by Sonia Shah
It was several years and thousands of deaths later before a drug that fought the virus appeared on the scene. Articulate, angry, and accomplished activists such as Larry Kramer, an impassioned playwright, were convinced that if they pushed the NIH, the FDA, and the drug companies hard enough, viable AIDS treatments would be found. “Laboratories have drugs that they’re not giving us,” fumed Kramer in 1995. “I think that they should go before the equivalent of a Nuremberg Tribunal for War Crimes.”6
Retrovir (AZT), released in 1987 by a company that would later become part of GlaxoSmithKline, wouldn’t exactly be the answer to their demands. AZT, a nucleoside analogue, incorporated itself into the RNA of the virus, rendering it ineffective. A sizable public investment had gone into the development of AZT. The compound had been synthesized by government-funded scientists in 1964, the National Cancer Institute had run the tests that revealed its anti-HIV properties, and the government had helped conduct clinical trials on the drug. Nevertheless, the drug’s manufacturer decided to charge poorly insured and dying AIDS patients $8,000 for a year’s worth of treatment. Aware that it was about to release the only approved drug available for a deadly disease, the company would make AZT its “largest contributor to revenue and earnings,” analyst Jonathan Gelles gushed in 1987. “The profit margin will be about three times the company’s 13 percent average.”7
The New York Times, among others, called the price tag “inhuman,” and public demonstrations forced the company to moderate its fee, but by 1994, Retrovir was indeed the $1.6 billion company’s second bestselling drug, bringing in over $300 million a year.
Lucrative or not, AZT was no cure-all. The drug worked only after being metabolized into its active form, and persisted in the body for just two hours.8 Half of those who tried it quit soon afterward because of its toxic side effects, such as fatigue and bone marrow problems. Nevertheless, the network of hospitals and researchers organized by the government to coordinate studies of experimental AIDS therapies, the AIDS Clinical Trials Group (ACTG), was recharged with new focus. Perhaps the drug would protect HIV-infected people from neurological damage or from coming down with AIDS altogether. It might even prevent infected pregnant women from passing the virus on to their babies. Soon ACTG researchers would launch massive new trials using the problematic drug. “People were very nervous about having this drug used in thousands of patients so fast,” said Maureen Myers, an AIDS researcher with the National Institute of Allergy and Infectious Diseases, but “we also knew we were going to have limited time to do the things we wanted to do.”9 It would be eight years before the drug industry released a new kind of HIV drug.
Throughout those years the public pressure to do something was intense. Already, the ACTG had come under fire for its methodical ploddings. “The AIDS Clinical Trials Group has proved to be a massive, dysfunctional failure in its inept efforts to lengthen the lives of HIV-infected people,” the activist organization ACT UP charged in 1990. “This skewed application of increasingly limited government research funds must stop immediately,” another activist railed in a letter to the Washington Post. “We cannot wait.”10
And yet, few HIV-positive Americans and their physicians were willing to take part in ACTG studies that compared AZT to a placebo, such as one that measured the effects of the drug in retarding neurological damage. Even though patients eligible for the trial were not yet sick and would only be involved in the study for a short while, neither patients nor physicians were willing to risk forgoing the newly available AZT, no matter how limited its benefit. After eleven months of recruiting, the study had enrolled only forty out of a needed three hundred subjects. The researchers were forced to drop the placebo group.11
Such problems did not plague one of ACTG’s most important early trials. In its trial testing whether AZT might prevent pregnant HIV-positive women from infecting their babies—a trial coded “076”—researchers had happened upon their first real breakthrough. In placebo-controlled trials in the United States and France, AZT had slashed the transmission of HIV from mother to child from 24.9 percent on placebo to just 7.9 percent. In the study 100 mg of AZT had been administered five times a day to infected pregnant women for months before delivery; during delivery, the women got an IV infusion of the drug, and the baby got a dose of AZT syrup every six hours during its first six weeks of life. Given the extensive volumes of drug required, and the med’s still costly price tag, the entire regimen cost around $800.12 As soon as the effect of the drug was clear—the data was analyzed about midway through the trial—the placebo group was dropped and all the mothers were given the AZT regimen, saving one of every seven of their babies from the deadly infection.13
