By Merrill Goozner

One morning in August, a 24-year-old Karen tribeswoman living in a remote village in northeast Myanmar woke with a rapidly mounting fever. Though five months into her fourth pregnancy, she walked two hours to the rain-swollen Moei River, the poorly patrolled border with Thailand. After paying a boatman five baht (about 15 cents) to make the dangerous crossing, she arrived at a clinic in Mae Kon Ken, Thailand.

A physician's assistant at the clinic, which is operated by the Shoklo Malaria Research Unit (SMRU) of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Program, immediately diagnosed malaria and gave her one of the most powerful weapons in the global armamentarium for fighting the disease: an artemisinin-derivative called artesunate. Because the fast-acting antimalarial - which Chinese scientists first derived in the early 1970s from qinghaosu, the sweet wormwood bush (Artemisia annua) - is cleared from the body in a matter of hours, the physicians in charge of her care contemplated giving her another antimalarial to prevent a recurrence of the disease.

Such combination therapy is crucial to preventing the emergence of artemisinin resistance. While the drug is the most efficient malaria parasite killer ever discovered, it's short half-life requires another, longer-lasting drug that can kill any parasites that survive the initial onslaught or emerge later in the parasite's life cycle. "What am I to do with this pregnant woman?" wonders François Nosten, as local volunteers scrambled to find a suitable blood donor to combat the woman's lingering anemia, even as the artesunate began rapidly clearing most of the parasites and saved the woman's life. "The other drugs are toxic," says Nosten, who founded SMRU 20 years ago after several years as a young volunteer for Medicine Without Frontiers and built it into one of the most innovative and productive malaria research outposts in the world.

"There have been 13 papers since the 1960s on how to treat pregnant women with malaria, and we have done nine of them," Nosten says.(1) Yet there is still little understanding of how artemisinin-based derivatives and the other drugs used in combination might affect a pregnant mother or the developing fetus. Indeed, there is an unfinished research agenda on how the many different artemisinin-based combinations now being tested affect various subpopulations such as small children or people with co-infections (combinations either in use or being tested around the world add lumefantrine, mefloquine, piperaquine, amodiaquine, proguanil, or atovaquone to an artemisinin derivative such as artesunate or artemether). "We have to do studies on what are the risks and benefits of ACT [artemisinin-based combination therapy] in pregnancy."

THE PROOF: IT WORKS

If a research team led by Nosten and his mentor, Nicholas White of Mahidol University in Bangkok (whom many consider the world's leading malariologist), lead the way to better protocols for treating pregnant women and others with ACT, it won't be the first time that the duo has used the tools of clinical science to teach the world new methods for combating this age-old scourge. In 2001, the World Health Organization (WHO) declared ACT the preferred method for treating malaria, especially the most deadly form of the parasite, Plasmodium falciparum, which in most parts of the world has evolved resistance to older drugs such as chloroquine. WHO's 2001 decision was based largely on clinical trials that SMRU had conducted during the early 1990s.(2)

This breakthrough came despite the fact that artemisinin's mechanism is poorly understood. When the parasite invades a red blood cell to reproduce, it destroys the hemoglobin and frees up iron. In the presence of artemisinin, this free iron forms highly reactive oxygen radicals that some scientists believe inhibit the parasite's ability to digest more hemoglobin, thus breaking the chain in its lifecycle.(3) By contrast some older drugs such as chloroquine disrupt membrane function, thus disabling the invaded blood cell's ability to disgorge the newly formed parasites.

Not knowing the chemistry hasn't stopped the drug's deployment in the field, though. Early in this decade, SMRU spearheaded a joint public health program with the Thai government that trained rural health workers, most of them recruited from local villages, to use test kits to diagnose malaria and then administer ACT. The campaign also attacked the Anopheles mosquito that spreads the disease by conducting indoor home spraying with deltamethrin, a pyrethroid ester insecticide considered one of the safest in the world. (DDT, recently resuscitated by WHO, was banned in Thailand in 1997.) Distribution of insecticide-treated bed nets was also part of the campaign.

The result? Malaria in mountainous Tak province was reduced by 34% and mortality was cut in half.(4) Though the program was cut short when the Thai government's funds were depleted, it proved that even in remote areas, where people live exposed to the elements and have no formal healthcare system, it is possible to roll back malaria.

That's the goal of the campaign that world health officials launched in 1998 to cut the incidence of malaria in half by 2010. The campaign has so far fallen woefully short of expectations. This year will see an estimated 500 million cases of malaria, two-thirds more than the 300 million cases estimated in 1999. Somewhere between one and two million people will die of the disease, most of them children under the age of five in sub-Saharan Africa.

