The Fever: How Malaria Has Ruled Humankind for 500,000 Years (18 page)

Chloroquine-resistant
P. falciparum
infected more than eighteen hundred American soldiers fighting in Vietnam, too. Only twelve died, thanks to the ministrations of that quaint old drug quinine.
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But the only quinine available to the Vietnamese came from the black markets of Hong Kong. For China’s Chairman Mao, overseeing the Cultural Revolution, this meant that reeducation for some of the nation’s top scientists would have to wait. Mao launched top secret Project 523, a crash research effort to find a new cure for malaria. “In many cases, we had to ‘borrow’ [the scientists] for a few days from the hands of the
Red Guards or armed factions,” recalled the military scientist Zhou Yiqing. “They were very glad to join the project, too.”

The scientists gathered at a Beijing restaurant in May 1967 and hatched their plan to comb through traditional medicines and ancient Chinese medical writings for leads.
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Tucked inside an ancient medical document called “52 prescriptions,” dating from 168
BC
, they found descriptions of the medicinal properties of
Artemisia annua
, or sweet wormwood tree,
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an unpretentious little shrub related to sagebrush and tarragon
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that will grow, like a weed, in any kind of disturbed environment.
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Inside
Artemisia
flows a fragile compound called artemisinin, which can kill malaria parasites the way bleach kills microbes, by exerting oxidative stress on their cell membranes.
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The ancients knew it, too: in
AD
340, the physician Ge Hong described how a bitter tea of
Artemisia
provided relief from fever (earlier writers described it as a remedy for hemorrhoids).
¹⁴⁶

Artemisinin was among the first ten compounds of the ancient Chinese
materia medica
screened by the scientists of Project 523. But they didn’t heed Ge Hong’s instructions. He’d written that the entire fresh plant should be soaked in water and wrung out, and the juice used. This recipe would probably have retained the delicate artemisinin, which doesn’t dissolve in water or ether, and is extremely sensitive to heat.
¹⁴⁷
Instead, as part of the screening process, most likely the Project 523 scientists used the dried leaves, or applied heat to the plants, destroying the artemisinin.

Not finding any antimalarial activity, they moved on.
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Some years passed before the Project 523 scientists looked at
Artemisia
again. This time, they took the recommendations of the ancients more seriously, and by 1972 they had successfully isolated artemisinin.
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Artemisinin kills malaria parasites faster, with less toxicity and in a completely novel way, than quinine or chloroquine. Even if a malaria parasite could spit out chloroquine, it would still be susceptible to artemisinin’s effects.
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The drug can even kill some of the infective forms of the parasite, the gametocytes, against which quinine and chloroquine do nothing at all.
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Used by the troops in
the final stages of the Vietnam War, artemisinin slashed malaria’s death toll by 30 percent.
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Project 523’s Li Guoqiao, now a professor of traditional Chinese medicine at Guangzhou University, and Zhou Yiqing, now of the Chinese Military Academy of Medical Sciences, are no longer bound by Chairman Mao’s edicts on secrecy. Together they’ve revealed the story of artemisinin’s discovery, replete with code names, ancient writings, and raging war, and have captivated the press. The
Far Eastern Economic Review
called the story a “scientific fairy tale.”
¹⁵³

Somewhat less enchanting is the story of what happened after the drug’s discovery: obfuscation, neglect, and misunderstanding that delayed artemisinin’s widespread distribution for decades, even as drug-resistant parasites slayed scores.

The first few years of artemisinin’s cloistering could hardly be avoided, thanks to the war. The Chinese considered the drug’s antimalarial powers a military secret, Li Guoqiao said.
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The first English-language paper on the drug didn’t appear until 1979, seven years after the drug was isolated.

But despite the news of artemisinin’s extraordinary powers against the rampaging malaria parasite, the drug still remained obscure outside China and Vietnam.
¹⁵⁵
Western scientists frowned upon the unorthodox method of extracting it. A German translator mistranslated the instructions for doing so. Copy editors—suspecting an error, perhaps—suggested deleting mention of it from academic papers.
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Scientific commentators pointed out that the Chinese scientists had used equipment that was “rudimentary” and “obsolete” by Western standards.
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WHO refused to approve the drug unless production facilities moved to the United States, a requirement with which the Chinese scientists refused to comply.
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A chasm of mistrust between Chinese and Western science sucked artemisinin into its vortex.

Between 1980 and 1990, artemisinin drugs slashed China’s malaria caseload from two million to ninety thousand.
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But the
Chinese developers of the drug couldn’t interest a world-class drug maker in producing the world-class drug until 1994.
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That year, drug giant Novartis bought the rights for a pill containing an artemisinin derivative called artemether and another antimalarial drug called lumefantrine, developed by the Chinese team to counter the parasite’s ability to develop resistance.
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(Bombarded by two drugs with different destructive mechanisms, the parasite would be hard pressed to develop resistance to both.) Novartis launched the combined drug five years later, in 1999.
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A single dose of chloroquine or Fansidar, the cheap old standbys, cost less than twenty-five cents. Aimed at wealthy European travelers on safari and the like, Novartis’s artemisinin drug Riamet cost forty-four U.S. dollars per course.
¹⁶³

After World War II, killers such as diarrhea and pneumonia steadily weakened their grip on
Homo sapiens
around the globe, taking fewer and fewer lives annually. Meanwhile, malaria’s death toll steadily grew.
¹⁶⁴
The average annual number of reported malaria cases quadrupled between 1982 and 1997 compared to the period 1962–1981.
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It wasn’t just that clinicians witnessed more malaria cases, as chloroquine treatment at home failed and the sick rushed to clinics, where they could be counted. Long-term surveys showed that the resistant parasites actually killed more people, reversing chloroquine’s gains. By the mid-1990s, the mortality rate in Senegal had doubled from that of just ten years before.
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The risk of death from childhood malaria increased by elevenfold.
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“In poor countries like ours, children have only one chance,” said Fred Binka, an epidemiologist from the University of Ghana. “They struggle just to visit a health service, and if they get the wrong drug the first time, they are then found dead.”
¹⁶⁸

