Chapter 9
Clinical Trials and Tribulations

The Search for New Directions (1992–1993)

"Outsmarting Science"

The ever fragile optimism of treatment activists strained to the breaking point in late 1991. The second generation of antiviral AIDS drugs—the non-nucleoside reverse-transcriptase inhibitors that had been engineered specifically to fight HIV and that had looked so promising in vitro—performed poorly in clinical trials. Merck's "L" drugs, nevirapine, and another drug called TIBO were all shown to have little individual efficacy against the virus because the viral gene that produced reverse transcriptase proved capable of mutating in a matter of days or weeks to resist these compounds. For some time now, the avowed goal had been to use the little-loved nucleoside analogues, AZT, ddC, and ddI, to keep people alive just long enough to get better drugs into circulation. Now people would have to depend on the first-generation drugs for much longer—while those who ceased benefiting from them would have no obvious therapeutic recourse standing between them and complete immune collapse.

The news about the non-nucleoside reverse-transcriptase inhibitors "was nothing short of shattering," said Theo Smart of ACT UP/New York. "So many hopes had been pinned to [these drugs'] effectiveness."^[1] "Researchers openly wondered, 'What are we going to do next?'" reported Jesse Dobson of ACT UP/Golden Gate and the Community Constituency Group, describing an ACTG meeting in late

1991.^[2] "Activists Despondent and the Movement Is Splintering" was the headline of one of a series of articles in the San Francisco Examiner by reporter Jayne Garrison, describing the state of affairs. Garrison quoted Peter Staley, a prominent New York activist: "As far as I'm concerned I'm going to die, Magic Johnson is going to die and the million Americans who are presently infected will die."^[3] Concluded Garrison: "So far, the virus is outsmarting science."^[4]

Martin Delaney, projecting the generally upbeat message of Project Inform, rejected the "gloom and doom" and stressed instead the continued importance of combination therapy with nucleoside analogues, the apparently large numbers of "long-term survivors" who had been living with HIV for a decade or more, and the promised protease inhibitors and tat inhibitors then on the horizon.^[5] Unfortunately, the ongoing saga of Hoffman-LaRoche's tat inhibitor—the only such drug in development—was hardly reassuring. For reasons that were inexplicable to the Johns Hopkins researchers who had been contracted to conduct the study, the company summarily postponed its Phase I trial in May 1991. Activists had generally found this company less cooperative than most; now they could only speculate that Hoffman-LaRoche wished to avoid subsidizing another parallel track program, having given out free ddC to more than three thousand AIDS patients.^[6]

At first the company announced that it would sell its tat inhibitor to the highest bidder; then, half a year later, Hoffman-LaRoche changed its mind, saying it would develop the drug after all. "Apparently the company decided that this drug was too good to sell—especially in view of the disappointing results with the competing class of non-nucleoside reverse-transcriptase inhibitors," suggested John James in AIDS Treatment News .^[7] But throughout 1992, Hoffman-LaRoche sat tight. In early 1993 activists declared open warfare on the company with the mass resignation of the members of the Community Advisory Board that the company had established. "There can be no more polite dialogue with your company," said TAG and ACT UP/New York in a letter sent to Hoffman-LaRoche in late January threatening a boycott of its products, laboratories, and home care services.^[8] In his column in the Advocate , Delaney proposed that the government seize the drug "in the national interest": "Eminent domain is frequently used to seize private property for such national emergencies as highway construction. Is AIDS less important?"^[9]

As John James observed, the lesson of the tat inhibitor extended

well beyond the cupidity or irresponsibility of a single company. Here was a type of drug that "leading AIDS scientists" considered to be "perhaps the single most promising approach to developing better AIDS treatments"; furthermore, potential tat inhibitors could easily be discovered through known screening methods. There was no reason, in theory, why there couldn't be fifty tat inhibitors in development; "instead, the whole pharmaceutical industry (or rather, that small part of it which has any interest in AIDS) seems to be waiting to see what happens with the only tat inhibitor drug now in human testing. …" It was a maddening picture: "In the middle of a major worldwide epidemic, the most promising approach to treatment development has been abandoned to a single project with a single drug in a single company." The problem was not just Hoffman-LaRoche; the problem was the whole notion that the "invisible hand" of the free market would somehow function in the service of the public good and not just private gain—a notion that the NIH was unwilling or unable to challenge. And, separate from the issue of political economy, there remained the additional, nagging question: Why did Hoffman-LaRoche seem to have "so little interest in its own drug"? "What might it know that we don't?" asked James.^[10]

A "New Paradigm" for Treatment Activism

In keeping with the grim news from the treatment front, the Eighth International Conference on AIDS, held in Amsterdam in June 1992, was "somber" in atmosphere. One striking expression of official pessimism came from the editor of JAMA , Dr. George Lundberg, who predicted that AIDS would remain a common disease a century from now. Lawrence Altman, covering the conference for the New York Times , noted some of the effects of discouragement: "Even demonstrators who have disrupted previous conferences and attacked health officials and scientists for their slow, step-by-step approach conceded that there was an urgent need to return to basic science," he wrote.^[11]

These were the sentiments that motivated the lengthy report "AIDS Research at the NIH: A Critical Review," prepared by Gregg Gonsalves and Mark Harrington and presented by the Treatment Action Group at the 1992 conference.^[12] The two authors had sat down and read every NIH grant that had funded AIDS research through each of

the NIH institutes, and they had tried to envision a logical, cohesive approach to organizing that research effort.^[13] "Since 1987," wrote Gonsalves and Harrington, "the activist critique of AIDS research has worked its way back: from drug approval at the regulatory level of the US Food + Drug Administration …, to expanded access for drugs still under study (Parallel Track), to the design and conduct of the controlled clinical trials themselves by the National Institutes of Health …, pharmaceutical companies, and community-based clinical trial centers." Now activists had come to realize that in order for their efforts to succeed, they would have to focus their attention on an even earlier phase of the research process: "If the reforms won by activists are not to become mere stratagems for craven pharmaceutical companies swiftly to develop and market a whole series of additional nucleoside analogues (d4T, FLT, 3TC, etc.), activists must become more involved in the basic research process itself, forcing academic and industrial researchers to turn their attention to novel treatment approaches to HIV-induced immune suppression.…" This was a tall order, one that "[required] that activists become as familiar with the $800 million AIDS program of the NIH as they have with its major clinical component," the ACTG. The ACTG "is but one eighth of the NIH AIDS program. A cure will never be tested by the ACTG unless it's discovered somewhere else first." Clinical trials were the late stage in the game—to get drugs into development, activists had to influence the course of basic AIDS research at the NIH, within NIAID as well as the various other agencies, like the National Cancer Institute, the National Institute of Child Health and Human Development, and the National Institute of Neurological Disorders and Stroke. "This is a new paradigm for AIDS activists," the TAG authors made clear: "We have to familiarize ourselves with a wide range of disciplines."^[14]

It was a significant shift, but a risky one, for the course of action that now seemed most crucial also appeared to be one in which activists were by no means guaranteed to succeed. Gonsalves and Harrington grasped the point clearly: "Activists' claim to expertise in clinical trials came out of lived experience. Most of us cannot claim the same for basic biomedical research." At best, activists could "hope to serve as catalysts for better and more coordinated work within the research realm, and as agitators with Congress and the Administration for enhanced resources in the public realm."^[15] Indeed, it was in the realm of public policy that the report itself had the most impact. Upon the election of President Bill Clinton, who had promised to prioritize

AIDS research, Senator Ted Kennedy made the TAG report the basis for an amendment tacked onto the NIH authorization bill. Following the blueprint laid out in the report, Kennedy called for a strengthened Office of AIDS Research within the NIH, which would have jurisdiction over all AIDS-related research in each of the NIH institutes.^[16]

The Science of "Concordology"

As treatment activists focused on such drugs as the non-nucleosides, the tat and protease inhibitors, and still more experimental approaches, controversy continued to swirl around AZT. This made sense: AZT was still, by far, the most commonly prescribed AIDS antiviral, and it was considered the best drug with which to begin antiretroviral therapy. The drug had a high profile, in part because Burroughs Wellcome's marketing of the drug was sophisticated and relentless: the company's efforts included promotional videos mailed to doctors, a toll-free "AIDS information" hot line designed to peddle the company's product, and mass media and billboard ad campaigns preaching the benefits of knowing one's antibody status and initiating antiretroviral treatment early. Yet questions about the drug's use had never fully been answered to the satisfaction of many.

