Parasite starting to overcome frontline drug regimen
WASHINGTON — Like a basketball team that plays best against its toughest opponents, the parasite that causes malaria is showing signs of thwarting the most potent drugs currently used against it. Scientists report that top-line drugs called artemisinins take nearly twice as long to knock out the parasite in people who contract malaria in western Cambodia as the drugs take in other areas — suggesting the parasite is finding ways to thwart the drugs’ effects.
Physician Arjen Dondorp of Mahidol University in Bangkok presented the findings on October 27 in Washington, D.C. at a joint meeting of the Infectious Diseases Society of America and the American Society for Microbiology.
Hints of artemisinin weakening have emerged bit by bit over the past few years in a handful of reports from Southeast Asia, and most scientists are still loath to call the trend outright drug resistance. But the reports are worrisome, says Philip Rosenthal, an infectious disease physician at the University of California, San Francisco.
“If we lose the artemisinins, that would be a major problem,” he says. “The pipeline for new antimalarial drugs … is very limited now. We’re dependent on artemisinins to be the backbone of therapy for years to come.”
Many scientists share Rosenthal’s uneasiness about the Cambodia findings.
“It could potentially be disastrous,” says Steven Meshnick, a parasitologist at the University of North Carolina at Chapel Hill. Ironically, the unsettling news comes at a time when malaria seems to be in retreat in some parts of the world, thanks in part to increased funding for programs, he says.
Artemisinins are playing a substantial role in that favorable trend. Derived from sweet wormwood extracts, the artemisinins have shown dramatic success against even Plasmodium falciparum, the parasite that causes the most lethal bouts of malaria. But because artemisinins are quick-acting, potent drugs, they work best when taken in tandem with one of the other slower-acting antimalaria drugs. The artemisinin wipes out most of the parasites, and the other drug lingers to mop up the stragglers. That keeps any lingering parasites from surviving to cause resistance, says Meshnick.
The World Health Organization now recommends such combination therapy with artemisinins as a first-line therapy against malaria worldwide.
But in Cambodia, up to three-fourths of artemisinins are taken on their own. And many people stop taking them early, making parasite clearance from the body less than a sure thing.
What’s more, since artemisinins have been used in Cambodia for decades, malaria in that region has had a long time to evolve a way around them, Dondorp says.
To assess any budding signs of resistance, Dondorp and his colleagues tested 40 malaria patients in western Cambodia and 40 others being treated in nearby Thailand. Patients in Cambodia took more than 80 hours on average to clear the parasite from their bodies after receiving a standard combination therapy that included an artemisinin. In Thailand, clearance took only 48 to 60 hours after a similar treatment. There were also more cases of outright treatment failure in the Cambodian group.
Cambodia has been a crucible of resistant malaria for decades. As early as the 1950s and 1960s, public health officials in Cambodia started to see resistance to other antimalaria drugs. The trend has continued in recent decades.
Many factors may be conspiring to give Cambodia this dubious distinction. The hot climate is certainly right for malaria. But beyond that, Meshnick says, people from all over Southeast Asia show up in western Cambodia for gem mining, and mosquitoes that spread malaria there might mix many parasitic strains by hopping from person to person. That scenario invites gene recombination and mutations, risking the development of virulent drug-resistant strains, he says.
Also, the people in western Cambodia aren’t particularly poor. Ironically, a decent income makes them less dependent on regulated, government-supervised drug programs for malaria and allows them to buy drugs on the open market — with risks.
Dondorp says roughly half of unregulated artemisinin pills bought in Cambodia are fake. This thriving trade in counterfeit artemisinin began with pills without any drug content whatsoever, but these were foiled by dye tests that exposed them. Now the black-market sellers add 10 percent artemisinin to circumvent simple dye tests that detect a lack of the drug.
“This is actually worse,” Dondorp says, since a weak dose exposes the parasite to the drug and increases the risk of resistance.
The plan for Cambodia starts simply enough: “First we need to get monotherapy out of the market and replace it with combination therapy,” Dondorp says. “If we do that, malaria cases will go down by 60 to 70 percent.”
While that strategy would help in the short run, the surviving parasites would be more resistant than ever, he concedes. “We would have to continue double therapy until eradication, and our models show that that would take 10 years.”
From a joint meeting of the Infectious Diseases Society of America and the American Society of Microbiologists, Washington, D.C., Oct. 27, 2008
Abstract # 3643
Dondorp A. Resistance to artemisinin-based malaria treatment regimens: Does it exist?
Wongsrichanalai C and Meshnick SR. Declining Artesunate-Mefloquine Efficacy against Falciparum Malaria on the Cambodia–Thailand Border. 2008. Emerging Infectious Diseases, May, Vol. 14.