'Homing in on basic research'

The beginning of this year marks TAG's tenth anniversary as the nation's only organization focused exclusively on advocating for more and better AIDS research, speeding discovery, development, approval, and distribution of better treatments, a cure and a vaccine. While the latter two goals remain elusive, the past ten years have seen significant progress—much of it instigated or accelerated by TAG. The NIH AIDS research budget has tripled in size, from $800 million to $2.4 billion per year. After TAG's pivotal 1992 report, AIDS Research at the NIH: A Critical Review, the AIDS research program at the National Institutes of Health was reformed and reorganized.

In the mid-1990s, TAG played a major part in forcing the drug companies developing protease inhibitors to study the drugs more rapidly and to provide more reliable information on how to use them. TAG also played a critical role in speeding up research on the opportunistic infections and cancers which were the leading killers of people with HIV. Since 1996, with the introduction of highly active antiretroviral therapy (HAART), protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and viral load testing, antiretroviral treatment strategies have undergone a revolution.

Over the past seven years AIDS mortality dropped by two-thirds in the U.S. and other industrialized countries. Nonetheless, significant problems remain with anti-HIV drug adherence, cost, resistance, and toxicity. As people with HIV live longer, new problems such as lipodystrophy and liver disease now cause more problems among people with HIV living in the United States. Meanwhile, internationally, despite several years of intensified mobilization, the HIV pandemic spreads unchecked by effective prevention and existing treatment, let alone an HIV vaccine. TAG remains committed to completing our mission.

As we move forward in 2002, we will also look back at the work which brought us here, investigating key TAG projects and campaigns, interviewing leading researchers and activists who worked with TAG, and remembering those we have lost. Our first article focuses on TAG's formation in 1992, its dual missions of direct action and critical research analysis and oversight, our critique of the NIH AIDS research program and our call for an increased emphasis on the basic science of HIV infection—all themes which remain timely despite the progress of the past ten years. Mark Harrington transports us back to the dark days of the early 1990s.

Nineteen ninety two was a year of crisis for people with AIDS. Twelve years into the epidemic, despite the mobilization of thousands of activists, the deployment of millions of dollars in federal and pharmaceutical research funds, and significant accomplishments in speeding development and approval of three drugs for HIV and several more for its associated opportunistic infections, AIDS research was at a low point.

AZT had been approved by the FDA in 1987 and recommended for wider use in 1991, the same year that the FDA approved ddI (Videx), the second antiretroviral. These drugs extended life and health by just a year or two, and failed to durably suppress the virus. In 1992 it was still unclear whether hoped-for new therapies such as inhibitors of the HIV tat or protease enzymes would prove effective. In the meantime, the AIDS and death tolls mounted relentlessly.

Activists had won entrée into the councils of the Food & Drug Administration (FDA) and the National Institutes of Health (NIH) AIDS drug development programs and oversight bodies, and had helped to broaden the research agenda to include more research on the opportunistic complications of HIV—and on women and children with HIV. Nonetheless, the prospects for treatment looked unpromising.

Scientists did not yet have a clear picture of the pathogenesis of HIV infection. It was still widely and incorrectly believed that HIV "hid" somewhere in the body in the period between acute infection and the development of AIDS ten years later. Available tests to quantify viral levels in the body were crude at best. Only a few researchers were looking for the virus in body compartments such as the lymphoid tissue, as opposed to the easier to sample bloodstream. It was not yet known how HIV destroyed the immune system and led to AIDS.

Without a better understanding of how HIV led to disease, it would be difficult to develop better treatments. Yet at NIH, despite an AIDS research budget that had steadily mounted to almost $800 million per year, the research effort was poorly coordinated. It lacked a central place where the overall research agenda could be planned, budgeted, and evaluated. Eighteen different NIH institutes each conducted their own AIDS research programs as they saw fit. Scientists in the field were depressed about the lack of progress on both the therapeutic and on the preventive vaccine fronts.

