A Long Road Traveled: Conflicts, Community and Clinical Trials

The historical record of progress in AIDS research lies not only in the medical literature, but also in the community-produced clinical trial directories that have tracked experimental protocols as they opened and closed over the years. Studies of failed treatments generally don't get published, and many of yesterday's therapeutic hopefuls have faded from the collective memory. Pick up an old clinical trial directory, however, and you can find the entry criteria for a "tat inhibitor" study that people once traveled across the US to try and join. The directories also reflect the effects of increasing community involvement in designing research protocols, such as increased study of opportunistic infection treatments, less restrictive entry criteria and greater attention to protecting the interests of trial participants. The very creation of the publications reflected a thirst for information about experimental treatments that most scientific investigators had never previously experienced.

"To rely solely on official institutions for our information is a form of suicide," wrote John S. James in the May 9, 1986 issue of his groundbreaking San Francisco-based newsletter, AIDS Treatment News.

Looking back over two decades of trials, important themes emerge that continue to sound in current debates about the direction of HIV/AIDS research. Most prominently, the agendas of the various stakeholders -- people with HIV/AIDS, the pharmaceutical industry, the government and the scientists -- have regularly collided, with the outcome often decided by who wielded the most money and political power rather than the logic of a given position. Unsurprisingly, it was people with HIV/AIDS and their advocates who had to battle hardest to be heard and, despite significant victories, this remains the case today.

Find a Bug, Find a Drug: AZT with Everything (1987-1989)

The identification of HIV in 1983 prompted a hunt for an antiretroviral magic bullet that one activist characterized as "find a bug, find a drug." But people with AIDS were dying from infections such as pneumocystis carinii pneumonia, or PCP, that could potentially be treated with older off-patent drugs that the brand name pharmaceutical industry -- and the researchers that relied on them for funding -- had little interest in studying.

The saga of aerosolized pentamidine starkly illustrates the point. Pentamidine, an old antiparasitic treatment, was known to have activity against PCP but, for optimal preventive use, it had to be inhaled using a nebulizer, a device used for asthma treatments. Although some doctors began using the drug for PCP prevention, insurers would typically not reimburse for it due to the lack of official FDA approval. The urgent need for a clinical trial turned attention to the newly established, government-sponsored AIDS Clinical Trials Group (ACTG), which was set up to address such critical research questions. The ACTG, however, appeared to inherit from the government an ability to take a simple task and, assisted by endless committee discussions, transform it into an unassailable morass of confusion and complexity.

Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) and thus ultimate head of the ACTG, went as far as telling activists attending a 1987 meeting that there was no data to suggest PCP prophylaxis was beneficial and that it may, in fact, be dangerous. While the ACTG continued to agonize over exactly how a pentamidine trial should be conducted, the HIV/AIDS community stepped in to fill the void. The then newly established CRI in New York, headed up by Dr. Joseph Sonnabend, worked with their counterparts in San Francisco to initiate and complete an independent study which led to the approval of aerosolized pentamidine for PCP prevention in 1989. Subsequent studies would confirm the survival benefit associated with this relatively simple intervention.

The ACTG appeared more efficient when it came to setting up trials of anti-HIV drugs. AZT was approved in 1987 based on evidence of a short-term survival benefit in people with advanced disease (a previous episode of PCP or T-cells less than 200), but the ACTG rushed to implement studies that might expand the drug's use to people who hadn't yet developed symptoms. A few ACTG-affiliated researchers, seemingly whipped into a froth of therapeutic euphoria by AZT's arrival, advocated early use of the drug without any supporting evidence whatsoever. Many people living with AIDS had reason to be less enthusiastic about the drug, particularly those whose nights were interrupted by clanging alarms reminding them to take their next every-four-hours AZT dose (the horrifying schedule for the equally horrifying 1,500 mg daily dose used at the time).

A Seat at the Table (1990-1993)

"The companies who want their profits, the bureaucrats who want their turf, and the doctors who want to avoid making waves have all been at the table. The persons with AIDS who want their lives must be there, too."

-- John S. James, AIDS Treatment News, May 9, 1986

Frustration with the ACTG's monomaniacal approach led to a legendary protest in May 1990, when over a thousand activists stormed the campus at the National Institutes of Health demanding a seat at the table. Anthony Fauci, always the consummate politician, calmed the situation by inviting a few protesters into his office for a meeting. The end result was the birth of the ACTG's Community Constituency Group (CCG).

The CCG included more than 30 activists who distributed themselves across each of the various committees of the ACTG, including the executive committee. Imperfect as the system may have been, there is evidence in clinical trial directories of the era that the community input was valuable. For example, there were 13 ACTG trials of opportunistic infection treatments in the New York State directory published by AIDS Treatment Resources in the winter of 1990. By winter '93, the number had expanded to 21, and two trials were specifically studying treatments for opportunistic infections in women.

