Efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in western Cambodia

02 Mar 2016

Rithea Leanga, Sara E. Canavati, Nimol Khim, Lasse S. Vestergaard, Isabelle Borghini Fuhrer, Saorin Kim, Mey Bouth Denis, Pisal Heng, Bunkea Tol, Rekol Huy, Stephan Duparc, Arjen M. Dondorp, Didier Menard and Pascal Ringwald

Antimicrobial Agents and Chemotherapy

DOI:

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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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