The Fever

by Sonia Shah

  And yet despite the humiliating pill popping and the stinky repellent smearing, malaria rampaged. Every week, another seventy soldiers came down with the disease. The day before a brigadier visited, a falciparum-infected lieutenant colonel became so sick he had to be evacuated.118

  It must have seemed to officers that the New Guinea troops were in the throes of some kind of willful defiance. The instructions to take the quinacrine had been clear and unequivocal. Such a dangerous breakdown of order would have been shameful enough. But what the higher-ups found, when they arrived to investigate, might have been even worse.

  Utterly cowed, the soldiers weren’t just taking the drugs, they were wallowing in them, taking even more than required. They took twice the recommended dose. They took it not just to prevent malaria but for aches and pains of all kinds. “One combatant officer said the troops preferred [quinacrine] to aspirin for headaches.”119

  Finally, Fairley arrived on the scene to evacuate some infected troops to Cairns for study. Perhaps the quinacrine was not being absorbed properly, he thought. Or perhaps the troops had been infected by some new, more virulent kind of malaria. Or perhaps they didn’t have malaria at all and had been sickened by something else entirely. He’d study their blood, make sure they were getting enough drug, and pinpoint the pathogen that had struck them.

  Back in Cairns, Fairley found that malaria parasites had infected at least seven out of nine soldiers. But all of them, incredibly, had quinacrine coursing through their veins. It was a finding, one malariologist later wrote, “without precedent in the history of man’s fight against malaria.”120

  The obvious conclusion was that malaria parasites had achieved the ability to circumvent quinacrine’s killing mechanism. Perhaps a strain of the parasite had mutated.121 Most of the soldiers would have had no acquired immunity to P. falciparum, so the parasite inside their bodies would have been able to multiply prodigiously, providing ample opportunity for the development of mutations, which occur at a rate of one in a billion.122 Or perhaps the drug-resistant parasite had been there all along, its hidden abilities unnoticed until quinacrine came along.

  Wherever this parasite came from, it rapidly spread, thanks to heavy quinacrine use among not only the Australians but also the similarly malaria-plagued enemy troops, positioned nearby. And the more religiously the soldiers took their quinacrine, the more successful the impervious parasite grew.

  But Fairley could not bring himself to face what these findings meant. It was difficult enough getting the troops to take quinacrine without suggesting its abject failure. He still suspected that the troops—not the quinacrine—had played some role in diluting the drug’s killing power. After all, only half as many officers got infected as troops. And why would the parasite defang the drug only in New Guinea and nowhere else? So Fairley did his best to protect the reputation of the drug he’d worked so hard to elevate. When he wrote up his results, he allowed that a few parasites circumvented quinacrine, but most of the cases of malaria had occurred, he said, because of failures of “discipline.”123

  To be fair, there was no way for Fairley to have known how this quinacrine-resistant parasite incubating in New Guinea would fare elsewhere in the world, or even over time in New Guinea. It could have been a one-off occurrence, an instance of a strange mutant parasite that would never be seen again. Perhaps it would die out on its own, poisoned by some other mutation that came along with its drug-resisting capacities. Circumventing a drug designed to kill couldn’t be easy. Surely the ability placed some kind of compensatory burden on the parasite, the way, say, an Olympic swimmer might not be able to run very well. If the drug-resistant parasite had to compete for blood and mosquito with the usual array of malaria parasites, it would be hobbled, a world-class athlete in a neighborhood street fight. It wouldn’t be able to spread far.124

  Which is why the international community—despite having formed, after World War II, a body to oversee global public health, the World Health Organization—equivocated over reports of malarias that resisted chloroquine, too.

  The first hints of malaria’s retaliation against chloroquine emerged from Colombia and along the Thai-Cambodia border in 1957, just twelve years after the drug was introduced. One day two geologists who had been working for an oil company in Colombia staggered into a Dallas hospital. They were suffering falciparum malaria. But chloroquine, the king of antimalarial drugs, failed to cure them. Not long after, doctors in Bethesda treated a patient who contracted P. falciparum in Thailand. Chloroquine didn’t work for this patient, either. “Oh my God, here we go,” the malariologist Robert G. Coatney remembers thinking.125

  Chloroquine kills the malaria parasite by concentrating inside its food vacuoles, where the parasite digests its meal. The parasite attempts to expel the drug, but normally can’t do so fast enough. But parasites with a gene called pfmdr1 can spit chloroquine out of their food vacuoles fifty times faster than normal.126 Such parasites, commented the Centers for Disease Control’s Peter Bloland, could “eat chloroquine for lunch.”127 Not just chloroquine. Parasites endowed with pfmdr1 can resist other synthetic antimalarial drugs, including amodiaquine, introduced in the early 1950s,128 mefloquine, introduced in the mid-1970s,129 and halofantrine130 and quinidine,131 introduced for malaria in the early 1980s.132

