Fang Huang1, Shannon Takala-Harrison2, Christopher G Jacob2, Hui Liu3, Xiaodong Sun3, Henglin Yang3, Myaing M Nyunt2, Matthew Adams2, Shuisen Zhou4, Zhigui Xia4, Pascal Ringwald5, Maria Dorina Bustos6, Linhua Tang4, Christopher V Plowe2. 1. 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. 2. Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore. 3. Yunnan Institute of Parasitic Diseases, Puer, PR China. 4. 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. 5. Drug Resistance and Containment Unit, Global Malaria Programme, World Health Organization, Geneva, Switzerland. 6. World Health Organization-Mekong Malaria Programme, Bangkok, Thailand.
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.
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.
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