To Nosten, who has devoted his life to fighting the resurgence of drug-resistant malaria, it's inexplicable that global health officials and policymakers haven't moved faster to deploy the knowledge and tools that he helped to create - especially the three-day regimen of ACT. (Two combinations tested by Nosten and colleagues included artemether-lumefantrine and mefloquine-artesunate, both of which proved more than 96% effective against P. falciparum.(5) "The death toll is enormous. It's like five jumbo jets filled with children crashing every day," he says. "By 2010, there could be twice as much malaria. That, to me, is a failure."

THE ECONOMICS OF ANTIMALARIALS

Part of the problem is availability. Presently only Novartis, the Switzerland-based pharmaceutical giant, sells a two-drug ACT in a single-pill formulation called Coartem, which combines the artemisinin derivative artemether with lumefantrine. Health officials prefer the two-in-one pill because it improves patient compliance, which is crucial if artemisinin is to avoid the fate of chloroquine, which has become virtually useless against most strains of P. falciparum because of drug resistance.

A Coartem pill, however, costs $2.40 for the three-day treatment. While the company says it earns no money at that price, it is still far more than most of the world's malaria victims can afford, which could explain why chloroquine, at 10 cents per dose, is still in widespread use in Africa and South Asia. Moreover, the profit markups and graft that plague the supply chain in many parts of Africa make Coartem all but unaffordable except through aid-financed programs. Surveys of local clinics and pharmacies report that Coartem often sells for eight dollars and more in the private market.

Since these new artemisinin combinations are still months if not years away from regulatory approval, demand for Coartem is skyrocketing. Novartis expects to ship 58 million treatments this year from its production facility in Suffern, NY, nearly double the 2005 level. The plant has the capacity to produce more. In September Novartis began subsidizing ACT deployment by reducing the average price to one dollar per dose. "We have the capacity to make 100 million doses but don't have that many orders so price is clearly an issue," explains Robert Laverty, a spokesman for Novartis' malaria initiative. "We wanted to improve access to what is clearly the most effective treatment out there."

Lower-priced options should be arriving soon. Medicine Without Frontiers' Drugs for Neglected Diseases Initiative (DNDi) plans to introduce two new, single-pill artemisinin combinations by the end of this year. Its artesunate-amodiaquine combination, besides reducing the number of pills swallowed daily from eight to two, will sell for just one dollar for an adult treatment and half that for a child. The industrial partner, Sanofi-Aventis, is managing the manufacturing and registration of the combination pill, and has promised to offer the technology for free to any manufacturer that can produce the drug at world standards for less. DNDi's second combination, which Brazil's Far-Manguinhos produces, combines artesunate with mefloquine to combat the strains of drug-resistant malaria that are endemic in southeast Asia and parts of Latin America.

TESTING NEW COMBINATIONS

Physicians led by Nosten and White conducted the final registration trial of the artesunate-mefloquine combination at SMRU during the first half of 2005. This year, a team of physicians led by the duo is collaborating with the nonprofit Medicines for Malaria Venture (MMV) in a 2,550-patient trial across two continents that should, if all goes well, lead to the registration of a dihydroartemisinin-piperaquine combination. (Dihydroartemisinin is the active metabolite of the other forms of artemisinin: artemether, arteether, and artesunate.) This one will be the first manufactured by an independent Chinese company - Chongqing Holley Holding - that meets global standards for good manufacturing practices (GMP). Another industrial partner, the Italian drug firm Sigma Tau, is managing the registration of the single-tablet combination, which should sell for about one dollar for a three-day treatment.

While the need for cheaper alternatives is compelling, Nosten has mixed feelings about the dihydroartemisinin-piperaquine trial, which is focused only on proving efficacy to register the drug, something he's done numerous times before for other artemisinin-based combinations. "Registration trials are a pain in the neck; it's a lot of bureaucracy," he says while driving a Toyota 4WD along the rutted road that leads to the clinic on the Thai-Myanmar border. The 49-year-old physician-researcher is wearing blue jeans, a khaki vest, and a pair of old sneakers, crushed in the back so he can slip them on and off easily (the local custom) when entering one of his clinics.

