With the identification of naturally occurring genetic mutations that can protect against HIV infection and disease progression, academic scientists and pharmaceutical company investigators have rushed to look into ways to mimic these effects. Many teams are trying to develop molecules that could block the CCR5 and CXCR4 receptors or enhance production of the chemokines that naturally bind to these receptors. TAG's Gregg Gonsalves brings us up to date on this burgeoning area of molecular research and notes that chemokine biology in HIV infection has joined an already vigorous effort to find new ways to treat inflammatory diseases such as allergic airway inflammation, arthritis, and ischemia-reperfusion injury.
The field of HIV co-receptorology has exploded since the landmark discovery a couple of years ago of two surface proteins that HIV needs to get into its host cells in addition to the CD4 molecule. Those coreceptors, called CXCR4 and CCR5, allow for the entry into cells of, respectively, T-cell tropic and macrophage-tropic strains of the virus. CCR5-using strains are generally thought to be the viral strains transmitted from person to person. They generally predominate early in disease and are associated with slower disease progression. CXCR4-using strains, by contrast, predominate later in the course of HIV infection and are associated with faster CD4+ T-cell decline and disease progression. The notoriously lethal "syncytium-inducing" viral isolates seen later in disease have been shown capable, however, of using both the CXCR4 and CCR5 co-receptors.
The expansion of co-receptor usage to include CXCR4 doesn't seem to knock out the ability of these viruses to use CCR5. Both of these hijacked receptors are the docking stations for a class of soluble proteins called chemokines (i.e., SDF-1, RANTES, MIP-1-alpha and MIP-1-beta) which the immune system uses to communicate. After grabbing onto its host cells' CD4 molecule, the virus latches onto the chemokine receptor using parts of its own envelope. It fuses with the cell membrane, injecting its RNA into the cytoplasm where it is reverse transcribed into DNA. Once transcribed, it heads for the nucleus.
Since the discovery of these two original coreceptors for HIV, a host of other molecules have cropped up with the same perverted purpose. They include the chemokine receptors (CCR2b, CCR3, CCR8, and US28) and other chemokine-like receptors with innocuous sounding names like BOB and BONZO and letter-number combos like STRL33, TYMSTR, GPR15 and V28. Recent work, however, has shown that these other receptors -- with the possible exception of CCR3 -- are generally not used to gain entry into cells by primary isolates (viral strains coming directly from patients rather than laboratory-derived strains of HIV), although primary isolates of SIV (HIV's simian cousin) have been shown to use some of these other receptors.
One of the other exciting discoveries revolving around HIV co-receptors was the identification of individuals who were protected from infection by macrophage-tropic strains of the virus. The CD4 cells of these individuals were found to contain a 32-base pair deletion in both of the genes for the CCR5 receptor. These mutations are seen in only a small percentage of people of European descent (about 10% have mutations in one of the genes and about 1% have mutations in both of them) and are not present in people of Asian or African ancestry. This mutation, however, even if present in both genes, does not protect against infection with T-cell tropic strains of HIV, since productive infection with CXCR4-using, T-cell tropic strains does occur on occasion (10% or fewer of primary infections studied to date).
Individuals with the same deletion in only one of the genes for the receptor have increasingly been shown to benefit from slower disease progression and in some, but not all studies, also show reduced susceptibility to infection with HIV. This protection seems to result from a combination of reduced expression of CCR5 on cells and increased production of the chemokines (RANTES, MIP-1-alpha and MIP-1-beta) that are the natural binding agents (or "ligands") for this receptor. This means that HIV has fewer CCR5 receptors for docking onto cells and less of a chance to find CCR5 receptors that are not being already used by these binding proteins.
Subsequent to the discovery of these salutory genetic mutations, researchers went out hunting for other genetic correlates of these phenomena. In short course, several other mutations in the gene for CCR5 have been uncovered. One of them is called "m303." This genetic mutant encodes a truncated and non-functional CCR5 receptor. When the m303 mutation is found in combination with the earlier reported 32-base pair deletion in one of the CCR5 genes, resistance to HIV infection appears to be strengthened. But m303 is an extremely rare mutation; the significance of other mutations in the CCR5 gene that have been described to date has not been well characterized.
