Nature Medicine | Spoonful of Medicine

Antimalarial armament remains strong, despite lingering concerns over drug resistance

naturemed20111108.jpgEarlier this month, Indian regulatory authorities granted conditional approval to the country’s first homegrown drug, a malaria-fighting pill that combines a new synthetic form of artemisinin with an older antimalarial compound called piperaquine. If the decision is ratified by the country’s Central Drugs Standard Control Organization, the new drug — developed from start to finish by the New Delhi-based pharmaceutical company Ranbaxy Laboratories — will add to doctors’ armament of artemisinin-based combination therapies (ACTs), the World Health Organization’s medicine of choice for tackling the parasite. Yet with so many options, the question is: which ACT is actually best at treating the infectious disease?

A study comparing four ACTs should go a long way to answering that question. In a randomized clinical trial involving more than 4,100 newly infected children at 12 sites across seven sub-Saharan African countries, three widely-used artemisinin variants proved equally effective at ridding youngsters of the malaria parasite. All three ACTs cleared the infection in more than 95% of trial participants up to 63 days post-treatment. But a fourth combo drug — a newer antimalarial that combines chlorproguanil, dapsone and artesunate — proved only around 85% effective, and was removed from the study after its maker, London-based GlaxoSmithKline, pulled it from the market in 2008 because of adverse effects. The results were published today in PLoS Medicine.

“This should reassure people that these are good drugs that are highly effective and well tolerated and that we should get them to people that need them,” says Nicholas White, a malaria epidemiologist at the University of Oxford in the UK, who was not involved in the study.


The three favorable ACTs are, naturally, combinations of synthetic forms of artemisinin, the active ingredient found in the Chinese medicinal herb Artemisia annua, with other anti-malaria drugs that are included in the mix to reduce the chance of malaria parasites developing resistance to the stronghold artemisinin. The most widespread and oldest ACT — called AL for artemether-lumefantrine — was first used in clinical trials in 1998. Although it is still quite effective throughout the world, its twice-daily dosing creates compliance issues. The combination of artesunate and amodiaquine, or ASAQ, only requires once-daily dosing and has been quickly adopted since its release in 2007. The new kid on the block is a once-daily combination of dihydroartemisinin and piperaquine, or DHAPQ, which was approved in the EU under the brand name Eurartesim earlier this year.

Although all three were equally robust at eliminating malaria from the bloodstream after a single infection, two of the medicines — DHAPQ and ASAQ — provided better protection against secondary infections than AL, the new study found.

The authors suspect that these two ACTs may persist in the blood longer, acting as a prophylactic against new infectious mosquito bites. But the longer action of these drug combinations comes with a price: it may allow new parasites to adapt and become resistant to the drugs, an effect that has plagued malaria treatment worldwide. The anti-malarial chloroquine, once used extensively, is no longer effective in some parts of the world because of parasite resistance, and mosquitoes are developing resistance to pyrethroids, the insecticides used on bednets. In Southeast Asia, ACTs are less successful at treating malaria, raising concerns about resistance to the first-line arteminisin-based medicines in that region — and the possible spread of those parasites to Africa.

The high and comparable efficacy of ACTs in Africa, as demonstrated in this study, suggests that such resistant parasites have not yet reached the region, says White, who won last year’s Gairdner Prize for his work on developing arteminisin as an anti-malaria drug. “A great worry is that if those parasites would get to Africa, these results would no longer be excellent,” he says. “We have to be vigilant about keeping resistance from getting to Africa.”

Image: bottle of cloroquine, which has been replaced by ACTs as the recommended anti-malaria medication due to parasite resistance. Photo by Mat Honan on flickr under Creative Commons licensing

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