The political situation was also troubling. During twelve years of Republican presidencies, most federal action on AIDS had been instigated by—and sometimes obstructed by—Congress. The country had just emerged from a distracting war in a far-off Islamic country, and it was in recession. Health care costs were rising uncontrollably, and increasing cries were heard for the government to do something to broaden access to health care. It was difficult for AIDS and health care activists to get the attention of President George Bush.

Meanwhile, the AIDS activist movement itself was in crisis. The largest activist group, the AIDS Coalition to Unleash Power or "ACT UP," was increasingly riven by infighting, while many of its leaders and members were falling ill or dying.

Within ACT UP's Treatment + Data (T+D) Committee, a dozen treatment activists were determined to focus their efforts on research and treatment advocacy. Infighting was getting in the way of that focus, and so in January 1992 they split off from ACT UP and formed the Treatment Action Group. TAG's early focus included a series of direct actions targeting drug companies whose development plans were too slow: Dai-Ichi pharmaceuticals, for their glacial development of an anti-Kaposi's sarcoma (KS) angiogenesis inhibitor; whose expanded access programs were inadequate: Hoffmann-La Roche, for refusing to provide expanded access to ddC; or whose prices were too high: Astra, for the excessive price of the anti-CMV drug foscarnet. Despite widespread publicity, these civil disobedience "zaps" were becoming less effective than they had been in ACT UP's early days.

The litany of drugs which the FDA did approve over the course of 1992 showed just how slow the research progress was, and how grim the prognosis for most people with HIV. The third anti-HIV drug, Roche's ddC (Hivid), was approved in June—even though there was no evidence that ddC improved health or prolonged life. It was approved based on minute and transient increases in CD4 cell counts. ddC would go on to be the least widely used drug of its class. Then, in a rush of year-end drug approvals, the FDA approved two drugs for advanced AIDS—Adria's rifabutin for prevention of mycobacterium avium complex (MAC) and Unimed's dronabinol (Marinol), an appetite stimulant, for treatment of HIV-associated anorexia and weight loss.

An additional TAG focus was analyzing and reforming the AIDS research program of the NIH. Starting in February 1992, TAG's Gregg Gonsalves and Mark Harrington gathered information on every NIH AIDS research grant and program. By the International AIDS Conference that July in Amsterdam, they published AIDS Research at the NIH: A Critical Review. The report called on Congress and the Administration to strengthen the NIH Office of AIDS Research (OAR) and to provide it with the authority and ability to plan, evaluate, and budget a coordinated, streamlined, accelerated AIDS research program across all the NIH institutes and centers.

We also called on the government to double the entire NIH budget for biomedical research. That summer and fall, TAG worked on building an alliance with AIDS researchers across the country who would be willing to support the reform efforts when legislation was introduced in Congress during early 1993. TAG also met with NIH Director Bernadine Healy and the directors of the NIH institutes—particularly Tony Fauci at NIAID and Sam Broder at the National Cancer Institute—although the institute directors generally were opposed to any plan which would subject them to evaluation or oversight. With the election of Bill Clinton as President in November 1992, the stage was set for Congress to enact sweeping reforms of the NIH AIDS program in the reauthorization legislation of early 1993.

Finally, during 1992 TAG was the first activist organization to call on researchers to refocus the AIDS research effort on fundamental basic research dedicated to elucidating the pathogenesis of HIV disease and AIDS. TAG's pathogenesis project met monthly. We began working with basic scientists as well as with clinical researchers as we had in the past. In his 1992 speech at the Amsterdam AIDS conference, TAG's Mark Harrington spoke on "Pathogenesis and Activism" and showed slides of his own HIV-infected lymph node as an example of how activists and people with HIV could contribute to and participate in basic research as well as in clinical trials.

It was clear that progress would be slow. Over the course of 1992, 79,595 Americans were diagnosed with AIDS and 41,623 of them died of the disease. At the time it seemed that those numbers would only go up for the foreseeable future.

