Every year, Keystone Symposia sponsor two parallel conferences on HIV pathogenesis and vaccines. The meetings take place at the Keystone Resort high in the Rocky Mountains, allowing researchers to mix the latest data with a daytime trip to the ski slopes. This year's event offered no earth-shattering new insights, but provided some glimpses of future directions in HIV research. Richard Jeffreys was there to digest and report it all. His full report is up on the TAG web site, www.treatmentactiongroup.org

Many individuals who appear to be failing protease inhibitor-based antiretroviral drug combinations-based on detectable viral load and the presence of drug-resistance mutations-continue to do well both clinically and immunologically. At Keystone, Mike McCune from the Gladstone Institute in San Francisco reviewed efforts to explain this type of discordant response, which poses a challenge to traditional definitions of "treatment failure." In collaboration with clinician Steve Deeks from San Francisco General Hospital, McCune started out by generating a series of hypotheses:

• Protease inhibitor-resistant virus may have reduced replicative capacity compared to wild-type virus.
• Reduced replicative capacity may be associated with reduced T cell activation and turnover.
• Reduced replicative capacity in thymic tissue may spare T cell production by the thymus.
• Reduced replicative capacity may facilitate the generation of stronger HIV-specific CD4 and CD8 T cell responses.

The first hypothesis, suggested initially by test-tube data, was confirmed by Steve Deeks in a treatment interruption trial. In this study, individuals with resistant virus who were stable on a protease inhibitor-containing combination stopped treatment for twelve weeks. Over the first few weeks after interruption resistant virus remained detectable and CD4 T cell counts stayed stable, but then wild-type (non-resistant) HIV rapidly emerged and entirely replaced the resistant virus population. This emergence of wild-type virus was associated with a significant increase in viral load and a decline in CD4 T cell counts.

Moving onto the second hypothesis, McCune measured markers of T cell activation and turnover in three groups of individuals: seventeen untreated, 36 with virological failure (defined as a viral load >2,500 copies/ml for >24 weeks despite being on protease inhibitor-containing treatment for at least eighteen months) and eighteen with virological success (defined as a viral load of <50 copies/ml for >24 weeks after receiving protease inhibitor-containing treatment for at least eighteen months). Comparing expression of the activation markers CD38 and HLA-DR on CD4 T cells between groups, McCune reported that they were significantly reduced in the virological failure group compared to the untreated controls. Activation markers were also significantly lower in the virological success group compared to the virological failure group.

A similar picture emerged when the same activation markers on CD8 T cells were measured. The proliferation marker Ki67 exhibited a somewhat different pattern: in CD4 T cells, expression was significantly higher in untreated individuals compared to those with virological failure or success, but there was no significant difference between the latter two groups.

McCune also measured T cell turnover in seventeen individuals with virological failure using the deuterated glucose technique pioneered by Marc Hellerstein from the University of California at Berkeley. In this case, data were compared to historical controls (both untreated and those with virological success) from a previous study using the same technique. CD4 T cell turnover was significantly reduced in the virological failure cohort compared to untreated individuals, but, as seen with Ki67, the difference between the virological failure and success groups was not significant.

The median CD4+ T cell half-lives for the three groups were 22 days (untreated), 68 days (virologic failure) and 82 days (virologic success). McCune emphasized that in untreated HIV infection, viral load correlates with the degree of T cell activation and turnover, whereas in individuals with protease inhibitor-resistant virus this correlation is lost. He speculated that this situation may be analogous to that of sooty mangabey monkeys, which sustain high SIV viral loads but manifest little evidence of T cell activation and no disease progression.

Addressing the third hypothesis, McCune noted that direct viral effects on thymic production are tough to prove in people. The thymus is not easily sampled, and direct measures of T cell output from this organ are still lacking. The strongest support for the idea that protease inhibitor-resistant virus may be easier on the thymus comes from a study using a culture system.

Both protease inhibitor-resistant and wild-type HIV isolates were taken from participants in Steve Deeks' treatment interruption study. The ability of these isolates to replicate in thymic organ culture was then compared and, as predicted, protease inhibitor-resistant viruses reproduced poorly compared to their wild-type counterparts.

McCune was able to produce a larger body of data in support of his fourth hypothesis. The Gladstone team employed intracellular cytokine staining to measure the magnitude of the HIV-specific CD4 and CD8 T cell response (this technique captures HIV-specific T cells based on their ability to produce the cytokine interferon-gamma when stimulated with viral antigens).

This analysis included 28 untreated individuals, 66 experiencing virological failure on protease inhibitor-based treatment and 87 categorized as a virological success on protease inhibitor-based treatment. McCune reported that the total gag-specific CD4 T cell response was significantly higher in the virological failure group than either the untreated or virological success groups. There was a significant correlation between gag-specific CD4 and CD8 T cell responses in all groups.

McCune highlighted the fact that the magnitude of the HIV-specific CD8 T cell response correlated with maintenance of a stable viral load over four months of follow-up. Looking at the magnitude of the virus-specific T cell response and viral load from a single timepoint, McCune found that the data fitted a "bell-shaped curve": individuals with viral loads less than 1,500 copies showed a positive correlation between the size of the gag-specific T cell response and viral load, whereas those above the 1,500 copy cut-off exhibited a negative correlation.