There is also a mutation in the gene for the chemokine receptor CCR2, which seems to delay HIV disease progression. This is a common variant of the gene, and the mutation seems to be linked with another mutation in the promoter for the gene for CCR5. (A promoter is a regulatory element associated with a gene which promotes the transcription of the DNA of that gene into RNA by the RNA polymerase.) A mutation in both of the genes for SDF-1, which binds to and blocks HIV's access to the CXCR4 receptor, also seems to strongly delay disease progression. This may be simply be due to increased production of SDF-1.
Recent work has identified a mutation in the CCR5 promoter alone which strongly delays progression of disease. This is a very common variant and is found in almost 60% of people of European descent studied so far. Importantly, the mutation has also been found in 43% of people of African descent, 47% of people of Asian descent and in 68% of people of Latino descent. This mutation may function by down regulating the production of CCR5, rather than through a direct effect on the nature of the receptor itself.
Many groups are continuing to search for genetic correlates that may protect against or enhance the susceptibility to infection with HIV -- or slow or speed disease progression in infected individuals. We can expect to see a steady stream of papers on this topic in the years ahead. With the identification of naturally occurring genetic mutations that protect against HIV infection and disease progression, academic scientists and pharmaceutical company investigators have rushed to look into ways to mimic these effects. Many teams are trying to develop molecules that could block the CCR5 and CXCR4 receptors or, alternatively, enhance production of the chemokines' natural ligands. Chemokines are also important factors in many inflammatory diseases. And the search for ways to modify chemokine biology in HIV infection has joined an already vigorous effort to find new ways to treat diseases such as allergic airway inflammation, arthritis, and ischemia-reperfusion injury. But a word of caution: chemokines are important mediators of the immune response, and tinkering with these molecules and their receptors will need to be done carefully in order to avoid impairing the body's immune defenses -- or setting off unwanted and dangerous inflammatory responses. Nonetheless, the work of basic researchers is once again paving the way for new advances in the treatment of HIV disease.
This report was based on two recent papers: Zhang L, He T, Huang Y et al. Chemokine coreceptor usage by diverse primary isolates of Human Immunodeficiency Virus type 1. J Virol 72(11):9307-12 and McDermott DH, Zimmerman PA, Guignard F et al. CCR5 promoter polymorphism and HIV-1 disease progression, Lancet 1998; 352.
At last month's 4th International Congress on Drug Therapy in HIV Infection (Glasgow, Scotland, U.K.), TAG's Mark Harrington was invited to speak at the opening ceremony which convened Sunday evening at the Scottish Exhibition and Conference Center along the river Clyde. The topic? "The Role of Community Activists: Lessons From the First Decade of Treatment Activism." A lightly edited transcript of his remarks appears below.
Ten years ago last month, 1,500 AIDS activists from around the USA surrounded the headquarters of the U.S. Food & Drug Administration in Rockville, Maryland, to demand that the FDA revolutionize its regulatory approach to the testing and approval of new drugs for AIDS. That demonstration was successful beyond our wildest dreams and we are living with its consequences still. Indeed, I and many thousands of others might not be living today had it not been for the unprecedented activism spawned by the AIDS epidemic over a decade ago.
Tonight I will examine where AIDS treatment activism came from, what it has created, and -- because I don't have a crystal ball -- where it might be going. Although I was asked to address "lessons from the first decade of treatment activism," I would like to reframe this by referring to four principles which were suggested to me by an activist from Hong Kong whom I met at an international community treatment workshop held in Geneva just before the international conference this past July. He stated that ACT UP-style tactics wouldn't work in Hong Kong, but from groups like TAG -- who he knew only through the internet and through our reports -- he'd evolved an activist strategy which consisted of:
Incidentally, these principles are useful for researchers as well as activists who seek to influence policy. I will attempt to integrate them into my review of four eras in the evolution of AIDS treatment activism.