Many of TAG's founding members were ourselves HIV-infected. Among the many activists who died of AIDS in 1992 were 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 only be a matter of time—and not too long—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. ¤

The fate of monkey #798

January 2002 proved to be a month of mixed blessings for the AIDS vaccine field. A slew of new papers in the prestigious journal Nature publicly highlighted both the promise and potential pitfalls of new immunization strategies, raising the volume of scientific debates that have been quietly preoccupying researchers for some time. At the center of it all were two back-to-back articles released on January 17: one from a team of Merck researchers led by John Shiver, publicly debuting encouraging data from studies comparing multiple HIV vaccine constructs (including Merck's proprietary adenovirus-based vaccine vector) in rhesus macaques; the second from Dan Barouch and Norman Letvin's group at Harvard, presenting a cautionary tale of viral escape from vaccine-induced T-cell responses in the same animal model system. TAG's new Project Director for Basic Science, Richard Jefferys, sifted through the data and commentary to prepare this report.

The debate sparked by these data sets revolves around the level of protection that might be afforded by the induction of T-cell immunity against HIV. The immunization strategies employed in both studies successfully induced virus-specific CD4+ helper and CD8+ CTL (cytotoxic T-lymphocytes) responses, but neither afforded full protection from infection. Instead, the success of the vaccines was measured by their ability to stimulate the immune system to control viral replication and thus preserve CD4+ T-cell counts and prevent clinical disease, at least in the short term.

This type of outcome contrasts with the Holy grail of vaccinology, "sterilizing immunity," wherein infection is entirely prevented or rapidly cleared, leaving no detectable trace (except for, sometimes, long-lasting immunity).

The conventional wisdom is that sterilizing immunity can only be achieved with the aid of neutralizing antibodies, and HIV has thus far proven resolutely resistant to this type of immune response (although experiments using high levels of infused lab-created antibodies, "passive immunization," have prevented infection in an SIV model). The pursuit of partial protection has thus been promoted as something of a stop-gap measure while researchers continue to try to solve the antibody challenge.

Public dissent regarding this two-tiered approach has been muted—until now. It is the Harvard data that has finally drawn several partial protection pessimists into the open because it raises a chilling possibility: that a vaccine which offers only partial protection could end up leading to a worse outcome than no vaccination at all.

In the study, Barouch and his Harvard team found that a single viral mutation led to viral rebound, CD4 cell decline, symptomatic disease and ultimately death in one of eight vaccinated macaques. Up until that point, the monkey in question had been clinically and immunologically healthy for six months after an intravenous challenge (with the pathogenic SIV/HIV hybrid SHIV89.6P, either six or twelve weeks after the final immunization; see note). The mutation was apparently selected for by the vaccine-induced virus-specific CTL response.

Interviewed in a Mark Schoofs Wall Street Journal piece, primate researcher David Watkins raises the specter of such escape mutations occurring in vaccinated humans and being transmitted onwards, potentially leading to the emergence of (yes, that media favorite): a "supervirus." While this appears to echo some of the extremely speculative arguments against global implementation of HAART, a recent modeling experiment by Andrew Read and colleagues from Edinburgh actually offers some basis for Watkins' concerns. Read modeled the potential effects of vaccines that ameliorate disease but do not prevent infection and found that under some circumstances they could potentially select for pathogens with increased virulence. Importantly, however, this result becomes less likely if the vaccine also reduces onward transmission of the infection. The potential for enhanced virulence would also be reduced if the vaccine were able to fully protect some proportion of immunized individuals.

The views of Watkins illustrate the theoretical basis for an increasing bifurcation of opinion among HIV vaccine researchers. On one side, there is a cadre displaying considerable enthusiasm and optimism about prospects for T-cell based vaccines, including Norm Letvin and the U.K.'s Andrew McMichael. On the other, an increasingly vocal group—including Watkins but perhaps most often associated with Harvard primatologist Ron Desrosiers—argues for caution, even going so far as to characterize the current mood of optimism over new vaccines as "irresponsible." Somewhere in the middle, stoic realists such as antibody expert John Moore from Cornell acknowledge that T-cell based vaccines are well worth testing, but expect that the addition of an effective antibody-based approach will be required to achieve truly protective immune responses.

