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On January 22, 2012, the Treatment Action Group marked its twentieth anniversary. Over the past two decades, we have helped to accelerate a historically unprecedented therapeutic revolution: the introduction of highly active antiretroviral therapy (HAART) in 199596, followed by its rollout to nearly seven million people worldwide. TAGline will publish a series of articles this year to examine the role of AIDS activism -- and its evolving strategies -- in these accomplishments, and how these experiences can help us build the long road towards the cure still ahead.
TAG was formed by a group of activists from the AIDS Coalition to Unleash Power (ACT UP)/New York's Treatment and Data Committee (T+D), which had spearheaded ACT UP's work on accelerating HIV drug approval by the U.S. Food and Drug Administration (FDA), increasing community engagement in clinical trials conducted by the National Institutes of Health (NIH), fighting industry to bring down high drug prices, and demanding innovative expanded-access programs for people with AIDS unable to enter clinical trials of lifesaving experimental drugs.
ACT UP had won significant concessions from the FDA, leading to parallel track in 1989 and accelerated approval in early 1992, and from the NIH, leading to the formation of the Community Constituency Group (CCG) in 1990 and to activists and persons with AIDS being represented on all research committees of the AIDS Clinical Trials Group (ACTG) and other NIH AIDS research networks. By 1992, two drugs were approved to treat HIV and a handful more were approved to treat or prevent the most common opportunistic infections.
Despite these early victories, effective combination therapy was still years away. The death toll kept rising, seemingly impervious to the interventions of ACT UP and other activists, as well as those of the research establishment. There was no national strategy to deal with AIDS, and no national research plan. For twelve long years, the Reagan and first Bush administrations had turned a deaf ear to the enormity of the AIDS crisis. Congress (then led by Democrats in both houses) had taken halting legislative action at several points, funneling money to the NIH for AIDS research, as well as creating a weak coordinating entity at the NIH to help its many institutes. In 1990, Congress had passed the Ryan White CARE Act, which created a funding mechanism to pay for expensive AIDS treatments, though there were as yet insufficient drugs to make a dent in the epidemic's deadly swath.
Within ACT UP, disagreements about strategy, tactics, and targets were inflamed by the desperation all around us. With the promise of new drug classes in the pipeline and proof-of-concept combination treatment still in clinical trials, TAG's founders believed that the solutions and ultimately the end of the HIV pandemic would come from more -- not less -- community engagement with research to accelerate the development of better treatments, a cure, and a vaccine. It would require a dedicated cadre of treatment activists working full-time with organizational support. It was clear that we were in it for the long haul.
Spurred by the changing environment and the upcoming presidential and congressional elections in 1992, TAG decided to try out a think-tank approach to changing the nation's response to AIDS. Frustrated by three years of activist experience inside the ACTG -- which spent only one-eighth of the $800 million Congress was appropriating for AIDS research by 1992 -- TAG pursued two initial strategies to address the apparently unstoppable pandemic. The first was to rectify institutional failures at the NIH by examining its research investment in detail and proposing more effective ways to ensure progress. The second was to advocate for moving beyond drug development and clinical trials to the basic science, where the still critically unanswered questions of how HIV destroyed the immune system could, if unlocked, pave the way to better therapies, and -- it was hoped -- eventually a cure and a vaccine.
First, TAG decided to deconstruct the entire AIDS research program at the NIH and to recommend reforms to ensure that all critical scientific questions were addressed. Just as ACT UP's Treatment and Data Committee in its 1989 Critique of the AIDS Clinical Trials Group had examined what studies were being done, who was leading them, who sat on the key committees, and who controlled the money, so in 1992 TAG's Gregg Gonsalves and I undertook a comprehensive examination of the NIH AIDS research program.
To do so, we went to the NIH campus in Bethesda, Maryland, and met with the staff of the weak and underfunded Office of AIDS Research (OAR), whose director was Anthony S. Fauci. Fauci was also the director of the largest NIH recipient of AIDS research dollars, the National Institute of Allergy and Infectious Diseases (NIAID). This created an obvious conflict of interest as well as a disincentive for OAR to probe too deeply into the spending decisions of other institutes, since it would seem to be one institute director criticizing his peers. We met with OAR deputy director Jack Whitescarver and his indomitable senior advisor Wendy Wertheimer. They provided us with valuable information about the OAR and its workings, and gave us key contacts at all the institutes. Gregg and I spent several months plowing through crates of documents sent to us by OAR, NIAID, and the other institutes. We read every NIH-funded AIDS research grant as well as the program descriptions supplied by the institutes.
