The study, which was funded by the Global Malaria Programme of the World Health Organisation, the Wellcome Trust and the Li Ka Shing Foundation, was the work of researchers from the Wellcome-Mahidol University Oxford Tropical Medicine Research Programme, based in Bangkok, Thailand, and colleagues at other research centers, and is published in the 30 July issue of the New England Journal of Medicine, NEJM.
The Research Programme in Bangkok is a collaboration between Mahidol University, Bangkok, and the University of Oxford, supported by the Wellcome Trust. The WHO Programme funds came from grants provided by the Melinda Gates Foundation and the Western Pacific Regional Office.
Malaria is a potentially fatal disease that kills more than a million people every year; mostly young children and pregnant women. The disease is caused by a parasite called Plasmodium that enters the bloodstream or lymphatic system of humans via bites from the parasite-carrying Anopheles female mosquito.
The most deadly form of malaria is caused by the parasite Plasmodium falciparum which kills 9 out of 10 of the people it infects.
The recommended first line treatment for P. falciparum malaria is combination therapies that use drugs derived from artemisinin which comes from the sweet wormwood plant (Artemisia annua) used by practitioners of Chinese medicine for centuries under the name Qinghaosu.
Drugs based on arteminisin are considered better than other anti-malaria drugs like chloroquine and mefloquine because, until now, malaria parasites appear unable to resist it.
However, recent reports from the Thai-Cambodian border, where resistance to anti-malaria drugs has occured a number of times before, suggest that a strain of malaria parasite is emerging that is resistant to artemisinin-based drugs.
The authors decided to investigate this further by conducting two open-label (that is unlike a blinded trial, doctors and patients knew which drugs they were getting) randomized trials to compared the effectiveness of two anti-malaria treatments in two groups of 40 patients.
One group of patients was in Pailin, western Cambodia, and the other was in Wang Pha, northwestern Thailand.
Each patient received the relevant dosage appropriate to their body weight of either artesunate or a combination of artesunate and mefloquine. (Artesunate is an artemisinin derivative). Thus 20 patients in each country received monotherapy (artesunate on its own) and 20 received combination therapy.
The results showed that on average, the patients in Thailand were clear of the parasite within 48 hours, but in western Cambodia it took nearly twice as long for the parasite to clear: there it took 84 hours.
Another way to test for drug resistance is to see if the disease recurs after treatment. If the drug is effective, the number of parasites should fall during the treatment period and the infection should clear.
In the trials the researchers found that among the patients in each country who received monotherapy, infection recurred in 6 out of 20 patients in western Cambodia and in only 1 of the 20 patients in Thailand.
Similarly, of the 20 patients in each country who were treated with combination therapy, infection recurred in 2 in Cambodia compared with only 1 in Thailand.
Lead author Dr Arjen Dondorp of the Faculty of Tropical Medicine at Mahidol University told the media that:
"Our study suggests that malaria parasites in Cambodia are less susceptible to artemisinin than those in Thailand."
"This means that it takes longer to kill the parasites," added Dondorp, explaining that:
"Artemisinin should clear the parasites at an early stage, preventing them further maturing and reproducing. When the drug's action is impaired, it becomes more difficult to eliminate the parasites from the body."
As the artemisinin derivative loses its potency, artemisinin-based combination therapies (ACTs) begin to rely increasingly on the weaker partner drug, which increases the chance that resistance will also evolve toward the partner drug.
"This has very important consequences for the lifespan of ACTs. Losing ACTs would be a disaster for malaria control," warned Dondorp.
Speculating on what may have caused this decrease in suscpetibility, there are a number of possible contributing factors, although the study iteself did not examine them.
One is the fact that western Cambodia has relied on artemisinin-based drugs for the last 30 years and was one of the first to use ACTs in 2001.
But unfortunately a big problem is the relatively unregulated private sector from which many patients in the region get their anti-malaria drugs, which are often obtained as monotherapies and the treatment courses are often not completed.
Add to this the problem of counterfeit and substandard drugs with insufficient quantities of artemisinin, and you have a high risk scenario for the emergence of drug-resistant forms of malaria.
Whatever the reason, there are also signs that artemisinin-resistance is spreading to other parts of Cambodia and Thailand, and Dondorp says there is no time to waste: we have to act swiftly.
"Preventing the spread of resistant parasites when they emerge is crucial," said Dondorp.
"The use of combination therapies is very important for this. I would like to see a ban on artesunate monotherapy except for specific cases," he added.
Co-author Professor Nick White, Chair of the Wellcome Trust South-East Asia Programme, said the study points to potentially devastating consequences:
"Artemisinins are essential weapons in our war against malaria," he said, and if they become ineffective:
"Elimination of malaria will not be possible and millions of lives could be lost."
"Artemisinin Resistance in Plasmodium falciparum Malaria."
Dondorp, Arjen M., Nosten, Francois, Yi, Poravuth, Das, Debashish, Phyo, Aung Phae, Tarning, Joel, Lwin, Khin Maung, Ariey, Frederic, Hanpithakpong, Warunee, Lee, Sue J., Ringwald, Pascal, Silamut, Kamolrat, Imwong, Mallika, Chotivanich, Kesinee, Lim, Pharath, Herdman, Trent, An, Sen Sam, Yeung, Shunmay, Singhasivanon, Pratap, Day, Nicholas P.J., Lindegardh, Niklas, Socheat, Duong, White, Nicholas J.
N Engl J Med, Volume 361, Number 5, pp 455-467, July 30, 2009.
Additional source: Wellcome Trust .