Ten years ago, a group of us from ACT UP/New York's Treatment and Data Committee left the organization to form the Treatment Action Group. When this happened, I had been in New York only a year and had hardly grown used to the vociferous and heady rush of the city's AIDS activism before we swept out of the anarchic hubbub of the Great Hall at Cooper Union into the conspiratorial confines of Charlie Franchino's apartment. Then Marvin Shulman's loft.

While most of my new TAG cohorts had been through the fires of the early days of ACT UP, I was new to AIDS activism, only having joined a smallish ACT UP/Boston in 1990. Once I got to New York, I was working as a technician in a molecular biology lab up at Columbia University, but quickly found my evenings and weekends taken up with the work of the new group. It was clear to me as 1992 drew to a close that I was passionate about what TAG was doing and that I wanted to devote more time to this strange brew of science, politics, cultural criticism, romance, camaraderie and anger.

In the last issue of TAGline, Mark Harrington described some of the work we were doing together back then and while I am tempted to reminisce, I thought it might be more important to take a look at where we are now, after ten years, and where we might be in another decade.

The epidemic has drastically changed since TAG began. What first seemed to start as an epidemic among urban, gay men and drug users in the United States has clearly cut its worst swath through heterosexual communities in Africa and Asia and among poor African-American and Latino communities in our own country. AIDS is largely now a disease of the poor, and most of the well-off gay men who were the vanguard of AIDS activism have died, retired or sunk into antiretroviral amnesia, where they can ignore the brunt of the epidemic, erecting a wall of denial that the drugs they are taking or will take will keep them from its reach. U.S. treatment activism now relies on a small band of alumni from ACT UP chapters in New York or San Francisco, a scattered group of younger leaders like those of ACT UP/Philadelphia, and a few individuals who have come to the cause from Oakland to Madison to Newark, but who largely remain isolated and without support. It has never been clearer that we need to figure out a way to sustain the work of treatment activism and support new people to devote their efforts to the cause. We need AIDS activism more than ever, for while there are some scattered successes over the past ten years, things are much worse than anyone could have predicted in those days in Charlie's apartment, in Marvin's loft.

Many will discount my gloom and doom, pointing to the advent of HAART in the middle of the last decade. However, despite Andrew Sullivan's reckless contention in 1996 that protease inhibitors spelled the end of AIDS, they certainly do not offer any hope to the millions of people around the world who have no access to them and only provide a limited respite for those who take them as I do.

Yes, many of my friends are alive today because of these drugs, and the steep decline in AIDS deaths in the United States can be counted as a true success of their effectiveness. Yet, the rise of resistance to these drugs was never far behind their introduction in the 1990s and now more than three-quarters of HIV patients with a measurable viral load who are receiving care in the United States carry strains of the virus that are resistant to drug therapy, according to an analysis of 1,647 men and women enrolled in the HIV Cost and Service Utilization Study.

While new drugs against HIV are in the pipeline, including those directed at novel targets like viral entry, it isn't clear that the rate of drug development will keep pace with the rate of viral mutations that outstrip each successive agents' utility. AIDS treatment activists should be helping to spur basic research so that truly new targets such as vif and RNAseH could be exploited for therapeutic use; pushing for larger expanded access programs so that PWAs don't have to play the therapeutic equivalent of the Powerball lottery in order to access new agents; pushing the NIH and the companies to do the important, large, randomized, long-term studies that are necessary to ascertain the distal effects of these agents over time and the clinical risks and benefits of different management strategies; asking Congress and the FDA to compel companies to do these important phase IV studies instead of giving away the store to them based on 48-week viral load data. Activists would be wise to push for a new investment in basic research on human immunology and the interactions between the immune system if we are ever to have an immune-based therapy or a vaccine against HIV.

One of the saddest developments for me over the past ten years is the rise of the rabid vaccine Pollyannas, who I call the Hecklerites, as they constantly underestimate the complexities of HIV vaccine development to a credulous and hopeful public, much as Ronald Reagan's Health and Human Services Secretary Margaret Heckler did when she forecast that we would have an AIDS vaccine within five years back in 1984.

As Harvard Medical School scientist Dr. Ronald Desrosiers, director of the New England Primate Research Center has said, "I fail to understand where this optimism is coming from–I find it totally astounding, to the point of it being irresponsible, in many cases. What are they thinking?" These are the researchers, officials and activists who have never seen an immunogen they haven't wanted to put into phase III trials, ignoring any research that would seems to point to their pet vaccine's inadequacies, saying that animal or human immunogenicity and breakthrough data count for nothing since we don't know what the correlates of protection are. That monkeys aren't men.