It was 1994, thirteen years after AIDS had emerged and ten years after the virus had been isolated, and finally a randomized controlled trial of an HIV prevention method had rendered a positive finding. “There had not been a single randomized trial that proved that any intervention for HIV prevention worked. Nothing!” remembers one HIV researcher. “It was a massive opportunity.”14 In a flurry of official action, the CDC announced its recommendation that clinicians offer the therapy to all pregnant HIV-infected women, regardless of their stage of disease or when they showed up at the hospital.15 Within months the FDA approved the new use of the drug. With a lifesaving intervention available, the Public Health Service announced their recommendation that all pregnant women receive prenatal HIV counseling and testing.16
Major breakthroughs followed hard on the heels of 076. At the end of 1995 the FDA approved the first of a new class of anti-HIV drugs, called protease inhibitors, that disable the virus by preventing it from reproducing within immune cells.17 Less than a year later the first of a third new class of antiretroviral drugs appeared, nonnucleoside reverse transcriptase inhibitors, which block the virus’s RNA from converting into DNA, thus preventing it from taking over immune cells.18
Bombarding the virus with all three antiretroviral fighters seemed to defang the virus almost entirely. Although pricey—the combination of brand-name drugs could run to $15,000 a year—and complicated, the U.S. news media along with many HIV-positive Americans breathed a collective sigh of relief.
The most pressing questions, it might have seemed, now revolved around how to ensure universal access to the new solutions. But rather than working to overcome the inevitable barriers of poverty and inequity, many AIDS researchers felt compelled to accommodate them. Though combination antiretroviral therapy might turn the deadly disease into a lifelong chronic condition, U.S. officials and researchers alike seemed to believe this was a solution only for HIV-positive people in the moneyed West. Impoverished Africans and Asians might be suffering the brunt of the global burden of AIDS, but in Africa, “they don’t have running water and they don’t have watches,” Hopkins AIDS researcher Tom Quinn said in 2000.19 Helping ailing Africans gain access to antiretroviral therapies might save lives, according to leading virologist Robert Gallo, but “it will be a tragic mistake if it’s not done right.” Since Africans “don’t know what Western time is,” as the director of the U.S. Agency for International Development claimed in 2001, they were unlikely to take their pills on schedule.20 They might miss a few doses, opening the door for viral mutations that would render the drugs ineffective. “You’ll have ‘Eureka’ and ‘Thank you America!’ for two or three years—but then you’ll get multi-drug resistance,” worried Gallo.21
Likewise the World Health Organization did not start strategizing about how best to secure sufficient AZT and distribute it to the pregnant HIV-positive women around the world who were passing on the virus to half a million infants every year. With some governments spending as little as $2 a year on health care for each of their citizens, shelling out $800 to save a single baby from HIV struck officials as impossibly expensive. Not only that: according to University of Natal HIV researcher Hoosen Coovadia, the 076 regimen was “scientifically inapplicable to African populations.”22 Most pregnant women in developing countries didn’t sh
ow up at hospitals in time to start the therapy, typically bearing their babies far from medical clinics where health care workers could administer the IV drugs. And then, even if a baby were saved from infection at birth, the mother was likely to spend months feeding the baby infected milk from her breast.23
At a 1994 meeting convened to discuss the 076 breakthrough the WHO decided not to endorse AZT for global use among pregnant women infected with the virus. The regimen had “a number of features (cost and logistical issues, among others) which limit its general applicability,” the WHO reported. Nor would WHO devote resources to figuring out how to make 076 work. Instead, “simpler and less costly” therapies for use solely during delivery should be “urgently studied.”24
The question was: how could researchers conduct ethical experiments in search of solutions that could very well prove less effective than 076?