After Novartis launched artemether-lumefantrine, another five years passed before the international actors who shape international malaria policies threw their collective weight behind the drug. The
World Health Organization’s guidelines on antimalaria drug use are followed by health ministries and malaria clinics across the developing world. In 2001, WHO revised those guidelines, recommending that artemisinin combination therapy (ACT) be the very first drug given in malaria cases.
¹⁶⁹
Under pressure, Novartis offered to drop the price of Riamet, with a two-dollar-per-pill version called Coartem.
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That wasn’t enough, however. Coartem still cost ten to twenty times more than, say, chloroquine. Few if any health systems in malarious countries could afford to make the drug available at their clinics and hospitals without outside support. But the Western funders who might have subsidized the cost balked. According to Dennis Carroll of the U.S. Agency for International Development, Coartem was “not ready for prime time.”
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Better to restrict the use of this expensive combo drug, agreed Rick Steketee of the Centers for Disease Control, and distribute cheap bed nets instead.
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In a 2003 malaria epidemic in Ethiopia, the United Nations Children’s Fund expressly refused to pay for artemisinin combination drugs. There wasn’t enough supply on hand, they said, and the new drug therapy would cause confusion.
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On the Myanmar-Thai border, the agency supplied nearly useless chloroquine instead.
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In 2003, the international health financing agency the Global Fund to Fight AIDS, Tuberculosis and Malaria allocated three times more funding for chloroquine and another World War II–era drug, sulfadoxine pyrimethamine, than it did for artemisinin combo drugs.
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And so, between 1999 and 2004, 95 percent of children with malaria in Africa got treated with the old standby chloroquine. At least half the time, the drug failed to work. Some patients improved slightly, and perhaps felt a bit better, thanks to the drug’s fever-reducing effects,
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but they remained infectious, and were likely to relapse. Others simply failed to recover at all.
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This situation, after the world’s leading health authorities had clearly sanctioned better drugs, led to a huge and caustic outcry among African and malaria aid physicians. Donors’ reluctance was “frankly, very difficult to understand,” said Médecins Sans Frontières’
Bernard Pécoul.
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“I couldn’t believe my ears,” said Binka. “If a physician went to Burma and prescribed chloroquine, they would be negligent,” said Canadian health lawyer Amir Attaran. “When UNICEF does the same,” he added archly, “it’s called ‘international aid.’”
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International capital finally started to mobilize for ACT drugs in the years after 2004. The Global Fund agreed to provide funding for health ministries to purchase the drugs,
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and other drug companies, in partnership with nonprofit aid organizations, started developing alternative ACTs, loosening Novartis’s monopoly.
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The nonprofit Institute of Medicine of the National Academies recommended a new global subsidy, to the tune of $500 million every year, to help pay for ACTs (and future malaria drugs), and international experts started scheduling meetings to explore the possibilities.
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In late 2008, the Global Fund agreed to bankroll a preliminary $6 million for the subsidy.
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When there is a lucrative market to be tapped—say, arthritis sufferers or people with high cholesterol—drug makers can rush a new drug from the lab to the market in under a decade. The system for developing and distributing drugs for public health—to supply to people who earn less than a buck a day—is significantly slower. Between artemisinin’s development in 1972 and the international community’s support in 2004, more than three decades passed. But by then it was arguably already too late.
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Over the decades, while the international community argued and deliberated, the malarious masses grabbed hold of whatever artemisinin they could, and the drug leaked out, in hobbled, diluted forms. Drugmakers seeking to turn a small profit, vendors unable to maintain the drug’s exacting conditions, downright criminals—together they all attenuated artemisinin’s potency against
Plasmodium
.

In the financial and regulatory vacuum throughout the 1980s and 1990s, an underground market in artemisinin drugs thrived.
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The French company Sanofi-Aventis and Belgian drug makers Arenco
and Dafra earned a snappy income selling artemisinin—untethered by a partnered co-drug—across Africa, to those who could afford it.
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Dafra earned $13 million a year doing this.
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Chinese and Vietnamese companies launched a plethora of stand-alone artemisinin drugs, too.
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Exposing the malaria parasite to an artemisinin unfortified with another drug dared the parasite to develop resistance. The barely regulated private channels through which stand-alone artemisinin drugs flowed—the sweltering corner shops and street vendors of Africa and Asia—could not ensure the exacting standards that heat-and humidity-sensitive artemisinin requires. Given the unreliability of electricity and refrigeration, even the most well-manufactured drug can deteriorate by the time it appears on vendors’ shelves in rural Africa. In a study in Nigeria, nearly half of almost six hundred drugs available on the market—antimalarials, antibacterials, and antituberculosis drugs among them—were found to be substandard. Nearly half of the sulfadoxine-pyrimethamine tablets on sale wouldn’t even dissolve in liquid.
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Without the oversight of WHO or local health ministries, drugmakers dreamed up their own dosing instructions. Many of the artemisinin drugs they sold came packaged with recommendations for a five-day course—enough to make the patient feel better, but not enough to kill the parasite
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—turning every fevered patient who took the too-short course into a walking incubator for drug-resistant strains. Most alarming of all, the popularity of these drugs spawned a host of even cheaper, and less effective, copies. In 2004, surveyors reported that more than one third of the artemisinin drugs on sale across Asia were downright fakes, pills filled with minuscule quantities of artemisinin, if any.
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