Abstract
The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions. In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009-2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed. A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89-7.28) hours in Pailin versus 3.42 (2.20-4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68). Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum. Clinical Trials Registration. ISRCTN15351875.
Highlights
The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control
The current study explored whether increasing or splitting the once-daily AS dose increased efficacy, defined as parasite half-life [9], in patients with uncomplicated malaria in Pailin, western Cambodia, an area of artemisinin resistance, and in Wang Pha, in northwestern Thailand, where ACT has sustained efficacy since 1994 [10], a recent decline has been observed here [4]
Study Design In 2 open-label, randomized clinical trials, we compared different AS dosing regimens in patients with uncomplicated falciparum malaria presenting in Pailin, western Cambodia (2008–2010) and in Wang Pha, northwestern Thailand (2009– 2010), areas with low and seasonal transmission
Summary
In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009– 2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a oncedaily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Study Design In 2 open-label, randomized clinical trials, we compared different AS dosing regimens in patients with uncomplicated falciparum malaria presenting in Pailin, western Cambodia (2008–2010) and in Wang Pha, northwestern Thailand (2009– 2010), areas with low and seasonal transmission. Patients Patients with acute uncomplicated falciparum malaria, monoinfection, and asexual stage parasitemia between 10 000 parasites/μL and 175 000 parasites/μL assessed by microscopy were eligible provided that written informed consent was obtained from all patients or their guardian (for children). Antimalarial treatment within 48 hours of screening, known hypersensitivity to study drugs, or splenectomy were exclusion criteria
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