While they have served to highlight these outstanding questions pertaining to T-cell based HIV vaccines, neither the Merck or Harvard paper claims to provide data that can resolve them. And there may be a danger of the data's being over-interpreted. The initial goal of both groups was to consistently raise CTL responses, a not-insignificant challenge as is evidenced by the decade-long travails of the ALVAC canarypox vector (see "A Tale of Two Trials"). Also, in keeping with the preliminary nature of these experiments, only a limited number of viral antigens were employed: env and gag in the Harvard study and gag alone in Merck's.

The details of Barouch's work provide additional reasons for caution. The data derives from a study that was widely publicized when first published in Science in the fall of 2000. A DNA vaccine construct encoding SIV gag and HIV env was administered four times to rhesus macaques. Four animals received the DNA vaccine alone, while two additional groups of four animals each received a low dose of an IL-2 fusion molecule (IL-2/Ig) in either protein or DNA plasmid form at the time of the first two immunizations. Six weeks after the final booster, all macaques were intravenously challenged with SHIV89.6P. All animals became infected, but at the time of the publication of the Science paper, recipients of the vaccine plus IL-2 had controlled viremia and preserved their CD4 counts over 140 days of follow-up.

By contrast, four of eight controls had died and only two displayed some degree of immunologic control of the challenge virus. But subsequent to this initial report, one animal that received the vaccine plus IL-2 in protein form—monkey #798—began to lose control of viremia at around week 24 post-challenge. This was followed by a loss of CD4 T cells (week 36), symptomatic clinical disease (week 44), and death from simian AIDS (week 52).

It is the sobering tale of this macaque that forms the basis of the Harvard group's Nature paper. In collaboration with Northwestern University virologist Steve Wolinsky, the researchers went over the data to look for explanations for the apparent vaccine failure. Genetic sequencing of the virus revealed that between weeks 14 and 20, immediately prior to the viral breakthrough, a mutation occurred in a region of the gag protein targeted by the vaccine-induced CTLs. The mutation involved a single amino acid change (from threonine to isoleucine) which was absent from 8/8 viral isolates sampled at week 14, but present in 10/10 isolates sampled at week 20. Upon further analysis, CTLs targeting the original epitope were found to be 1,000-fold less efficient at recognizing the mutant virus than the original strain. Barouch concluded that it was this single point mutation which ultimately triggered the cascade of events leading to the death of monkey 798.

The data raise the question of whether such escape tactics will prove to be the Achilles heel of all T-cell based vaccine strategies. If such vaccines cannot prevent infection, will eventual immune escape and disease progression be inevitable? Could such escape variants be transmitted, and thus further diminish vaccine efficacy at the population level? The Harvard team notes that the best strategy for preventing escape may be broadening the vaccine-induced immune response (e.g., by including antigens other than just gag and env) and attempting to drive viral replication to the lowest level possible post-challenge.

In an interview with National Public Radio after the study was announced, Norman Letvin noted that, prior to the emergence of the CTL escape mutant, monkey 798 appeared to have slightly higher levels of viral replication than the other immunized animals. He also reported that these remaining seven macaques have continued to control viremia for more than 600 days of follow-up. Taken together, these observations suggest that while it is probably premature to conclude that all CTL-based vaccines are doomed to failure, the unavoidable implication is that increasing CTL selection pressure by vaccination could have unpredictable effects on the evolution of HIV. Careful long-term monitoring and follow-up will be critical in both animal and human studies of these approaches. ¤

Note: SHIV89.6P is a hybrid SIV/HIV construct which contains the envelope of HIV and the core of SIV. More specifically, it was constructed by combining the genes tat, vpu, rev and env from the Dutch HIV-1 isolate 89.6 with the remaining genome of SIVmac239. The gag proteins of challenge virus (SIVmac239) and vaccine are therefore precisely matched, or "homologous." SHIV89.6P is noted for its ability to cause an unusually rapid and typically irreversible CD4 T-cell loss, accompanied by the swift onset of simian AIDS and death. While use of this virus allows for a rapid analysis of vaccine-mediated protection from clinical disease, many researchers raise the point that SHIV89.6P does not reproduce the more prolonged course of HIV infection observed in humans—and therefore may not be truly representative of the human in vivo situation. The Merck investigators themselves concede that, "the relevance of the SHIV 89.6P monkey challenge... has not been firmly established."

