Drug-resistant malaria in Cambodia

Malaria parasites in western Cambodia have become resistant to artemisinin-based therapies, the first-line treatment for malaria, according to a study by Oxford University researchers based in Thailand and published in the New England Journal of Medicine.

Signs of artemisinin resistance have been reported in the region already, but this new research is the first detailed study of the problem. Resistance to the drugs could eventually render them obsolete, putting millions of lives at risk.

Professor Nick White, co-author of the study, believes the implications of the findings are potentially huge: ‘Artemisinins are essential weapons in our war against malaria. If they become ineffective, we have no immediate replacement. The consequences could be devastating. Elimination of malaria will not be possible and millions of lives could be lost.’

Malaria kills more than a million people each year, mainly young children and pregnant women. It is caused by malaria parasites, which are injected into the bloodstream by infected mosquitoes. The most deadly form, Plasmodium falciparum, is responsible for nine out of ten deaths from malaria.

Artemisinin is the most effective anti-malarial drug we have. Artemisinin derivatives have the advantage over other anti-malarial drugs, such as chloroquine and mefloquine, in having few side effects and – until now – malaria parasites had no resistance against it.

Although the drugs – most commonly in the form of the derivative artesunate – can be used on their own as a monotherapy, fears over the possible development of resistance mean that they are usually given in conjunction with one or more other drugs. These artemisinin-based combination therapies (ACTs) are now recommended by the WHO as the first-line treatment for uncomplicated falciparum malaria in all endemic countries.

Following increasing reports that the efficacy of artemisinin monotherapies and combination therapies were declining in western Cambodia, researchers at the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme, based in Bangkok, studied the susceptibility of P. falciparum parasites to the drugs. The Research Programme is a collaboration between Mahidol University in Bangkok and the University of Oxford, supported by the Wellcome Trust.

The researchers studied 40 patients in Pailin, western Cambodia, and 40 patients in Wang Pha, north-western Thailand. Each was given either the artemisinin-derivative artesunate or a combination of artesunate and mefloquine.

On average, patients in Thailand were clear of parasites in 48 hours; in western Cambodia this took 84 hours – in other words, it took almost twice as long to clear the parasites in Cambodia as it did in Thailand.

Out of the 20 patients treated solely with artesunate in each country, there were recurrences of the infection in six patients in western Cambodia compared to just one person in Thailand. Of the 20 patients treated with the combination therapy, infection recurred in two patients in Cambodia compared to one in Thailand. These results again suggest that artemisinin was less effective on the Cambodian parasites.

'Our study suggests that malaria parasites in Cambodia are less susceptible to artemisinin than those in Thailand,’ says Dr Arjen Dondorp, lead author of the study. ‘This means that it takes longer to kill the parasites. 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.

'With artesunate losing its potency, ACTs rely much more on the weaker partner drug, increasing the risk that resistance also evolves towards the partner drug. This has very important consequences for the lifespan of ACTs. Losing ACTs would be a disaster for malaria control.’

With signs of artemisinin-resistance occurring in other areas of Cambodia and Thailand, Dr Dondorp says swift action is required to contain the spread.

‘Preventing the spread of resistant parasites when they emerge is crucial,’ he says. ‘The use of combination therapies is very important for this. I would like to see a ban on artesunate monotherapy except for specific cases.’ 

The study was funded by the Wellcome Trust, the Li Ka Shing Foundation, and the Global Malaria Programme of the World Health Organisation (through grants from the Bill and Melinda Gates Foundation and the Western Pacific Regional Office).