There is an inherent perversity in controlled clinical trials, which is that by relying on the contrast between two groups treated differently, one group must suffer worse outcomes than the other. In HIV prevention trials that means that one group must suffer more HIV infections than the other. It also means that uninfected people must expose themselves to the virus. Subjects must venture into the ring with the lion, some equipped with armor, the others bare fleshed. It doesn’t behoove researchers to hand out shields and swords, though that might save their subjects—then the researchers could never determine whether the armor worked. The more stripped-down the subjects are, the more viciously the lion tears into them, the easier it is for scientists to quickly discern the value of their preventive tools.
A few HIV researchers noticed the potential conflict-of-interest early on in the business of HIV prevention research. Investigators testing new HIV prevention methods would have a built-in incentive to slack off on providing other protective methods to their subjects. When a group of HIV researchers pressed their colleagues in a 1994 paper to ensure that their test subjects were all armed with the best protective measures available, including counseling, free condoms, and sterile needles, the response was tepid at best.25 “Why would you do that?” a senior scientist grilled one of the authors. “You’d be cutting off your nose to spite your face! Let them get infected! You want to see a difference!”26
That paper was written just as HIV vaccine researchers were attempting to circumvent conflict-of-interest problems by siting risky trials in poor countries. By then, the leading HIV vaccine candidate, Genentech’s gp120 vaccine, had been roundly condemned as a dud. The vaccine triggered antibodies, but they had no effect whatsoever on HIV. The immune response the vaccine provoked was nothing like the one seen in the handful of extraordinary people who had been exposed to the virus but somehow had resisted infection. The NIH, which had initially planned to help push the vaccine into large-scale human trials, withdrew its support in June 1994.27
Big clinical trials of such a vaccine posed too great a risk to experimental subjects, NIH advisers decided. A dangerously misleading sense of security might fall over those taking an experimental vaccine with the NIH imprimatur. “People will make the assumption that if the NIH and the groups that have come together have felt that we should go ahead, they must really believe that it’s going to work,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. Such subjects were at real risk of not taking adequate protective precautions, generally difficult in the first place for the high-risk subjects researchers would need to recruit for the trial. Finally, vaccinees would test positive on HIV tests even if they were not infected, by virtue of having taken the vaccine. This might open them up to discrimination. Some vaccine researchers even worried that the vaccine could make its recipients more susceptible to HIV infection. Genentech started to dismantle its AIDS vaccine program.28
Later the same year, however, the World Health Organization met to discuss whether the vaccine trial could, in fact, move forward—in Thailand. Thai government officials needed to “try something,” as journalist Jon Cohen put it in his book on AIDS vaccines, Shots in the Dark, “even something that had only an outside chance of working.” The sexually transmitted infection was decimating their country, including, notably, their commercial sex industry, which was not only their top source of foreign exchange but also almost universally patronized by Thai military recruits. Some critics of the vaccine accused the WHO of being in the pocket of drug companies. “How much did Genentech pay you?” Jean-Paul Levy, then director of France’s top AIDS research agency, bellowed at the organizer of the meeting.29
In 1995 researcher Don Francis started a new company, VaxGen, devoted to developing gp120. With the Thais behind him he didn’t need the imprimatur of the NIH. Instead, VaxGen would use $30 million raised from private investors. After all, despite its shoddy showing to date, valuable data might be garnered from subjecting humans to the vaccine, Francis argued. Animal studies were inconclusive at best, and studying how HIV sparred with the vaccine in human bodies could prove useful to developing a better vaccine. VaxGen had already manufactured thousands of doses of experimental vaccine in preparation for a trial.30 VaxGen would run trials of the vaccine in both the United States and among intravenous drug users in Thailand.