The DOD's trial is to be conducted in Thailand, and plans to enroll 15,800 heterosexuals (the DOD's regulations don't allow them to work with gay men or intravenous drug users) into a trial of an ALVAC vector (vCP1521) encoding gp120 from a subtype E isolate, along with gp41 and gag/pro from subtype B. All volunteers will also receive two boosts with Vaxgen's bivalent subtype B/E recombinant gp120 vaccine. The estimated cost is $35-40 million and the current proposed start date is mid-2002. The NIH trial is being planned for the United States, the Caribbean and South America through the HIV Vaccine Trials Network (HVTN) and is slated to involve 11,080 volunteers comprising both gay men and high-risk heterosexuals. The protocol uses a slightly different ALVAC vector (vCP1452) encoding env, gag/pro and regions of pol and nef that are rich in CTL epitopes. One arm of the study includes a boost with Vaxgen's clade B gp120 vaccine. Estimated cost for the HVTN study is $60-80 million. (Plans for both studies are discussed in detail in the new IAVI Report, online at www.iavi.org.)

In addition to pointing out that the slender differences between these trials render them duplicative, John Moore also raises several scientific questions relating to the study designs. Chief among these is the notoriously poor immunogenicity of the ALVAC vector. In what must surely be a record for any experimental medical intervention, ALVAC's tortuous history has included over 40 phase I and II trials involving around 1900 volunteers. The vaccine has shown an ability to induce low-level HIV-specific CTL responses in about a third of participants at best, and these responses are rarely directed at more than one epitope. Moore also questions the scientific rationale for including a gp120 boosting component. No animal model study has shown an advantage to this approach, and recently presented data from Harriet Robinson's group at Emory reported that adding a gp120 booster to a DNA/MVA vaccine actually reduced efficacy rather than improving it. Moore points out that efficacy data from Vaxgen's phase III trial of gp120 will be available later this year, which will surely shed more light on this question.

To avoid duplication and wasted resources (and the potential of two huge failed trials further denting public confidence in the vaccine effort), Moore suggests that the DOD ALVAC trial go forward (perhaps with a more rational boost, for example, gag instead of gp120), while the HVTN concentrate on newer and more promising third-generation vaccine constructs such as Merck's adenovirus and the DNA/MVA prime-boost regimen being developed by the International AIDS Vaccine Initiative (IAVI). While a counter-argument is that these newer agents are not yet ready for phase III evaluation, it is entirely conceivable that they will reach this milestone within the next two years. And even if both proposed ALVAC trials begin as scheduled, enrollment is likely to be a lengthy process. Alternatively, Moore offers that the HVTN could assume responsibility for conducting a single ALVAC trial while DOD concentrates on bioterrorism defense. Although John Moore's advice is clearly not intended to be proscriptive, the overarching and long-overdue message of his commentary is clear: it's vital that the plans for both ALVAC trials are subjected to open public discussion before they are finalized. RJ ¤

The explanation may relate to a fundamental tenet of T-cell immunology. CTL maven Rafi Ahmed has long noted that vaccine-induced T-cell responses need to reach a "resting memory" state in order to respond optimally to a subsequent boost or challenge. The canonical T-cell response to a vaccine involves a peak of proliferation, followed by a "death phase" and ending with a stable but lower-level population of resting memory cells. It can take several weeks for this process to play out in mice, and how long it takes in higher primates is currently unclear. It is possible that for the macaques in the Merck study that received Ad5 or MVA alone, the additional six weeks of rest between the final immunization and challenge may explain the otherwise counterintuitive results. This will be a key question to explore in future animal studies, and, according to Emilio Emini, data is forthcoming that will address the question more directly. RJ ¤