I. Gestation (1981-1987)
Treatment activism took its initial model from the civil rights, women's rights and gay rights movements. But, unlike them, our targets were not only social and political, but also biological. We'd grown up during an unprecedented era -- that of the antibiotic bubble -- during which people in our generation expected that all infectious diseases could be rapidly conquered by research and pharmacotherapy. We were wrong, but the sense that AIDS could be conquered gave us boundless hope in the early days.
II. Birth & Growth (1987-1992)
ACT UP, the AIDS Coalition to Unleash Power, was perhaps the most effective, and certainly the most noticeable, social change movement to occur in the U.S. during the Reagan-Bush years. Its tactics represented a unique fusion of strategies taken from the civil rights, women's and gay rights movements of the 1960s and 1970s with a new infusion of skills such as manipulating the media and generating the scientific understanding to play a role in scientific policy decisions within structures established by the FDA, the NIH and the drug companies.
From 1987 to 1992, ACT UP inspired a five-year period of mass mobilization. Its goals included bringing AIDS to the nation's attention, making it a priority for intervention, and securing greater support for the rights and role of people with AIDS. ACT UP took on a broad array of targets, including the U.S. FDA, the NIH, pharmaceutical and biotechnology companies, policy makers in the executive and legislative branches and the media. The popular, democratic and somewhat chaotic model of activism which ACT UP represented was effective for several years. But in the light of changing political and scientific circumstances, it became less effective after a series of initial victories, and was succeeded by a series of more focused groups such as Project Inform in San Francisco and, from 1992, the Treatment Action Group (TAG) in New York. New structures supported with Federal funds such as the Community Constituency Group (CCG) were formed to represent PWAs in the NIH AIDS Clinical Trials Group (ACTG), along with its local community advisory boards (CABs). Some drug companies formed CABs as well, with mixed results.
After ACT UP's successful FDA demonstration in October 1988, it needed to form a specialized subgroup, the Treatment+Data Committee (T+D), to continue the research policy work as it became more specialized and as activists began to become more integrated within research structures. By mid-1989, the T+D Committee put forth the first AIDS Treatment Research Agenda at the Montréal AIDS conference, which led directly to the establishment of the "Parallel Track" program to provide expanded, pre-approval access to new treatments and the later "Accelerated Approval" program, which allowed licensure of drugs based on changes in so-called "surrogate markers" of HIV disease such as CD4 cell counts and, later, plasma viral load. After ddI was distributed to over 25,000 PWAs (from 1989 until the drug's approval in 1991), Parallel Track became an integral part of drug development -- as did Accelerated Approval. This led to a lowering of the evidentiary requirements for drug approval, with the danger that sponsors, marketing permission in hand, would fail to complete studies demonstrating actual clinical benefit of their drugs. However, it also increased incentives for industry to invest in AIDS drug development.
Once the FDA conceded these changes, activists worked their way back through the pipeline from drug approval to drug development. In the late 1980s most drug development took place under the aegis of the NIH ACTG, which was reluctant to allow PWAs and activists to attend, let alone participate in, its meetings. This led us to the May 1990 "Storm the NIH" demonstration, at which a thousand activists marched on the bucolic greensward of the NIH campus in Bethesda, Maryland to demand that activists and PWAs be admitted to policy-making roles within the ACTG, and further to demand that the ACTG rebalance its focus to include AIDS-related opportunistic infections and cancers.
Again, the demonstration was successful, leading to the formation by NIH of the Community Constituency Group (CCG), comprised of over 30 activists representing all sectors of the HIV-affected community, who began to participate on each of the ACTG's research committees and its Executive Committee. Importantly, the CCG was Federally-subsidized, as community groups lacked the resources to send 30 activists to three annual meetings in Washington, D.C., let alone the infrastructure to support the countless conference calls and protocol reviews which this work entailed. However, neither NIH nor the activists devoted sufficient resources to training new activists.