Attempts to involve a wider community also led to the opening of a second Federally-sponsored clinical trials network, the Terry Beirn Community Program for Clinical Research on AIDS (CPCRA). Terry Beirn was a dedicated activist who served as managing editor of the first national HIV clinical trials directories published by the American Foundation for AIDS Research (amfAR). While the ACTG studies were conducted at academic centers around the US, the CPCRA included community-based clinics with the aim of involving a more representative and diverse population of people with HIV. The approval of drugs studied primarily in gay white men (while partly a testament to initial activism and altruism on their part) represents not only a political but also a critical scientific issue for women and communities of color, and it was hoped that the CPCRA would help address the problem. Today, the CPCRA is having to fight for its existence, demonstrating that the lack of diversity in trials remains another of the recurring, unresolved themes of HIV/AIDS research.

The sad coda for this period was the 1993 International AIDS Conference in Berlin. The ill-founded enthusiasm for early AZT treatment crashed and burned with the results of the Concorde study, which showed no survival benefit and a hint of just the opposite, wreaking psychic havoc on people with HIV but apparently leaving the researchers that had advocated the approach unscathed.

Protease Inhibited (1994-1996)

The first protease inhibitor crept into human safety trials in 1991. By 1994, Ro 31-8959, now known as saquinavir, had made it as far as an ACTG Phase II/III study (dubbed ACTG 229). In getting there, however, saquinavir provided a lesson in the limitations of community input into the ACTG process. On September 30, 1992, CCG representative Mark Harrington wrote a polite but concerned letter to principal investigator Ann Collier about the slated trial:

"I remain perplexed about the current design of ACTG 229. In particular, I share the CTRC's (Clinical Trials Review Committee) concern about 'the selection of 600 mg tid [three times a day] as the dose of Ro 31-8959 [saquinavir] since there is no established maximum tolerated dose.' Doses as high as 1200-1800 mg tid have been tested in HIV-negative patients and found to be safe . . . but people with HIV have only been given doses up to 600 mg tid. I would concur with the CTRC that 'the need for the pharmaceutical sponsor to be forthcoming with data from their European trials' is pressing as we proceed towards opening ACTG 229."

The dose selected by the ACTG was (surprise!) 600 mg tid. The fallout from this decision was profound. The final results of the study, employing a new technique called PCR to measure the amount of HIV's genetic material in the blood (the now familiar viral load test) revealed a slightly better reduction in people taking saquinavir combined with AZT and ddC (Hivid) compared to the double combination of AZT and ddC. A similar incremental benefit in T-cell count increases was also observed. But, due to the low dose of saquinavir, the effects were short-lived. Yet worse, many trial participants developed resistance to the drug that would turn out to blunt the effect of newer protease inhibitors which, although no more potent against HIV in the test tube, were being given at doses that led to dramatically better viral suppression and immunologic recovery. Had Harrington's warning been heeded, this disaster could have been avoided. A high-dose saquinavir study eventually confirmed what the CTRC suspected: antiviral activity was dramatically enhanced without significant additional toxicity.

Thankfully, 1995 saw more impressive results from studies of saquinavir's protease inhibiting brethren, ritonavir (Norvir) and indinavir (Crixivan). Combining a protease inhibitor with two nucleoside analogues was shown to lead to prolonged suppression of HIV replication and a surprising rebound in T-cell counts and functional immunity. Although low-dose saquinavir was eventually approved in December '95, the more effective drugs followed rapidly on its heels, receiving approval in March '96. These events followed two studies showing a survival benefit (and a correlation between survival and viral load reduction) with dual nucleoside therapy, lending credibility to the notion that the addition of a protease inhibitor would further prolong life. The 1996 International AIDS Conference in Vancouver launched the idea of these triple combinations into the public imagination, inaugurating the era of Highly Active AntiRetroviral Therapy (HAART).

HAART Realities (1997-2000)

At the community level, it rapidly became apparent that HAART could produce remarkable health rebounds in people with symptomatic disease and AIDS. The drugs did not work for everyone, but the advantages over single and dual nucleoside treatments were abundantly clear. The availability of HAART altered the research landscape by finally making more effective treatment available outside of clinical trials. Efforts to compare regimens continued and added two nucleoside analogues plus a non-nucleoside (NNRTI) drug to the HAART roster, but the past few years are perhaps best characterized by the trials that either didn't happen or were achingly slow to get started.