McCune concluded his presentation with the provocative "Goldilocks Hypothesis:" that in some cases, the persistent presence of protease inhibitor-resistant virus may be beneficial in terms of preventing immune activation, sparing thymic output and fostering functional anti-HIV CD4 and CD8 responses. This appears to account for the "disconnect" seen in the Deeks cohort and other virologic "failures" who maintain or increase CD4 cell counts and do not progress clinically despite continually measurable viral load. Understanding the underlying cause of this change in viral pathogenicity could potentially shed light on the long-standing mysteries of the benign SIV infections seen in sooty mangabey and African green monkeys and thus open up new avenues of HIV research. ¤

Survey the leadership of major AIDS advocacy organizations, scan the mastheads of treatment publications, and chances are you'll come across name after name of T+D and TAG alumni/ae. Peppered throughout the ranks of medical residency programs, AIDS service organizations, HIV vaccine groups and research labs across the land are the young men and women who were first initiated into the heady mix of science, social policy and protest through the living room training ground of 1990s treatment activism.

And as these same pioneers, many of them surprised to find themselves still among the living, slip gracefully into their (often staid) middle years, they leave in their stead somewhat of a dwindling pool of fresh recruits. The activist M.A.S.H. units have long ago rolled up their tents and left town. Activist apprenticeships are now something of an anachronism, if not extinct entirely. The NATAFs and ATACs and CCGs promise to institutionalize the identification and training of ambitious new protégé(e)s. But will they prove sufficient, in this post-millennial activist age, to ensure a steady maturation of quick-witted, crackerjack idealists? David Barr surveys the landscape, past and present, to ponder what we've given up to get where we are today.

One of the things that made ACT UP so special was that it was made up of ordinary people who wanted to make a difference in the struggle against the neglect of the AIDS crisis. Many of us had AIDS ourselves, and our activism provided us with a way to fight back and find strength. Particularly for those of us who got involved with treatment and research activism, the work was a constant and challenging learning process. Most of us had little to no background in science or medicine. We taught ourselves and each other about how drugs are developed, how clinical research is conducted, how to understand the study results.

As new people would come into the fold, they would learn from those who had already developed some understanding. We had teach-ins, trainings, and countless meetings where issue after issue would be discussed and debated. People would volunteer for projects: become "drug buddies" following the research progress of each new drug, devising a plan to move the research faster or make it better. The new people learned from the more experienced people. That was how the model of the treatment activist was created.

When we split off from ACT UP in 1991 to form TAG, the structure of the new organization did not really differ from that of ACT UP's Treatment & Data (T+D) Committee. We were still an all-volunteer group that conducted our business through our weekly Tuesday night membership meetings-held initially at Charlie Franchino's Downing Street apartment, then later at Marvin Shulman's Fifth Avenue loft in the Flatiron District. The priorities were set by a vote of the members. New people learned and came up through the ranks by attending those meetings, joining committees, volunteering for projects and being mentored by others. This not only allowed newcomers to find a place for themselves and, therefore, fulfill their personal need for activism. It also meant that TAG had an institutional mechanism for bringing in more and more people to do the work, expand the organization's agenda, and replace those people who needed to stop working when their illness would finally overwhelm them. This structure also provided us with a sense of community and security that was as important as the work itself-if not more so.

Those TAG meetings produced some monumental work, but the dinners that often followed them were just as important to me. The camaraderie we felt provided solace and support. Yes, it was often a competitive environment, but the friendships created through TAG in those years were strong and, despite the competition and constant bickering, deep and fulfilling.

As time went on, however, the work became more complex, more specialized. As activists became more of a part of the research process, the need for full-time workers grew. A small group of people became responsible for the most of the work. These people needed financial support from the organization in order to do this work full-time. Also, because the TAG leadership was becoming responsible for the bulk of the work, they needed the authority to make decisions and set priorities for the group. Administrative and fundraising needs also grew. The success of the organization required a change in structure.

TAG moved to a more traditional model of an advocacy organization-one governed by a Board of Directors and led by a paid staff. This change-the "professionalization" of the treatment activist-was essential. Without this change, the next phase of the work would not have been accomplished. That work, including the pivotal report on the AIDS research effort at the NIH and the passage of the NIH Revitalization Act, required full-time staff who received the support-financial and administrative-that only a Board/staff structure could provide. The value of that structural shift is seen in the continued success of TAG and other treatment advocacy organizations like it.

But that change also came at a cost. What was sacrificed was the membership. TAG was no longer a place where newcomers could learn how to become treatment activists. It was no longer a place where you could learn by volunteering for a project and work your way up through the ranks into a position of leadership. Those opportunities became few and far between. Also lost was the sense of support and community that the membership model provided. Of those who have survived, so many have drifted away because they no longer had a role to play.