Developing a vaccine that will actually protect against HIV infection is a daunting task. Even the substantial increases in vaccine funding at the NIH and the establishment of institutions like the International AIDS Vaccine Initiative don't guarantee us anything like success. Richard Jeffreys, TAG's new basic science director, offers a sober assessment of the prospects for an AIDS vaccine in the January/February 2002 issue of TAGline. It should be required reading for all the big vaccine makers.

Now that AIDS vaccines are garnering more attention and support, what we truly need is rigorous and courageous scientific leadership that is willing to accept the sheer difficulty of the work ahead, to refuse to offer easy answers to the public, and to support the most rigorous science, even if it means "going back to basics" and forgoing phase III studies of less than mediocre candidate vaccines–despite years of commercial, professional, intellectual and emotional investment by companies, scientists, and activists alike.

The development of new treatments for HIV and a vaccine and a microbicide against the virus depend on the health of the AIDS research effort, both public and private. TAG has worked for a decade on improving the conduct of research at the National Institutes of Health, beginning with the push for the strengthening of the Office of AIDS Research back in 1992. The changes at the NIH since the "new" OAR began its work have been generally salutary, especially with the strong leadership of its first director, William E. Paul, and his successor, Neal Nathanson. Bill Paul redirected the NIH's focus to the essential work of basic research on HIV/AIDS and shepherded through a much needed review of the NIH's entire AIDS program. Neal Nathanson pushed for a new investment in prevention sciences, which put vaccines in a continuum of prevention approaches to be supported with generous new funding.

Both of the OAR directors in the 1990s helped reinvigorate the NIH's AIDS program, nicely supplementing the leadership of Anthony Fauci at the National Institutes of Allergy and Infectious Diseases, who, despite his many talents and protests to the contrary, could never effectively oversee both the whole NIH program and his own institute's work.

Ten years later, the OAR directorship remains vacant, and a NIH director has only just been announced almost a year and a half into the Bush Administration. Activists need to push for the appointment of a new OAR director of the stature of Bill Paul and Neal Nathanson to lead us into the third decade of AIDS. After the successive stewardships of Paul and Nathanson, it would be good to have someone take the helm at OAR with a vision of therapeutic research.

Research on HIV, OI and immune therapies has seemed to be on autopilot for most of the late 1990s, with the necessary scrutiny and substantial new resources devoted to long-ignored areas of research like vaccines and microbicides. While the development of HAART might be seen as evidence of the supreme strength of the NIH's program in this area, I would make the case that there was a bit of luck involved in the resurrection of an old cancer drug and cousins of the renin inhibitors–and that the challenges of developing novel agents and paving the way for their global deployment require new and visionary leadership. ¤

Gregg Gonsalves, a founding member of the Treatment Action Group (TAG) and Policy Director of the organization from 1993-2001, is currently the Director of Treatment and Prevention Advocacy at the Gay Men's Health Crisis (GMHC) in New York City.

For TAG, 1993 began with a rush and a push. The election of Bill Clinton as president released a torrent of legislative initiatives which had been blocked under the first Bush administration. High on the list was legislation reauthorizing the National Institutes of Health (NIH), which had been held up due to right-wing opposition to biomedical research focusing on fetal tissue and stem cells, issues which have once again moved to the center of the political debate under the second Bush. Back in January 1993, Senator Edward Kennedy (D-MA) and Congressman Henry Waxman (D-CA) planned to introduce NIH legislation as the first item of business in the 93rd Congress. Staffers Mike Iskowitz in the Kennedy office and Tim Westmoreland in the Waxman office both planned to introduce TAG's proposed reforms strengthening the NIH Office of AIDS Research (OAR) into the new law.

The NIH bill would strengthen the OAR by giving it a full-time director; the ability to plan, coordinate, and evaluate the AIDS research programs carried out by the 18 NIH institutes; and the ability to propose and administer a centralized AIDS research budget, distributing the money to the various institutes in line with an annual strategic plan developed with extensive input from outside scientists. In addition, the OAR would have an emergency discretionary fund and the ability to move AIDS funds from institute to institute. The plan was designed to eliminate gaps in research, reduce redundancy, address emerging opportunities, and create a more well-rounded and coordinated AIDS research system.

Panic in Bethesda
The Senate moved first. Kennedy introduced S.1, the NIH Revitalization Act of 1993, on the first day of the new administration. The reaction of the NIH institute directors in Bethesda, Maryland, was one of panic. The key players in the new Administration included HHS Secretary-designate Donna Shalala, her special assistant Patsy Fleming–who had until November served as legislative aide to New York Congressman Ted Weiss (who had attended the Amsterdam press conference at which TAG's Gonsalves and Harrington first presented the report recommending the OAR reforms), and NIH Director Bernadine Healy, who had been temporarily reinstated by Clinton.