Longtime opponents of AZT, including HIV dissenters such as John Lauritsen and Chuck Ortleb, attacked those who had climbed aboard the AZT bandwagon. Lauritsen labeled Project Inform and the Gay Men's Health Crisis as "gay quisling groups" for their endorsement of nucleoside analogues, while the Native referred to John James as an "AZT pimp."^[17] Such attacks became more vehement after some of the treatment activist groups began accepting donations from Burroughs Wellcome. In 1992 Project Inform received a $150,000 grant from the company to upgrade its computer equipment. TAG and ACT UP/Golden Gate received small donations, but TAG also brokered a $1 million grant from the company to AmFAR in support of community-based research.^[18] "If I have to take money from the devil to save my life and the lives of my friends, I'll do it," said Peter Staley of TAG.^[19] Yet even if the donations came without strings attached, the acceptance of such funds left treatment groups vulnerable to attack by opponents of AZT. One leaflet that made the rounds in San Francisco in 1992 and purported to come from a group called "ACT UP/Underground" described Burroughs Wellcome's "blood payment" to Project

Inform. In a memorable phrase, the leaflet accused the organization of having "promised to deliver its own community to nucleoside slavery, bound in the chains of corporate greed!"^[20]

At a different volume level, mainstream authorities continued to debate the merits of early intervention with AZT in people who were asymptomatic. "After 5 Years of Use, Doubt Still Clouds Leading AIDS Drug" was the New York Times headline of a 1992 article by Gina Kolata that charted the undercurrents of uncertainty.^[21] No study had yet demonstrated that AZT actually prolonged life in people who started taking the drug when they had fewer than 500 T cells, although the Veterans Administration study, once completed, indicated that AZT did prolong the length of the disease-free state.^[22] (Concerns about racial differences in response to AZT based on a preliminary report from the study were generally allayed by retrospective analyses of earlier studies that showed no treatment differences based on race.)^[23] This study was considered too small to provide a definitive answer to questions of survival; instead, researchers now looked to the completion of the Concorde study in Europe.

Meanwhile, doctors and patients grappled with uncertainties: Was it better to start treatment early, before the immune system had deteriorated and while the patient could more easily tolerate a serious drug, in the hope of delaying the onset of symptoms, thus keeping the patient healthy until more effective drugs arrived on the scene? Or was it better to wait, sparing outwardly healthy patients a toxic drug that could cause anemia or liver damage and avoiding the development of resistance, so that the drug would be effective later in the course of illness at the point when there was clearer evidence that it actually provided a benefit? As a 1992 survey of 448 physicians reveals, the vast majority simply followed the NIH guidelines and the FDA labeling, prescribing AZT for anyone with fewer than five hundred T cells per cubic millimeter.^[24] But doctors and patients who tracked the science of AIDS more closely were often less certain about the best course of action.

Still, nobody seemed quite ready for the news when the Concorde researchers released their preliminary report on April 1, 1993, in a brief letter to the editor in Lancet .^[25] Eight hundred seventy-seven patients, asymptomatic upon entry into the study, had been randomized into the "immediate treatment" arm of the study and had received one thousand milligrams of AZT daily; 872 had been placed in the "deferred treatment" arm, receiving a placebo unless they became symptomatic,

at which point they were put on AZT. In total, the study provided 5,328 person-years of data, making it the largest and longest study of its kind. The researchers reported that the patients in the "immediate treatment" arm experienced more of a CD4-count boost, on average, than those in the "deferred treatment" arm. However, "by contrast with the differences in CD4 count, there was no significant difference in clinical outcome between the two therapeutic strategies." The three-year survival rate was 92 percent for those who had begun taking AZT early and 93 percent for those who were put on the drug later. And similarly, there was no significant difference between the two groups in terms of disease progression and the development of opportunistic infections.

In the eyes of the Concorde investigators, Ian Weller in Britain and Jean-Pierre Aboulker in France, the study did not so much contradict 019 and the other studies of AZT use in asymptomatic patients as subsume them by proceeding for a longer period of time. The investigators had found an initial trend suggesting benefit in the early use of AZT, similar to that found by Paul Volberding in ACTG 019. But since the trend wasn't statistically significant, the trial was kept going, and as time passed the benefit simply disapeared. The bottom line, according to the Lancet report, was this: starting AZT early, as opposed to starting it later, did not extend survival or even the disease-free state. And CD4, the "surrogate marker" that had been employed in the licensing of ddI and ddC in the United States, could not be considered predictive of long-term treatment differences.

It was a painful moment that left many people dazed—or defensive, or angry, or jubilant, depending on their previous commitments in the AZT controversies. "Rarely have a mere eight paragraphs sparked such fury, hysteria and hyperbole," said an article in a San Francisco lesbian and gay newspaper.^[26] Not long afterward, one researcher with the World Health Organization would suggest that "a whole tropical rain forest has disappeared as a result of this study," which ushered in a brand new domain of scientific inquiry he dubbed "Concordology."^[27] And in the space of a few days following the report in Lancet , the stock value of Wellcome PLC dropped by more than $500 million.^[28]

Billed as the "definitive" study of AZT use in asymptomatic HIV infection, Concorde initially appeared to settle nothing; it seemed almost infinitely malleable in the interpretations it could generate. "You can interpret [Concorde] as your bias dictates," said the director of

inpatient services at San Francisco General Hospital.^[29] Weller, the British principal investigator, who described himself as having already been "very conservative in the use of zidovudine [AZT] monotherapy in asymptomatic patients," now said: "Those physicians like myself who tended to wait until symptoms appeared are going to be more sure they were doing the right thing."^[30] Douglas Richman, one of the principal investigators in the AZT studies in the United States, commented: "This is a chronic active persistent infection. It's incomceivable to me that not treating it is the way to go."^[31] One "knowledgeable and compassionate AIDS doctor told [GMHC's publication, Treatment Issues ] privately that he would continue to prescribe AZT for his asymptomatic patients even if it did not work. He said there was nothing else for him to do."^[32]

Those who wanted to score political points had plenty of opportunity. Larry Kramer, for instance, used the study to highlight the overall failure of the research effort in an overwrought editorial he penned for the Advocate , entitled "AZT Is Shit."^[33] Other responses followed predictable patterns. "Advocates of the AZT-is-poison school have had a field day," wrote Tim Kingston, a reporter for the San Francisco Bay Times . "Not only do they assert that early AZT intervention is ineffective, but also that all AZT treatment and all HIV antiretroviral therapies are ineffective."^[34] One example was the comment of HIV dissenter and AIDS activist Michael Callen, quoted in the Los Angeles Times: "Taking AZT is like aiming a thermonuclear warheard at a mosquito."^[35] A San Francisco gay newspaper whose AIDS writer had been opposed to AZT ran a cover graphic of a hand tipping a gigantic bottle of Retrovir (the brand name of AZT), with capsules spilling onto tombstones in a graveyard.^[36]

A Los Angeles-based group of AZT dissidents, called Project AIDS, International, sought to spread the word to AZT "victims": "You need to know your rights. Ask yourself the following questions: Were you misled by the U.S. studies or information that was given you through theFDA or CDC? Were you pressured into taking AZT … by your doctors or an AIDS organization? … If you have answered yes …, you have a right to compensation.…"^[37] In London, newspapers reported that the widow of a person with AIDS was suing Wellcome PLC, claiming that her husband had died from the effects of AZT.^[38] And a London group calling itself Gays Against Genocide picketed an AIDS organization and a hospital where a clinical trial of AZT in children was in progress, accusing their targets of "murder"

and "baby-killing," respectively.^[39] Meanwhile, opponents of these views argued that if Concorde did anything it disproved , once and for all, the notion that AZT is poison: after all, a large number of people had taken a high dose of AZT for four years and only a small percentage experienced adverse reactions to the drug.^[40]

European AIDS authorities, by and large, tended to accept the study conclusions as given. But U.S. authorities rushed to explain that nothing really had changed. Until more data were available, "no physician or patient should change the approach they're using based on this study," Daniel Hoth of NIAID told USA Today .^[41] David Kessler, the FDA commissioner, told the New York Times that the results of Concorde were not a surprise, since experts "have known that AZT has real but limited benefit"; this of course sidestepped the issue of the FDA's labeling of AZT for use in any HIV-infected person with fewer than five hundred T cells.^[42]

East Coast AIDS groups, less well-disposed overall to the nucleoside analogues, criticized the official "spin control." GMCH's publication, Treatment Issues , commented: "The blizzard of press releases responding to Concorde reveals the extent of the personal and professional investment many U.S. researchers have in AZT's efficacy. While one should expect a profit-driven corporation like Burroughs Wellcome to interpret the data favorably, U.S. government agencies should be held to a different standard."^[43] But West Coast groups like Project Inform and publications like AIDS Treatment News that were more committed to early intervention reacted quickly to the study, and they rushed out their methodological heavy artilerry. Fighting against the "black-boxing" of Concorde, they strove to highlight as much contingency, messiness, and uncertainty as they possibly could.