Most notably, the key question of when it is best to begin HAART treatment has gone unanswered to this day. In a woeful bout of collective amnesia, many of the same researchers that championed early intervention with AZT argued that HAART should be given to almost everyone with HIV. A panel dominated by these supposed experts was created by the government in 1996 to produce guidelines on using HAART, leading to a recommendation that treatment be started when the T-cell count fell below 500 or if viral load rose above 20,000 copies. The handful of community representatives involved (supported, it should be emphasized, by a few brave doctors on the panel) had to threaten a walkout in order to have the following text inserted as a footnote: "some experts would defer therapy until the CD4 count falls below 350." Earlier this year, the guidelines were revised to reflect this more cautious approach and, once again, the early intervention cheerleaders have somehow held on to their jobs and reputations.

The guesswork employed to guide initiation of therapy was echoed in recommendations for second and third line regimens aimed at people with multiple drug resistance. An unappealingly small market for industry, it was left to a small group of committed activists and doctors -- the Coalition for Salvage Therapy (CST) -- to beat the bushes for trials that might help guide those running out of treatment options. This uphill battle is still being fought today and, tragically, many people (including several sorely missed members of CST) have died as a consequence.

The idea that HAART may produce cumulative and unpredictable side effects was also largely ignored by many (although not all) researchers. Instead, it became popular to blame the strange syndromes being reported by the community on HIV itself. Thus, "HIV-Associated Lipodystrophy (HAL)" was christened, despite the fact that HIV had little, if anything, to do with the drug-induced syndrome of elevated blood fats and mitochondrial damage (mitochondria are vital energy-producing components of human cells). Reports by women of sex-specific toxicities also went unheeded for several years, something that might not have occurred had there been adequate representation of women in HAART trials. Treatments for these problems, and strategies for uncovering their cause and reducing their incidence, have been slow to reach clinical trials, as is evidenced by the grand total of eight listed in the most recent New York State clinical trial directory.

Yet another significant, and under-appreciated, assumption about HAART was that it had to be used continuously to produce sustained health benefits. Dr. David Ho solidified this idea by proposing that HIV might be eradicated with prolonged therapy. The shocking lack of biological plausibility did not prevent Ho's hypothesis from being embraced by large swathes of both the scientific and (perhaps more understandably and forgivably) HIV/AIDS advocacy communities. It took the increasing burden of treatment fatigue and toxicity to give pause to eradication enthusiasts, and the real world perspectives of clinicians like Bill Powderly to eventually note that perhaps treatment interruptions could be both safe and beneficial if a careful eye was kept on immune system function and health.

Percolating around the issue of interrupting treatment was a radical claim made by immunologist Bruce Walker at the 1998 International AIDS Conference in Geneva: "Eradication is not required -- the immune system can control HIV." Although supported by considerable evidence from animal studies -- and some hints from humans -- the notion was greeted with skepticism and, in some cases, outright disdain. The lack of interest on the part of the pharmaceutical industry is perhaps not surprising, given that the emphasis was reducing time on drug therapy. However, like the broadening of opportunistic infection studies in the early '90's, activism by many groups has helped force the issue. Get a copy of CRIA's latest clinical trials directory for New York State, and you'll see the first few multi-site studies of both treatment interruptions and interruptions accompanied by therapeutic immunizations that might conceivably enhance control of HIV in the absence of HAART. Even large companies like Merck and GlaxoSmithKline are now exploring these strategies in studies, making this an area to watch closely as research moves into the new millennium.

Eyes on the Prize (2001-?)

The disheartening persistence of agendas that ill serve people with HIV/AIDS cannot undo the successes of the post-HAART epoch. The number of deaths and AIDS diagnoses has plummeted in the wealthier nations of the world, providing some respite from the horror of the epidemic's early years. But as the mainstream media reflect on two decades of AIDS, it is disturbing to read quotes that so selectively portray the effects of community activism and exaggerate the role of leaders who have so often let down people with HIV. Anthony Fauci, who has kept his job as director of NIAID, credits advocates for making clinical trials "user friendly," but chooses not to mention the PCP prevention trial that CRI pulled off when no one else would. The pharmaceutical industry lauds the accelerated approval mechanisms that have hurried drugs to market, but cannot seem to conduct post-marketing studies to identify new side effects or define how the drugs should best be used. Robert Schooley, who once described a colleague as "imbecilic" for advocating delayed initiation of HAART, still runs the ACTG. While sobering, these facts serve as a reminder that continuing activism and community involvement in HIV/AIDS research is essential if the oft-forgotten, but surely ultimate, goal is to be reached. A cure.

Richard Jefferys, formerly Access Project Director at the AIDS Treatment Data Network, now writes for the IAVI (International AIDS Vaccine Initiative) Report.