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Annus Mirabilis

A Look Back at an Extraordinary Year for Basic and Clinical Research on AIDS -- and the Questions Raised

Additional Surprises Expected

December 1996

The year 1996 witnessed seismic developments in AIDS research. On many fronts -- the basic and the clinical, the biomedical and the behavioral -- the very ground has shifted under our feet. It appears that we may have the opportunity, previously just a distant hope, to preserve health and life for many more people living with HIV than ever before. At the same time, we face difficult, new and sometimes bitter contradictions: effective preventive strategies are stymied by political leaders for political reasons; the direction of AIDS vaccine research remains unclear and its accomplishments scant; new therapeutic approaches are inaccessible to over 90% of the world's people living with HIV; and the future direction of the entire research enterprise is still a matter of contentious debate.

The struggle for the future of AIDS research operated simultaneously on many fronts: a political front, in continued contention between the Congress, the administration, scientists and advocates; a policy front, in the release of an unprecedented expert external evaluation of the NIH AIDS research program by the so-called "Levine Committee" (named after its chair, Princeton virologist Arnold J. Levine), and in subsequent bureaucratic opposition to its implementation; and, most importantly, on the scientific front, where fifteen years of accumulating knowledge and effort finally yielded a series of explosive discoveries which brought scientific understanding of the disease to new heights.

Unlocking Mysteries of Pathogenesis

Undoubtedly the most exciting development on the basic research front this year was the discovery by a number of research teams of a group of intracellular messenger proteins, or chemokines, and their receptors, which unlocked several key mysteries of AIDS pathogenesis. While it had long been known that HIV required binding to the CD4 molecule on the surface of CD4+ T lymphocytes and macrophages in order to infect them, it had also been clear that binding to CD4 was necessary, but not itself sufficient. A second receptor, or several, appeared necessary to mediate binding and entry into the host cell. Over the years many teams proposed putative second receptors, and each of these, in turn, was discredited. In December 1995, however, Cocchi et al. noted in Science that three beta chemokines, MIP-1-alpha, MIP-1-beta and RANTES, appeared to block infection by macrophage-tropic (also called "non-syncytium-inducing" or "NSI") HIV strains in vitro, setting off a frenzied search for the mechanism for this blockade. By April 1996 Berger et al. discovered a receptor, LESTR or fusin (now renamed CXCR4), which mediated infection of so called T-cell tropic (also called "syncytium-inducing" or "SI") HIV strains. Soon, it became apparent that these reciprocal discoveries could help unlock several longstanding mysteries of pathogenesis: how HIV entered susceptible cells; how it switched its tropism from macrophages and T cells to T cells alone over the course of disease, as the virus evolved from NSI to SI strains; how some people proved resistant to sexual infection despite repeated exposure; and how some progressed more slowly than others. These discoveries precipitated an avalanche of research over 1996, and it became clear that NSI strains require the chemokine receptor CC-CKR-5 (now renamed CCR5) to enter susceptible cells; that SI strains require fusin (now called CXCR4); and that these events can be blocked by the natural intracellular ligands of these receptors, the three beta chemokines (MIP-1-alpha, MIP-1-beta and RANTES) and SDF-1 (stromal cell derived factor 1), respectively.

Building on the discovery that some persons exposed but uninfected expressed high endogenous levels of the beta chemokines, researchers from the Aaron Diamond AIDS Research Center and others showed that about 1% of people from Western European backgrounds have a homozygous genetic defect in their CCR5 gene which blocks sexual infection with NSI strains, explaining some factors contributing to genetic resistance to HIV infection. Moreover, persons heterozygous for the defective CCR5 gene appear to progress to AIDS more slowly than those who are homozygous for wild type. More recently (Lapham et al., Science, October 1996), it has been shown that CXCR4 binds directly to the HIV gp120/CD4 complex, thus raising the possibility that CXCR4 mediates the second phase of viral entry, when the HIV protein gp41 is exposed and pierces the cell wall, allowing the virus to enter. These discoveries demonstrate how a serendipitous convergence of research from unrelated areas of immunology helped unlock several important longstanding mysteries of HIV pathogenesis, and may well have vital implications for vaccine and drug development.