First, patients in the study had received an unusually high dose of AZT—twice the dose that had become standard by the time of the study's terminatinn. From the "pragmatic" perspective on clinical trials, this meant that the study had questionable relevance to the real-world treatment decisions of 1993. A larger concern was the modification of the study protocol in midcourse, after the results of ACTG 019 had come out. To satisfy ethical requirements, the Concorde investigators had allowed patients with fewer than five hundred T cells to choose at any point to begin open use of AZT rather than remain in the double-blinded trial. In all, 282 of the 872 patients in the deferred treatment arm had switched from placebo to AZT. The accepted statistical practice, however (called the "intent-to-treat" rule), was to

analyze patients as if they remained in the original groups to which they had been randomly assigned . That is, the 282 patients who began taking AZT prior to progression to illness were analyzed as if they had been on placebo all along.^[44]

The purpose of the intent-to-treat rule in biostatistics is to put the burden of proof on the drug whose efficacy is under investigation.^[45] For example, if some subjects in the placebo arm of a trial accidentally receive the study drug, researchers continue to count them in the placebo group. Then, if a difference in outcome is still found between the two arms of the study despite the blurring of regimens that occurred, the researcher can be especially confident about the results. The problem, however, is that if no difference is found, the researcher might reasonably wonder: is the drug really useless or did the contamination of the original study design prevent a true difference from manifesting itself? No one representing the Concorde study was suggesting that the change in the study protocol might account for the negative outcome—that if no placebo patients had switched to open-label AZT, the "deferred treatment" arm would have done worse relative to the "immediate treatment" arm. But to many U.S. researchers (and certainly to Burroughs Wellcome) this seemed eminently plausible.^[46] In effect, they argued, two roughly similar groups were being compared, so it was no surprise when the outcomes were similar.

John James also raised questions about the surrogate markers issue, which, as he noted, was so vital to the program of accelerated approval of new drugs. The Lancet letter had reported only that the median CD4 counts over time failed to predict the outcomes of the two arms of the study. Most U.S. researchers, wrote James, thought it was insufficient to look just at the median counts: "This question must be addressed by case-by-case analysis of whether individual patients whose T-helper counts rose after starting the drug seemed to show improved prognosis as a result."^[47] Meanwhile, treatment activists around the country worried that the initial reports from Concorde would fuel a backlash against the changes that had been instituted at the FDA to approved drugs more rapidly. "The spin, I predict, will be 'This is all the activists' fault," wrote Larry Kramer. "New York Times chameleon Dr. Lawrence Altman said as much in his ineptly reported article.…"^[48]

Altman had written a follow-up to his initial news article on Concorde, a commentary entitled "AIDS Study Casts Doubt on Value of Hastened Drug Approval in U.S."^[49] The article explained how Concorde

researchers had "persisted" against the prevailing construction of belief about AZT, continuing their study even after ACTG 019 had ended. That persistence had paid off in a finding that overturned the conventional wisdom. Furthermore, "in challenging the reliability of the CD-4 count in evaluating AZT, the Concorde study rekindled a long simmering dispute between many European and American researchers over the validity of surrogate markers in H.I.V. and AIDS," wrote Altman, noting that the British government had refused to license ddI on the basis of surrogate markers. Altman quoted Ian Weller, the British principal investigator, about the "lesson" in the Concorde study: "Don't stop trials too early…. Whatever the pressures are, keep going as long as possible."

Some reacted defensively to such charges, while others were despondent. Yet all the responses seemed to reflect the same underlying disquiet. It wasn't just the study; it was the whole state of the science, and Concorde was merely the last straw. An editorial in GMHC's Treatment Issues did a good job of capturing the sentiments that seemed to feed many of the reactions to the study: "Concorde underscores the uncertainty many AIDS researchers and clinicians feel. A few years ago, many physicians believed that the nucleoside analogs … would transform AIDS into a so-called 'chronic manageable' condition. There is now a deep and growing sense among many that some of the basic assumptions underlying AIDS drug development need to be reexamined."^[50]

Berlin

These were the clouds hanging overhead as thirteen thousand people from 166 countries assembled in Berlin's vast and labyrinthine conference center in June for the Ninth International Conference on AIDS. A cover story by Science reporter Jon Cohen had set the stage for the scientific proceedings. "The more we learn, the less certain we are" was the message Cohen had gleaned from a survey he conducted of 150 leading AIDS researchers: "After more than a decade of struggling in frustration as the epidemic gallops on, researchers are being forced to reexamine assumptions they once held without question." Even as "politicians and AIDS activists [were] demanding results immediately," researchers confronted a series of "collapsing certainties," including the virtues of antiretroviral therapy in asymptomatics, the trustworthiness of surrogate markers in evaluating

treatments, and the reliability of certain key vaccine experiments. In addition, "many researchers who once believed almost all the damage caused by HIV could be explained by the virus's direct killing of cells now think indirect mechanisms must also be at work."^[51]

Progress certainly was being made in the understanding of pathogenesis, as conference presentations by top scientists such as Fauci and Jay Levy made clear.^[52] On one hand, better laboratory techniques such as PCR had revealed higher concentrations of infected cells throughout the body (and not just in the bloodstream); this lent credence to claims that direct cell-killing could play an important role in AIDS, while arguing against those, such as Duesberg, who had been maintaining that HIV could not be the true cause of AIDS if so few cells were infected (see chapters 3 and 4). On the other hand, few now thought that direct cell-killing was the only factor at work. Levy's recent, one hundred-page journal article on pathogenesis had listed more than a dozen factors he believed were involved in HIV-induced immune deficiency.^[53] HIV and its constituent proteins appeared to have a range of effects on both infected and uninfected cells, as well as on their associated cytokines; aberrant signaling by the cytokines then caused cascading effects throughout the immune system.

Better understanding could be gleaned, perhaps, from the study of so-called "long-term survivors" or "long-term nonprogressors"—this was a direction that activists had been promoting and that was increasingly emphasized in Berlin. "There's a growing sense that there is no magic bullet for AIDS, so we should shift research to see why some people do well …," said ACT UP/New York's Aldyn McKean.^[54] But as Robin Weiss had pointed out in an article on pathogenesis in Science , there might be nothing "special" about long-term survivors: since "the rates of progression … are also consistent with a stochastic, random occurrence of AIDS after HIV infection …, 'long-term' survival could be pure luck."^[55]

Gallo, in his address, offered a dazzling array of future, high-tech treatment possibilities. Gene therapy and "antisense" therapy might be used to prevent infection of cells. Drugs could be developed that targeted cellular products used by the virus, rather than directly targeting the virus. HIV-infected people could be given a genetically engineered protein of HHV-7 (human herpes virus, number seven), a virus that "competes" with HIV for CD4 receptor sites; the protein would then beat the virus to the CD4 molecules on the T cells and prevent infection.^[56]

This was all very nice, but what treatments were available in the short run? What could the assembled physicians (or at least, those from rich countries) go back and tell their patients, symptomatic or asymptomatic, about the options that were open to them? What was the "state of the art"? One crucial set of facts was offered by the Concorde researchers, who presented a range of data that went beyond the limited report in Lancet .^[57] Overall, the Concorde trial gained in credibility at the conference, though some found ways to bracket or qualify its findings. Martin Delaney claimed there were still data he would like to see, but that it "wasn't worth fighting about." Concorde was "just one of many studies out there" and not a particularly relevant one, at that. Concorde had asked "one question": Does a daily gram of AZT initiated early in the course of disease prevent progression? But since no one routinely took a gram a day of the drug, it wasn;t clear "what that means for early intervention in general or even for AZT."^[58]

The big story, however, was the result from ACTG 155. This was Margaret Fischl's Phase II study that many had been awaiting in order to see whether the AZT/ddC combination, licensed the previous year, would perform as well in a long-term study as surrogate marker evidence had predicted. At a satellite symposium held in Berlin on the eve of the international conference, Fischl tried to put the best face on the study's outcome. The sad facts were that 42 percent of the subjects receiving AZT, 43 percent of the subjects receiving ddC, and 39 percent of the subjects receiving the combination had progressed to serious illness or death; there was no statistically significant difference between the three treatment arms of ACTG 155. The subjects receiving the combination therapy did get a larger CD4 count boost, just as they had in the promising early study, ACTG 106. But they didn't live any longer in the end.