Moreover, the formation of the CCG led to tensions within ACT UP and between ACT UP and the those communities who had just secured representation at the ACTG. Within ACT UP, tensions arose between the original street activism and the more sophisticated, but elitist and demanding, data- and labor-intensive treatment activism. Moreover, it became clear that ACT UP did not and could not represent all HIV-affected communities equally. This became blindingly clear when a group of women activists from ACT UP attempted to prevent ACTG researchers from meeting with the CCG about ACTG 076, the AZT vs. placebo trial for prevention of perinatal transmission. Just when black and Latino community women had obtained representation within the ACTG -- and regarding a trial concerning those communities -- a faction from ACT UP attempted to stifle the exchange of information between researchers and other community activists.
Ultimately the tensions within ACT UP, combined with the burn-out of the street-based activist agenda with which we had started, led the core of ACT UP's T+D Committee to leave and, in January 1992, establish the Treatment Action Group, focused exclusively on research and treatment activism.
III. Maturity & Transition (1992-96)
The Berlin AIDS conference in 1993 represented the low point of the nucleoside era, with the release of the results of the Concorde study and ACTG 155 casting doubt on the old strategy of early intervention with AZT and the new hope of combination therapy. It seemed more important than ever to re-invigorate basic research, and to re-evaluate our efforts to obtain rapid release of new drugs.
These pressures came to a head in the summer of 1994, when Roche made preliminary inquiries at the FDA about whether it could file for Accelerated Approval of saquinavir based on ACTG 229, a 300-patient, six-month study showing marginal activity for the saquinavir hard-gel capsules in 100 AZT-experienced patients who had added ddC and saquinavir to their regimen. We were concerned that this would set a poor precedent for the development of the protease inhibitors as a class. We wrote to FDA requesting a public hearing to discuss how best to develop the protease inhibitors. Our position represented a significant revision of our original approach to Accelerated Approval and we faced a firestorm of community opposition to our call for caution. Eventually Roche agreed to expand the size of its pivotal studies to demonstrate clinical benefit rather than simply surrogate marker activity, and Abbott adopted our standard-of-care control arm for its pivotal ritonavir study, leading to the first-ever full approval based on clinical endpoints since AZT in 1987.
By fall 1995, when saquinavir was approved, it was already clear that the drug was only weakly potent in its hard-gel capsule formulation and that, at least in vitro, it could lead to significant cross-resistance to other more potent protease inhibitors. Luckily, however, its approval was followed in fewer than three months by that of the more potent protease inhibitors ritonavir and indinavir. When the results of ACTG 333 later showed that early saquinavir use had led to significant cross-resistance to indinavir, it became clear that our intervention in 1994 prevented an epidemic of cross-resistance to the other protease inhibitors and, thus, our call for caution in 1994 had been justified.
In the meantime, our re-evaluation of the NIH AIDS research portfolio (which in 1992 consumed $800 million spent by 18 different institutes without any central planning, coordination or evaluation) led to a legislative proposal to strengthen the NIH Office of AIDS Research (OAR) and to provide a coordinated AIDS research effort with a consolidated budget. This led to legislation passed by Congress and signed by President Clinton in 1993. In just five years, we had gone from acts of civil disobedience to acts of Congress. President Clinton provided major increases for AIDS research funding in each of his six years in office. The revitalized OAR increased support for basic research by 40% in its first year, and commissioned a sweeping external review of the NIH portfolio, the so-called "Levine Committee" report, which led to a major course correction at NIH, including reinvigorated prevention and vaccine research efforts.
