The Threat of Artemisinin-Resistant Malaria

An article co-authored by MORU’s Professor Arjen Dondorp and published in the New England Journal of Medicine highlights the challenges posed by the emergence of artemisinin resistant malaria parasites on the Cambodia-Thailand border, and what this means for the worldwide fight against malaria.

The threat posed by artemisinin-resistant malaria requires an effective response that ensures that critical operational and basic research questions be answered quickly. The authors call on researchers, funders, and policy leaders to recognize the urgency of the problem and take action to address the important knowledge gaps, and highlight that it is essential to share data and research tools.

In the last decade, artemisinin-based combination therapies (ACTs) and insecticide-treated nets have contributed to significant reductions of the malaria burden in many areas of the world. Losing the artemisinins to resistance would be a disaster for the control and treatment of malaria and would bring eradication efforts to a standstill.

MORU is currently leading the “Tracking Resistance to Artemisinins Collaboration” (TRAC), a unique multicentre multinational collaboration, funded by DFID, to describe the epidemiology of artemisinin resistant falciparum malaria in the region and beyond, which also provides a unique platform for basic research into the biology and molecular mechanisms underlying artemisinin resistance.

The full article can be viewed here: http://www.nejm.org/doi/full/10.1056/NEJMp1108322

AQUAMAT Abstract

AQUAMAT; an open randomised comparison of artesunate versus quinine in the treatment of severe falciparum malaria in African children

Background

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 recent evidence from a large multicentre trial in Asia suggests that artesunate is associated with a lower mortality.

Methods

An open label randomised comparison of parenteral artesunate and parenteral quinine in children (< 15 years) with severe falciparum malaria was conducted in 11 centres in 9 African countries from October 2005 to July 2010.

Findings

In total 5425 children were enrolled. Following artesunate treatment 8.5% (230/2712) of the patients died compared with 10.9% (297/2713) following quinine, an odds ratio stratified for study site of 0.75 (95%CI 0.63 to 0.90), and a relative reduction of 22.5% (95% CI 8.1 to 36.9%, p=0.0022). There were no differences in the incidence of neurological sequelae, but both the development of coma (65/1769; 3.7% with artesunate and 92/1716; 5.4% with quinine: OR 0.68; 95%CI 0.49 to 0.94) and convulsions (224/2712; 8.3% with artesunate and 273/2713; 10.1% with quinine; OR 0.80; 95%CI 0.66 to 0.97) were significantly less frequent in artesunate recipients (p=0.0200 and p=0.0199 respectively). Post treatment hypoglycaemia was also less frequent in artesunate recipients 48/2712 (1.8%) compared with quinine 75/2713 (2.76%); OR 0.63 (95% CI 0.43 to 0.91), p = 0.0134. Artesunate was very well tolerated and there were no serious drug related adverse effects.

Interpretation

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 everywhere as the treatment of choice for severe falciparum malaria.

View the AQUAMAT abstract at The Lancet website

Download the full manuscript and comments here.

Media release from the Wellcome Trust
6 November 2010

MAJOR CLINICAL TRIAL PROMPTS CALL FOR CHANGE TO TREATMENT GUIDELINES FOR SEVERE MALARIA WORLDWIDE

The largest ever clinical trial in patients hospitalised with severe malaria has concluded that the drug artesunate should now be the preferred treatment for the disease in both children and adults everywhere in the world. The study, funded by the Wellcome Trust, is published today online in the journal The Lancet.

An international consortium of researchers, led by Professor Nick White of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme in Bangkok, Thailand,  compared treatment with artesunate, which is used in Asia to treat severe malaria, against quinine, which has been in use worldwide for over three hundred years. The trial – known as the African Quinine v. Artesunate Malaria Trial (AQUAMAT) – was carried out over a five year period in hospitals across nine African countries and studied 5,425 children with severe malaria.

Severe malaria kills nearly a million people each year, mainly young children and pregnant women. It is caused by parasites which are injected into the bloodstream by infected mosquitoes. Severe malaria is often the main reason why children are admitted to hospital in Sub-Saharan Africa, and one in ten of these children die.

For over three centuries, doctors have relied upon the bark of a South American tree to treat tropical fevers. This bark gives quinine, a bitter medicine used to flavour tonic water, prevent night cramps, and cure malaria. Quinine is a reliably effective drug, but it is difficult to give by injection and has unpleasant side effects, some of which are potentially dangerous.

AQUAMAT compared quinine against the more recent drug artesunate both given either intravenously or by intramuscular injection, and showed that treatment with artesunate reduced the number of deaths from severe malaria by 22.5% compared with quinine. With artesunate treatment 8.5% of the patients died, compared to 10.9% with quinine. The results were very similar in all the study sites.

Children treated with artesunate were also less likely to slip into a deeper coma or have seizures after the treatment was started. Severe hypoglycaemia – dangerously low blood sugar – was also less common in children treated with artesunate. In addition, artesunate was easy to administer, well tolerated, and proved very safe.

Professor White comments: "For over a century, quinine administered by injection has been the best treatment available for treating severe malaria, but thanks to the development of the artemisinin compounds, we now have a safer and much more effective treatment. We recommend that artesunate should now replace quinine for the treatment of severe malaria in both children and adults everywhere in the world."

Artesunate is derived from a Chinese herb called qinghao (Artemisia annua). Nearly forty years ago, Chinese scientists reported that an extract of this herb called was an effective anti-malarial. These reports were treated initially with suspicion but the compounds derived from it (such as artemisinin) have steadily gained acceptance throughout the world. In uncomplicated malaria, artemisinin compounds such as artesunate are now part of the artemisinin-based combination treatments (ACTs) recommended everywhere in the world.