TAG's NIH report came out at the Amsterdam AIDS conference in July 1992; the conference had been moved from its original site, Boston, because of George H. W. Bush's ban on HIV-positive immigrants and tourists from visiting the United States.
We presented our findings at a press conference in Amsterdam on July 22, 1992. In attendance along with the press was Patsy Fleming, an AIDS advisor to New York Congressman Ted Weiss. Less than six months later after the election of Bill Clinton as president, new Health and Human Services Secretary Donna Shalala appointed Fleming as a senior advisor, a role that enabled her to push for TAG's recommended reforms inside the new administration.
Throughout 1992, a wave of activist colleagues from ACT UP and TAG died of AIDS, including ACT UP/San Francisco's Michael Wright in January, TAG's Scott Slutsky in May, artist/writer David Wojnarowicz in July, and ACT UP/New York's Mark Fisher just before the November elections. When we marched uptown on election eve, 1992, bearing Mark's body to Bush's New York City campaign headquarters in midtown, most of us felt that it would be only a matter of time -- and not much time -- before we too died of AIDS. But we were determined to push for changes in the research system so that later generations of the infected would have a better prognosis and a chance for a longer life.
Clinton's victory opened up a new path for NIH reform. President Bush had been holding back an overdue legislative renewal of NIH's mandate due to concerns about fetal tissue research -- which were to recur a decade later early in his son's administration with stem cells. Congressional leaders were determined that the NIH reauthorization should be one of the first bills to move in the new Congress. Indeed, Senator Edward Kennedy introduced the NIH Revitalization Act of 1993 as Senate bill 1 on January 21, 1993, just one day after Clinton's inauguration. The bill included all of TAG's recommendations from the July 1992 report in its title XXIII, which would lead to a sweeping reorganization of AIDS research at the NIH, the departure of Fauci from his post as head of OAR, and a long-overdue external scientific review of the whole program.
Despite opposition mobilized by Fauci and the other institute directors,who disliked the NIH Reauthorization Act's removal of their authority over AIDS research spending decisions to OAR, the bill passed in the Senate by a bipartisan supermajority (the bill was cosponsored by Kansas Republican Senator Nancy Kassebaum, one of a number of then-dwindling, now virtually extinct, moderate Republicans in Congress). In the House, Fauci's allies had time to mobilize. A number of professional societies testified against the bill. On the side of reform were Art Ammann and Elizabeth Glaser of the Pediatric AIDS Foundation, Mathilde Krim of amfAR, and David Ho of New York's new Aaron Diamond AIDS Research Center. The House passed the bill on a party-line vote, and President Clinton signed it in the Rose Garden on June 10, while TAG was in despair at the early results of combination HIV treatment studies at the International AIDS Conference in Berlin.
In August 1993, Clinton named Nobel Prizewinning virologist Harold Varmus as the new NIH director. In turn, Varmus named NIAID immunologist William E. Paul -- a legendary basic scientist and author of the leading immunology textbook -- as the new OAR director in February 1994. Following TAG's recommendations from 1992, Paul convened a blue-ribbon panel -- dubbed the Levine Committee after its chair, virologist Arnold Levine from Rockefeller University -- to conduct an extensive external review of the entire NIH AIDS research effort. Numerous TAG members and other activists participated in this review, which issued its final report in 1996. The report recommended 14 top priorities for NIH AIDS research, including the formation of an NIH Vaccine Research Center (VRC), coordination of clinical trials, and the prioritization of basic science and pathogenesis research.
Just as TAG's early examination of the failures of the institutional structure at the NIH led to reforms there in the following decade, so TAG's early emphasis on revitalizing basic science led to a surge in research to reveal how HIV causes disease, or pathogenesis.
This work began with T & D in the early 1990s when Gregg Gonsalves, who had recently left Tufts University and was working in Columbia University's famous Morgan genetics laboratory, proposed that the NIH hold a series of meetings on why certain people seemed to be protected from HIV infection despite repeated exposures (the so-called exposed uninfecteds), while others seemed to progress much more slowly to full-blown AIDS (the so-called long-term non-progressors, later dubbed elite controllers). This led to a series of scientific investigations in these unusual people who had some biological ability to resist HIV infection or disease progression.
