Towards real-time monitoring of artemisinin resistance
Authors: Didier Menard, Frédéric Ariey
Journal: The Lancet Infectious Diseases (2015)

The discovery that mutations in the kelch propeller domain of the K13 gene (PF3D7_1343700) were major determinants of Plasmodium falciparum artemisinin resistance has been validated by several studies in the Mekong region.1Ariey F Witkowski B Amaratunga C et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature. 2014; 505: 50-55Crossref PubMed Scopus (1219) Google Scholar, 2Ashley EA Dhorda M Fairhurst RM et al.Spread of artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2014; 371: 411-423Crossref PubMed Scopus (1359) Google Scholar, 3Straimer J Gnadig NF Witkowski B et al.Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.Science. 2014; 347: 428-431Crossref PubMed Scopus (428) Google Scholar The particularity of this discovery is that it took place less than 10 years after the detection of the first clinical cases of artemisinin resistance in western Cambodia and probably before the spread of the mutations to neighbouring malaria-endemic regions and beyond.4Dondorp AM Nosten F Yi P et al.Artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2009; 361: 455-467Crossref PubMed Scopus (2417) Google Scholar This context is very unique and favours real-time monitoring of artemisinin resistance in endemic areas and anticipation of the risks associated with the emergence and spread of the artemisinin-resistant parasites, a major public health issue. Indeed, this situation is completely different to that which took place in the late 1970s, when resistant parasites emerged to the previous generation of antimalarial drugs (ie, chloroquine, sulfadoxine, and pyrimethamine) and whose associated molecular markers (eg, Pfcrt, Pfdhfr, and Pfdhps) were discovered only after their spread to Africa, leading to an unprecedented increase in morbidity and mortality.5Roper C Pearce R Nair S Sharp B Nosten F Anderson T Intercontinental spread of pyrimethamine-resistant malaria.Science. 2004; 305: 1124Crossref PubMed Scopus (379) Google Scholar, 6Wootton JC Feng X Ferdig MT et al.Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.Nature. 2002; 418: 320-323Crossref PubMed Scopus (586) Google Scholar, 7Trape JF Pison G Spiegel A Enel C Rogier C Combating malaria in Africa.Trends Parasitol. 2002; 18: 224-230Summary Full Text Full Text PDF PubMed Scopus (152) Google Scholar This favourable situation should now be used to track the spread of artemisinin resistance and mitigate its effect on malaria treatment and control programmes, especially in sub-Saharan Africa. In The Lancet Infectious Diseases, Kyaw Tun and colleagues8Tun KM Imwong M Lwin KM et al.Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.Lancet Infect Dis. 2015; (published online Feb 20.)http://dx.doi.org/10.1016/S1473-3099(15)70032-0PubMed Google Scholar present a detailed molecular study of K13 from P falciparum field isolates obtained from symptomatic patients at more than 50 different sites in Myanmar during 2013–14. The work presented here is important and very relevant, because foremost it helps identify the extent of resistance in this key country in the regional surveillance system. Indeed, the malaria burden in Myanmar is the largest in southeast Asia (1·4 million malaria cases and 2900 deaths in 2012) and, because of its localisation close to the historical epicentre of the emergence of multidrug-resistant parasites, this country is considered the main route by which drug-resistant falciparum malaria will spread contiguously from southeast Asia to the Indian subcontinent and then to Africa.9WHOEmergency response to artemisinin resistance in the Greater Mekong subregion: regional framework for action 2013–2015. World Health Organization, Geneva2013Google Scholar Second, from a methodological point of view, Tun and colleagues' study is a model of what needs to be done: a countrywide collection of samples associated with a predictive, fine-scale (5 × 5 km) geospatial representation of the prevalence of K13 mutants. Such mapping provides a powerful instrument with which to predict the prevalence of K13 mutant alleles (or other data) in unsampled areas. The mapping also enables national programmes to obtain clear and useful information about the extent of resistance and thus implement appropriate actions. For the present study, the molecular data provide strong evidence that artemisinin-resistant falciparum malaria in Myanmar extends across much of Upper Myanmar, including areas close to the Indian border in the northwest. These data, associated with information about the presence of K13 mutant alleles in Bangladesh, advocate for a rigorous molecular survey to be implemented without delay in the Indian subcontinent.10Mohon AN Alam MS Bayih AG et al.Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009–2013).Malar J. 2014; 13: 431Crossref PubMed Scopus (68) Google Scholar One of the major technical issues raised in the study is the low extraction–sequencing success rate for samples obtained with rapid diagnostic tests (26%). Although this approach should be promoted because it allows the collection of blood samples of all malaria cases recorded at least in the health system, the low extraction–sequencing success rate shows that a major effort should be made to improve the performance of the DNA extraction or the PCR amplification, or to modify the format of rapid diagnostic tests for use not only as point-of-care testing for malaria, but also as blood sample sources. In the past few decades, substantial developments have been made in plasmodium molecular biology and they have greatly increased understanding of malaria epidemiology. Previously, only incidence and prevalence were used to assess the effect of malaria control measures, but nowadays, with the introduction of high-sensitivity molecular assays, researchers can investigate the origin and the flow of malaria-resistant parasites.11Miotto O Almagro-Garcia J Manske M et al.Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia.Nat Genet. 2014; 45: 648-655Crossref Scopus (326) Google Scholar In all endemic areas, a falciparum gene-flow map should be envisaged to help implementation of control measures and identify key sites for malaria monitoring. Importantly, in endemic countries where artemisinin resistance has been recorded, a greater parasite biomass will be exposed to partner drugs and thus molecular surveys must include partner drug monitoring, with use of molecular markers if available.2Ashley EA Dhorda M Fairhurst RM et al.Spread of artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2014; 371: 411-423Crossref PubMed Scopus (1359) Google Scholar, 12WHOStatus report on artemisinin resistance. September, 2014. World Health Organization: WHO, 2014Google Scholar Real-time detection and monitoring of the geospatial distribution of antimalarial drug-resistant parasites is now a possibility, as is prevention of their dissemination in neighbouring endemic areas. However, substantial work remains to be done to harmonise and validate collected data. Currently, a major concern is the interpretation of molecular data because of the high diversity of the K13 gene: except for four mutations (C580Y, R539T, R543I, and Y493H), no clinical or in-vitro data have been associated with the other K13 mutant alleles.1Ariey F Witkowski B Amaratunga C et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature. 2014; 505: 50-55Crossref PubMed Scopus (1219) Google Scholar, 3Straimer J Gnadig NF Witkowski B et al.Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.Science. 2014; 347: 428-431Crossref PubMed Scopus (428) Google Scholar We believe that the scientific community working on artemisinin resistance should now create a consortium around a K13 reference centre that could take over the management and data validation, the harmonisation of molecular biology techniques, the provision of control samples, and the organisation of a quality assurance system, to recommend the best therapeutic options—a prerequisite to move effectively toward malaria elimination. We declare no competing interests. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular markerArtemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Full-Text PDF Open Access