The Imaginations of Unreasonable Men (23 page)

In early 2009 the World Health Organization (WHO) announced the discovery of malaria parasites along the Thai-Cambodia border that were proving resistant to commonly used derivatives of artemisinin called artesunate and arthemeter.

Prior to this there had been a hugely optimistic surge of interest, research, and spending on combination therapies using artemisinin. Chinese companies developed numerous forms of artemisinin and combined it with another antimalarial drug called lumefatrine so that the parasites would be less likely to develop resistance. China’s own malaria caseload went from 2 million in 1980 to 90,000 in 1990. Colonel Peter Weina, who, as chief of the pharmacology department at Walter Reed Army Institute of Research from 2002 to 2009 had led the U.S. Army’s effort to develop a drug against the most severe form of malaria, went so far as to admit that, “there was an assumption and there was a hope and there was a prayer that resistance to artemisinin would never happen.”
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History teaches that we should have known better. Resistance to malaria medicines has always been a question of when, not if. In previous decades malaria had become resistant
to once potent drugs like chloroquine in the 1960s and mefloquine by the 1990s. A category of drugs known as SPs (for sulfadoxine pyrimethamine) was introduced in 1977 with a 100 percent success rate. Though it remains widely effective in Africa, within five years SPs were effective in only 10 percent of patients in some areas of Southeast Asia.

Wishful thinking held that artemisinin might be the exception. But the new discoveries are showing that artemisinin, which once cleared parasites from the blood in two days, is taking three or even five days in a large number of those infected, the first sign of growing resistance.

The Chinese sold the rights to the drug to Novartis in 1994. Novartis sold it at $44 a course to Western travelers but agreed to sell it to the World Health Organization at $2 a course. Even at that price it was ten to twenty times more expensive than previous drugs, such as chloroquine, and USAID and CDC officials considered it too expensive for Africa. Then, an underground market developed. Underground markets, by definition, are unregulated. As a result bad things happen.

One of those bad things was counterfeit drugs. Paul Newton, head of the Wellcome Trust Southeast Asian unit in Laos, concluded that tablets with low doses of artesunate—insufficient to kill the parasites, but enough to lead to resistance—were the main source of the growing problem. Pills with only small quantities of the active ingredient, instead of the full amount, are dangerous because they wipe
out only the weakest parasites, enabling the hardiest to survive and multiply. When a malaria victim infected with resistant parasites is then bitten by another mosquito, and that mosquito bites another human, the resistant parasites have a chance to thrive and multiply some more. And on and on it goes, like a breeding plan for more and more drug-resistant parasites. After a while, the genuine drugs will no longer work.

The pirated drugs are often sold in packaging indistinguishable from the real medicine and contain small amounts of active antimalarial substances in order to pass quality-control tests. Studies have found that between one-third and one-half of artesunate tablets across Southeast Asia were counterfeits. The criminal trade in these cheap imitations was made attractive by the relatively high cost of the real drug—about $2 for a course of treatment, or up to $10 in the private sector. A course of chloroquine, by contrast, costs only 10 cents.

Another contributing factor was the widespread availability in the region of high-quality artesunate tablets from China and Vietnam. The artesunate in these tablets was present as a single ingredient, rather than in a combination of ingredients, which also gave the parasite a better chance of developing resistance.

In addition, because of the relatively high cost of the drugs, poor people were often not completing their courses—they stopped taking the tablets when they felt better, giving any resistant parasites a chance to survive and proliferate.