"We have already studied this treatment in thousands of people," says Nosten. "We know its pharmacokinetics and pharmacodynamics. You have drugs that have been studied by us and the Chinese for decades. I accepted to do this new study because I thought it would be useful to get this drug more quickly to African children." He pauses for a moment, as if pondering how what he was about to say might be interpreted by his funders in Geneva. "It is not that interesting," he says. "My main thing in life is to learn new things."

FROM CHINA TO THAILAND

Artemisinin was a relatively new thing in 1983 when White, then 32, and his colleagues met Li Guoqian, who was the first to use the drug (see "The first 13-year-old patient"), on a trip to Guangzhou, China. "He gave us some ampoules (of artesunate) and said, 'this stuff is really good,'" recalls White, who had been studying malaria resistance since moving to the Mahidol University faculty from Oxford in 1980. White was thrilled to have an alternative to chloroquine, which was quickly becoming useless against resistant strains, and the almost new mefloquine, which had been touted as a miracle drug but was already beginning to lose its effectiveness.

White, soon joined by Nosten, moved a Chinese version of the drug into a series of clinical trials. Because patients cleared the artemisinin derivative so quickly, initial regimens needed to last seven days to hit every phase of the parasite's life cycle. Patient compliance was terrible. To shorten the regimen, they began experimenting with various combinations that included longer-lasting drugs. "We were forced by events; we've always been, in a way," White says.

Combination therapy was already common in other parts of the world where infectious diseases were being treated. It was first used against resistant strains of tuberculosis. Then in the early 1990s, researchers on the front lines of HIV/AIDS research were turning to combination therapy. But malaria drugs? Physicians had always used them sequentially. White realized that this was the field's fatal mistake.

"Nick White deserves credit for the theme of using antimalarial drugs in combination, and he was relentless in pursuing it," says Thomas Brewer, a former military researcher of anti-infectious disease drugs. He now runs the malaria program at the Bill and Melinda Gates Foundation. "For a long time, people were resistant to that, like any paradigm shift in medicine."

In an interview in his cramped Bangkok office, White, whom one colleague described as equally at home on the cricket patch as he is in a research lab, attributes his insights to his willingness to delve into the math behind the drug's activity. "I could see what was happening to the drug levels in the blood - which is opaque to most physicians, they avoid it - and what that was doing to the parasite," he says. He calculated that if patients faithfully followed a two-drug combination that included artemisinin, the odds of a mutant parasite emerging that was resistant to both drugs was a once-in-a-century event.

Even White's critics, including Harald Noedl of Medical University of Vienna, admit that "artemisinin resistance is still extremely rare or even nonexistent." Noedl believes it is only a matter of time, however, before resistance emerges, because some people won't follow the combination regimen as it comes into more widespread use.(6)

ARTEMISININ TAKES THE GLOBAL STAGE

After publishing his analysis in Antimicrobial Agents and Chemotherapy in 1997 (7), White began organizing the world's leading malaria clinicians to press WHO for a dramatic change in its recommended policy for treating malaria. "To treat tuberculosis or AIDS with a single drug is no longer regarded as ethical," wrote White, Nosten, and 15 colleagues in "Averting a malaria disaster," a June 5, 1999, Lancet viewpoint. "We believe the same principle should apply to the treatment of malaria."

The wheels of the global health bureaucracy moved slowly, however. It took two more years before WHO endorsed ACT, and even then, few nations placed orders with Novartis, which had the only GMP-qualified combination on the market, a artemether-lumefantrine combination called Coartem. Though the company offered to supply the drug at cost, its relatively high price kept it beyond the reach of most African nations until international aid began flowing. Then, in 2004, when nations finally began placing substantial orders, supply bottlenecks emerged.

Not surprisingly, non-GMP-made artemisinin tablets began infiltrating the market, creating the potential for a public health disaster. In January 2006, WHO malaria chief Arata Kochi issued a stern rebuke to the 18 firms manufacturing the tablets in eight countries. The fear is that parasites exposed to artemisinin alone will quickly develop resistance, just as they have to all the other drugs. "In some countries, 60 to 70 percent of the people get their treatments directly from pharmacies, where they have access to monotherapy," says Awa Marie Coll-Seck, the former Senegalese health minister who is now executive secretary of the Roll Back Malaria (RBM) partnership. "We're saying, no, no, no, you must follow the WHO policy."

Coll-Seck's own experience in Senegal, a nation of 11 million people on the West African coast, reveals the difficulties in forcing adherence to the new approach. She was among the first group of African health ministers to adopt ACT as the preferred treatment, in 2002, but it didn't become widely available in her country until last year. "It takes one year to change policy, one to find money, and one year to change the (local health) plan," she says. "You have to train the nurses and the physicians to ensure that the new treatment will be properly used."