Reducing HIV to "Undetectable" Plasma Levels

Meanwhile, ten years of therapeutic research provided a series of more immediately useful breakthroughs. New and powerful assays to quantify HIV levels in the peripheral blood provided researchers with an unprecedentedly clear picture of HIV pathogenesis, while new and powerful treatment strategies enabled them to exploit this understanding to reduce plasma concentrations of virus to levels never seen in the natural history of HIV disease, below levels seen even in long-term non-progressors, and ultimately to levels beneath the limit of detection of even the newest and most powerful viral load tests.

In 1995 and 1996, several research teams, and in particular the Aaron Diamond AIDS Research Center in Manhattan, used new plasma HIV RNA tests to measure HIV levels in the peripheral blood during all phases of infection. They then applied powerful new agents such as protease inhibitors to perturb HIV levels, revealing an epic, decade-long struggle between the immune system and the virus. This furtive battle of attrition had been virtually invisible before the development of sensitive viral load assays and drugs more powerful than those seen before.

It became clear that virus production and immune clearance maintain a deceptive quasi-steady state for ten years or more before the virus erodes the immune system's competence to the point where clinical AIDS develops; as many as ten billion HIV copies are produced and cleared in an infected person's body each day. Moreover, plasma virus concentrations could be reduced by up to 99% within three months of starting therapy with potent new antiretroviral drugs. Finally, despite such dramatic reductions, the virus appeared able to develop resistance within a matter of months even to the most potent single drug regimens, demonstrating that the monotherapy approaches of the past were inadequate for achieving long-term control of HIV in vivo.

Researchers also continued to elucidate the factors which predisposed some people to rapid progression and some to slower progression towards AIDS. In some people, infection with a defective virus strain lacking a functional nef gene appeared to correlate with slow progression. In others, a more vigorous initial immune response appeared to correlate with slow progression. After the resolution of primary infection and the burst of initial viremia, patients whose viral load reached a low steady-state "setpoint" progressed to AIDS more slowly than those whose viral setpoint was higher. Indeed, 1996 saw a plethora of studies strongly indicating that viral load is the best single long-term predictor of an individual's risk of progression to AIDS, in all populations. Thus, the ability of new treatment strategies to hold virus levels down below levels seen even with long-term non-progressors held out the hope that these strategies -- properly applied on a large enough population -- could alter the natural history of HIV disease, keeping tens or hundreds of thousands of people healthy longer and extending their lives.

Therapeutic Breakthroughs

Evidence that this might be possible began to emerge in February, when researchers from Abbott Laboratories showed that the new protease inhibitor ritonavir, when added to a regimen of underlying nucleoside analogue therapy, halved rates of progression to AIDS and death in a six-month, 1,000-patient study. Such dramatic, albeit short-term, effects on survival had not been seen with any new antiretroviral drug since 1987, when AZT demonstrated a dramatic short-term effect in a smaller population over a shorter period.

Considering the barbaric state-off-the-art of managing AIDS in 1987, compared with the far more sophisticated prevention and treatment of opportunistic complications prevalent in the mid-1990s, the impact of the ritonavir study was even more dramatic, demonstrating that potent new agents could rapidly prove clinical efficacy, and that antiretroviral therapy was still effective even in advanced symptomatic patients. A cautionary note, however, was the apparent creep of HIV RNA levels back towards baseline at six months in a large proportion of patients, suggesting that HIV was evolving resistance to ritonavir and that the short-term benefits measured might not last.