For the first time ever, NATAF (newly renamed from the National AIDS Treatment Activists Forum to the North American AIDS Treatment Action Forum) took place outside of the U.S., in the beautiful Canadian city of Vancouver, British Columbia. Over 450 delegates from around the U.S. and Canada joined others from Eastern Europe, Poland, Russia, Cuba, Puerto Rico, Mexico and Costa Rica in what was the first truly international NATAF. Mark Baker, editor of Provincetown Positive, was there to chronicle blow by blow the events of the three-day get-together. "Once again," Baker writes, "those gathered consisted of people living with HIV and their advocates—all from a multitude of diverse backgrounds, cultures and races. There were men and women; straights, gays, lesbians and people with histories of intravenous drug use; Caucasians, African-Americans, Latino/as and Asians. But for all our diversity, we had two unifying factors in common—HIV disease and our desire to become better treatment advocates and activists." A pared down version of his 2001 NATAF report follows. Thanks, Mark.

As HIV/AIDS treatment issues were becoming more and more important in the early 1990s, a few dedicated treatment activists realized the need to create a place in which fellow treatment activists could share treatment information and further develop treatment and research advocacy. As they discussed how to do this, it became increasingly obvious that a mechanism needed to be developed to transfer the knowledge of experienced treatment advocates to members of all communities infected and affected by the AIDS epidemic. The goal was clear: create a mechanism to help educate people about treatment issues who could then take home what they learned to further educate their communities about increasing access to care and treatment. As this basis for NATAF solidified, it also became clear that the complex issues of public policy, funding and HIV prevention also had to be included due to their effects on treatment and research priorities. Out of all this, the first NATAF was born in 1995.

December 2nd was the first day of NATAF 2001. It began with a pre-conference orientation that gathered all of us together to learn how to gain the most from the next three days of plenaries and workshops. At the front of the room was a handmade timeline that began with the year 1980 and ended with 2001 entitled, "The History of HIV/AIDS." Of particular interest to me was the note at the start of the timeline indicating that 1959 was the year in which a man died in the Congo from an unidentified illness. An analysis of a saved blood sample later found him to be the first confirmed case of HIV infection—in 1959. The timeline was a graphic illustration of the events, both good and bad, that have shaped the North American HIV/AIDS epidemic. It was an apt reminder that we who call ourselves "advocates" help make history. Whether it's history in HIV/AIDS policy, treatment research and development, and/or in an individual's access to care and treatment, it's been the HIV/AIDS advocates at the center of historical landmarks.

The opening plenary that night was called, "From Where I Stand." It began with an address from a Native North American chief whose indigenous people once numbered 10,000 in this territory, yet today number a mere 360. He spoke eloquently about the parallels faced by Native Americans and people living with HIV, noting that hopelessness in our communities is caused and perpetuated by the media images which stereotype gays, PWAs, and IDUs. The fight is made easier when we come together, at places like NATAF, to work collectively to defeat the ignorance of the broader community. He ended with a moving song, traditional for his people, in tribute to all those that have died from this disease.

Anuar Luna of Mexico gave the first keynote speech. He stressed that the "official numbers" of people living with HIV or AIDS in Mexico—50,000—is not an accurate picture of the estimated 150,000 people in actual need of access to HIV care and treatment. The epidemic in Mexico is centered among gay men ages 15-44, but women are increasingly affected. Only roughly 75% of these—usually the ones that work—have access to treatment, but the quality of the care varies greatly. Sometimes anti-HIV drugs are available, sometimes they are not; sometimes PWAs have access to lab tests for viral load, most do not; and genotypic and phenotypic tests are still a rarity. AIDS services organizations provide limited services, mostly peer education and support. There are a limited number of "drug banks"—places that gather unused supplies of anti-HIV drugs and redistribute them to those in need. Only recently have Mexican AIDS activists started to meet with the political decision-makers to advocate for more money—$48.5 million—needed for HIV/AIDS treatment for Mexican PWAs, as well as more human resources and technical assistance to combat the disease.

