Pyronaridine-artesunate efficacy in uncomplicated P. falciparum malaria was assessed in an area of artemisinin resistance in western Cambodia. This non-randomized, single arm, observational study was conducted between in 2014-2015 (Clinical Trials Registration. NCT02389439). Eligible patients were adults or children with microscopically confirmed P. falciparum infection and fever. Patients received pyronaridine-artesunate once daily for 3 days, dosed according to body weight. The primary outcome was day-42 adequate clinical and parasitological response (ACPR), estimated using Kaplan–Meier analysis, PCR-adjusted to exclude reinfection. One hundred twenty three patients were enrolled. Day-42 PCR-crude ACPR was 87.2% (95%CI: 79.7-92.6) for the overall study, 89.8% (95%CI: 78.8-95.3) for Pursat and 82.1% (95%CI: 68.4-90.2) for Pailin. Day-42 PCR-adjusted ACPR was 87.9% (95%CI: 80.6-93.2) for the overall study, 89.8% (95%CI: 78.8-95.3) for Pursat and 84.0% (95%CI: 70.6-91.7) for Pailin (log-rank test p=0.353). Day-28 PCR-crude and adjusted ACPR was 93.2% (95%CI: 82.9-97.4) and 88.1% (95%CI: 75.3-94.5), for Pursat and Pailin, respectively. A significantly lower proportion of patients achieved day-3 parasite clearance in Pailin (56.4% [95%CI: 43.9-69.6]) versus Pursat (86.7% [95%CI: 76.8-93.8]; p=0.0019). Fever clearance was also extended at Pailin versus Pursat (p<0.0001). Most patients (95.9% [116/121]) harbored P. falciparum kelch13 C580Y mutant parasites. Pyronaridine-artesunate was well tolerated; mild increases in hepatic transaminases were consistent with previous reports. Pyronaridine-artesunate efficacy was below the World Health Organization recommended threshold at day 42 for medicines with long half-life (90%) for first-line treatment of P. falciparum malaria in western Cambodia, despite high efficacy elsewhere in Asia and Africa.
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