Nevertheless, Fischl framed the outcome as positive by stressing that the combination therapy did show an advantage in the subset of patients whose CD4 counts at the outset were between 150 and 300 per cubic millimeter.^[59] Since these were the subject with the highest initial CD4 counts in the study, the "spin" that Fischl was pushing was that patients benefited from the combination unless they were already too far along in their illness. NIAID supported this interpretation, issuing a press release with the headline: "Effectiveness of AZT/ddC Combination Depends on Pretreatment Immune Cell Count."^[60]

Yet as the distressing word of the study's overall findings spread

through the halls of the conference center, reporters witnessed the unusual spectacle of a NIAID representative yanking the press release from the media center and hastily replacing it with a new, more sober one: "The Effectiveness of AZT Alone, ddC Alone or AZT/ddC Combination Is Similar Overall for Patients with Advanced HIV Disease."^[61] Fischl, undeterred, repeated her original conclusions at the formal conference session.^[62] No sooner had she finished than activists from TAG sprang to the microphone. "The answer to the study you designed is that the study shows no difference between combo and monotherapy," insisted a furious David Barr. "You have staked your career on these drugs," yelled Barr. "I have staked my life."^[63]

Barr and other activists characterized Fischl's stratification of the subjects by CD4 count as a methodologically unjustifiable violation of the fundamental principles of randomization, indeed, as a post hoc fishing expedition for results that would make the study appear a success. As much as activists had wanted to believe in the combination therapy, they now had no patience for any sugarcoating of the bad news. (Or perhaps, to the extent that they felt disillusioned, Fischl provided a convenient focal point for their anger: it's more satisfying, after all, to direct one's wrath at a researcher who appears to be cheating than at a virus that appears to be winning.) "How much is Roche paying you?" yelled out activists in the audience, referring to Hoffman-LaRoche, the manufacturer of ddC, which had already been the target of an activist protest during the conference's opening ceremonies because of the company's slowness in conducting its own, postmarketing studies of ddC as required by the FDA.

Whether Fischl was casting about to salvage her study or describing a genuinely important auxiliary finding was, in some sense, beside the point. Activist rage had more to do with the predicament the patient community now found itself in. As Mark Harrington noted in a heated challenge to Fischl voiced from the conference floor, the response to Concorde by U.S. experts had been to play it down, to claim that, after all, combination therapy was the real standard of care for asymptomatics. "The truth is," said Harrington bitterly, "we have no standard of care for asymptomatics." There was no disputing Harrington's point, nor did the conference presentations on non-nucleosides, tat inhibitors, and protease inhibitors suggest that answers lay just around the corner. Insiders already knew the gossip about Hoffman-LaRoche's tat drug: after years of stalling, the company had finally

determined that the drug had no efficacy, at least at the dosage tried so far. And the results from the protease inhibitors were preliminary and carried little weight.

Doctors, Researchers, and "Cookbook Medicine"

The deep uncertainties about antiviral therapy were aired in Berlin at a "Meet the Experts" session entitled "When to Start Antiretroviral Treatment"—though as Martin Delaney aptly noted, it could just as well have been called "Whether to Start Antiretroviral Treatment."^[64] The session was an elaborate dance between practicing physicians requesting advice and experts reluctant to commit.^[65] Robert Yarchoan of the NCI listed the options as he saw them: You could begin monotherapy early. You could begin combination therapy early. Or you could wait for the development of symptoms or until the CD4 count dipped below 200 and then initiate either monotherapy or combination therapy. In short, no logical option could be ruled out! As Delaney noted, the more we knew about pathogenesis and the extent of covert infection, the more sense it made to intervene early; but the more we learned about the therapies that were available, the less confident we became about the current efficacy of doing so. The challenge of AIDS, said Delaney, was precisely "to make decisions in the face of uncertainty": "I think maybe 019 gave people the illusion we weren't dealing with uncertainty."

Some doctors in the audience stressed the virtues of case-by-case decision making on the basis of the "art" of clinical judgment—the strategy of "try it and see what happens." "I feel, personally, I learn more about how to treat a patient by treating the patient than by looking at the results of clinical trials," said one physician. Others were anxious for formal guidelines. A member of the audience pressed one of the panelists, the British researcher Anthony Pinching, to say what he would tell a patient who was asymptomatic and had a T-cell count of 300. Pinching explained that he would describe the various studies, analyze the patient's T-cell trend over time, and then present the patient with a choice. "Why do we need all this cookbook medicine?" asked Pinching: "I have yet to meet a patient who is unwilling to make a choice." And if the patient wanted to know your opinion? the questioner persisted. Pinching replied that, in his experience, there

were "two types of patients": "interveners" and "don't rock the boaters." "If they insist on advice, I try to identify their nature as one or the other."

It was a revealing comment and, by one reading, an enlightened response. Resisting doctors' cries for prescriptive advice, Pinching was emphasizing the patient's autonomy in deciding on a course of treatment. Against reliance on inflexible rules ("Do this if your T cells drop below 500, do that if they fall below 200"), Pinching was insisting on the uniqueness of the individual patient. And rather than speaking beyond the limits of his knowledge, Pinching was candidly exposing the extent of medical uncertainty. Yet the response was also more than a little disconcerting. Thirteen years into the epidemic, at the key international conference at which leading scientists reviewed the state of the art of antiretroviral treatment, the best advice about early intervention that an eminent AIDS authority could offer to the doctors of the world was a handy bit of folk wisdom about the psychological propensities of patients.

Living with Uncertainty (1993–1995)

AZT: More "Pieces of the Elephant"

Later that month, the NIH would ratify uncertainty as the new wisdom, dressing it in the language of bureaucratese.^[66] After a three-day meeting, an expert advisory panel offered up recommendations: Asymptomatic HIV-infected patients with three hundred to five hundred T cells should begin taking AZT. But not taking AZT, and continuing to monitor the immune system, was "an equally valid option." Patients in stable condition with more than three hundred T cells who were already taking AZT should stay on it, the panel recommended. However, the chair, Dr. Merle Sande of the University of California at San Francisco, told the New York Times that "stopping AZT for such people would be a medically sound and logical conclusion from the recommendations." In short, the NIH recommended that patients do X , but if they wanted to do not-X , that was "equally valid."

Sande blamed the current predicament on the competing conceptions of the purpose of clinical trials. He complained to Lawrence Altman that the various trials of the nucleoside analogues had been designed with FDA regulatory questions in mind, rather than the clinical

questions that doctors wanted answered: "We were in a hurry four to six years ago to get drugs approved, so the studies were designed in that way and not necessarily to answer the clinical medical questions that we face in making decisions today. … We are a prisoner of those studies."^[67] Altman's article suggested that much of the blame also lay with the activists for having pressed so hard to get drugs approved quickly. In fact, though, it had been activists who had insisted all along that clinical trials were asking the wrong questions—that they should be oriented to the real-life issues confronting patients and doctors rather than the thumbs-up/thumbs-down logic of FDA approval.

To complicate the picture further, barely a month after the new guidelines were issued the New England Journal published the results of the European-Australian Collaborative Group study, a three-year, double-blind, placebo-controlled study of AZT use in 993 asymptomatic patients with CD4 counts above four hundred per cubic millimeter upon entry.^[68] The study found that early administration of AZT did delay the onset of symptoms, supporting the view "that most patients with HIV infection should be treated," in the words of an accompanying editorial.^[69] The study did not address the issue of survival benefit. Merle Sande commented to the New York Times: "I think all the studies are showing the same thing: that there is a little benefit from AZT for a short period of time." Douglas Richman stressed the differences in endpoints and follow-up periods compared to those used in Concorde and said: "This study looks at another piece of the elephant. … But we can't say if five years from now the two curves of the two different patient groups won't come together. It's part of the complexity of a clinical investigation—but that's life in the big city."^[70]

"It's really resulted in incredible frustration," acknowledged Paul Volberding, the UCSF researcher, in 1994: "No one feels they know what to do. No one trusts the guidelines, even though the guidelines have been put together as best as people could do. People want an answer and there isn't one."^[71] Volberding's own long-term follow-up study of the participants in ACTG 019 (the study that first had suggested benefit from early use of AZT in asymptomatics) was, in fact, consistent with the results of Concorde. First presented in Berlin and published in JAMA in 1994, the follow-up concluded that the benefits of AZT were time-limited and that early administration conferred no additional survival benefit over late administration.^[72]

The overall credibility of AZT received a boost in early 1994, when NIAID announced the results of a trial called ACTG 076, which had

studied whether administration of the drug to pregnant women could prevent transmission of the virus to their fetuses. The results were striking: more than a quarter of the babies born to women who received a placebo became HIV positive, but only eight percent of the babies whose mothers received AZT became infected with the virus.^[73] The study left many questions unanswered: What, for example, were the long-term health risks to the baby when AZT was administered to a woman during pregnancy? Did the benefit outweigh the risks, given that, even without AZT, three-quarters of the babies would emerge seronegative?^[74] And the study ignited new controversy about the policy implications: Should all pregnant women now be required to take an HIV antibody test?^[75] Such questions notwithstanding, there was room for exultation. For the first time, in one particular context, AZT appeared to mean the difference between life and death.

