Donald I. Abrams, MD, Editor

Next Meeting

The next meeting of the Community Consortium will be held on Wednesday, June 21, 2000 at 6:00 p.m. at the Davies Campus of the California Pacific Medical Center in the auditorium on B Level at Castro and Duboce Streets in San Francisco. Refreshments will be served and free parking is available in the lot. Following brief announcements, the featured presentation for AIDS Clinical Grand Rounds will be "Sexual Dysfunction in HIV Infection" by Charles Moser, Ph.D., M.D.

Dr. Moser is an internist with a private practice in sexual medicine and a professor of sexology at the Institute for Advanced Study of Human Sexuality in San Francisco. He has published extensively on issues relevant to sexual minorities and most recently has been interested in sexual dysfunction in patients with HIV infection. This is clearly a topic of importance and relevance to all of us caring for patients infected by HIV. It promises to be a most informative and provocative session. Please make every effort to attend.

While you're marking your calendar, or more likely inputting into your Palm Pilot, please also note that the July 19 Consortium meeting will feature an update from the 13th World AIDS Conference to be held in Durban, South Africa. As usual, we will have a summer break and delete the August meeting, with resumption of AIDS Clinical Grand Rounds in September.

This program is sponsored by the University of California at San Francisco (UCSF) School of Medicine. UCSF is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The office of CME designates this continuing medical education activity on an hour-for-hour basis in Category I of the Physicians Recognition Award of the American Medical Association and the Certificate Program of the California Medical Association. In addition, nurses may obtain CEU credits but must keep a record of their own attendance. 1 hour credit is available for this meeting.

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Community Consortium 15th Anniversary Celebration

A special Gala 15th Anniversary celebration of the Community Consortium's founding was celebrated on May 24, 2000 at the San Francisco Maritime Museum. Consortium members old and new and Community Consortium staff enjoyed a fabulous repast with a glorious vista of the bay. We are all most appreciative of the support from Agouron, Glaxo-Wellcome, Merck, Roxane and UNIMED, which made the evening possible. Donald Abrams, M.D., Community Consortium Chair, took the opportunity to review highlights of the Consortium's 15 year history and outline the key landmarks and the evolution of community-based clinical trials in HIV.

The first meeting of what has subsequently become the Community Consortium was held at the San Francisco Medical Society in March 1985. At that time, Mayor Dianne Feinstein requested Paul Volberding, M.D., Chief of the AIDS Program at San Francisco General Hospital, to assemble a group of community physicians to establish an ongoing dialogue. Noting at the first meeting that most of the community physicians were members of Bay Area Physicians for Human Rights (BAPHR) and therefore friends of Donald Abrams, Paul suggested that Donald take over the role of establishing a communication network with the community physicians. One of the initial roles of the "County Community Consortium" (CCC) was to institute a monthly educational forum. It was recognized that the investigators at the "County" (San Francisco General Hospital), being academic clinicians, had more opportunity to travel to the increasing number of AIDS conferences and meetings that were held, often held on the east coast. It was hoped that monthly meetings of the group would serve as a way to exchange information and keep the community physicians updated on news coming from these specialty conferences.

The AIDS Program at San Francisco General Hospital in 1985 was also embarking on a number of clinical trials, even before the establishment of the NIH-funded ACTG network. Another early function of CCC meetings was to inform providers in the community about clinical trials that were being conducted at San Francisco General that may be of interest to their patients. There was also a concern at San Francisco General Hospital not to become a facility where the medical service was comprised entirely of people with AIDS diagnoses. Therefore, another early goal of the CCC was to allow clinicians at the County to refer patients requiring hospitalization to private providers and their facilities should more than 30 patients be hospitalized at SFGH at any given time. Ah! Remember the days of pre-managed care medicine!

Shortly after establishing a routine of monthly meetings, it became evident that the resources of the CCC were quite valuable -- particularly the number of patients being seen by AIDS care providers in the community, which was quite substantial. After hearing a litany of clinical trials available at the San Francisco General Hospital AIDS Program in one meeting, Jim Campbell, M.D. stated "You know, Donald, we can do clinical trials, too, right in our own practices." Tantalized by this possibility, the group turned its attention to establishing its first community-based clinical trial.