IV. The Treatment Revolution and Its Consequences (1996-98)
Yet it is clear that HAART is just a temporary way-station on the road to more widely-useable approaches. Eradication of HIV from an infected person by HAART alone appears increasingly unlikely. Between 20-50% of people -- even the treatment-naïve -- appears to fail within two years, and it is unlikely that the majority of patients will respond indefinitely, let alone for a lifetime. Problems of adherence, expense, resistance and toxicity are already apparent and are likely to become more serious over time. To quote my friend and colleague David Barr, "Lots of patients will break through on treatment for the following reasons: 1) Sub-optimal pre-treatment (a large, but finite group); 2) Development of side effects; 3) Inadequate adherence; 4) Misuse of medication due to inadequate education of doctors and patients. The data are really clear as to how poorly patients are able to comply, especially over the long term. Equally dangerous, if not more so, are the data that show how badly doctors implement new treatment practices. We are going to see growing problems with HAART. More and more patients will start breaking through, and eventually HAART won't matter much."
Activists, like scientists, have yet to fully acknowledge or respond to the new challenges posed in the HAART (or, for some, the post-HAART) era. We need better strategies to deal with adherence and resistance. We need simpler regimens and new antiviral targets. To make a difference globally, we will need much cheaper regimens as well.
Finally, international treatment advocacy is reaching a new level of sophistication and maturity. Recent controversies over the ethics of perinatal AZT trials in developing countries remind me of the ACTG 076 controversy of 1991, and of the ethical arrogance displayed by some from ACT UP/New York in telling the affected communities of color how to feel about that study. The UN is developing a pilot treatment access project in four "developing countries": Uganda, Côte d'Ivoire, Vietnam and Chile. This project depends on drastic price reductions by pharmaceutical companies. Some, such as Merck, have a "one world, one price" policy which will effectively bar the use of their drugs among 85% of the world's infected population. Activists from North and South will need to work together to put new pressure on donor nations and NGOs to reduce drug prices worldwide.
Issues of class, literacy, health care infrastructure, civil liberties and economic development will make for very different forms of treatment advocacy around the world. The future of treatment activism lies in broadening and deepening contacts among activists, and among activists, researchers and policymakers, from a variety of settings around the world. Here in Europe you have already pioneered a unique and powerful supranational model, the European AIDS Treatment Group (EATG), which is conducting vital work across the European Union and in adjoining nations. Next year, I trust that you will ask one of the EATG to speak at the opening session of this meeting.
I want to close with a question for which I don't have an answer. Ever since the Glasgow meeting of 1994, this meeting has provided an off-shore marketing and publicity opportunity for drug companies to hype new approaches and new data about drugs which has an enormous and disproportionate impact on community demand. That year, Glaxo released provocative preliminary data about 3TC which created instant worldwide demand for the drug. Of the 35,000 people who received it on Expanded Access, many did not need a new antiretroviral at that time, and all who began it in bi-therapy with AZT developed resistance within weeks. As with saquinavir in the same year, the short-term marketing needs of the sponsor, Glaxo, did not match the long-term public health needs of the community. Avoidable resistance was fomented by inappropriate marketing. The company did it again with its AZT+3TC control arm in its studies of abacavir and amprenavir.
All too many of the studies we will hear about this week are driven by marketing imperatives and not by public health. Sometimes it seems as if the ACTG in our country has become a wholly-owned subsidiary of the pharmaceutical industry. I am not saying that industry is the enemy, for we need them, but we also need answers to questions which it is not always in their interest to answer. When to start antiretroviral therapy is one obvious question which no one has stepped up to the plate to answer. Moreover, as prices for new drugs such as Sustiva and, likely, Ziagen and Agenerase, creep upwards, limited only by what the sponsors hope the developed world market economies can bear, access becomes a more and more distant chimera to people from poor countries. Activists, researchers and drug company staff need to work together to re-balance the research portfolio so that it serves the long-term needs of the maximum number of the world's HIV-infected population, and not just the short-term needs of drug companies for profits, researchers for work, and PWAs for access. The world has changed since the advent of HAART, but our approaches to research, treatment and advocacy have a long way to go. Let's start working on figuring out how to get there. Thank you.