In 1992 at the Amsterdam AIDS conference, alongside the presentation of TAG's recommendations for NIH reform, I gave a talk, "Pathogenesis + Activism," laying out the urgent necessity of activist and scientific attention to the unsolved questions of how HIV caused disease. It was still thought in the early 1990s that HIV lay dormant in some unknown parts of the body, before becoming reactivated and causing progressive immunodeficiency. Fauci had spoken of this unsolved medical mystery issue at the 1991 AIDS Conference in Florence.
In April 1992, I met with gastroenterologist Don Kotler at St. Luke'sRoosevelt Hospital in New York, and underwent a lymph-node biopsy. Immunologist Giuseppe Panteleo, then at Fauci's NIH lab, put it on ice and flew it to the NIH where Fauci, Jan Orenstein, and colleagues could examine my immune-system tissue to find out more about where HIV was hiding and replicating, and how it was damaging the body.
In Amsterdam I showed giant slides of the lymph-node biopsy to the International AIDS Conference audience, and described the uncanny and frightening feeling of being infected with a pathogen whose damage was devastating yet often for many years clinically silent. The slides showed an outwardly healthy lymph node (my CD4 count was 660 cells/mm3, and viral-load tests were in their infancy), but on closer examination, when stained with a dye that bound to HIV, they showed that -- in Don Kotler's inimitable phrase -- my lymph nodes were "crammed with virus." More magnified images, which looked like galaxies of stars in formation, showed singly infected cells producing a series of greenish viral particles.
Just as Peter Staley at the San Francisco AIDS Conference in 1990 inaugurated a new era in activist-scientist relations by calling for scientists and activists to work together -- just two months after ACT UP's "Storm the NIH" demonstration at the NIH campus in Bethesda -- so in Amsterdam I called for activists to work not only with clinical but with basic science researchers to unlock the mysteries of AIDS. I called for a revitalization of basic science, more funding, better communication between activists and basic scientists, and for basic science to use clinical samples from actual patients rather than the more artificial laboratory-adapted strains then in common use.
In spring 1993, while Congress was still debating the fate of the Office of AIDS Research, Gregg Gonsalves set out on a nationwide tour to interview some 36 leading AIDS researchers to better understand the issues they were facing and what they needed to make progress. Gregg's report, The Basic Science of HIV Infection: A Report from the Front, presented at the grim Berlin AIDS Conference where the failed results of so many combination therapy trials pushed the field towards despair, laid out a number of ways to improve AIDS research by making it more relevant to the people with the disease and not limiting it just to artificial laboratory viral strains and immune cells. He called on researchers urgently to investigate the so-called correlates of protective immunity to HIV, to examine the interaction of the virus in the living, complete host ("in vivo veritas"), to better understand HIV pathology in vivo, and to better understand the viral life cycle. He described the still-harsh conditions facing new researchers with the legacy of the Reagan-Bush funding crunch at the NIH and proposed incentives to bring new researchers and experts from other fields into AIDS research. Gonsalves's 1993 report still reads like a clarion call for what is needed to scientifically understand, defeat, and ultimately eradicate HIV.
Hand in hand with the OAR legislation, the Levine Committee report, and the reforms that resulted came a doubling of the NIH AIDS research budget in the first Clinton administration. In the second, Clinton and Congress agreed to double the NIH budget as a whole. Thus, from 1992 to 2002, the AIDS research budget at the NIH rose from $800 million to $2.4 billion. In 2012, it is about $3.1 billion, or 10% of NIH's $31 billion.
The OAR campaign led to a massive reinvestment in basic science, drawing a new generation of scientists into AIDS research. The NIH founded the Vaccine Research Center in the wake of the Levine Committee report. Other changes were harder to obtain, such as the coordination of clinical trials across multiple institute lines. In the end, Fauci and the institute directors gained from the OAR legislation as it helped sharpen the focus of each institute on what it did best.
