Researchers pile on evidence of artemisinin resistance at Thai-Cambodia border

by Tatum Anderson, TropIKA.net:

A study published in the New England Journal of Medicine (NEJM) last week has confirmed that malaria parasites in patients living on the border between Cambodia and Thailand are showing signs of resistance to artemisinin-based combination therapies (ACTs).

Researchers showed that patients with malaria in western Cambodia required almost double the amount of time - 84 hours - to overcome malaria ( or clear malaria parasites from their blood) after being treated with ACTs compared with patients in Thailand.

The study, which was carried out by a team of researchers from UK, Thai and Cambodian Institutions (including Mahidol University in Bangkok and the National Center for Parasitology, Entomology, and Malaria Control in Phnom Penh) compared 40 patients with malaria in Pailin Referral Hospital in western Cambodia with 40 patients in the Shoklo Malaria Research Unit (SMRU) clinic at Wang Pha, north western Thailand. In order to establish a more detailed picture of patients' responses to drugs than earlier studies, the Mahidol-led trial, published on July 30, tracked parasite levels in patients at shorter intervals. Researchers also carried out pharmacokinetic studies and other tests including to establish whether the longer clearance times could be attributed to other factors - such as a difference in the ability of the two study groups to absorb the drug. Their tests confirmed that lingering parasites were the result of increased resistance to artemisinin-based drugs. Their findings are of particular concern to malaria control programmes as scientists worry that millions of lives will be at risk if resistance to artemisinin-based therapies develops fully and spreads.

The border between Thailand and Cambodia has historical significance in relation to resistance to anti-malarial drugs. It was here that the first cases of resistance to previously effective anti-malarial drugs - sulphadoxine-pyrimethamine (SP) and chloroquine - were reported. Resistance to these drugs subsequently spread to Africa, where malaria is deadly. Public health experts fear that artemisinin resistance could follow the same trajectory as SP and choloroquine with alarming consequences (see TropIKA.net news stories -1 , 2). A report by US broadcaster PBS on ongoing research at the border is here (https://worldfocus.org/blog/2009/07/16/cambodia-fears-growing-resistance-...).

This latest study is one of four clinical trials commissioned to establish the true extent of artemisinin resistance following anecdotal reports that anti-malarial drugs have been failing in the area over recent years. These trials fall under a multinational programme called the Artemisinin Resistance Confirmation, Characterization and Containment Project (ARC3), a WHO collaboration that is funded by the Bill & Melinda Gates Foundation (the Mahidol trial was also funded by other donors including Wellcome Trust and Li Ka Shing Foundation).

Professor Nick Day, director of the Mahidol - Oxford Tropical Medicine Research Unit at Mahidol University said: "We have to act to stop it from turning into full resistance and spreading to Africa. If we get resistant parasites in Africa, it is an impending disaster."

Concern that drug-resistant strains were emerging was so great that ARC3 was set up in advance of publications such as this latest NEJM one. Pascal Ringwald, who currently oversees ARC3 at WHO, recounted how a presentation on artemisinin resistance at the 2006 meeting of the American Society of Tropical Medicine and Hygiene in Atlanta (by Harald Noedl from the Medical University of Vienna) prompted the first ARC3 meetings. "We had raw data and data from Noedl, and called for a meeting in January 2007, and then everything went very quickly," he said.

ARC3 subsequently began four trials, including one led by Noedl with AFRIMs (the Armed Forces Research Institute of Medical Science, a joint US-Thai military biomedical research institution) that also published a paper in December on artemisinin resistance in western Cambodia. Importantly, the latest NEJM study also showed that drug resistance had not shifted location since the Noedl trial.

Other trials under ARC3 include an AFRIMS trial at Tasanh (another Cambodian site), which aims to establish whether increasing the dose of artemisinin-based therapies can overcome drug resistance without increasing toxicity. The Mahidol-led team are also investigating this at Pailin, Cambodia. Meanwhile a team in Bangladesh has established a control site in the Bandarban region of Bangladesh to confirm that artemisinin-based therapies are effective there.

ARC3 has also tasked other groups (from Baltimore to South Florida), to look at laboratory-based methods to identify and characterize drug resistance. For instance, researchers are investigating the amount of drug that is required to kill a parasite using in-vitro laboratory tests. TropIKA.net has reported on other ARC3 groups searching for parasite genotypesor genetic mutations. These mutations could act as molecular markers to predict whether patients are carrying drug-resistant strains of malaria from simple blood tests. Such markers already exist for chloroquine and SP but not artemisinin-based therapies.

Characterizing artemisinin-resistance is only the beginning. ARC3 has spawned a large containment project aimed at stopping drug-resistant strains before they spread. This Artemisinin Containment Effort project, also funded by the Bill & Melinda Gates Foundation, (see earlier TropIKA.net story), is a US$22.5m collaboration between groups including WHO and the national malaria programmes of both Cambodia and Thailand. It is establishing new drug policies, distributing bed nets and working with the private sector to withdraw artemisinin monotherapies (thought to contribute to drug resistance). The containment project involves extensive screening for malaria, or scouring local villages for asymptomatic carriers of drug-resistant malaria. Public health officials will use malarone, which has no artemisinin component, to treat such patients.

The containment strategy is an audacious plan to avert a public health crisis, but nothing is guaranteed. "This is the first time we have done this kind of containment effort and we do not know if it will be a success," says Ringwald. "Success will depend on whether or not artemisinin resistance spreads."