Unfortunately for Burroughs Wellcome, news about ACTG 076 coincided with formal publication of the Concorde study.^[76] Burroughs Wellcome took the occasion to issue a spirited defense of its product: "Several independently sponsored studies have clearly demonstrated the benefits and advantages of early therapy," commented David Barry, the vice president of research, in a press release.^[77] There were indications, however, that doctors and patients were drawing different conclusions about the drug. JAMA reported that a study in the Canadian province of Ontario showed a 45 percent decline in the number of patients beginning therapy with AZT in the months following the preliminary report on Concorde. Even many patients who were symptomatic were apparently forgoing use of the drug. Burroughs Wellcome acknowledged that sales of the drug were down, particularly in the United States.^[78]

The Holy Grail of Statistics

As dissatisfied as activists were with AZT and its chemical cousins, in practice it was impossible for activists not to invest their energies in staking out positions on the use of antiviral drugs that were most readily available. The problem was that the data concerning combinations of nucleoside analogues such as AZT and ddC did not lend themselves to unambiguous interpretation. ACTG 155, Fischl's study of the AZT/ddC combination, was an important and telling illustration: debates about the significance of ACTG 155 demonstrated the interpretative flexibility that could make AIDS clinical trials a source of uncertainty rather than the mechanism by which uncertainty

was resolved. "People believe passionately on both sides of the question as to whether [the combination therapy] worked," Deborah Cotton, the dissenter on the Antiviral Advisory Committee, commented more than a year after the Berlin conference. "There are schools of thought. There are the believers and the nonbelievers, and … I don't think anything is going to change. I really don't."^[79]

The ACTG 155 researchers were quick to insist,^[80] and the published study was careful to point out, that the controversial subgroup analysis presented by Fischl in Berlin was not "post-hoc": "The three CD4 cell count subgroups were specified by the study chairpersons in June 1992, which was before any interim review of the primary end-point data," Fischl and her coauthors argued.^[81] But this did not settle the issue, because the subjects were not randomized into treatment arms from the outset according to this particular breakdown in CD4 counts. Biostatisticians are typically cautious about pulling subsets out of clinical trial populations after randomization—or at least, cautious about overinterpreting what they find.^[82] Susan Ellenberg, formerly the chief biostatistician for the ACTG trials at NIAID, praised the TAG activists' suspicion of subgroup analyses: "I think that that is the kind of thing that they have learned. They have become very methodologically astute," reflected Ellenberg.^[83]

Declaring that "several potential explanations exist for the overall findings in our study," the authors in fact presented a series of arguments for why combination therapy might be advantageous even though the trial seemed to suggest otherwise.^[84] Because patients had taken AZT before enrolling in the study, it was possible that they were already resistant to that drug. In that sense, what was really being studied was not combination therapy but ddC alone. Or perhaps the best time for combination therapy was simply earlier in the progression of HIV disease, before certain phenotypic changes in the virus associated with late-stage AIDS occurred. Finally, the report pointed to the consequences of "intent-to-treat" analysis. Because of the way the protocol was worded, many patients who experienced strong side effects from either AZT or ddC were taken off all their drugs. But in accordance with the logic of intent-to-treat, these patients were still counted as part of the treatment arm to which they were originally randomized. The effect was potentially to blur the difference between the different arms, creating a higher standard for establishing efficacy. But biostatisticians argued that to remove from analysis the patients who go off a drug can bias trial results, because there is no reason to assume that people who go off medications are typical of those who

remain.^[85] Some clinical researchers found the logic maddening all the same: How could they study the effects of a drug in patients who weren't even using it? "As a clinician, what I really want to know is, is a drug working while a patient is taking it—not six months after he stopped taking it," commented Martin Hirsch, a virologist and one of the principal investigators on ACTG 155.^[86]

The debate over intent-to-treat analysis was a perfect example of the clash in perspective between infectious-disease researchers and biostatisticians. "I don't think that statistics is the holy grail," complained Hirsch, at the same time affirming his strong general support for the methods of the randomized clinical trial. "Many of us clinicians think that an 'as-treated' analysis … gives us at least as much information that is useful clinically as does 'intent-to-treat.'"^[87] And indeed, the authors of the published report on ACTG 155 undertook "an exploratory analysis to gain insight into the possible association between early treatment cessation and treatment outcome." That is, they performed an "as-treated" analysis, ceasing to count people in the study two months after they stopped their treatment. The results: "combination therapy was associated with a significantly lower rate of disease progression or death than were either [AZT] or [ddC] monotherapy." In other words, from this standpoint, the study was quite simply a success, and combination therapy worked . Yet "caution should be used when interpreting this exploratory analysis," the authors quickly added, because "this type of analysis is known to be biased."^[88]

For all the careful disclaimers, what was noteworthy about the published report on ACTG 155 was how intent it seemed to be on reaffirming the conclusion from which everyone began—that combination therapy really was better. Douglas Richman insisted that the results from ACTG 155 were "compatible" with those from ACTG 106; he added that ACTG 106 had now been corroborated by the final results from the Burroughs Wellcome study of the AZT/ddC combination.^[89] By contrast, Mark Harrington of TAG argued that "the high baseline CD4 group (150–300)—the one with the claimed 'benefit' of combination therapy—was exactly the arm with the fewest clinical events, thus the least [statistical] power." Harrington's bottom line: "Combination therapy with AZT/ddC in the 155 population is 50% more toxic and no more effective than monotherapy with AZT alone."^[90]

What were the true "results" of ACTG 155? How, and in what way, can we take data produced by such an experiment and apply

them to the real-world dilemmas of patients who demand answers? The point here is that clinical trials do not occur in a vacuum—and when the environment in which trials are conducted and interpreted is so contentious, then these experiments, rather than settling controversies, may instead reflect and propel them. Consider the range of factors and pressures that structured the determination of the "meaning" of ACTG 155 as well as that of its precursor, ACTG 106: the methodological (and jurisdictional) disputes between infectious-disease researchers and biostatisticians; activist demands for access to drugs, plus or versus activist conceptions of "good science"; the social construction of hype; the profound need experienced by patients, and the kinds of pragmatic decisions that patients and research subjects make in response to their immediate perceptions of their interests; the marketing strategies of pharmaceutical corporations and the incentive structures to which these companies respond; the complicated role of practicing physicians in interpreting the data produced by clinical trials; the politics of regulation and deregulation; and the distinctive character of regulatory science as practiced by expert advisory bodies. In such an environment—given these stakes—is it any wonder that the interpretation of key trial results is often up for grabs? AIDS trials are not unique in this regard, as studies of cancer trials make clear.^[91] But insofar as the participation of knowledge-empowered activists increases the number of claims-makers and alters the distribution of credibility among them, AIDS trials may be particularly inclined toward conflicting readings.

East Coast, West Coast

From the perspective of TAG activists, the evidence from trials like ACTG and Concorde was clear enough: neither AZT monotherapy in asymptomatic patients nor combination therapy in patients at any stage of illness had been proven efficacious. And the predictive power of the CD4 surrogate marker, in their estimation, was in grave doubt. In the summer of 1994, as the FDA granted accelerated approval to yet another nucleoside analogue, d4T, and announced an upcoming meeting to review accelerated approval, TAG activists began making noise. In August, the finance magazine Barron's ran a cover story called "Rushing to Judgment," which quoted TAG members about the risks of accelerated approval.^[92] Similarly, Time magazine described the evolution of AIDS activists who in the past "threw

smoke bombs at the National Institutes of Health" but now were "changing their minds" about the fast-track drug approval policies they once had promoted.^[93] Alarmed, Project Inform circulated a "consensus statement" on the need for accelerated approval and gained the endorsement of AIDS activist organizations around the country.^[94]

At the Antiviral Advisory Committee meeting held in September 1994 more than forty activist groups presented their positions, including activists from the Midwest and the South who insisted that neither the East Coast nor the West Coast activists spoke for them on questions of access to drugs.^[95] Kessler assured the audience that accelerated approval would continue to be FDA policy, and he promised to issue clearer guidelines for companies to follow in preparing applications for such approval.^[96] TAG activists did not call for an end to accelerated approval, but they issued a hard-hitting evaluation of the program to date. Accelerated approval, these activists suggested, might well be creating structural incentives for drug companies to crank out mediocre drugs that resemble the mediocre AZT rather than invest in the development of novel treatments with other mechanisms of action.^[97] (Others responded that accelerated approval created greater incentives for small companies to move into AIDS research: the alternative, long-term Phase II studies, was too expensive and too much of a risk.) Furthermore, argued TAG members, some of the companies were ducking their responsibility to perform postmarketing studies. "We pay huge amounts of money and we suffer through major toxicities, and we have to take the drug company's word for it that the drugs work. That's supposed to be empowerment?" complained TAG member Spencer Cox in comments to the New York Times .^[98]

Preserving the policy of accelerated approval, as most players preferred to do, presumed finding a better surrogate marker or markers. By fall 1994, attention had focused on new, high-tech measures of viral load, such as assays that used PCR technology to quantify viral RNA. From the standpoint of Anthony Fauci (the most prominent backer of the use of CD4 counts as a surrogate marker in the early 1990s), viral load was "fundamentally … better as a marker. I don't think there's any question about it."^[99] Fauci explained: "There's a lot of virus floating around, and when you treat somebody, you can see dramatic decreases in that virus." Here Fauci was referring to an important, recent finding about the pathogenesis of HIV infection: rather than a slow, subdued "latency," it now appeared that HIV disease was characterized by "rapid turnover" of both virus particles and T

cells^[100] —what the New York Times described as "a pitched battle from the very start of infection," with hundreds of millions of virus particles and hundreds of millions of infected cells dying every single day.^[101] This new conception of the dynamics of HIV infection implied that viral load was a crucial indicator of disease progression.

