51. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia
- Author
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Bouasy Hongvanthong, Tran Tinh Hien, Christopher S. Pepin, Nguyen Thanh Thuy Nhien, John C. Tan, Wasif A. Khan, Harald Noedl, François Nosten, Shannon Takala-Harrison, Christopher G Jacob, Jason A. Bailey, Didier Menard, Stuart D. Tyner, Paul N. Newton, Aung Pyae Phyo, David L. Saunders, Frédéric Ariey, Myaing Myaing Nyunt, Christopher V. Plowe, Delia Bethell, Dominic P. Kwiatkowski, Mallika Imwong, Joana C. Silva, Taane G. Clark, Tyler S. Brown, Myat Htut Nyunt, Youry Se, Peter Starzengruber, Maniphone Khanthavong, Nicholas J. White, Matthew Adams, Arjen M. Dondorp, Mark M. Fukuda, Michael P. Cummings, Bronwyn MacInnis, Odile Mercereau-Puijalon, Myat Phone Kyaw, Chanthap Lon, Cesar Arze, Hans-Peter Fuehrer, Olivo Miotto, Michael T. Ferdig, Mayfong Mayxay, Paul Swoboda, Pascal Ringwald, University of Maryland School of Medicine, University of Maryland System, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], U.S. President's Malaria Initiative [Bangkok, Thaïlande], Division of Parasitic Diseases and Malaria [Bangkok, Thaïlande] (DPDM), Centers for Disease Control and Prevention [Bangkok, Thaïlande], Centers for Disease Control and Prevention-Centers for Disease Control and Prevention-Centers for Disease Control and Prevention [Bangkok, Thaïlande], Centers for Disease Control and Prevention-Centers for Disease Control and Prevention, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Institute of Specific Prophylaxis and Tropical Medicine, Medizinische Universität Wien = Medical University of Vienna, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Department of Molecular Tropical Medicine and Genetics [Bangkok, Thaïlande], Faculty of Tropical Medicine [Bangkok, Thaïlande], Mahidol University [Bangkok]-Mahidol University [Bangkok], Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Immunologie moléculaire des parasites, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), National Center for Malariology, Parasitology and Entomology, Ministry of Health [Mozambique], Institute of Parasitology [Vienna], University of Veterinary Medicine, Vienna, Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Eck Institute for Global Health, University of Notre Dame [Indiana] (UND), Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (LSHTM), The Wellcome Trust Sanger Institute [Cambridge], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Oxford-Mahidol University [Bangkok], University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and University of Oxford
- Subjects
MESH: Mutation ,Plasmodium falciparum ,MESH: Asia, Southeastern ,malaria ,Drug resistance ,artemisinin resistance ,Biology ,medicine.disease_cause ,kelch ,MESH: Genotype ,chemistry.chemical_compound ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,MESH: Artemisinins ,parasitic diseases ,Genotype ,medicine ,Immunology and Allergy ,Kelch protein ,MESH: Protozoan Proteins ,MESH: Plasmodium falciparum ,Genetics ,Mutation ,MESH: Humans ,MESH: Polymorphism, Single Nucleotide ,MESH: Malaria, Falciparum ,Haplotype ,medicine.disease ,biology.organism_classification ,Southeast Asia ,MESH: Antimalarials ,3. Good health ,Infectious Diseases ,chemistry ,Artesunate ,MESH: Drug Resistance ,Malaria - Abstract
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.
- Published
- 2016
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