The Shay Rebellion | Christopher Shay

The growing threat of drug-resistant malaria

Near the Thai – Cambodian border, one fatal strain of malaria shows signs of overcoming even the most potent drug designed to destroy it.

Artemisinin, a drug first isolated by Chinese scientists four decades ago but only recently embraced by the international community, was supposed to be the frontline medicine against malaria for years to come, and in Cambodia, it is the only effective drug against the most lethal form of malaria, Plasmodium falciparum.

“Artemisinin combination therapies are the most important antimalarial drug in the armoury of antimalarials and central to global efforts to control malaria,” Shunmay Yeung, a researcher at the Health Policy Unit at the London School of Hygiene and Tropical Medicine, said. “They are the fastest acting. They are safe and well tolerated… and can be used in both uncomplicated and severe malaria.”

But for five decades, western Cambodia has been the world’s crucible for drug-resistant malaria, and artemisinin appears to be following the same path of previous antimalarials to obsolescence. First, chloroquine became ineffective, then sulfadoxine-pyrimethamine, and more recently the parasite became tolerant to mefloquine.

But this time, if artemisinin falls by the wayside, there are no known drugs that can replace it.

“If the parasite becomes resistant to artemisinin, we don’t have another drug for treatment in the world. Artemisinin is the only one that is strong enough to kill enough parasites” Duong Socheat, the director of the National Centre for Malaria, said, “If malaria becomes resistant to Artemisinin, many in the world will die,” he said.

Amir Attaran, who holds Canada Research Chair in Law, Population Health and Global Development Policy at the University of Ottawa, echoed Duong Socheat’s fears.

“If the artemisinin drugs were lost to resistance before an alternative were found — and none is on the horizon — then there’s nothing else and malaria is untreatable. We are back to the Stone Age, basically,” he said.

Every year since 2000, the National Centre for Malaria has run tests determining the effectiveness of artemisinin in western Cambodia, and every year the drug takes longer to clear the malaria parasite from the body, indicating that the disease is quickly developing resistance.

“The drug used to take 24 hours to clear the parasite now it can take more than 72 hours,” Duong Socheat said.

A few factors conspire together to make western Cambodia the epicentre for malaria drug resistance. People from all around the region come to this area for gem mining, according to Duong Socheat. The transient population from across southeast Asia allows different strains to mix together when mosquitoes bite more than one infected person, increasing the likelihood of gene mutation.

Plus, almost all the pharmacies in the region are unregulated private providers, who are rarely properly trained and often prescribe improper treatments and dosages. One common practice is to sell cheap sachets filled with unknown drugs, which often include quinine, vitamins and artemisinins.

“It’s not a proper treatment,” Duong Socheat said, “Even the right drug with the wrong dose is a problem. When you don’t have proper treatment, dosages, or good doctors, you have contributions to resistant.”

Even if patients avoid drug cocktail sachets, monotherapy dosages of artemisinins are still widely available. Monotherapy rapidly increases the tolerance rate of the malaria parasite. Artemisin is a fast-acting, potent drug, but it needs to be prescribed with a slower partner drug to wipe out any residual malaria parasites which might be resistant to artemisinin.

“Artemisinin and its derivatives… are recommended for use in combination with other groups of antimalarial drugs and not by themselves. Thus, it is important that national policy in Cambodia be in line with the international and World Health Organisation guidelines of not using artemisinin as monotherapies. This will prolong the effectiveness of the artemisinin,” Awash Teklehaimanot, the director of the malaria program at Columbia University, said.

Currently, the policy in Cambodia does emphasize combination therapy, but experts with local experience say more needs to be done.

“A ban on the import and selling of oral artemisinin monotherapies is going to be issued, but everybody agrees that this is not enough in itself. It needs to be accompanied by enforcement, training, lots of communication and incentives to change the behaviour of providers and consumers,” Shunmay Yeung said.

The National Centre for Malaria with the help of the World Health Organization has been working closely with the private pharmacists, educating them about the importance of proper combination therapies, but with the pharmaceutical distribution system still relying on unlicensed distributors, the National Centre for Malaria faces an uphill battle in changing people’s behaviours.

Despite efforts by the National Centre for Malaria to encourage combination therapy, there’s evidence that patients sometimes avoid taking the partner drug even when combination therapy is properly prescribed. Currently, the nationally recommended therapy is artemisinin and mefloquine blister-packaged together, allowing people to avoid taking the partner drug, mefloquine, which has more adverse side effects.

“Ideally, the drugs should be co-formulated, ie both drugs in one tablet so they cannot be taken separately,” Shunmay Yeung said, “The main reason being that at a global level there has been a long delay in a good quality, effective co-formulated ACT [artemisinin combination therapy] becoming available.”

To top it all off, counterfeit malaria drugs, which contain just enough artemisinin to pass a dye test indicating they contain the drug, have contributed to malaria resistance, according to a 2006 report written by 21 of the world’s top malaria experts..

“We work with private providers in the area to make them stop providing monotherapy treatments and asking them to use combination therapy,” Duong Socheat said.

Clive Schiff, a professor at the Johns Hopkins Malaria Research Institute, emphasized the importance of the National Centre for Malaria’s success in the global fight against the disease that infects nearly 250 million people every year, according the World Health Organisation.

“It would be a global disaster to lose artemisinin… It must be used with care and in the proper manner to conserve its efficacy and to manage any signs of resistance or tolerance by the malaria parasite,” he said.

This rising threat comes at time when real gains have been made against the parasite in Cambodia. According to Duong Socheat, ten years ago more than a 1,000 Cambodians died every year from malaria, and now, about 200 Cambodians die.

But modeling done by the Mahidol-Oxford Tropical Medicine Research Unit suggests that the only way to stop a resistant malaria parasite in Cambodia is to eradicate the most fatal strain of malaria completely.

“The mathematical modeling department from our unit has modeled different containment strategies. All strategies tested reveal that the only way to get rid of the resistant phenotype is by getting rid of all falciparum malaria in Western Cambodia,” Arjen Dondorp, the deputy director of Mahidol-Oxford Tropical Medicine Research Unit, said.

Dondorp recommended a three prong attack against the disease. He stressed the need to get artemisinin monotherapies out of the private sector and replace them with combination therapy, distribute insecticide-treated bednets and repeatedly do mass screenings and treat the infected with combination therapy.

Though Duong Socheat is optimistic that Cambodia can eliminate malaria parasites in the country by 2015, Amir Attaran paints a darker picture. Though reduction is possible, he says “to talk of eradicating malaria is nonsense.”

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