Effect of high dose or split dose artesunate on parasite clearance in artemisinin resistant falciparum malaria

(See the Major Article by Sutanto et al, on pages 685–93 and see the Editorial Commentary by Dondorp, on pages 694–6.) The emergence of partial artemisinin resistance in Plasmodium falciparum on the Cambodia-Thailand border and more recently on the Myanmar-Thailand border jeopardizes the renewed global efforts of control and elimination of malaria [1–4]. This poses a danger that malaria could become untreatable, as no good alternatives to artemisinin-based combination therapy (ACT) are currently available [5]. Increasing the dose of the artemisinin component in ACT might partly overcome decreased sensitivity, in case the concentration-effect relationship has merely shifted to higher concentrations in this parasite population. Increasing the dosing frequency could be another strategy to increase artemisinin efficacy. A unique property of the artemisinin drugs is their broad-stage specificity including young ring-stage asexual parasites [6]. There is evidence that artemisinin resistance particularly involves ring-stage parasites [2, 7, 8]. This can affect the dosing frequency of the short-half-life artemisinins, which have therapeutic drug concentrations until approximately 6 hours after the dose [8]. A mathematical model predicted that twice-daily dosing of artesunate (AS) would be more effective than the conventional once-daily dose [8]. 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], although a recent decline has also been observed here [4].