Drug-resistant malaria on Burma border threatens malaria control

The concern is that this will open the way for resistance to spread to India and then Africa, where most deaths from malaria occur. Eliminating malaria might then prove impossible.

The path from South-East Asia to Africa is how resistance to other antimalarial drugs has spread in the past.

The new research from a joint programme between Oxford University and Mahidol University in Thailand is reported in The Lancet.

The study coincides with research by the same group published in the journal Science. Along with colleagues in the USA, they identify a major region of the malaria parasite genome that is associated with resistance to these drugs.

These two studies, funded by the Wellcome Trust and the National Institutes of Health, follow the first reports of drug resistance in 2009 from western Cambodia.

The new cases of resistance have been observed 800km away, at the Thailand-Burma (Myanmar) border.

Professor Nick White, one of the study’s lead scientists, said in a video interview for Oxford University: ‘The concern was that [resistance] would reach Myanmar-Burma where malaria control is very poor. It would be pretty much cat out of the bag at that point. And I have to say that the recent evidence suggests that it has spread.

‘How long would it take for the resistance to reach Africa? Key question.

‘Glass half empty would say: you can be working in a factory in a forested area of Cambodia, hop on a plane and be in Africa within 24 hours to infect mosquitoes there.

‘Glass half full would say: Hopefully these parasites, which are Cambodian parasites, have not yet adapted to the mosquitoes in Africa.’

Could render our best drugs obsolete

The most effective antimalarial drug is artemisinin. The artemisinin derivatives, most commonly artesunate, have the advantage of acting more rapidly and having fewer side-effects than other antimalarial drugs and, until recently, malaria parasites had shown no resistance against them.

They are recommended to be used only in conjunction with one or more other drugs as artemisinin-based combination therapies (ACTs) because of fears over the possible development of resistance. ACTs have contributed substantially to the recent decline in malaria cases in most regions.

Resistance to artemisinin makes the drugs less effective and could eventually render them obsolete, putting millions of lives at risk.

François Nosten, Director of the Shoklo Malaria Research Unit – where the work was carried out – and professor of tropical medicine at Oxford University, said: ‘We have now seen the emergence of malaria resistant to our best drugs, and these resistant parasites are not confined to western Cambodia.

'This is very worrying indeed and suggests that we are in a race against time to control malaria in these regions before drug resistance worsens and develops and spreads further. The effect of that happening could be devastating. Malaria already kills hundreds of thousands of people a year – if our drugs become ineffective, this figure will rise dramatically.’

Evidence for drug resistance

In the Lancet study, Oxford-Mahidol University researchers based at the Shoklo Malaria Research Unit on the border of Thailand and Myanmar measured the time taken to clear parasites from the blood stream of over 3,000 patients over a 10 year period between 2001 and 2010.

The average time taken to reduce the number of parasites in the blood by a half – known as the ‘parasite clearance half-life’ – increased from 2.6 hours in 2001 to 3.7 hours in 2010. This is a clear sign that the drugs are becoming less effective.

The proportion of slow-clearing infections – defined as a half-life of over 6.2 hours – increased over this same period from 6 out of every 1000 infections to 200 out of every 1000 infections.

By examining the genetic make-up of the parasites, the researchers provide compelling evidence that the decline in parasite clearance rates is due to genetic changes in the parasites which make them resistant to the drugs.

This finding is supported by the evidence reported in Science identifying a region in the genome of the P. falciparum malaria parasite that shows a strong association with slow parasite clearance rates. While the actual mechanism involved is not clear, the region contains several candidate genes that may confer artemisinin resistance to the parasite.

Challenge to contain resistance

Professor White of Oxford University, who is chair of the WorldWide Antimalarial Resistance Network (WWARN), added: ‘This new study suggests that containing the spread of resistance is going to be even more challenging and difficult than we had first feared.’

He recently wrote an article in the International Herald Tribune with Frank Smithuis of Medical Action Myanmar, saying: ‘Myanmar, which has the largest malaria burden in the region, is the next frontier in the spread of artemisinin resistance, and the likely conduit for its spread west. Lying between the Andaman Sea and the Himalayas, it is in a unique position to halt the spread of resistance to India and Africa.

They add: ‘It is estimated that spread of artemisinin resistance to Africa could cost 100,000 to 200,000 children’s lives per year. The world cannot afford to lose this battle. Immediate and large scale action in Myanmar is needed to prevent further spread of these artemisinin-resistant malaria parasites. Myanmar needs substantial financial support to prevent a looming malaria catastrophe.’