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, led by Professor Nick White of Oxford University, compared treatment with artesunate, which is used in Asia to treat severe malaria, against quinine, which has been in use worldwide for over 300 years.
Funded by the Wellcome Trust and published in the medical journal The Lancet, the trial 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 1 million people each year, mainly young children and pregnant women. It 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.
In this major study, an international consortium of researchers compared quinine against the more recent drug artesunate, both given either intravenously or by injection. They showed that treatment with artesunate reduced the number of deaths from severe malaria by 22.5%.
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.
‘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,’ says Professor White of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme in Bangkok, Thailand.
‘We recommend that artesunate should now replace quinine for the treatment of severe malaria in both children and adults everywhere in the world.’
Children treated with artesunate were also less likely to slip into a deep coma or have seizures after the treatment was started. 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.
Dr Olugbenga Mokuolu from the University of Ilorin in Nigeria, one of the trial centres, says: ‘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 8 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.
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 artemisinin) have steadily gained acceptance throughout the world.
In uncomplicated malaria, artemisinin compounds such as artesunate are now part of the artemisinin 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 current study. The new trial 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.
A major factor limiting the use of artesunate has been the lack of availability of a product satisfying international good manufacturing standards. The most widely used product, evaluated in this study, does not yet have this certification but still proved to be superior to quinine.
The trial has been welcomed by Sir Mark Walport, Director of the Wellcome Trust: ‘This is an extremely important clinical trial of the treatment of malaria, showing improved survival of patients with severe malaria in Africa. 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.’