  One by one, the malaria parasite defanged each drug thrown at it. The more effective and widely used the drug, the faster the parasite subjugated it. The antimalarial drug proguanil begat the drug pyrimethamine. The parasite resisted both. Pyrimethamine was combined with a drug called sulfadoxine—a popular combination known as SP, or by its brand name, Fansidar. Parasites resistant to the drug emerged the same year they were introduced in Thailand.133 Hoffmann–La Roche launched the antimalarial drug mefloquine commercially in 1975. Parasites resistant to the drug emerged a year later.134

  In 1961, WHO gathered its experts to consider the problem. They agreed that the implications of malaria’s resistance were “serious,” indeed. But like Fairley, they dragged their feet on sounding an alarm. First, the WHO experts wanted to know all the circumstances under which each “alleged” case of resistance had appeared. They wanted confirmation that the drug in question had, in fact, been appropriately consumed and absorbed. They wanted the allegedly resistant parasite to be captured, and for its passage into an uninfected, nonimmune person to be observed.

  As serious as the silent spread of drug-impervious malaria was, the need for discretion, they decided, was even more serious. “It is evident that this and other similar records demand the fullest and strictest investigation,” their final report advised, “before reports on them are circulated or published.”

  After all, malaria’s drug resistance had not emerged as a coordinated strike, with all drugs failing everyone every where. It was more like guerrilla warfare, with rebellions confined by time and place. The old drugs still worked, at least a bit, for some people in some places some of the time. And so the drug war against malaria continued. Only the most exceptional ecological, demographic, and political circumstances could motivate the development of a new chemical weapon, one that could directly challenge the parasite’s insurrection.

  As WHO cogitated, conditions in the wet jungles of Southeast Asia deteriorated. There, the chloroquine-resistant falciparum parasite enjoyed a fortuitous and unpredictable stroke of luck. Its edge over other parasites was not restricted to the interior of bodies dosed with chloroquine, however prevalent those may have been. Inside two malaria vectors, the Southeast Asian mosquito, Anopheles stephensi, and Anopheles dirus, from the western Pacific islands, the drug-resistant parasite was able to develop more effectively than drug-sensitive parasites.

  What were the odds? But this was just the edge the drug-resistant parasites needed. Its numbers gained on those of its rivals until its descendants, uniformly endowed with the ability to repel chloroquine, had by the early 1960s become not just a pesky guerrilla tribe but the dominant strain in parts of Southeast Asia and wester
n Oceania.135

  The unlikely partnership between drug-resistant P. falciparum and Southeast Asian malaria mosquitoes happened to coincide with the political and geographical disruptions of the 1959–1975 conflict between communist North Vietnam and U.S.-supported South Vietnam. Just as the drug-resistant parasite achieved its hegemony, hundreds of thousands of unwitting, nonimmune people from the lowlands poured into the malarious foothills of northern Vietnam, resettled by the North Vietnamese government to provide logistical support for the burgeoning war effort. For five to ten years, these people suffered “near-starvation and constant illness,” according to Pamela McElwee, an environmental historian of Vietnam,136 while their malaria-naïve bodies provided ample fodder for the drug-resistant parasite to feast. The Vietnamese jungle soon became the world’s premier incubator of drug-resistant malaria.

  Had the impending epidemic been confined to the resettled villagers, the military authorities in Vietnam would not necessarily have done much about it. But the exigencies of battle soon turned that malarious jungle into the very lifeline of the war effort. The American bombs started falling in 1965. With the U.S. Navy blocking sea traffic, the North Vietnamese started using the jungle’s twelve thousand miles of shaded, mosquito-ridden track as a supply route, sending troops en masse to march through the jungle. They called it the Ho Chi Minh Trail.137 And it was a deadly one. Exposed to the bites of mosquitoes and fed by the malarious locals, the troops had ample contact with the drug-resistant malaria parasite. After one month-long journey down the trail, only 120 of a regiment of 1,200 Vietcong soldiers were fit to fight. “They had a saying,” one Vietnamese battlefield doctor remembers. “‘We fear no American imperialists, only malaria.’”138 The bodies of the people who died on the trail fill twenty-two cemeteries.139

  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.140 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.141 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,142 an unpretentious little shrub related to sagebrush and tarragon143 that will grow, like a weed, in any kind of disturbed environment.144 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.145 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.148

  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.149 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.150 The drug can even kill some of the infective forms of the parasite, the gametocytes, against which quinine and chloroquine do nothing at all.151 Used by the troops in the final stages of the Vietnam War, artemisinin slashed malaria’s death toll by 30 percent.152

  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.154 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.156 Scientific commentators pointed out that the Chinese scientists had used equipment that was “rudimentary” and “obsolete” by Western standards.157 WHO refused to approve the drug unless production facilities moved to the United States, a requirement with which the Chinese scientists refused to comply.158 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.159 But the Chinese developers of the drug couldn’t interest a world-class drug maker in producing the world-class drug until 1994.160 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.161 (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 1999.162

  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 1962–1981.165 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.166 The risk of death from childhood malaria increased by elevenfold.167 “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 wro
ng 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.170

  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.”171 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.172 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.173 On the Myanmar-Thai border, the agency supplied nearly useless chloroquine instead.174 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.175