Phill Wilson of the U.S., a 21-year AIDS survivor and a gay man of color, spoke next listing the possible repercussions of the 9/11 terrorist attacks on democratic freedoms that could affect policies governing healthcare issues such as HIV/AIDS.

Louise Binder of Canada completed the opening plenary. The leading Canadian AIDS activist decided early on that treatment information would save her life. She believes that the 1996 World AIDS Conference held in Vancouver—heralded as "The Cure Conference"—was actually the birth of AIDS complacency in North America. Combination therapy—including the fabled protease inhibitors—was credited with creating the Lazarus-effect whereby PWAs who were formally on their deathbeds had tremendous initial response to HAART and rebounded to seemingly much healthier lives. Even though this effect is complicated by the toxic side effects of the drugs, most of the world breathed a collective sigh of relief, believing that the epidemic was over.

But because today's HIV treatments are a reprieve and not a cure, the need for both activism and advocacy still exists. We still need new clinical trials, new drugs, expanded access to treatments (both in North America and globally), and advocacy for improvements in the social ills that feed epidemics like HIV and AIDS—poverty, homelessness, and illiteracy. The question is—will the younger generation now being infected rise to activism to demand the cure that still eludes us? We all need to unite to create a truly global community of activists and advocates to defeat this global epidemic.

Monday, December 3rd began with a breakfast plenary entitled, "The Making of an Epidemic: The Implications of Public Policy." Martin Schechter of the University of British Columbia started with a presentation of statistics. As of 2001, 40 million people worldwide are infected with HIV—half of which were women. In 2001 alone, there were 3 million deaths worldwide from AIDS and 5 million new infections. That translates to 14,000 new infections every day—95% of which are in developing countries, like South Africa where 1 in 3 people are infected. Against this dismal backdrop, there are new regions of the planet that hold great concern for the continued spread of HIV/AIDS. These "hot spots" include China, India, Indonesia and the states of the former Soviet Union where, globally, the epidemic is now growing the fastest.

The afternoon workshop session IV called, "Antiretroviral Strategies: Activist Intervention and When to Start, STIs, Salvage Therapy, Long-Term Effectiveness, Adverse Events and Beyond" had the longest title of any workshop offered at NATAF. Mark Harrington of TAG joined Bob Huff of GMHC and Ben Cheng of Project Inform in San Francisco to present. Mark began with an overview of the evolution of the U.S. HIV treatment guidelines that were issued starting in 1997. He noted the troubling controversy that centered on the Guideline's recommendation for all people with <500 CD4 cells to begin triple-drug HIV therapy. This was recommended even though all the studies done to date at the time proved HAART's effectiveness only in people with counts <200 CD4 cells. The recommendation was based on the overwhelming belief in Dr. Ho's "Hit Early, Hit Hard" treatment theory, the possibility of HIV eradication and the goal of preventing irreversible damage to the immune system.

Due to the ensuing, almost immediate, widespread application of the new 500 CD4-based "standard-of-care" treatment guidelines, to this day the question of "When to start anti-HIV therapy?" has not been answered. Unfortunately, that key question is unlikely to be answered. Of course, today science has proven that damage to the immune system caused by HIV infection is partially reversible—CD4 cell counts can and do rebound from low nadir levels. And these new T-cells produced in the thymus do their jobs quite well.

Ben Cheng ended the workshop by addressing the new drugs in the HIV treatment pipeline. Besides new drugs in the existing NRTI, NNRTI and protease inhibitor classes, Ben mentioned the latest development of integrase inhibitors and entry inhibitors—the most widely known one of which is T-20. Some of the new drugs in development may be too toxic to be taken orally, but may be successfully developed as topical microbicides. On the whole, though, Ben believes that the drug pipeline is not healthy, mainly due to the fact that big pharmaceutical companies are swallowing up smaller, more HIV-specific drug companies and not necessarily increasing the size of their HIV research and development capabilities.

