SummaryBackgroundSevere malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.MethodsThis open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054.Findings5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63–0·90; relative reduction 22·5%, 95% CI 8·1–36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49–0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66–0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64–0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43–0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects.InterpretationArtesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.FundingThe Wellcome Trust.

Four predictors were independently associated with an increased risk of death: acidosis, cerebral manifestations of malaria, elevated blood urea nitrogen, or signs of chronic illness. The standard base deficit was found to be the single most relevant predictor of death.

Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokineticpharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log 10 scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.A rtemisinin combination therapies are now the recommended first-line treatment for uncomplicated falciparum in all malaria endemic countries, and artesunate is the recommended treatment for severe malaria in adults (1). The emergence of artemisinin resistance on the Cambodian-Thai border is therefore alarming (2). The genetic basis for artemisinin resistance is currently unknown. Artemisinin resistance was characterized by significant reductions in in vivo parasite clearance rates (2) and has been shown to be heritable (3), but was not reflected by conventional in vitro drug susceptibility tests (2). Conventional tests do not differentiate between stages of parasite development and are therefore unsuitable for assessing stage-specific drug resistance phenotypes. Furthermore, the constant drug exposure in vitro is very different from the profile of in vivo exposure for rapidly eliminated drugs such as the artemisinin derivatives.Key pharmacological differences between the artemisinin derivatives and other antimalarials are their rapid elimination and broad stage specificity, which includes the circulating ringstage parasites (4, 5). These drugs have a greater effect on ring stages than any other antimalarial class (4). It is this effect that accounts for the more rapid parasite clearances with the artemisinin derivatives compared with all other antimalarial drug classes. It has been hypothesized that loss of artemisinin sensi...