At the same time, the ritonavir study marked the end of an era. Once the drug and its cousins saquinavir and indinavir were on the market, by spring 1996, studies comparing them to a background of nucleoside analogues would become increasingly anachronistic. Indeed, the study of single therapies itself would increasingly come to be replaced by the studies of competing therapeutic strategies. Meanwhile, it became clear that plasma HIV RNA levels were the most powerful surrogate marker for antiretroviral treatment effect, and that changes in plasma RNA levels would come increasingly to be used for initiating and for changing treatment regimens.

Over the spring and summer of 1996, as the protease inhibitors were introduced in the United States, the picture was complicated by the inequitable, patchwork nature of the American health care system, by the disorganized block-grant mechanism through which new AIDS drugs were distributed to states for indigent patients, and by physician and patient uncertainty about how to use the new treatments and the new viral load tests, one of which (Roche's Amplicor RNA PCR assay) was approved by the FDA in June. Protease inhibitors were much more expensive than the previous generation of drugs, and were recommended for use over a background of nucleoside analogues.

Thus, the cost of antiretroviral treatment reached new heights, while clinical data on who should take these drugs -- and when -- remained scant, despite the ritonavir study in late-stage patients. Moreover, the protease inhibitors each demanded rigorous adherence to a complex treatment regimen; some of the drugs were highly toxic, while others demanded dietary austerity; all had complex interactions with other therapies commonly used by people with HIV; and, finally, failure to use the therapies as indicated was likely to lead not only to resistance to that particular therapy, but in some cases to cross-resistance to one or more other protease inhibitors. Thus, despite the excitement generated by their licensure, patients and physicians were trapped within a labyrinth of questions about access, adherence, compliance, convenience, cost, toxicity and optimal use, which they faced in an information vacuum as the very ground shifted under their feet.

At the Eleventh International Conference on AIDS in Vancouver, British Columbia, during July 1996, all these developments converged to produce a new paradigm for treating HIV infection. With single agents, no matter how initially potent, HIV inevitably appeared able to escape by developing single or multiple protein mutations which rendered those agents inactive. With two or three potent agents, simultaneously applied, however, in a patient who had not previously used them, the results appeared dramatically superior, as viral levels were driven so low that the emergence of drug resistance appeared to be delayed, if not prevented. In Vancouver, six different studies of different regimens in different populations showed that plasma viral RNA levels could be reduced to very low levels in virtually all patients able to adhere to their regimens within three months. The studies ranged from combinations of three reverse transcriptase inhibitors (AZT, ddI and nevirapine) to those of two protease inhibitors (ritonavir and saquinavir), from newly-infected patients to those with just over 50 CD4 cells, and from those who were antiretroviral therapy-naive to those with extensive prior exposure.

This series of treatment breakthroughs posed a number of tough questions for clinical research. While it was clear that hitting the virus hard, with potent antiretroviral combinations, was possible, it was far from clear whether this strategy should be used for people at all stages of disease. While it was clear that people could become virtually aviremic in the peripheral blood, the effects on viral reservoirs such as lymphoid tissue, gut and brain, where 98% of the body's T cells (and hence HIV) dwell, have not yet been measured. No one has been on triple-drug therapy for more than 18 months; the ultimate duration of the effect is unclear. While mathematical models suggest that it may be possible to eliminate infectious HIV reservoirs after several years of therapy, the pathogenesis of HIV has continually outwitted the most ingenious theories of science, and additional surprises are to be expected. The likelihood of immune recovery from HIV-induced dysfunction and lymphoid destruction is unknown, and the restoration of immune function once significant damage has occurred will be a difficult task. Immunological approaches to therapy remain in their infancy, and basic questions such as whether to remove opportunistic infection prophylaxis from patients whose CD4 levels have rebounded remain unanswered.

On a public health level, assuring access to and information about new treatment strategies is an enormous task even in the developed world, and the chances of extending their use to the developing world where over 90% of HIV cases occur appear slender until and unless a new global commitment to providing health care to all emerges. Given the political landscape in the USA, where even its own citizens are routinely denied access to health care, this prospect seems remote. More likely is the recapitulation with HIV of what occurred with tuberculosis, when several generations of effective drugs were wasted by inadequate public health efforts, resistance to all of them emerged, and, after a hiatus of several decades, tuberculosis returned with a vengeance in a new, multi-drug resistant form, its re-emergence amplified by the widespread immune dysfunction triggered by the HIV pandemic.

