are key to guiding interventions that aim to contain resistance. To obtain actionable information from genetic data, additional work is needed, including the generation of molecular and clinical databases of parasite resistance across multiple geographic regions, the validation of molecular markers linked to resistance in different geographical settings (eg, markers associated with piperaquine and lumefantrine resistance), and the definition of appropriate sampling strategies and genotyping methods, to optimise routine surveillance and to build capacity for agile evidence-driven decision making in malaria-endemic countries. We recall Sun Tzu's precept (The Art of War): “know our enemy, if we want to win the battle without loss”. We declare no competing interests. Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational studyArtemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion. In the eastern Greater Mekong subregion a multidrug resistant P falciparum lineage (PfPailin) dominates. In Myanmar a long pfkelch Phe446Ile haplotype has spread widely but, by contrast with the eastern Greater Mekong subregion, there is no indication of artemisinin combination therapy (ACT) partner drug resistance from genotyping known markers, and no evidence of spread of ACT resistant P falciparum from the east to the west. Full-Text PDF Open Access