Artemisinin-Resistant Falciparum Malaria in Cambodia

Artemisinin-based combination therapies are recommended by the WHO as first-line treatment for falciparum malaria in areas where the disease is endemic. To assess the current efficacy of the artemisinin derivative artesunate, investigators conducted open-label, randomized trials comparing two regimens for uncomplicated falciparum at two sites: western Cambodia, where reduced effectiveness has been reported, and northwestern Thailand. Forty participants from each site — children and adults in Cambodia; adults in Thailand — were treated with artesunate at 2 mg/kg orally for 7 days or at 4 mg/kg orally for 3 days followed by two doses of mefloquine totaling 25 mg/kg. Patients were monitored in the hospital for 1 week with clinical, parasitological, and pharmacological studies and then assessed weekly until day 63.

Parasite clearance time was significantly longer in Cambodian than in Thai participants for both treatment groups (median, 84 vs. 48 hours; P<0.001). Ninety-six hours after starting therapy, 20% of Cambodian and 3% of Thai participants remained parasitemic. A significant dose-response relationship was not seen in Cambodia (median time to parasite clearance, 84 hours for 2 mg/kg and 72 hours for 4 mg/kg) but was evident in Thailand (48 vs. 54 hours, respectively; P=0.02). With artesunate monotherapy, recrudescence of Plasmodium falciparum infection >7 days after treatment initiation occurred in 30% of Cambodian and 10% of Thai enrollees. The investigators were unable to explain the reduced efficacy of artesunate therapy in Cambodia on the basis of pharmacokinetic or host differences or known molecular markers of resistance.