In 2008, the International Criminal Police Organization (Interpol) arrested twenty-seven people in raids across Asia and seized 16 million counterfeit pills worth at least $7 million. The global market for fake pharmaceuticals is estimated to be $75 billion. As Paul Newton of Wellcome Trust has pointed out, the crime really involves more than just making cheap drugs: “If you make a medicine that contains no active ingredient for a disease you know can be fatal,” he said, “at best that is manslaughter and at worst it is murder.”
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The crime is even greater when one considers all the consequences. On one level, selling the pirated drug could easily cause one person to die—the person who took that drug and as a result did not get better. But on another level, selling the pirated drug contributes potentially to the death of millions, since the imitations are causing the real artemisinin drugs to become ineffective. “Twice in the past, South East Asia has made a gift, unwittingly, of drug resistant parasites to the rest of the world, in particular to Africa,” according to Nick Day, director of the Mahidol-Oxford Tropical Medicine Research Unit. “If the same thing happens again . . . that will have devastating consequences for malaria control.”
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Virtually all malaria researchers would concur with Day on that point. “If we lose the artemisinins at this stage, just now when we dare to mention the word ‘eradication’ again, it would be a disaster for malaria control,” said Dr. Arjen Dondorp, lead author of a study about artemisinin resistance in Cambodia. “It would cause millions of deaths, without exaggeration.”
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There is yet another level of danger arising from these circumstances, with the consequences going far beyond even losing the benefits of a once-effective medicine, as serious as that would be. The greater problem is that the parasite could come back stronger than ever. Partial victory against malaria could ultimately be worse than total failure.

History offers one such example that traumatized the malaria community for nearly half a century. In 1955, the World Health Organization believed that malaria could be eliminated within ten years, thanks to the introduction of chloroquine in the 1940s and the discovery of DDT, the most effective insecticide in history, in 1939. Today we are more aware of the dangers of DDT than its benefits, but in 1948 the chemist who created it, Paul Müller, won the Nobel Prize in medicine for doing so.

WHO spent more than a billion dollars in its campaign against malaria, and the disease was wiped out in much of the Caribbean and South Pacific. Malaria cases in Sri Lanka dropped from 2.8 million in 1946 to a total of 17 in 1963. Likewise, in India there were 75 million cases in 1951 and only 50,000 in 1961.

But in the deep tropics, the disease remained untouched, and the program largely bypassed sub-Saharan Africa. Overuse of DDT by farmers (not by malaria fighters) led Rachel Carson, who is widely considered the founder of the environmental movement, to document its abuse in her book
Silent Spring
, and as a result of her revelations, much of the world outlawed it for agricultural use. DDT became politically
incorrect and difficult to procure. The political will for financing malaria eradication eventually began to fade, and resistance to chloroquine created epidemics of malaria even more difficult to treat. The disease came roaring back in India and Sri Lanka. Today the toll from malaria is almost twice what it was a generation ago.

So when a leading drug such as artemisinin, once considered infallible, begins to falter, attention shifts to other approaches. One result has been to look to vaccines as a promising alternative to drugs. Hence the intense competition among leaders in the race to a vaccine, like Steve Hoffman and GSK. But there is also competition from advocates of other strategies for defeating malaria.

Just as different branches of the armed services employ different weapons and tactics to achieve the same goal, the malaria community has always been divided into different branches to wage its war, and each branch vigorously champions its own particular capabilities and worldview. Vaccine developers believe that prevention would be the most effective and economical method of combating malaria. Without a vaccine, they argue, we will be trapped in a perpetual cycle, spending massive amounts of money and energy on treatments that the parasite will eventually be able to resist.

Those who develop drugs to treat the disease think a vaccine would be great but quickly point out that there has never been one for malaria, or for any other parasitic disease. So the old debate begins again: Do we encourage palliative treatment today that falls short of eradication, or
support a total cure that is years (and millions of deaths) away from universal application, if indeed it works?

And there are those in the malaria community who believe that resistance to both drugs and vaccines is just a matter of time and that we should focus on the only thing that has ever really worked: “vector control,” that is, using bed nets and insecticide sprays as the weapons of choice. Thus we would try to get rid of the malaria parasite by getting rid of the mosquitoes that house, transport, and deliver it. But even this option is not exempt from evolution’s toll. At the Fifth Multilateral Initiative on Malaria, held in Kenya in October 2009, it was reported that mosquitoes were adapting to bed nets by changing their feeding habits. Instead of trying to feed at night, when people were safely beneath their nets, the mosquitoes were getting their meals earlier in the evening when people were still out in the open. At the same time, there is evidence of the mosquito developing resistance to the pyrethrum-based insecticides used to treat the nets.