Ultimately, as William E. Paul, the director of the NIH Office of AIDS Research (OAR) pointed out in a cogent lecture at Vancouver, only a vaccine will be sufficient to control HIV on a global basis. All the promise of new therapies and all the progress in biomedical and behavioral prevention activities only buy us time, curtailing infection rates and slowing down disease progression in those infected until a safe and effective vaccine is developed. It is still far from clear whether this is possible, but the vaccine research front has been marked by the slowest progress, the most false starts, and the clearest deficiencies. Most candidate vaccine products studied to date were based on an outdated understanding of HIV pathogenesis, and used protein sub-units of the HIV envelope proteins gp120 or gp160 to elicit immunity to mostly irrelevant laboratory-adapted HIV strains such as the SI-tropic LAV (also known as IIIB), when in fact most people are infected sexually by NSI-tropic strains with different envelope proteins. The very use of envelope proteins and the goal of eliciting neutralizing antibodies has become controversial, as cell-mediated anti-HIV immunity, rather than just antibodies, appears critical to moderating HIV progression. All available animal models are imperfect, and most have been used inefficiently, so that too little is known about related diseases such as simian immunodeficiency virus (SIV)-induced AIDS in macaques. Clearly, as the Levine Committee recommended, the AIDS vaccine effort needs new scientific leadership, enhanced resources, and a focus on rigorously comparing competing pathogenetic hypotheses rather than simply comparing various proprietary molecules in vivo and measuring immune parameters which may or may not be relevant.

Political Obstacles to Scientific Progress

The U.S. funds 85% of the global AIDS research effort. In early 1996, the entire Federal research effort came to a standstill as the U.S. Congress twice shuttered the Federal government in a political dispute with the Executive Branch, while a series of blizzards enveloped Washington, D.C. and the entire eastern seaboard. The National Institutes of Health (NIH) and its many research programs were paralyzed; enrollment into NIH-sponsored studies ground to a halt. AIDS research (among thousands of other vital programs) was forced to wait for politicians to resolve their differences. When the second Federal shutdown ended and the government lurched shudderingly to its feet, so great was the confusion that administration lawyers failed to note ambiguous legislative language which confined the NIH Office of AIDS Research (OAR) and its mandate to plan, coordinate and evaluate the entire $1.4 billion NIH AIDS research program to a bureaucratic limbo.

At the same time, the need for a strong, effective OAR with budgetary authority over the entire NIH AIDS research program became clearer than ever with the release in March 1996 of the report of the AIDS Research Program Evaluation Working Group, (the "Levine Committee"). After an eighteen-month review involving over 100 scientists and community representatives, the Levine Committee and its six Area Review Panels concluded that the national AIDS research effort was due for a mid-course correction, one including a series of major reforms at NIH.

Throughout the 1980s, as Congress shoveled money for AIDS at NIH, bureaucrats at its 24 institutes diverted many of the funds to other research programs, as overall NIH growth stagnated. As a result, by 1993, the NIH AIDS research programs remained a collection of uncoordinated fiefdoms run by institute directors for whom AIDS was often not a priority. To correct this, Congress in 1993 passed legislation strengthening the NIH Office of AIDS Research and giving it power to budget, coordinate, evaluate and plan the NIH AIDS research effort. Shortly thereafter, NIH Director Harold E. Varmus named immunologist William E. Paul to direct the OAR; Dr. Paul, in turn, commissioned the Levine Committee to carry out its review.