Healy and the institute directors held an emergency meeting in Bethesda. The directors suggested she propose a one-year "study" of the OAR reforms, which would have effectively killed them. Instead she forwarded, without endorsement, a letter from the directors to Shalala. Healy, who wanted to keep her job, told me, "The Institute directors wanted me to walk the plank on this. I told them it was partly their own fault for not having their act together." The bill moved so fast that the NIH bureaucracy had little time to mobilize opposition. The Senate Labor and Human Resources Committee passed the bill unanimously on January 26.

Scientists and Activists Push NIH Reform
On February 3, Waxman held a hearing on the bill. TAG had created a strong coalition including mainstream groups such as amFAR and the Pediatric AIDS Foundation (PAF) in support of the reforms. At the Waxman committee, amfAR's Dr. Mathilde Krim testified on behalf of the reforms, as did PAF's Dr. Art Ammann and Dr. David Ho from the Aaron Diamond AIDS Research Center in New York City. It was a courageous move on Dr. Ho's part, as he was opening himself up to retaliation from the NIH powers-that-were. Shalala also endorsed the legislation. Testifying against it were an array of Washington-based scientific professional societies whose opposition had been arranged by certain institute directors. After the Waxman hearing, we met with Krim, Ammann, and Ho, and planned a nationwide campaign to get AIDS researchers in districts around the country to write to Congress in support of the legislation. Many scientists, dismayed about the state of AIDS research, were courageous enough to sign on.

In the House, the Republicans opposed giving the OAR power over the AIDS research budget. Without this budget authority, the OAR would continue to be a paper tiger. This authority was preserved by a single vote on party lines in committee, and the legislation headed for the floor.

Having a hand in legislation was a heady experience for TAG. Early in February 1992 TAG members were arrested conducting civil disobedience at Hoffmann-La Roche headquarters in Nutley, New Jersey, in a protest over sluggish and insensitive drug development programs. Eight days later, Gregg Gonsalves and I were in Kennedy's office watching the debate on S.1 on the Senate floor. For three days, the machinery of government came to a standstill as debate raged over an amendment proposed by Oklahoma Republican Don Nickles, who proposed a rider barring HIV-infected immigrants from the U.S.

The Nickles amendment, an attempt to codify a Bush-era regulation, and to make political points off the plight of thousands of Haitians who were escaping economic and political collapse and landing at Florida shores, was a good early example of how powerful and persistent the opposition would be to Clinton administration efforts to mitigate some of the bad AIDS policies of the previous era.

The Democrats were unable to stop the Nickles amendment from being attached to S.1; it was horrible to watch a racist and xenophobic policy being attached to legislation intended to improve AIDS research. Ultimately, the noxiously amended S.1 passed the Senate by a vote of 93-4.

On February 25 a tearful Bernadine Healy announced she would not stay at NIH: the administration had decided to replace her. The next day, terrorists set off a bomb in the parking lot underneath New York City's World Trade Center. Six people were killed, and hundreds injured.

Congressional passage of the OAR legislation ultimately took several months, but the outcome was clear: once the bill became law, and after Clinton named a new NIH Director, a search for a full-time OAR Director would be undertaken, and NIH AIDS research would be subject to new oversight, planning, coordination, and budget authority.

Back to Basics
Back in New York, TAG was incredibly busy. We met almost every week at Charlie Franchino's apartment or at Marvin Shulman's loft. In the spring, TAG received $100,000 from Red, Hot & Blue and $25,000 from the Royal S. Marks Foundation Fund. This enabled both Mark Harrington and Gregg Gonsalves to begin working full-time on helping to push through the OAR legislation. Gregg also flew around the country to interview thirty leading researchers for his report, Basic Research on HIV Infection: A Report from the Front.

Gonsalves' report was critical because it was a grim year for AIDS drug development. In April The Lancet published results from the British-French Concorde study comparing AZT with placebo in HIV-infected individuals without symptoms. While a similar study had been stopped in the U.S. in 1989 (when 2% of people on AZT progressed to AIDS, versus 4% on placebo), the Concorde had continued until its results could be generalized to a majority of participants. The results were grim: early AZT was no better, and possibly worse, than placebo. HIV mutated to become resistant to AZT, and the benefits of early AZT were so transient as to be eliminated after three years of therapy. The U.S.-supported guidelines recommending AZT for all HIV-infected individuals with fewer than 500 CD4 cells had been badly discredited.