The changes in structure of TAG were essential. TAG would not have continued to grow and be as effective as it became without them, but the costs were great. The membership knew the change was needed and voted to approve the shift to a Board/staff model. It was a difficult and painful discussion. Membership and committee meetings continued, but gradually, their value diminished. The real work was now taking place in between the meetings. Rather than strategy sessions, the meetings became reports. As people no longer felt their presence was helping to produce change, they stopped coming.

One negative result of this change was-and is-the difficulty of building new leadership. Another result was an increasing elitism among the small group of advocates who were now employed to attend meetings with government and industry, write reports, and implement strategies to affect change. Indeed, the initial process of coming up "through the ranks" was never successful at ensuring that all communities affected by HIV could participate in the work. Research advocacy is a luxurious area of activism. Activists from poorer communities often have to work on health care access, housing needs, and other priorities before they can turn their attention to the rarified world of clinical research.

There is an urgent need to create a more formal infrastructure to teach, train and promote a diverse group of activists to engage in the research and drug development process. Otherwise, we risk losing the gains we have made in the goal of creating a permanent voice for patients in the research and drug development process. There are some good attempts to do this: the National Institute for Allergy and Infectious Disease (NIAID) Community Constituency Groups have helped to serve this function; and the African American HIV Policy Institute has developed an ambitious treatment advocacy training program. Most recently, the formation of the AIDS Treatment Advocacy Coalition (ATAC) promises to provide an excellent training ground for new advocates as well as an infrastructure for greater inclusion.

In the 1980s and '90s, people with AIDS created a new role for patients in the research and drug development process. Our argument was always that including people living with HIV in this process would not only better meet our needs as consumers, it would make for better science. I believe that argument has been proven true over and over again. In order to continue that effort, we cannot rely on chance volunteerism. We have to provide education, training, financial support, and infrastructure. The importance of our work deserves that. ¤

Date: 3/29/2002 11:57:39 PM Eastern Standard Time
From: rastern@racsa.co.cr ("Richard Stern")
Reply-to: healthgap@CritPath.Org
Sent from the Internet (Details)

It was a breath of fresh air to read Mark's piece ("Comments on Problems in the Current Draft World Health Organization (WHO) Antiretroviral Treatment Guidelines for Resource Limited Settings," March 2002).I have been saying for a long time that a big piece of this puzzle is the failure of UNAIDS/WHO/(PAHO in Latin America, Pan American Health Organization) to provide an effective and coherent response to issues relating to access to treatment, but I have felt that this was an issue that others didn't pay too much attention to.

Although it sounds paradoxical, I would rather see the Global Fund give $50 million to WHO/UNAIDS so they can scale up to provide an international infrastructure, than to to give the money to country programs that will find a way to waste it (with the exception of funds that go directly to the purchase of antiretrovirals that will be delivered directly to people, under adequate medical supervision). Of course, providing additional funding for WHO/UNAIDS implies holding them accountable for quality outcome in terms of their reports, programs, and interventions. Mark has made many good recommendations.

Ironically, in most countries in Latin America that I have knowledge of, the Global Fund application process was supported by UNAIDS/WHO staffers who had the technical ability to help a Country Coordinating Mechanism write an intelligent application. But who is going to help the country carry out programs once they are approved? Understaffed national AIDS program staff are used to working with budgets [with] numbers in four figures (like $8,000 a year)! How are they suddenly going to "scale up" intelligently to carry out a program that provides a million dollars or more?

The UNAIDS "Accelerated Access" program, which can be effective where it has been carried out, muddles along like a lost turtle. Latin America has the infrastructure and some economic resources to take advantage of this program, but only in Trinidad, Chile, and now Honduras, has the program been carried out. The much praised Peter Piot has not asked for the resources he needs to do a good job with UNAIDS. By now, it's apparent that his well-intended rhetoric is not getting the job done, but he is strangely silent on the treatment access issue and [on] providing recommendations as to what it takes to create a really meaningful response.

UNGASS [a Special Session of the United Nations General Assembly-on HIV/AIDS] in most parts of the world is just lip service. The life of the average person [infected with HIV] has not changed at all. Those who are alive in 2002 are not going to benefit from UNGASS's (unenforceable) target dates of 2005 or 2010. The Global Fund remains an open question, as far as funding for treatment access and purchase of generics is concerned. Basic issues such as getting accurate price information to health ministries, getting generic products registered, (plus all the other issues that Mark raises) and getting an adequate assessment of who needs what kind of care in what country, could be addressed by international agencies which could provide quality level consultation to governments.

On a small scale, Médecins sans Frontières (MSF) has put together all the ingredients that it takes to deliver antiretroviral medications in resource poor settings with, of course, very small numbers of patients in selected programs. If MSF staff could just replace WHO staff, we would already be light years ahead. I would challenge this list-serv to devote some attention to trying to figure out if there are effective advocacy actions that could be taken in support of the issues that Mark is raising. This is a tricky issue, but a few demonstrations outside of WHO offices in Washington might not be a bad idea.

Richard Stern, Director
Agua Buena Human Rights Association
PO Box 366-2200
Coronado, Costa Rica
(506) 234-2411
www.aguabuena.org