Article

Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-label, randomised trial

Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
The Lancet (Impact Factor: 45.22). 11/2010; 376(9753):1647-57. DOI: 10.1016/S0140-6736(10)61924-1
Source: PubMed

ABSTRACT Severe 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.
This 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.
5425 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.
Artesunate 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.
The Wellcome Trust.

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    • "populations had been provided with the same level of hospital access as those living nearby (Dondorp et al. 2010; Maitland et al. 2011). There also appeared to be a gender bias in seeking care; the increasing proportion of male children with distance suggests that, where additional resources are required to seek care, boys are increasingly favoured. "
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    ABSTRACT: Objective To investigate the association, if any, between child mortality and distance to the nearest hospital.Methods The study was based on data from a 1-year study of the cause of illness in febrile paediatric admissions to a district hospital in north-east Tanzania. All villages in the catchment population were geolocated, and travel times were estimated from availability of local transport. Using bands of travel time to hospital, we compared admission rates, inpatient case fatality rates and child mortality rates in the catchment population using inpatient deaths as the numerator.ResultsThree thousand hundred and eleven children under the age of 5 years were included of whom 4.6% died; 2307 were admitted from <3 h away of whom 3.4% died and 804 were admitted from ≥3 h away of whom 8.0% died. The admission rate declined from 125/1000 catchment population at <3 h away to 25/1000 at ≥3 h away, and the corresponding hospital deaths/catchment population were 4.3/1000 and 2.0/1000, respectively. Children admitted from more than 3 h away were more likely to be male, had a longer pre-admission duration of illness and a shorter time between admission and death. Assuming uniform mortality in the catchment population, the predicted number of deaths not benefiting from hospital admission prior to death increased by 21.4% per hour of travel time to hospital. If the same admission and death rates that were found at <3 h from the hospital applied to the whole catchment population and if hospital care conferred a 30% survival benefit compared to home care, then 10.3% of childhood deaths due to febrile illness in the catchment population would have been averted.Conclusions The mortality impact of poor access to hospital care in areas of high paediatric mortality is likely to be substantial although uncertainty over the mortality benefit of inpatient care is the largest constraint in making an accurate estimate.
    Tropical Medicine & International Health 03/2014; 19(5). DOI:10.1111/tmi.12294 · 2.30 Impact Factor
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    • "While randomised trials may be the best way to come close to an unconfounded estimate of the effect size of a given intervention, they generally provide little information about how to take an intervention to scale in a given setting (Rawlins 2008). Over the last few years, large randomised controlled trials (RCTs) have shown convincing beneficial effects of artesunate over quinine to treat severe malaria, (Dondorp et al. 2010) male medical circumcision to prevent HIV infection (Siegfried et al. 2009) and limiting the use of fluid bolus in the management of paediatric septic shock (Maitland et al. 2011). However, several years after results of these trials were published, quinine remains the standard of care in most high-malaria-burden countries, (Ford et al. 2011) coverage of male medical circumcision in southern Africa is below 10% in most high-burden countries, (Njeuhmeli et al. 2011) and a year after the publication of the trial results, guidelines for the management of septic shock had yet to be revised in any Africa country (Ehrhardt & Meyer 2012). "
    Tropical Medicine & International Health 02/2013; DOI:10.1111/tmi.12075 · 2.30 Impact Factor
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    • "Since more than 40% of the world's population is at risk of malaria, antimalarial drugs have become a favorite target of counterfeiters. For instance, counterfeit artemisinins are a significant problem in Southeast Asia (Singh, 2004) and are expected to become a serious problem in Africa where artemisinin combination therapy is being implemented (Dondorp et al., 2010). It has been estimated that the counterfeit medicine market is worth some US$ 35 to 44 billion per year (Newton et al., 2006). "
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