Biostatistician Stephen Lagakos, while optimistic about the possible uses of these markers, also pointed to "overstatements" on the part of some of their advocates, and he described stories he had heard reporting "that some of the producers of these [marker tests are] trying to get clinicians to buy gobs of these kits and use them on everybody at $500 a crack."^[102] More emphatically, in an article subtitled "When Viral Load Is Crowned King," the Treatment Action Group railed in its newsletter against "frustrated scientists [who] have a new toy and biotechnology companies [who] have a new assay to sell."^[103] TAG was calling instead for large-scale trials—so-called "large simple trials" with as many as five thousand subjects—particularly for the upcoming protease inhibitors. The virtue of such trials, these activists argued, was that they could simultaneously tell us "if these new drugs prevent sickness and death" and "if the new viral load assays are useful predictors." Hoffman-LaRoche, manufacturer of a protease inhibitor called saquinavir, was in TAG's view "racing" to the FDA with "lukewarm" data, seeking accelerated approval on the basis of a single, twenty-four-week study.^[104] TAG proposed instead an expanded access program for saquinavir to accompany the larger, long-term studies.^[105]

By this point, the long-simmering dispute in tactics between East Coast groups such as TAG and the San Francisco activists had "become particularly intense and often bitter," as John James explained in AIDS Treatment News .^[106] In general terms, everyone avowed respect and support for his or her activist compatriots. But from the standpoint of the San Francisco activists, the TAG members had become scientific conservatives seeking to be more rigorous than thou. Said G'dali Braverman of ACT UP/Golden Gate: "There's an interesting evolution in terms of one's personal treatment activism. You reach that point where you start losing your sight of [the idea] 'We really are dealing with patients who need an option now,' and you start trying to think like a scientist." Such a tendency was "a difficult thing to temper," added Braverman.^[107] "You know why I really think there's a split?" reflected Brenda Lein of Project Inform. "Because the East Coast folks don't have a constituency of people living with HIV that

they work with on a day-to-day basis. I mean, I answer hotline calls from people who want access. They talk to each other."^[108]

Needless to say, TAG activists, many of whom were themselves living with AIDS and HIV infection, disputed these characterizations. They insisted they were not necessarily opposed to accelerated approval and certainly not to expanded access: Their motto was "access and answers." Nor did they oppose the right of the individual to have access to therapies. But they wanted to counterbalance that right against some conception of the greater good. And they criticized their San Francisco comrades for continuing to promote hype about up-and-coming drugs; they saw themselves as hard-nosed realists who had been burned too many times to ever contribute to the "hype cycle" again.^[109] This explained the venom behind TAG's attack on Margaret Fischl in Berlin—the sense on the part of activists that they were led to believe in combination therapy and manipulated into hopping onto a roller-coaster ride of exhilaration followed by despair. Mark Harrington made this point emphatically in his written critique of ACTG 155: "ACTG 155 was riddled with investigator bias and sponsor-disseminated hype from the very beginning. … Indeed, as early as August 1990, at a meeting with ACT UP, Roche's Dr. Whaijen Soo told us: 'I'd like to confide a remark of Margaret's. … The difference she sees among people on the ddC/AZT combination [in ACTG 106] is a big difference—like the difference between people on AZT versus placebo in the original trial. She can almost tell them apart by looking at their behavior.' Say that around the country for three years and you can create a huge demand for an unproved drug."^[110] TAG members were now vigilant against becoming the pawns of the pharmaceutical companies and resistant even to well-intentioned optimism. David Barr commented in 1994: "I've been pulled aside several times in the last couple of months [by people whispering], 'I'm really excited about the protease inhibitors.' … I have to say, 'Please, I understand you're saying that to me because you want to help me, but it doesn't help me .'"^[111]

Back to Basics

In the midst of cleavages on regulatory policies, activists could agree on one point: it was time for brand-new directions in AIDS research—new approaches that could arise only out of discoveries in basic science. Project Inform, for example, had begun assembling leading scientists and activists for periodic "Immune Restoration

Think Tank" meetings to brainstorm research directions in restoring immune system functioning.^[112] TAG had endorsed the emphasis on basic research in its report on NIH's AIDS research that it had presented in Amsterdam in 1992. A new report presented at the 1993 Berlin conference was all the more emphatic—and dramatic: "The world of basic research on AIDS is the final frontier for AIDS activists; it is here that we make our last stand," wrote Gregg Gonsalves. "We must forge a partnership with those scientists who have devoted their lives to studying the basic biology of HIV and the immune system and quicken the pace of discovery."^[113]

On the assumption that basic research, unlike clinical research, "has not had a powerful constituency to advocate on its behalf," TAG had conducted interviews with thirty-six researchers in the basic sciences—immunologists, virologists, and molecular biologists—most of them at work in academic settings. Above all, said Gonsalves, researchers stressed "the need to take basic AIDS research from the pristine in vitro laboratory setting to more difficult, but critical, work with wild-type HIV isolates and clinical samples, often using in vivo settings with animal models or humans." This was a restatement of the familiar problem—that scientists knew infinitely more about the structure of HIV than about how HIV causes AIDS. "In vivo veritas" was the slogan that TAG recommended: "Many of the interviewees criticized the relevance of in vitro work ('pristine, beautiful, irrelevant systems')."^[114]

The long-running activist critique of "purity," "cleanliness," and "elegance" was now applied to a new set of concerns: once again, as with clinical trials, activists were pressing for real-world "messiness" in place of pristine, ivory-tower science. Harrington had made this point in graphic fashion in a presentation the year before at the Amsterdam conference. Using slides of his own lymph tissue as backdrop, Harrington had demanded that scientists attend to "what is going on in our bodies, rather than exclusively in elegant and often artificial laboratory and animal models."^[115] With representational strategies such as these, activists could hope to bring the "politics of the body" to bear on the remotest regions of laboratory science.

Needless to say, not all clinical researchers were happy about the new activist agenda. "I think that … the basic science people now have the activist community in the palms of their hands," complained Donald Abrams in late 1993, "and they're going to run with it for a while. … I think it's too bad."^[116] However, activists were by no

means alone in articulating the need for a renewed emphasis on basic research. In May 1994, Gina Kolata wrote in the New York Times about a "new consensus … among many leading scientists that the nation's $1.3 billion AIDS research program is on the wrong track."^[117] The article cited an editorial just published in Nature by Bernard Fields, chair of the department of microbiology and molecular genetics at Harvard Medical School, entitled "AIDS: Time to Turn to Basic Science." "The focus on drugs and vaccines made sense a decade ago." wrote Fields, "but it is time to acknowledge that our best hunches have not paid off and are not likely to do so."^[118] Kolata also quoted Harold Varmus, the new head of the NIH: "Everyone agrees with Bernie's basic precept." And William Paul, the immunologist who recently had replaced Anthony Fauci as director of the newly reorganized Office of AIDS Research, said of the Fields manifesto: "We take that as our marching orders."^[119]

At the next International AIDS Conference, held in Yokohama, Japan, in August 1994, Paul made his priorities more explicit. This was the tenth annual conference; since the first such conference held in Atlanta in 1985, the number of cases of AIDS in the United States had climbed from about nine thousand to more than four hundred thousand. The number of AIDS cases around the world was now estimated at four million.^[120] "Realism was in the air," according to a commentary on the conference in Lancet ;^[121] and it was in a spirit of realism that Paul announced his intention to cut spending on clinical trials sponsored by the ACTG in order to put more money into the "revitalization and expansion" of basic research.^[122] Basic research was the "engine that will drive the entire AIDS research enterprise forward," Paul told the conference participants in his plenary lecture, reiterating the long list of fundamental, unanswered questions about HIV and the pathogenesis of AIDS.^[123]