Never before had AIDS research been evaluated by scientific area, rather than by institute, and never before had the entire portfolio been evaluated by outside scientists. The result was a sweeping critique of the status quo and a blueprint for the next five years of AIDS research. Governing the philosophy of the Levine Committee was the recognition that now most expertise in AIDS research rested with scientists in the extramural community and not, as in the early years, with intramural scientists or NIH program staff. Therefore, the committee called for a reorientation towards investigator-initiated research and away from programs designed and directed by NIH bureaucrats. It called for a doubling of support for investigator-initiated AIDS research grants, together with efforts to recruit senior investigators from related fields and enhance training activities for young scientists. In the first three years since OAR was restructured, the number of new AIDS grants funded each year by NIH has already risen by 40%.

The Levine Committee recommended that a revitalized and expanded AIDS vaccine research effort be initiated, with scientific leadership by a senior outside scientist, and that OAR coordinate AIDS vaccine research efforts throughout the Federal government. It also expanded research into the interaction between HIV and the human immune system, and related models such as SIV and primates, to help elucidate HIV pathogenesis; most immunology today rests on mouse models which are not always easy to extrapolate to humans.

Recognizing the inefficiency, gaps and redundancy in NIH's twelve clinical research networks studying treatments for HIV and its complications, the Levine Committee recommended consolidating and streamlining these networks into a more efficient mechanism, which will be necessary in any case as more people will need to be followed for longer periods of time in larger and more complex, strategy-based treatment studies. The Levine Committee also recommended integrating biomedical and behavioral approaches to prevention research at NIH, assessing the scientific basis for evaluating alternative and complementary therapies, increasing basic research into HIV-related opportunistic infections, and streamlining and broadening access to relevant animal models, tissue repositories and databases.The leitmotif of all these changes is that NIH requires a new philosophy of collaboration within and between institutes, and a new partnership between intramural and extramural scientists, one which replaces the previous, turf-conscious and hierarchical relationship, in which NIH proposes programs and disposes resources to run them. Finally, in order to carry out these recommendations, the panel emphasized that the continuation of a strong OAR, one endowed with authority over the entire NIH AIDS research budget, was vital for ensuring rapid progress on all fronts.

Unexpectedly, after the budget fiasco of early 1996, Congress provided a surprising resolution for 1997 to the long-standing struggle over NIH AIDS research funding. While still denying OAR the line-item budget specified in the 1993 NIH Revitalization Act, Congress provided that the NIH and OAR directors shall identify $1.5 billion for AIDS research in 1997 and distribute it to the NIH institutes in accordance with its strategic plan, reflecting the recommendations of the Levine Committee. For the first time, in addition, Congress provided OAR with the ability to transfer up to 3% of the total AIDS Research budget (or up to $45 million) between institutes over the course of the year in response to new research developments.

Thus, as we enter 1997, the OAR is finally, after four years of arduous struggle, endowed with both the budgetary authority and the strategic vision, based on the evaluation of the Levine Committee, to ensure that the nation's investment in AIDS research fulfills its potential. Nonetheless, the struggle over the future of AIDS research will continue, as Congress is due in 1997 to renew the NIH authorization, and another budget battle is certain to ensue.

The Role of Activism in Accelerating AIDS Research

While many of the developments of this incredible year in AIDS research might ultimately have occurred anyway, they probably would not have occurred in 1996 without the efforts of AIDS research and treatment activists. Activists prodded researchers in the early 1990s to study long-term survivors of HIV disease -- studies which led to the discovery of CC-CKR-5, of the existence of genetic resistance to HIV infection and of the related phenomenon of long-term non-progression. In 1992, activists urged a rededication to basic research, one which has paid off with startling rapidity and plenitude. Moreover, in 1992 activists allied with AIDS researchers from around the country to push for a stronger OAR. Thanks to this alliance, a stronger OAR is now in place, and many of the same scientists put their imprint on the Levine Committee's sweeping recommendations for reform.