Five years ago the then largest ever trial in patients hospitalized with severe malaria showed that artesunate, given by injection, reduced the death rate compared with quinine. However, this trial was conducted in Asia and most of the patients studied were adults, so there was uncertainty over whether artesunate injection should replace quinine as a treatment of severe malaria in children in Africa, where most of the deaths occur. Today nearly all the children admitted to hospital with severe malaria in Africa still receive quinine.

Dr Arjen Dondorp, Professor White and colleagues from Mahidol University and the University of Oxford, who conducted the original study in Asia, also led the AQUAMAT study. AQUAMAT was carried out in eleven hospitals across Mozambique, Tanzania, Kenya, Uganda, Rwanda, the Democratic Republic of Congo, Nigeria, Ghana, and The Gambia and involved over 200 collaborators. The trial was funded entirely by the Wellcome Trust, a global charitable foundation, and received no funding from the pharmaceutical industry.

Dr Olugbenga Mokuolu from the University of Ilorin in Nigeria, one of the trial collaborating centres, adds: "Severe malaria is a terrible burden on the African continent and across the developing world and we need the best treatments available to combat it. If half of the estimated eight million children annually who suffer from the disease could be treated with injectable artesunate, we could potentially save 100,000 young lives each year. For those of us who treat malaria in Africa, this trial is a turning point. Finally we have a better treatment to offer to our malaria patients."

The trial has been welcomed by Sir Mark Walport, Director of the Wellcome Trust, which supported both the original trial in Asia and the subsequent AQUAMAT study.

"This is an extremely important clinical trial of the treatment of malaria, showing improved survival of patients with severe malaria in Africa," says Sir Mark. "There are still many hurdles to overcome and we must be vigilant to protect against resistance to these new drugs and against a market in counterfeit drugs. But Professor White and colleagues have shown that we have the potential to save the lives of hundreds of thousands of children."

Contact

 Craig Brierley

Senior Media Officer

The Wellcome Trust

T: +44 (0)20 7611 7329

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Notes for editors

Dondorp, A. et al. AQUAMAT: an open randomised comparison of artesunate versus quinine in the treatment of severe falciparum malaria in African children. Lancet; e-pub 6 Nov 2010

About the Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk

AQUAMAT press release
6 November 2010

ARTESUNATE SUBSTANTIALLY REDUCES MORTALITY IN AFRICAN CHILDREN WITH SEVERE MALARIA AND SHOULD REPLACE QUININE AS TREATMENT OF CHOICE (AQUAMAT study)

Compared with the standard treatment of quinine, artesunate reduces mortality by around a quarter in children with severe falciparum malaria. Thus artesunate should replace quinine as the treatment of choice worldwide. This new study (the AQUAMAT trial) is published Online First and in an upcoming Lancet, and is being presented at the American Society for Tropical Medicine and Hygiene (ASTMH) meeting in Atlanta on November 6. It is written by Professor Nicholas White of the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and colleagues from the AQUAMAT study group. The study was funded by The Wellcome Trust.

Falciparum malaria is a major contributor to child mortality in Africa and one of the main causes of paediatric hospital admission across sub-Saharan Africa. Many deaths occur in or near home, but for children who are admitted to hospital with severe malaria and receive parenteral antimalarial treatment, about one in six will die. Despite being the standard treatment for children with severe falciparum malaria, quinine has its problems, causing a number of side effects.

Following the successful SEAQUAMAT trial (in which artesunate reduced malaria mortality in Southeast Asian adults to 14% from 23% with quinine treatment – which was coordinated by the Faculty of Tropical Medicine, Mahidol University in Thailand), WHO in 2006 changed its guidelines to recommend artesunate for severe malaria in adults. However, it was felt that the disease course could be different in African children and so a separate study – AQUAMAT- was needed to establish the benefits of artesunate in African children.

This randomised trial was undertaken in 11 centres in nine African countries, and was coordinated from the Faculty of Tropical Medicine, Mahidol University. Children (<15 years) with severe falciparum malaria were randomly assigned to intravenous or intramuscular artesunate on the one hand, or intravenous or intramuscular quinine on the other. 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 (11%) assigned to quinine treatment; thus relative risk of death was reduced 22.5% for artesunate versus quinine. Incidence of neurological side-effects did not differ significantly between groups, but the development of coma (3·5% with artesunate vs 5·1% with quinine), convulsions (8·3% vs 10·1%), and deterioration of coma score (6·1% vs 7·7% with quinine) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment low-blood sugar (hypoglycaemia) was also less frequent in patients assigned to artesunate than in those assigned to quinine (1·8% vs 2·8%). Artesunate was well tolerated, with no serious drug-related adverse effects.

The authors believe that this life-saving benefit of artesunate compared with quinine in severe malaria must derive from its greater intrinsic ability to kill multiple stages of the malaria parasite.

Furthermore, they point out that the ease and safety of parenteral artesunate are important practical advantages. Artesunate is more expensive to buy, but quinine is more expensive to administer. The authors say: “A major factor restricting the deployment of artesunate has been unavailability of a product satisfying international good manufacturing standards. The most widely used product, assessed in this study, does not yet have this certification, which has prevented deployment in some countries. This barrier must be overcome speedily so that parenteral artesunate can be deployed in malaria-endemic areas to save lives.”

They conclude: “Artesunate should now become the treatment of choice for severe malaria for children and adults worldwide. Malaria causes an estimated 800 000 deaths every year in African children. Severe malaria is often the most common admission diagnosis in febrile children, so a change in treatment policy from quinine to artesunate has the potential to save thousands of children’s lives every year. If 4 million African children with severe malaria every year were to receive prompt treatment with parenteral artesunate instead of quinine, and the benefits were similar to those recorded in this trial, then approximately 100 000 lives might be saved per year.”