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      The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study.

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          Abstract

          Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion.

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          Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.

          Chanaki Amaratunga, Pharath Lim, Seila Suon … (2016)
          Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin-piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia.
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            Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.

            John Wootton, Xiaorong Feng, Michael Ferdig … (2002)
            Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.
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              Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.

              Shannon Takala-Harrison, Christopher G. Jacob, Cesar Arze … (2015)
              The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Lancet Infect Dis
                Title: The Lancet. Infectious diseases
                Publisher: Elsevier BV
                ISSN (Electronic): 1474-4457
                ISSN (Print): 1473-3099
                Publication date (Electronic): May 2017
                Volume: 17
                Issue: 5
                Affiliations
                [1 ] Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand; Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Electronic address: noi@tropmedres.ac.
                [2 ] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
                [3 ] Buntharik Hospital, Amphoe Buntharik, Ubon Ratchathani, Thailand.
                [4 ] Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Vientiane, Laos; Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Laos.
                [5 ] National Centre for Parasitology, Entomology, and Malaria Control (CNM), Phnom Penh, Cambodia.
                [6 ] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Myanmar Oxford Clinical Research Unit, Yangon, Myanmar; Medical Action Myanmar, Yangon, Myanmar.
                [7 ] Defence Services Medical Research Centre, Naypyitaw, Myanmar.
                [8 ] Myanmar Oxford Clinical Research Unit, Yangon, Myanmar; Defence Services Medical Research Centre, Naypyitaw, Myanmar.
                [9 ] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
                [10 ] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Wellcome Trust Sanger Institute, Hinxton, UK.
                [11 ] Malaria Molecular Epidemiology Unit, Institut Pasteur in Cambodia, Phnom Penh, Cambodia.
                [12 ] Worldwide Antimalarial Resistance Network (WWARN), Bangkok, Thailand.
                Article
                Publisher Item ID: S1473-3099(17)30048-8
                DOI: 10.1016/S1473-3099(17)30048-8
                PMC ID: 5406483
                PubMed ID: 28161569
                SO-VID: 1d830f76-7667-45b3-aa9b-eaf96f5878be
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