What role could treatment activists play in facilitating the progress of basic science? Arguably, activists had a perspective on clinical trials that made them valuable contributors to the effort to conduct such trials smoothly and adequately. In focusing on basic research, however, it was less clear whether activists possessed a special vantage point from which to augment the production of knowledge. By one reading, the most activists could accomplish in this domain was to call for researchers to get on with it. For Martin Delaney, however, the point of Project Inform's Immune Restoration Think Tanks was not just to urge researchers to conduct basic research but to try to sketch

out, in discussion with them, the most fruitful avenues of inquiry. "We feel we have accomplished more and better research in this fashion than we ever could have achieved had we chosen to insist on being the researchers ourselves," said Delaney, suggesting a contrast with such earlier adventures as the "underground" trials of Compound Q.^[124]

To get a better feel for the conduct of basic research, TAG members actually began spending time in Anthony Fauci's laboratory at NIAID. "I don't think they make any pretenses that they're immunologists or microbiologists or virologists," said Fauci. "But they want to understand as much of the down-in-the-trenches science as they can." Activists didn't need to comprehend every detail or nuance of the research, Fauci explained, in order "to evaluate the broad strokes of the studies that come out."^[125] Activists themselves were forthright about the limitations as well as the possibilities inherent in this new approach. "I can't talk cell lines with the big boys, that's for sure, but who cares?" commented Derek Link of TAG. "That's not my role."^[126]

Aiding the activists as they negotiated relationships with the basic scientists was the relative accessibility and openness of these researchers. "Most basic scientists are very different than the star clinical researchers," explained Link. "These are people who labor away in a lab, pretty much in obscurity. They're thrilled to have somebody interested in their work. …" Brenda Lein of Project Inform echoed this observation: "If you think about it, it's sort of a lonely profession … because it's not like you go to a cocktail party as a scientist and people [say], 'Oh that's so fascinating, and what happened in the cell culture next?' And if you actually have someone who's interested, they're more than anxious to be able to talk about their work. … You know, there's not many people who get excited about epitope mapping. …"^[127]

Activists have cultivated these new relationships to bring the patient's perspective to the foreground in basic research—to force bench scientists to be fully cognizant of the day-to-day realities of sickness and suffering beyond the laboratory walls. In so doing, they have attempted to speed the process by which compounds move from the laboratory to testing in humans. "I probably wouldn't have four drugs in clinical trials without the activists having had some [effect on] me," commented Robert Gallo in 1994.^[128] Another way that activists influenced the knowledge-making processes of basic research was by performing a bridging, or "pollination," function, bringing together researchers from different specialty areas who were unfamiliar with

one another's work.^[129] Gallo, a participant in the Immune Restoration Think Tanks, agreed vigorously that activists have served as a "catalyst" that "forc[ed] people to communicate better" and to see beyond the limits of their individual specialty areas.^[130] Derek Link was also emphatic about the utility of this role: "There are numerous, numerous times when I'm talking to researcher X and saying, 'Researcher Y is now [working on such-and-such].' And [they say], 'Well, that's interesting.' And then there's some discussion about that."^[131]

"Cocktails" and "Synergy"

Basic research had produced one recent finding that held crucial implications for drug development: New techniques for measuring virus in the blood had indicated that HIV disease was characterized not by a long, subdued latency but by what researchers and reporters called a continuous "raging battle." Each day the immune system killed hundreds of millions of viral particles; each day the virus replicated to produce hundreds of millions more, killing T cells in the process. Gradually, the virus gained the upper hand in this high-cost war of attrition.^[132] Meanwhile, the more the virus replicated, the more it was likely to mutate. Simple math suggested that over the course of a few years, "every viable mutation at every position in the [viral] genome will occur," noted David Ho in a commentary in the New England Journal . The implication was that whatever individual antiviral drug researchers threw at the virus, it wouldn't take long before a mutant had emerged that was resistant to the drug. "Therefore, monotherapy as we know it is doomed to fail," argued Ho. "In the long run, effective treatment must instead force the virus to mutate simultaneously at multiple positions in one viral genome. This is best achieved by using a combination of multiple, potent antiretroviral agents." Ho envisioned a time in the near future when combinations of antivirals would be given to patients as early as possible, ideally just after infection, when the virus was most homogeneous. He argued forcefully that the relative lack of success of combinations of the nucleoside analogues (AZT, ddI, ddC, and d4T) was not an adequate test of the concept of early intervention. As soon as we had better antivirals, then it was, as Ho's article declared, "Time to Hit HIV, Early and Hard."^[133]

What made Ho optimistic were recent studies of protease inhibitors, as well as one nucleoside analogue combination, AZT plus 3TC. In trials, these drugs not only boosted CD4 counts, they also significantly

reduced viral load and did so to a greater extent than the approved therapies. Researchers were beginning to speak in optimistic terms of multidrug "cocktails"—such as AZT plus 3TC plus a protease inhibitor—that might inhibit viral replication for extended periods. "Psychologically we definitely have turned a corner," Robert Schooley, the new chair of the ACTG Executive Committee, told the Los Angeles Times in February 1995.^[134]

Promising results of two European AZT/3TC trials had been announced toward the end of 1994, and Glaxo, the Canadian drug company that manufactured 3TC, had established an expanded access program.^[135] TAG described the combination as "admittedly intriguing," but also warned that the results "are based solely on short-term surrogate marker changes: the same surrogate marker changes that brought us those all-powerful antiretrovirals AZT, ddI, ddC (a real winner) and d4T."^[136] Both Glaxo and Burroughs Wellcome were delighted by the apparent synergy of their respective products—especially after the 1995 merger that formed the world's largest pharmaceutical company, Glaxo Wellcome.^[137]

Meanwhile, by 1995 three companies—Hoffman-LaRoche, Merck, and Abbott—were conducting large-scale trials of protease inhibitors, and several other companies were following in their footsteps.^[138] Patient groups clamored for access to these drugs, but expanded access of the protease inhibitors posed special problems for the drug companies. These compounds were difficult to manufacture, and patients consumed them in much higher quantities than required with other antiviral drugs. In short, there just wasn't enough protease inhibitor to go around—at least, not without jeopardizing supplies for clinical trials.^[139] As a result, each of the three companies announced that it would hold a lottery to assign spots in its expanded access program. In summer 1995, 18,500 people competed for about 3,600 slots.^[140] Though lotteries seemed the most equitable solution in the short run, many observers expressed concerns about the pressures building for accelerated approval of the protease inhibitors, especially with rumors of the upcoming emergence of "underground" protease drugs.^[141]

As antiretroviral research embraced new possibilities, including an even newer class of drugs called integrase inhibitors,^[142] the pervasive gloom of 1993 and 1994 seemed to be lifting. And in late 1995, the Antiviral Advisory Committee recommended accelerated approval of two more drugs, based on the drugs' effects in boosting CD4 counts and lowering viral loads: 3TC (to be used in combination with AZT)

and saquinavir, the Hoffman-LaRoche protease inhibitor (also for use in combinations). FDA Commissioner Kessler took the opportunity to express his excitement about the protease inhibitors, calling them "the most active agents against HIV we have seen to date."^[143] With the agency's rapid endorsement of its advisory committee's recommendations, the number of approved antiviral AIDS drugs had risen from one in 1987 to six at the close of 1995.

Optimism increased in the early months of 1996, as the Antiviral Advisory Committee recommended approval of two other protease inhibitors, Abbott's ritonavir and Merck's indinavir. The FDA, then undergoing close scrutiny by Republican members of Congress concerned with speeding up the drug approval process, acted on the committee's recommendations in a matter of days. Indeed, approval of Merck's drug arrived just forty-two days after the company had first submitted its application to the agency.^[144] Abbott's drug, ritonavir, was given full (rather than accelerated) approval after an international study reported that the drug cut the death rate nearly in half in a group of 1,090 AIDS patients: the death rate was 4.8 percent among those who received ritonavir and 8.4 percent among those who received a placebo in place of the protease inhibitor. (Subjects in both groups were also free to take AZT or d4T if they chose.) Still, concerns remained about the long-term efficacy of ritonavir as well as the other protease inhibitors, given the likely development of resistance to the drugs.^[145]

None of these drugs was a "magic bullet"—a "penicillin" for AIDS; no expert expected that such a drug could be developed. From the perspective of Daniel Hoth, who came to NIAID originally from the National Center Institute, the development of antiretroviral AIDS therapies was—slowly but ineluctably—recapping the progress of cancer therapies. Clinicians started out with single-agent, palliative drugs: "That's cancer in the '50s. Then you go through another generation, you get some better drugs. And you start to get complete remissions, you start to get longer durations of partial remission. … And you gradually increase both the depth of the response … and the duration of it." This would be the likely pathway in the development of AIDS drugs, Hoth was convinced: "I think we're going to see a formal recapitulation of what happened in … cancer."^[146]

