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Malaria's Drug Miracle in Danger

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Science  14 May 2010:
Vol. 328, Issue 5980, pp. 844-846
DOI: 10.1126/science.328.5980.844

Like many others before it, the latest generation of malaria drugs is losing its punch. This time, can global disaster be averted?

On the frontline.

Chhay Meth, 9, suffers from malaria at her family's home in O'treng in Pailin, a province in western Cambodia where drugs are becoming less effective.

CREDIT: AP/DAVID LONGSTREATH

BANGKOK—Malaria rates are plummeting in many places, and scientists are optimistically talking about ridding entire countries of the disease—or even, in the long run, eradicating it worldwide. But in Southeast Asia, a new threat is looming—one that so far has received little attention but that could wipe out the recent advances and set back the global fight by decades.

Along the border between Thailand and Cambodia, Plasmodium falciparum, the most dangerous of malaria parasites, is showing unmistakable signs of becoming resistant to artemisinin derivatives, the group of powerful drugs that—as part of so-called artemisinin-based combination therapies (ACTs)—have become the cornerstone of malaria treatment worldwide.

For the moment, the drugs still work in the area; they just take more time to do the job. But that is alarming enough, scientists say. If resistance gets worse and starts spreading out from here, the results could be catastrophic. There are few other drugs in the pipeline, and those that are closest to the market may not work against the resistant strain (see sidebar, p. 846). One infected person flying to, say, India or Africa could unleash the resistant parasites there.

Plans are under way to minimize the risk of that happening. The idea is to control malaria as aggressively as possible in the border area, making sure patients don't pass resistant parasites on to mosquitoes, and keeping parasites from being exposed to nonlethal drug levels that could fuel more resistance. Already, large numbers of insecticide-treated bed nets have been distributed in the area, and Cambodia has enacted a ban on the sale of so-called monotherapies, pills that contain artemisinin but lack the double whammy provided by the second drug in an ACT.

General needed.

Nicholas White says the fight against drug resistance “is a war.”

CREDIT: M. ENSERINK/SCIENCE

The World Health Organization (WHO), which coordinates the containment effort, bills it as unprecedented; when previous malaria drugs started becoming ineffective, the world sat by and watched it happen, says Robert Newman, head of WHO's Global Malaria Programme. But some malaria experts aren't satisfied. “There have been endless meetings but not enough action,” says Nicholas White, who's widely considered the dean of malaria research in Asia. Because millions of lives are at stake, White, employed by the British Wellcome Trust and the University of Oxford but stationed at Mahidol University in Bangkok since 1981, says the best strategy would be to eliminate malaria from the border area altogether. That idea, discussed widely a few years ago, has so far gone nowhere.

Malaria scientists who talked to Science were careful not to come down too hard on WHO, because the agency is chronically understaffed and because they want to see Newman—a respected malaria veteran who's been on the job less than a year—succeed. But they say the agency needs to step up its efforts, and the world should pay more attention. “Blame is not relevant, but outrage is entirely appropriate,” says malariologist Christopher Plowe of the University of Maryland (UMD) School of Medicine in Baltimore. Given the huge stakes, White argues that the fight against resistence should “be prosecuted like a war. Because it is a war.”

Déjà vu

If, a decade ago, you had asked malaria researchers where artemisinin resistance might first crop up, they probably would have put their money on the Thai-Cambodian border, a region that has been the cradle of resistance multiple times. In 1957, chloroquine, discovered by Bayer in the 1930s and deployed widely after World War II, began failing here. Resistant P. falciparum started spreading in all directions in Asia, as well as to east and eventually west Africa. A separate resistant strain that arose along the Panamanian-Colombian border fanned out across South America, and by 2000, the drug was virtually useless in most parts of the world.

On the border.

WHO's containment plan focuses on areas where resistance has been confirmed but includes a much larger region considered at risk as well.

CREDIT: MAP ADAPTED FROM WORLD HEALTH ORGANIZATION

Chloroquine's main successor, sulfadoxinepyrimethamine (SP), also known as Fansidar, started losing its potency here in the 1960s; this time resistance spread much faster. SP's replacement, mefloquine—developed by the U.S. Army during the Vietnam War and notorious among Western travelers for its side effects—started failing in Southeast Asia in the early 1980s. It's still effective in most other parts of the world.

Why the region is such a hotbed isn't clear, and the reasons are probably diverse. Widespread overuse of drugs may have played a role, as may the trade in counterfeit drugs. Fake drugs often contain lower levels of a drug—enough to make the patient feel better but too little to kill the parasites. (The same can happen when patients take low doses of a legitimate drug.) Some scientists have also speculated that the parasite population in this region may be more genetically diverse than elsewhere, giving it an evolutionary leg up. Whatever the causes, history appears to be repeating itself, sooner than anyone anticipated.

Hard to track

Chinese scientists isolated artemisinin in the 1970s from sweet wormwood (Artemisia annua), a plant used to treat fever for centuries. The drug, along with more potent derivatives such as artemether, artesunate, and dihydroartemisinin, not only kills parasites effectively and fast but also disappears from the bloodstream in less than a day after administration. The hope was that this would give the parasite less chance to adapt and develop resistance, and that teaming each of the drugs with another, longer-lasting one that mops up any remaining parasites would further reduce chances of resistance.