Berlin
More bad news emerged at the International AIDS Conference in Berlin that June. A barrage of negative study results were presented on ddI (ACTG 116A, 118, CPCRA 002), on ddC (CPCRA 002, ACTG 155), on early AZT (Concorde), and on some new targets such as Roche's tat inhibitor and others.

ACTG 155 was a particularly egregious example. At the time, based on laboratory results, researchers believed the best combination therapy approach was dual therapy with AZT and ddC. ACTG 155 took people who had been on AZT for more than six months and randomly assigned them to continue AZT, add ddC, or switch to ddC monotherapy. The results showed that people did no better if they added or switched to ddC than if they simply stayed on AZT. Instead of admitting that combination therapy failed in this AZT-experienced population, the ACTG 155 protocol team conducted a post hoc subset analysis and tried to show that combination therapy benefitted those who entered the study with over 150 CD4 cells. Unfortunately, the study was not designed to look at subsets in this way, and there were too few endpoints in this stratum to reliably demonstrate anything. In Berlin the investigators presented their post hoc subset analysis, and the activists from TAG and GMHC angrily denounced them for presenting an "intention-to-cheat" analysis. A customarily mild mannered Derek Link sprang to his feet in the stadium sized lecture hall and demanded of 155 presentor Margaret Fischl, "How much is Roche paying you to say this?"

Berlin was the most depressing AIDS conference ever. The bad news abroad was only highlighted by the contrast with events in Washington, where President Clinton signed the NIH Revitalization Act of 1993 on the same day that researchers presented Concorde and 155 in Berlin.

A Wave of Death
In New York and around the country the AIDS death rate was rising sharply, proving the inadequacy of the available drugs for HIV. On June 1, 1993, the ACT UP affinity group "The Marys"–including many TAG members–held a political funeral in Washington, D.C., for activist Tim Bailey, whose embalmed body was borne in a demonstration at the Capitol Building. ACT UP/New York member David E. Kirschenbaum died on July 11, followed one day later by Jon Greenberg, who had founded the Treatment Alternatives Project. Activists held a public funeral for Jon on July 16 in Tompkins Square Park. Over Jon's open casket, performance artist John Kelly sang, "And I dreamed there was a cure for AIDS," to the tune of Woodstock, and a great wind drove through the trees.

Four days later TAG founding member, TAGline co-editor, and composer Chris DeBlasio died. On September 23, Project Inform's Jesse Dobson, who had founded the Immune Restoration Think Tank, died in Oakland. On October 12, ACT UP/San Francisco's Andy Zysman, who had focused on accelerating research on AIDS related cancers such as Kaposi's sarcoma and non-Hodgkins lymphoma, died in San Francisco.

Lont-Term [sic] Survival?
In the face of this barrage of death, TAG's focus on long-term survivors of HIV infection could be seen as one of denial, but it was also one of hope. While the great majority of people infected with HIV developed AIDS and died, a minority seemed to be able to avoid CD4 cell decline, immune system dysregulation, and progression to AIDS. What combination of viral, immune, and environmental or behavioral factors was associated with–or could explain–this long-term non-progression?

Researchers had previously ignored this area, but in the early 1990s it began to attract serious interest. NIAID held a workshop on the issue in summer 1993. Later that year TAG held a forum on the issue. In December the Institute of Medicine held a meeting on long-term survivors and those who were exposed to HIV, but uninfected. Slowly, NIH began to fund innovative research designed to elucidate the factors responsible for long-term non-progression and survival. This research would ultimately lead to discoveries such as the importance of HIV-specific CD4 and CD8 cells in protecting from infection and disease; the existence of genetic mutations which protected from HIV infection; and the existence of the HIV co-receptors CXCR4 and CCR5. These discoveries would lead to new drug candidates and new approaches to vaccine development.

Gregg's report on the basic science of HIV infection made a number of other recommendations which remain timely. He urged researchers to focus on physiologically relevant models of infection such as primate and human retroviral infection, rather than simply looking at the virus and T cells in laboratory dishes. He called for major increases in funding for basic, as opposed to NIH-directed applied, research grants. He called for an increased focus on immunology, new collaborative efforts, and a national network of tissue, cell, and specimen repositories to provide clinically relevant samples for interested researchers. He also cited the need for faster application of new ideas from laboratory research to the clinical setting.

