title: A Single Mutation in K13 Predominates in Southern China and Is Associated With Delayed Clearance of Plasmodium falciparum Following Artemisinin Treatment.
abstract: BACKGROUND
  Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and poses a threat to malaria control and elimination. Mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 have been associated with delayed parasite clearance following artemisinin treatment elsewhere in the region, but not yet in China.
  
  
  METHODS
  Therapeutic efficacy studies of artesunate and dihydroartemisinin-piperaquine were conducted from 2009 to 2012 in the Yunnan Province of China near the border with Myanmar. K13 mutations were genotyped by capillary sequencing of DNA extracted from dried blood spots collected in these clinical trials and in routine surveillance. Associations between K13 mutations and delayed parasite clearance were tested using regression models.
  
  
  RESULTS
  Parasite clearance half-lives were prolonged after artemisinin treatment, with 44% of infections having half-lives >5 hours (n = 109). Fourteen mutations in K13 were observed, with an overall prevalence of 47.7% (n = 329). A single mutation, F446I, predominated, with a prevalence of 36.5%. Infections with F446I were significantly associated with parasitemia on day 3 following artemisinin treatment and with longer clearance half-lives.
  
  
  CONCLUSIONS
  Plasmodium falciparum infections in southern China displayed markedly delayed clearance following artemisinin treatment. F446I was the predominant K13 mutation and was associated with delayed parasite clearance.
authors.affiliation: National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, World Health Organization Collaborating Centre for Malaria, Schistosomiasis and Filariasis, Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, PR China Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore.
authors.forename: Shannon
authors.initials: S
authors.lastname: Takala-Harrison
authors.affiliation: Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Jacob
authors.affiliation: Yunnan Institute of Parasitic Diseases, Puer, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Yunnan Institute of Parasitic Diseases, Puer, PR China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Yunnan Institute of Parasitic Diseases, Puer, PR China.
authors.forename: Henglin
authors.initials: H
authors.lastname: Yang
authors.affiliation: Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore.
authors.forename: Myaing M
authors.initials: MM
authors.lastname: Nyunt
authors.affiliation: Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore.
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.affiliation: National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, World Health Organization Collaborating Centre for Malaria, Schistosomiasis and Filariasis, Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, PR China.
authors.forename: Shuisen
authors.initials: S
authors.lastname: Zhou
authors.affiliation: National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, World Health Organization Collaborating Centre for Malaria, Schistosomiasis and Filariasis, Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, PR China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Drug Resistance and Containment Unit, Global Malaria Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ringwald
authors.affiliation: World Health Organization-Mekong Malaria Programme, Bangkok, Thailand.
authors.forename: Maria Dorina
authors.initials: MD
authors.lastname: Bustos
authors.affiliation: National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, World Health Organization Collaborating Centre for Malaria, Schistosomiasis and Filariasis, Key Laboratory of Parasite and Vector Biology, Ministry of Health, Shanghai, PR China.
authors.forename: Linhua
authors.initials: L
authors.lastname: Tang
authors.affiliation: Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002681:China; D004361:Drug Tolerance; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; C031327:artemisinin
keywords: China; Plasmodium falciparum; artemisinin resistance; kelch 13; malaria