Among the most exciting results of the new investment in basic science were the discovery in 199596 by several labs at the National Cancer Institute (NCI), NIAID, and Aaron Diamond, of the two cellular coreceptors that HIV uses to get into cells -- the CXCR4 (or X4) and CCR5 (or R5) receptors. Besides unlocking the cell to HIV along with its first receptor, CD4, these two molecules also unlocked a whole series of scientific mysteries long noted in the literature, such as why certain strains of HIV preferred to infect CD4 T cells while others infected macrophages, and led to the discovery and development of a whole new class of anti-HIV drugs, the CCR5 receptor blockers, the first to be approved of which was Pfizer's maraviroc (Selzentry) in 2007. The identification of CCR5 also provided the basic-science rationale for the bone-marrow transplant therapy in Timothy Brown, the only person to be cured of HIV infection to date.
These are some of the results of TAG's first years of activist efforts to reform AIDS research at the NIH, massively increase research funding, and turn the field back to fundamental basic science to better understand, so as to better control, how HIV causes disease.
Two decades later, treatments continue to improve, saving and prolonging the lives of millions of people around the world, preventing countless new infections, and bringing hope that the single documented case of an HIV cure can be replicated, while the ultimate objective of a cheap and widely accessible cure and vaccine remains elusive.
Despite the advent of HAART and its global rollout, we are far from the end of the pandemic. The same combination of smart advocacy, good science, and more money, which helped lead to the HAART breakthrough in the mid-1990s, is now needed to revitalize political leadership, increase research funding, and encourage a new generation of scientists to embark on the search for a cure and a vaccine, the two prerequisites for ending AIDS once and for all.
Just as in 1992, the current political situation is dire. Last year only 10% of all NIH grants submitted were funded -- meaning 90% of them were rejected. This is bad news for young scientists, some of whom are likely to leave research altogether. While last year President Obama called science and technology growth essential to America's future, this year he recommended a flat NIH budget for fiscal year 2013 -- a far cry from his original (2008) campaign promise to ensure that NIH funding would be doubled over the current decade. TAG recommends that the NIH as a whole, along with the AIDS research budget organized by OAR, increase by 15% per year, which would allow a doubling by 2020.
Similarly, while therapy continues to improve, scientists are at an impasse with efforts to discover a cure and a vaccine. High-risk and innovative science driven by a comprehensive and coordinated research agenda will be essential to making these goals into realities. Many of the tenets of Gonsalves's 1993 report remain central to AIDS research today -- as NIAID acknowledged in its recent funding opportunity announcement (FOA), "Targeting Persistent HIV Reservoirs (TaPHIR)," which is designed "to stimulate the development of innovative tools and strategies for curing HIV infection....Novel approaches are therefore sought to efficiently monitor and specifically target reservoirs of latently infected cells to facilitate the testing of strategies to cure HIV infection in vivo." The FOA specifically requires that "latently infected reservoir cells from HIV-positive individuals on optimized HAART should be used for validation studies whenever possible." (grants.nih.gov/grants/guide-pa-files/PAR-12-109.html.)
In addition, the FDA needs to be brought in early to participate in the discussions about how to optimally conduct cure-related clinical trials to ensure the proper balance of rigor, flexibility, ethics, safety, and ability to answer the questions. In 2011 TAG, along with amfAR, AIDS Policy Project, and Project Inform, held an international consultation to discuss how to advance this work. Recently, the FDA and NIH commissioned a high-level scientific working group to address these issues over the coming 18 months, to be coordinated by the Forum for Collaborative HIV Research.
Finally, the struggle for domestic and global treatment access remains daunting. In the United States, almost 4,000 people are on AIDS Drug Assistance Programs (ADAPs) waiting lists, and globally 8 to 10 million people will need antiretroviral therapy in the coming two years, while funding by the U.S. and others is being cut.
AIDS has not yet emerged as an issue in this presidential campaign. It needs to if we are to successfully engage the national leadership in the demanding the necessary work ahead to end AIDS.
In coming articles we will examine the serial disappointments of early combination-therapy trials in the early 1990s, the crisis of confidence that led TAG to call for more rigorous and longer-term trials to better define the clinical utility of the next generation of HIV drugs -- the protease inhibitors -- as well as TAG's work on HIV-associated opportunistic infections and cancers, and the unexpectedly electrifying, medically revolutionary results of the combination of triple antiretroviral therapy, the clinical use of quantitative viral-load tests, and the advent of HAART in 1996, whose use is still being refined, optimized, and in the meantime rolled out to almost seven million people around the world.