Perhaps that's why many didn't believe there was a serious problem when the Thai Ministry of Public Health first reported that treatment with the combination artesunate-mefloquine—the most-used ACT in Southeast Asia—occasionally failed in the province of Trat, which borders Cambodia, in 2003 and 2004. (Thailand is almost entirely malaria-free; the disease occurs only along its borders.) Most experts believed the problem was resistance against mefloquine, the partner drug, a well-known problem.

Fingering artemisinin wasn't easy, says Harald Noedl of the Medical University of Vienna, who carried out the pioneering resistance studies with researchers from the U.S. Armed Forces Research Institute of Medical Sciences in Bangkok. Scientists haven't yet found genetic markers by which they can easily identify resistant P. falciparum strains. The only surefire way to track artemisinin resistance is to treat patients with the drug—and without the partner drug—and check how fast they clear the parasites. WHO and ethical panels have concluded that this is ethically acceptable, says Noedl, provided subjects get a 7-day course of artesunate—instead of the standard 3 days for the combination—and they are followed carefully for up to 9 weeks. Such “treatment trials” are time-consuming and expensive, and they have been slow to get off the ground.

One study in western Thailand showed slightly increased parasite clearance times, but not nearly as dramatic as in Cambodia. It's impossible to say whether the change represents a very early stage of resistance; patients could also take longer to get rid of malaria because malaria control has been so effective that their immunity has waned, says François Nosten, who heads the Shoklo Malaria Research Unit in Mae Sot, a town on the Thai border with Myanmar. If resistance spills over into Myanmar, where the health infrastructure is poor and malaria is rife, most experts agree it would be impossible to stop it from spreading farther west to Bangladesh and India.

What's happening?

Action is needed, and the Thai and Cambodian governments, WHO, and a range of donors have all stepped up their efforts; the Bill and Melinda Gates Foundation alone has contributed $22 million. What's been lacking, however, is a clear plan, a common strategy, and strong leadership, says White. “I'm in the epicenter here, and even I have trouble finding out what's happening,” he says. When Science asked WHO, which coordinates the efforts, about the current strategy, Newman said WHO has a plan but conceded that no publicly available version of it existed; he had WHO staff members write up a strategy and a progress report, however, which he sent to Science on 28 April.

Among the accomplishments listed in the report: Cambodia is improving its surveillance and has recruited more than 1300 volunteer malaria workers to help diagnose patients early and give them the right treatment. Bed nets are ubiquitous, and malaria rates are dropping. Cambodia also banned monotherapies in 2009, and that seems to be working, at least in some places, says Arjen Dondorp, the head of malaria research in White's group; when Dondorp asked a Cambodian co-worker last year to see whether he could buy the drugs at local pharmacies in the province of Pailin, the man came back empty-handed.

But the challenges remain formidable. Western Cambodia has many migrants from neighboring countries looking for work, and they're difficult to find and treat. Nobody even knows how many people are in the area, says Charles Delacollette, the coordinator of WHO's Mekong Malaria Programme. Bed nets don't work as well here as in Africa because mosquitoes start biting earlier in the evening, before people go to bed, and bite outside homes as well.

The tensions between Thailand and Cambodia—just a few weeks ago, their armies briefly exchanged shots in a disputed border zone—don't help. One urgent question is whether a new, so-called synthetic artemisinin might work against resistant parasites. A study to find out was approved by ethical panels and ready to go when Cambodia's minister of health unexpectedly vetoed it; apparently part of the reason was that researchers from Thailand were involved, says Stephan Duparc, chief scientific officer of the Medicines for Malaria Venture, which supports the study. Still, experts from both sides of the border do meet frequently without political interference, says Wichai Satimai, director of Thailand's Bureau of Vector-Borne Disease.

The idea of wiping out malaria from the region altogether, meanwhile, has for now been shelved. On paper at least, the plan has potential. In terms of malaria, the area is almost an island, surrounded by non-malarious areas to the north, west, and east and by the Gulf of Thailand to the south. If the disease were eliminated, it might bounce back—but it would do so by being reimported from another region, such as eastern Cambodia, where there is no resistance.

White believes an approach called mass drug administration, in which everybody in the area receives drugs in a short time (see sidebar, p. 843), could do the job. “It would be a massive operation. You'd need global positioning systems, the military, and who knows what else to find all the people,” he says, “but I think it could be done.” But WHO is generally not in favor of mass drug administration, which targets people regardless of whether they have malaria and carries the risk of aggravating resistance if it's not carried out properly. WHO describes elimination as the “ultimate goal.”

Newman resents the perception that the threat is not being taken seriously enough. WHO has lobbied hard against monotherapies, he points out, and WHO Director-General Margaret Chan has raised the issue of artemisinin resistance multiple times. But UMD's Plowe says that isn't nearly enough. “There should be a czar for malaria elimination in Southeast Asia, with a strong international team,” he says. “Right now, I don't know anyone whose full-time job it is to contain resistance.”

White agrees; the stakes are high enough, he says. “I would hate for resistance to show up in Mali next year and to know that we didn't stop it. I think we would all feel that we had failed terribly.”

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