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Recent failures of dihydroartemisinin–piperaquine combination — first-line treatment for falciparum malaria in Cambodia — prompted a prospective cohort study to confirm resistance and study molecular mechanisms. Patients were aged 2 to 65 years with uncomplicated falciparum malaria in three geographically separated provinces. Prevalence of kelch13 mutations, a marker for artemisinin resistance, varied from 4% to 76% in the three provinces in 2011–2012. No genetic marker for piperaquine resistance has been identified. Study participants were hospitalized and treated with dihydroartemisinin–piperaquine tablets at 0, 24, and 48 hours. Parasite density was measured on serial blood films at 2-hourly intervals initially, daily, and weekly to 63 d…