Kicking off another workshop which focused on effective advocacy with U.S. government agencies, AmFAR's Jane Silver gave a brief overview of the National Institutes of Health (NIH) and the Office of AIDS Research (OAR). She noted that the NIH is currently spending $2.4 billion annually on AIDS research. That accounts for 85% of the world's publicly funded AIDS research effort. Silver recommended three improvements for federal AIDS research: First is a cross-government-agency, coordinated HIV research strategy with its own dedicated budget; second is a process to influence the direction of HIV research within the NIH; and third is a watchdog capability overseeing NIH's HIV research and budget. Finally, Silver argued for the further development of coalitions with advocates for other diseases in order to reach the goals that still elude us.

Gregg Gonsalves spoke further on where the present system fails us. First, there is little work being done to find new targets for HIV therapy, noting that there are fourteen proteins in the viral RNA of HIV, yet we have only targeted two of them with approved drugs at present. He strongly urged advocates to push for the study of new targets. Second, there is still not enough long-term follow-up research on the HIV drugs we now prescribe. Third, and perhaps most importantly, there remains a disconnect between HIV research and HIV drug development. Whereas the NIH funds basic HIV research and clinical trials, the pharmaceutical industry still controls drug development.

Gregg noted that there are models appearing that attempt to bridge this disconnect. IAVI (the International AIDS Vaccine Initiative) is the most visible, being a public/private partnership that first identifies promising vaccine candidates from research and then provides initial support for the vaccine development. Finally, Gregg noted that we still need a system in place through the NIH to do Phase IV long-term follow-up studies in randomized clinical trials.

In the closing plenary entitled, "Infections and Inequalities: International Issues and HIV," Dr. Julio Montaner of Vancouver's St. Paul's Hospital noted the disconnect in many countries between areas that have the greatest number of cases of HIV infection yet the fewest antiretroviral drugs available compared to the areas with the smallest number of infections yet most drugs available. He cited the 2001 article by Hogg and colleagues in JAMA that found that it proved viable to start HAART at CD4 counts >200 regardless of viral loads. The article indicates that CD4 counts appeared to be a better predictor of disease progression than viral load and suggested that a count of 200 CD4 cells be the new trigger level to start HAART.

Montaner reminded those gathered that after the 1996 World AIDS Conference in Vancouver, the prevailing theory in therapy was summed up by Dr. David Ho's infectious soundbyte, "Hit early, hit hard." Now in 2001, the theory is once you start HAART at CD4 counts >200 then "hit hard." He lamented that had he known back in 1996 what he knows today, 65% of HIV-infected individuals in British Columbia could have waited to start triple therapy. This would have represented a huge savings in drug expenditures, physician and lab costs, and sacrifices in quality of life.

He qualified this observation by noting that this new information is based on only 2-3 years worth of data. Therefore, there is still no definitive answer on the optimal time to start treatment. He concluded stressing that while viral load may not be as important as the CD4 count in determining when to start therapy, it is still important once treatment is started: to monitor response to treatment, viral breakthrough, the emergence of resistance and the likelihood of disease progression.

He then turned to the global front, citing the present day catastrophe of 40 million people HIV-infected worldwide and fewer than one million with access to treatment. He cited the new "hot spots" of HIV infection around the world, noting that if nothing is done soon, these places will experience an increase in HIV infection on par with that which Africa has seen in the fifteen years from 1984-99. As a result of this huge increase in poverty and a decrease in productivity, there will be financial and social ruin on a scale never before seen.

Montaner closed by noting that the idea of "human security" is increasingly based on the infrastructure needed to support people leading healthy lives. The provision of anti-HIV drugs alone will not solve the problems that face us globally. We need to promote the development of social systems that people need to be healthy, which will have a positive impact not only on AIDS, but on TB, malaria and malnutrition as well. The WHO has placed the dollar figure needed to stem the tide of HIV/AIDS by 2005 at $9.2 billion a year—the same amount that the U.S. spends annually on cosmetics and the Europeans spend on ice cream! The obvious conclusion: we either pay now or pay later, but later the bill will be much, much higher. ¤