The activist contribution to clinical research is also apparent. Without community pressure for expanded access and accelerated approval, fewer drug companies might have invested in developing protease inhibitors and other novel agents, such as nevirapine, which are now available. Activist-won gains, such as the increase in research on opportunistic infections, provided many people with HIV a window of opportunity during which the new treatments and treatment strategies were developed. Finally, it was activist pressure (if from but one sector of a highly disputatious community) which resulted in the design of Abbott's ground-breaking ritonavir study, which transformed the field in early 1996. Activists are now on the cutting edge of demanding new, flexible but rigorous study designs which evaluate new treatment strategies rather than single drugs in isolation, as has been the norm since the beginning of the epidemic.

Moreover, needless to say, without unflagging efforts by community activists who mobilized scientists from around the country, the recent major increases in Federal funding for AIDS research would not have occurred, nor would the OAR have emerged from the 1996-97 budget battle with its budget authority not only preserved, but enhanced. Finally, strategies pioneered by treatment activists are now being applied on many fronts, including basic research, prevention and vaccine research. Indeed, the community bears more responsibility for pioneering successful prevention initiatives, such as safer sex or needle-exchange programs, than the government, which has consistently refused either to fund such research (or programs which such research indicated would be effective), has conducted only politically-biased research designed to disprove the need for such interventions, or has ignored or distorted successful interventions. There can be no question that activists and community-based organizations can share credit for the breakthroughs of 1996.

Future Threats & Opportunities

We must redouble our efforts to consolidate these gains, build on them, and prevent opponents of AIDS research from interrupting or weakening the effort. Health research, along with other discretionary domestic programs in the U.S., remains threatened by the bipartisan consensus to balance the Federal budget by 2002. Opponents of AIDS research try to stir up disease-vs.-disease sentiment among other constituencies. The U.S. health care system remains in tatters, and many people with HIV lack access, information and the health care infrastructure required to exploit new advances. Punitive new laws targeting poor people and immigrants will only deepen the suffering, driving thousands of additional people away from the treatment, information and infrastructure they need to manage HIV infection in already distressed communities around the country where the epidemic is at its worst. Prevention research is stymied by Congressional hostility to studies of human sexuality, and prevention programs are stymied by bipartisan hostility to the idea of proven interventions such as needle exchange.

Globally, the picture is even more grim, as the epidemic continues its relentless advance over the Eurasian continent, where it is now well-established in India and spreading rapidly in China. As the epidemic's epicenter in Central Africa subsides again into civil war and chaos, its continued and uncontrolled spread there appears inevitable. There are a few bright spots, such as Thailand, where an army-sponsored campaign mandating 100% condom use in brothels has dramatically reduced infection rates, but such spots are rare. Ultimately AIDS cannot be solved on a national level; it must be solved globally or it will return to haunt us all.

As 1996 leaves us behind, we cannot yet tell whether it will ultimately be seen as a decisive turning point in the history of the epidemic, or merely a truce in a centuries-long battle between HIV and humankind. Research is giving us the tools, but political leaders are sure to avoid deploying them unless a global movement for a vaccine, a cure, and worldwide access to them erupts. How can activists help to instigate such an eruption?

Here in the United States, the landscape of health care resembles a wasteland across which are scattered ivory-tower academic medical units for people with access to new treatments, clinical trials and information, surrounded by areas of devastation in which millions of people lack access to all three. The bipartisan assault on entitlements, which began in 1996 with the repeal of welfare as we knew it, appears likely to continue, with Medicaid next on the list, possibly followed by Medicare and Social Security. Each of these programs is vital for many if not most Americans living with HIV. Activists who previously focused exclusively on speeding research on and access to experimental AIDS drugs will find their efforts increasingly futile unless they begin to take a larger role in the on-going national struggle for universal health care. This struggle, like many before it, is likely to last for generations. AIDS activists will need to develop broader coalitions to preserve biomedical research and forge a new consensus about how to achieve universal health care. While fighting to preserve what remains of a shredded social safety-net, it is imperative to begin preparing at once for a broader struggle to build an equitable health-care system which provides access to all.