Practitioners within any one branch tend to be consumed by developments in their own field and not especially knowledgeable about the others. They can be uninterested at best, and dismissive at worst. Steve Hoffman and Jay Keasling devote to each other, at most, a glimmer of recognition—and less than a glimmer of enthusiasm. Or maybe it is simply a matter of staying focused on what one does best. As Hoffman told me of Keasling’s work: “I admire what he’s done, but I leave his job to him and he leaves mine to me.” In each branch of the malaria war, there are many who believe their own approach
embodies the best mix of compassion, realism, and effectiveness, and therefore occupies the moral high ground.

New discoveries, technological advances, and policy shifts regularly reset the playing field, temporarily boosting one approach over another and causing tidal shifts in the flow of resources, money, and manpower from one branch to another. Over time, however, it has become apparent that the malaria parasite is too complex and evasive to succumb to the attacks of one branch alone. All are necessary.

“All” gets very expensive, very quickly. Even more, it creates a challenge: the need for scientists to coordinate with each other and work together. The various branches of our military forces have rarely been successful any other way. The various branches of the malaria community have rarely even tried.

I first heard about Judith Epstein, a U.S. Navy commander, from Steve Hoffman when he told me about the editorial she’d written in 2007 for the medical journal
The Lancet
, “What Will a Partly Protective Malaria Vaccine Mean to Mothers in Africa?,” which raised some of the same questions that Hoffman has asked about the RTS,S vaccine. The kind of humanistic themes she brought out are rare in scientific journal articles written by military personnel. Epstein argued for a vaccine that went beyond the partial effectiveness of RTS,S, even though the military—at least the army—was deeply invested in it.
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Epstein works at the Naval Medical Research Center, which is located near the imposing Bethesda Naval Hospital. As principal investigator at the Navy’s Center for Clinical Trials, Epstein was responsible for conducting and assessing the Phase I trials in 2009 of Steve Hoffman’s vaccine. She will yield the first official evaluation of the safety and efficacy of the vaccine Hoffman has worked on for all these years, determining whether the more than $60 million that foundations and government agencies have already invested in Hoffman’s effort will be followed by investments of even greater magnitude.
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The trials are not “make-or-break” so much as potentially “break.” It is only the first of numerous trials, but there is no Phase II without getting past Phase I.

I wanted to get to know Epstein, partly because a doctor who goes into tropical medicine sets himself or herself apart from 99 percent of the rest of the medical community. The difference goes beyond being smart, or altruistic, though the doctors who make this choice often are both. It has more to do with having made different choices about how to lead one’s life, choices that isolate one from the mainstream in medicine and that result in a way of being that is, by nature, rather solitary. I wanted to know more about the quality of character that enables people like Hoffman and Epstein to make such choices, and I thought Judy Epstein might help me understand this. She did not disappoint.

I drove out to NMRC—known as “Namric” in military parlance—on a Monday morning and waited to clear a checkpoint manned by a squad of five or six military police.
I was directed to pull in behind a line of cars parked on the helipad, which was marked by an enormous white cross in front of the naval hospital. Behind it lay a naval base that looked more like a rural college campus, with old buildings, leafy paths, and the stately residences of admirals instead of the offices of a college president and dean. Epstein pulled up, rolled down her window, and told me to follow her. As we went through the checkpoint, where she returned the salute of a military police officer, and proceeded to the grounds of the Naval Medical Research Center, I noticed how carefully and thoroughly she obeyed speed limits, stop signs, and traffic directions. Though fifty-four and an officer for nearly ten years, Judy still acted as if she were new to the navy, too new to take casually the numerous rules and regulations that are second nature to military life.