Failing to provide counseling, condoms, or sterile needles—all known to help people avoid getting infected—would hardly be possible in HIV vaccine trials run in the United States. IRBs wouldn’t allow it, nor would test subjects put up with it. But elsewhere the situation is different. In 1986, for example, renegade French scientist Daniel Zagury injected an experimental HIV vaccine into healthy children in Zaire even before establishing whether such cells would harm animals, arguing in his defense that conditions in Zaire were so bad that any risk was worth taking if it might save peoples’ lives. “You don’t know the situation in Zaire,” he protested to Cohen. “It’s like you’re in the desert and you’re talking about the level of calcium in the water!”31 In Thailand VaxGen would not provide their test subjects with the sterile needles that represented their best hope for averting infection. This had nothing to do with the fact that VaxGen’s financial future depended upon trial results showing that sufficient numbers of control subjects contracted HIV, Francis said. Rather, the company was loath to practice “therapeutic imperialism.” Thai officials didn’t provide clean needles to drug users, the logic went, so why should VaxGen?32
Lanky, affable Jay Brooks Jackson grew up in Ohio, in a family that ran a coal mine. His midwestern roots show in his slow, patient twang, which he punctuates with warm chuckles and folksy “I tell ya’s” and “yup’s.” He earned his MBA in order to work in the family business, but the coal mining life wasn’t for him. In his first year on the job union workers staged a long, violent strike. Jackson fled for the sunlit halls of academia.
His earthy pragmatism led him into pathology and chemistry, but then in the late 1980s, the Nobel Prize–winning polio researcher Fred Robbins asked the hardworking, meticulous Jackson to help him set up a new research venture in Uganda, where the AIDS epidemic was burgeoning. In contrast to Jackson’s apolitical practicality, the world of AIDS research medicine bristled with fast-talking, ideologically driven activists, scientists, and politicians. But Jackson agreed anyway, and spent the next several years importing computers, generators, and water distillers to establish a state-of-the-art lab at Mulago Hospital in Kampala, Uganda. He knew the esteemed senior scientist who had invited him to Uganda had lofty goals. Robbins wanted to, “you know, help Africa,” explained Jackson, awkwardly. But for Jackson it was simply a good job. Humanitarianism “wasn’t a conscious thought at the time,” he says, laughing and nodding his head. “It was more like, ‘Nobel Prize winner? Sure!’”33
By 1994, Jackson was a professor of pathology at Case Western Reserve University School of Medicine, and one among many researchers in the ACTG who met to discuss research priorities in the wake of the 076 results. Jackson suspected that a single powerful dose of an immediately active and much longer actin
g antiretroviral could potentially provide the same effect as the long, complicated regimen with short-acting AZT, at a fraction of the cost. Boehringer Ingelheim made an antiretroviral drug called nevirapine that might do the trick, because it was immediately active and potent for sixty hours with a single dose. At the time nevirapine had essentially fallen off the map in AIDS treatment because of its proclivity for nurturing resistant strains of HIV.
“There were people in ACTG who were talking about using it,” Jackson recalls. “One guy in particular . . . had mentioned it to me. I remember in the meeting he wanted to do it in Africa. You couldn’t do it here [in the United States]! Ethically you couldn’t even give AZT for two trimesters and then one dose of nevirapine! That was the problem.” No American doctor or patient would risk foregoing any part of the now standard 076 regimen, potentially endangering their baby.
But things were different at Mulago Hospital in Kampala, Uganda.34 Around four thousand HIV-infected pregnant women were delivering their babies at Mulago every year, and of these infants, more than a third would end up with HIV. None of the mothers were able to afford the 076 regimen. If Jackson wanted to test a new therapy out on them, he wouldn’t have to pit it against a long course of AZT, since women there would be unlikely to demand it. And he knew he wouldn’t be depriving them of something they could get elsewhere. The new intervention, whatever it might be, would be unlikely to work better than 076; Jackson’s prediction was that nevirapine might cut the HIV transmission rate down from 25 percent on placebo to 17 percent. But even if it couldn’t shake a stick at the 67 percent drop in infections that the 076 regimen could effect, it would be more affordable and so would represent a “highly relevant public health benefit,” Jackson contended, and one that was “much more plausible.”35