In August, President Clinton nominated Harold E. Varmus as NIH Director. Varmus, who won a Nobel Prize for helping to discover oncogenes (genes associated with cancer), had opposed the OAR reforms in the spring. When he arrived at the NIH, however, he discovered a lack of coordination within the AIDS research program, and was obliged to support the administration's reform policy. He began a series of meetings with leading researchers from around the country to discuss what to do about AIDS, and convened a search committee to find someone to direct the OAR.

The Crisis in Clinical Trials
In December 1993, my four years on the Community Constituency Group of the AIDS Clinical Trials Group (ACTG) ended. It had been exciting to help form the first group representing the community "within the system," but it had also been frustrating. For the first two years I served on the Opportunistic Infections Committee. Activist pressure helped force the ACTG to conduct a variety of OI studies which had languished in the late 1980s when the group was focusing its efforts on AZT studies at all stages of infection. In the early 1990s, however, the ACTG conducted studies which proved the safety and efficacy of Bactrim, dapsone, atovaquone, and trimetrexate for prevention and/or treatment of Pneumocystis carinii pneumonia (PCP); of ganciclovir for treating cytomegalovirus (CMV) retinitis; of clarithromycin for prevention of Mycobacterium avium complex (MAC); of fluconazole for prevention of disseminated fungal infections; and of several other drugs to prevent or treat various AIDS-related infections. The OI Committee was made up of smart, younger researchers open to activist input and eager to address the clinical problems of full-blown AIDS.

In 1992, however, I had moved over to the Primary Infection Committee, which dealt with anti-HIV drugs. Progress here was much slower. The pipeline was full of "me-too" AZT-like drugs such as ddI and ddC. Newer compounds such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors were still in phase I trials. Other new approaches such as recombinant soluble CD4 (rsCD4) and a tat inhibitor had failed to live up to their promise.

The Primary Infection Committee was the powerhouse committee of the ACTG, and less susceptible to pressure or influence from activists. In addition, HIV was more difficult to study and treat than many of the OI microbes. Moreover, some researchers still had sore feelings from earlier activist campaigns which had overstated their rhetoric, such as ACT UP's campaign against "the Gang of Five" in 1990. "We're scientists, not alchemists," ACTG chair Larry Corey had told me, somewhat plaintively–but correctly, in 1990 after a particularly contentious discussion about the failure of soluble CD4.

In 1992, the Primary Infection committee approved ACTG 229, a phase II study of Roche's protease inhibitor saquinavir, even though Roche had failed to define a maximum tolerated dose. I felt frustrated because my efforts to get the ACTG to address such issues were met with inaction. Eventually the failure to define the proper dose of saquinavir would lead to a lot of problems, and many people with HIV would develop resistance to other protease inhibitors because they had been given suboptimal doses of saquinavir.

In December 1993 I released a report on The Crisis in Clinical AIDS Research at the 17th ACTG meeting in Washington. It was a blistering critique of several poorly designed, conducted, and interpreted AIDS treatment trials, including the Army's phase I study of recombinant gp160, the ACTG 155 study of AZT/ddC in AZT-experienced persons, and the laboratory studies at Harvard which had led to the flawed ACTG 241 study of AZT, ddI and nevirapine in people who were AZT-experienced.

Nevirapine was the first non-nucleoside RTI to enter the clinic. Used as monotherapy, it had potent antiviral activity for a couple of weeks, until HIV mutated a single amino acid and became a hundred-fold less susceptible to nevirapine. In the test tube, however, combinations of AZT, ddI, and nevirapine appeared to suppress HIV replication completely: the now notorious "convergent combination" strategy. This led the ACTG to design the 241 study. Unfortunately, there were problems both with the lab work and with the study design. The lab work had been based on constructing mutations which inadvertently rendered HIV non-infectious: this had nothing to do with the triple therapy. The 241 study, like ACTG 155, was conducted in AZT-experienced persons; thus the benefit of combination therapy was lessened because of pre-existing AZT resistance.

Because studies like 155 and 241 suggested that combination therapy did not work in AZT-experienced people, it took longer than it should have to carry out similar studies in AZT-naïve persons. Eventually a AZT/ddI/nevirapine study (called INCAS) would show that triple combination therapy, when used in AZT naïve persons, could reduce viral load beneath the limit of quantitation in 50% of participants–with associated clinical benefit. Unfortunately, these results were three years off and wouldn't be presented until the Vancouver AIDS Conference in 1996. It is tempting but ultimately futile to look back ten years on and wonder how many people could have been saved if highly active antiretroviral therapy–with two nucleosides plus nevirapine, rather than plus a protease inhibitor, used in people before they had taken AZT as monotherapy–had been discovered a few years earlier. ¤