Since 2001, 34 countries have adopted ACT as the first-line defense against malaria, but only 17 are currently deploying it. Even so, RBM projected global demand at 60 million treatments last year. Novartis expanded production, but the orders didn't appear. Since artemisinin has a relatively short shelf life of 18 months, some of that production had to be destroyed. This year, things have gone more smoothly: 50 million courses were shipped through the end of June, and 80 million courses are projected for the entire year.

While more nations are committed to switching to ACT, global donors have not yet solved the core economic problem. Even at one dollar for a three-day regimen of the new products about to come on line, chloroquine at a fraction of the price is still widely available in the private networks of most African and South Asian countries.

In 2004, an Institute of Medicine committee, which was chaired by Nobel Prize-winning economist Kenneth Arrow and included White, recommended that global donors pool their resources into a single agency that could buy ACT at market prices and make it universally available at a competitive 10 cents a treatment. The World Bank, whose antimalaria efforts have been revamped after widespread criticism, is designing the subsidy program.

"We're consulting with a number of partners to develop an arrangement for this subsidy. How will it work in practice?" asks Olusoji Adeyi, a Nigerian physician who coordinates public health programs for the World Bank. And then it must find the money, which could run as high as $400 million to $500 million per year. "We're still looking for the subsidy itself," he says.

TOOLS ARE NOT ENOUGH

White has no patience with such dallying in the face of what he believes is the world's biggest public health crisis. When I first walked into his university laboratory a few blocks from Victory Monument in central Bangkok, he was staring at his computer while on the telephone with Nosten. The topic wasn't their latest trial. He was reading to his protégé the oft-circulated scientific joke about the newly discovered element, administratium, which impedes every reaction with which it comes in contact.

It's a good time for the malaria-control community, he admits. President Bush and Prime Minister Tony Blair are talking about it. Money is pouring in, not just for research, but also for healthcare delivery systems in poor countries where malaria is endemic (and armed conflicts are not underway). But, he says, "the failure of the global eradication campaign in the 1960s left a deep, deep scar."

In the wake of that failure, a generation of research has produced better strategies for deploying bed nets and insecticides. It has produced a powerful new drug that, if massively and properly deployed, can sharply reduce the levels of circulating parasite, including those most resistant to existing drugs. "We've got the tools, he says. "We need to recapture the idea that you can get rid of it."

Speaking to me in a border clinic nearly 200 miles to the north a few days after I saw White, Nosten agrees that it can be done, but he can see the hurdles that remain. His well-stocked clinics provide first-rate care to the thousands in Karen who find their way to his doorstep. For instance, the SMRU staff eventually found a blood donor for the 24-year-old pregnant woman, and they administered artesunate alone for seven consecutive days. Under their careful supervision, the treatment was long enough to ensure that all the parasites were cleared from her body. A week after becoming ill with malaria, she returned to her home in Myanmar in excellent health.

But on the day I visited the clinic, the day Nosten wrestled with how to treat her, he stared across the river into her homeland, once known as Burma. A military junta rules the country and does very little to combat the malaria plague on its mountainous borders. "Our clinics cannot replace a failing public health system," Nosten says. "We're here to do research."

References
1. See, for instance, R. McGready et al., "A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy," J Infect Dis, 192:846-53, 2005.[Pubmed]
2. For the earliest published result of a randomized clinical trial using artemisinin-based combination therapy, see F. Nosten et al., "Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination," J Infect Dis, 170:971-7, 1994.[Pubmed]
3. A.V. Pandey et al., "Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite," J Biol Chem, 274:19383-8, 1999.[Pubmed]
4. V.I. Carrara et al., "Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak malaria initiative," PLoS Med, 3:e183, June 6, 2006.[Pubmed]
5. R. Hutagalung et al., "A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand," Malaria J, Sept. 22, 2005 (www.malariajournal.com/content/4/1/46, accessed Nov. 4, 2006).[Pubmed]
6. H. Noedl, "Artemisinin resistance: how can we find it?" Trends Parasitol, 21:http://www.gooznews.com/mt/mt.cgi?__mode=view&_type=entry&blog_id=7&id=578&saved_changes=1#404, 2005.[Pubmed]
7. N.J. White, "Assessment of the pharmacodynamic properties of antimalarial drugs in vivo," Antimicrob Agent Chemother, 41:1413-22, 1997.[Pubmed]