Whatever the speed of development of therapies, political and economic factors dictated that their distribution would be highly uneven. To the extent that existing antiretroviral therapies had important benefits—for

example, in the apparently sharp reduction of transmission of HIV from pregnant women to fetuses—such findings remained, in the mid-1990s, irrelevant to most of the world's population. As Science 's AIDS reporter Jon Cohen explained: "Poorer countries can't afford either AZT or the sophisticated clinics used in [ACTG] 076. In addition, 076 calls for repeatedly dosing the mother with AZT during her pregnancy, and many women in developing countries don't visit medical clinics until they are in labor—if then." Nor were the pharmaceutical companies likely to provide the solution. "I doubt very much that it will be Glaxo Wellcome giving away unlimited amounts of AZT," a company spokesperson told Cohen.^[147] In countries that spent only a handful of dollars per capita on health care in a year, what, then, was the likelihood that any antiretroviral therapy developed in the West would actually see widespread use? Even in the United States, with federally funded health insurance programs such as Medicaid under increasing attack, the ability of people with AIDS and HIV to afford multiple combinations of drugs that were each quite expensive seemed increasingly in doubt.^[148]

Promoting "Good Science"

The mid-1990s saw the U.S. public engrossed by popular nonfiction like The Hot Zone and Hollywood films such as "Outbreak," which presented terrifying images of the sudden and devastating illness caused by the rare Ebola virus.^[149] AIDS and the fears it had provoked in the 1980s were often the unspoken subtexts in these representations. Yet ironically the ongoing brutalities of the AIDS epidemic seemed to fade from the public eye—even as the number of cases in the United States passed the half-million mark and U.S. health authorities reported that AIDS had become the leading killer of twenty-five- to forty-four-year-olds.^[150] Seen less as a raging plague than as a chronic plight, AIDS, like homelessness and drug use, had merged into the background landscape of late-twentieth-century social life.^[151]

Activists struggled to bring AIDS back to center stage. For a while, it had seemed as if a Democratic administration might make a difference, that it might offer a different "political opportunity structure" for movement activism.^[152] But whatever President Clinton's sympathies, AIDS was far from the top of his agenda. One apparently promising step was the establishment of an eighteen-member presidential

commission, the National Task Force on AIDS Drug Development, designed to bring together representatives of government agencies, the pharmaceutical industry, the research community, and activist groups to recommend ways to streamline the discovery and testing of new AIDS drugs.^[153] The panel included Ben Cheng of Project Inform, Peter Staley of TAG, and Moisés Agosto of the National Minority AIDS Council and TAG. Daniel Hoth, who had left NIAID for private industry but was a member of the task force, noted the key difficulty confronting them: "Very few of the problems are amenable to executive proclamation."^[154] By early 1996 the group had disbanded, acknowledging that they had been unable to remove the obstacles that stood in the way of faster development of new AIDS drugs, and citing lack of clear support from President Clinton.^[155]

In debates over how to improve the drug development system, activists were just one player and held relatively few cards. The pharmaceutical companies, by contrast, could often push research as their interests dictated. Drug companies could collaborate with one another, sharing data when it suited their purposes: fifteen of them had formed an entity called the "Inter-Company Collaboration for AIDS Drug Development" to test combinations of drugs produced by different companies.^[156] But drug companies could also go their own ways or exit the arena altogether. Many biotechnology firms, for example, were finding the AIDS arena too risky and were choosing to invest their resources in more promising efforts.^[157]

By the mid-1990s, AIDS activism in general was in a period of decline, and the "treatment activist" subset looked considerably different from its incarnation in the late 1980s. The dominant wing of treatment activism—which encompassed groups such as TAG, Project Inform, and subgroups of ACT UP chapters around the country, along with representatives to the CCG and local community advisory boards—was small, committed, relatively expert, and relatively professionalized. As the mainstream treatment activist groups have moved into the mid-1990s, their work has proved to be a vital but less visible, and in many ways less hopeful, political endeavor.

There are many factors that have contributed to the current juncture. While all social movements confront the issue of burnout and renewal, few find that on a regular basis their leaders become ill or die. More generally, much of the difficulty has lain in the vicissitudes of the research process and the sheer intractability of the scientific problem. Garance Franke-Ruta, a TAG activist who was 17 when she first joined ACT UP, recalled the evolution: Activists first gained access

to the system at a time of relative optimism, when drugs such as AZT suggested the hope of keeping patients alive until a better drug came along. By the early 1990s, when the much-disliked and marginally effective AZT was still the first-line therapy, activists had come to adopt a longer view.^[158] "Most of us are just simply not going to see the answer to this in our lifetime," commented San Francisco activist G'dali Braverman. "And I think there was an excitement in the early days and this feeling that we could change everything—which we will! —and that we would live to see it and that the answers were already there, we just hadn't seen them, or hadn't been told them. We know better now."^[159]

With this perspective came a further shift in strategic thinking away from the simple strategy of "drugs into bodies" and toward the promotion of "good science." As Moisés Agosto put it, "A lot of treatment activists got involved [in the 1980s] believing that through their activism they were going to be able to save their lives." Strategies, therefore, were based significantly on the desire to get something—anything —through the pipeline—to get "drugs into bodies" fast enough to matter for the health of the current generation of activists. Agosto continued: "Now, my personal [belief] is, 'No, I'm not going to be able to save my life.'" In the ongoing tension between "access" and "answers," activist strategy had moved toward the opposite pole: "It's about having good science that develops good therapies [so] that we may have a cure or therapy someday."^[160]

In this current period of adjustment, groups such as TAG, ACT UP/Golden Gate, Project Inform, and others around the country have accelerated their engagement with the AIDS research effort, but the details of their work have receded from public view. As the issues become ever more complex and technical, they also become more difficult to summarize on a leaflet or in a sound bite. Nor has it proven easy to recruit new activists into a movement with such a high degree of accumulated technical expertise. "The training program is sink or swim," Derek Link commented. "People who are totally intimidated are not going to do well."^[161]

To the extent that polarization between "us" and "them" increases the tendency for social movement actors to sacrifice for the cause,^[162] the evolution of relatively more cooperative relationships between activists and their interlocutors in research and government may have made it somewhat harder for the movement to stoke the fires of passion. Some activists, such as the novelist Sarah Schulman, who are critical of those in groups like TAG believe that the decline in the use

of direct action techniques spelled the end of effective treatment activism.^[163] But others reject what they see as a fetishizing of confrontational direct action—trying to "scream a cure out of a test tube"—insisting that tactics should be suited both to the task at hand and to the stage in the evolution of the movement. "It would have been stupid to do a large demo when you could have picked up a phone and made a couple of phone calls and gotten just the same results," commented Harrington.^[164]

Implicit in this evaluation, however, is not simply a practical insistence on "doing what works," but also a transformed conception of the identity of the antagonist.^[165] In place of the charges of genoc ide that activists had used in the early days of ACT UP to frame their critiques of the research establishment, these activists were now often inclined to acknowledge the good intentions of researchers. "There's a new respect for the scientists," said Gregg Gonsalves in an interview in the gay magazine the Advocate: "There is more of a willingness to focus on the problems that the scientists are really facing rather than what we once thought of as the scientists' malice." If so, Anthony Fauci has certainly endorsed the change of heart. He told the same reporter: "I have to admit it's gratifying that people who are highly qualified—and most of the activists that I have gotten to know are—have come around to support us. … In the late '80s we were getting pushed around to put people in clinical trials for drugs that we really didn't think were very promising anyway. … Now that we are in agreement about the need for basic research, maybe we will have better drugs and vaccines one day."^[166]

Is this co-optation? Or is it well-advised realism that is the fruit of (sometimes bitter) experience? Garance Franke-Ruta's reflections suggest the ways in which the acquisition of the "realistic" perspective of the educated participant in science can constrain utopian imaginings, even as it paves the way for a more focused and sober activism: "When ACT UP started, people didn't know as much, and demanded much more. And there was something in ACT UP initially that was really wonderful, which was that out of ignorance of what is possible, you are sometimes able to do the impossible—whereas once you know what is possible and what is not possible, you let that define what it is that you're willing to ask for. So the more we learned, in some ways the less we were able to ask for , until eventually we knew so much that we felt—we feel—like sometimes we don't know that we can ask for anything [emphasis added]."^[167]

There is, of course, virtue in self-doubt and critical reflection. Scientists, too, could be heard reporting their own. "I think we got a little bit too cocky too early," a Princeton molecular biologist told the New York Times in 1994, describing the need to refocus on basic research.^[168] Such sentiments are a useful antidote to hubris and to a surplus of faith in what science can accomplish. Over the course of less than a decade and a half, researchers had vastly expanded the knowledge about AIDS, while treatment activists had garnered their own expertise and reshaped the conduct and contours of biomedical research. In the end, however, neither activists nor scientists could force a cure into being, no matter how committed their efforts or how sophisticated their interventions.