The first task was to find a clinical question that was relevant and could be answered outside of the confines of a tertiary care research institution. Recall that in late 1985 and early 1996, Pneumocystis carinii pneumonia was the biggest killer of patients with AIDS. At that time, secondary prophylaxis following an initial episode of PCP was not widely practiced. Therefore, after a number of monthly meetings where various trial designs were discussed, we decided to launch a 4-arm trial investigating daily dapsone, weekly fansidar, monthly intramuscular pendamidine, or no treatment in patients who had a prior episode of PCP. A protocol was written and approved by the University of California San Francisco Institutional Review Board. A randomization sequence was generated and Zach Weingart became the first Consortium staff member, essentially loaned from the AIDS Program, to give out the randomization assignments when providers called in with eligible patients. The trial was launched in July 1986. Ultimately, 20 patients were randomized. In these early days of community-based clinical trials where not everyone had clinical equipoise prior to randomization, stories abounded of physicians calling and receiving a treatment assignment for their eligible patient and then saying "Oh, no, my patient decided that they don't want to be in the trial!" The study was terminated prematurely, following the release of AZT in September of 1996. At that time, it was mandated that patients receiving AZT should not be taking any "unnecessary" oral medications as that may interfere with the antiretroviral treatment. As PCP prophylaxis was not yet standard of care or proven effective, patients with a history of PCP chose to be treated with AZT and lost interest in participating in prophylaxis trials. Community providers sent their AZT registration and follow-up forms to Donald Abrams in hopes that the CCC could generate their own database of patients taking the first approved antiretroviral. However, a lack of data entry and data analysis staff hampered this project significantly.

In early 1987, a number of events transpired. Inhaled pentamidine had been demonstrated by Bruce Montgomery, M.D., and colleagues at San Francisco General Hospital to be an effective treatment for patients with documented PCP. Many patients in the Bay Area who had a prior history of PCP were now receiving inhaled pentamidine as prophylaxis. However, there were no data that indicated that this intervention was effective for preventing subsequent episodes of PCP. At this time, the NIH had also put out a request for applications to expand their 19 site AIDS Treatment and Evaluation Units (ATEUs). UCSF/SFGH already had ATEU status. However, Donald Abrams felt that the Community Consortium, as a community-based clinical trial group, should apply for NIH funding. The application required that the group describe their infra-structure for conducting clinical trials as well as propose a clinical trial to perform. The Community Consortium application was submitted with an accompanying clinical trial to investigate three different dosages of inhaled pentamidine as prophylaxis for PCP in patients who had a prior episode of PCP. Community physicians were eager to begin enrolling patients on the clinical trial. A preliminary leak suggested that the NIH Review Group had favorably reviewed the Consortium's application to become part of the expanded ATEUs (now known as the ACTG). In truth, when the evaluation was received, the Consortium did not receive a score within the fundable range. However, enrollment onto the aerosolized pentamidine trial had begun and 200 patients had been randomized by the time that we were notified that funds would not be forthcoming.

This created quite a dilemma. Lyphomed, the pharmaceutical manufacturer of pentamidine, was not interested in providing financial support for the clinical trial because they were not involved in its design. Ultimately, however, Gifford Leoung, M.D. headed up the PCP prophylaxis team, which did finally receive funding from Lyphomed to complete the Consortium's landmark aerosolized pentamidine study. The trial demonstrated a dose response for efficacy of inhaled pentamidine in preventing second episodes of PCP, which ultimately led to a lead article in the New England Journal of Medicine as well as FDA approval of aerosolized pentamidine as the first prophylaxis for an AIDS-related opportunistic infection.

Despite the success with the aerosolized pentamidine study, the Consortium was essentially without funds. To assist with what was viewed as a nascent, but promising, community based clinical trials program, both the National Institutes of Health and the American Foundation for AIDS Research (AmFAR) provided the Consortium with seed money in 1988 that enabled the Consortium to hire a project director. Myrna Cozens was brought aboard as the first full-time Consortium staff person. Myrna's original charge was to spend time with community providers, to learn how they kept records and to devise a set of case report forms that could be used as a generic data collection tool for con-ducting future community based clinical trials. Through Myrna's efforts, the Consortium developed a six-page data collection tool, one page of which served as the chart notes for most of the early Consortium clinicians and investigators. Tom Mitchell, M.P.H., replaced Myrna as the project director in September 1988 and Carroll Child, R.N., joined the staff in November as the first clinical research nurse devoted to Community Consortium studies.

Equipped with data case report forms, the Consortium launched two database projects. These were observational studies where information was collected from patients being followed in primary providers' practices using the standard set of forms. The AZT Database was launched to collect information on all patients who were being treated with the nucleoside analog monotherapy prior to its expanded indication for everyone with < 500/mm3 CD4 cells. It was widely recognized that providers in the Bay Area were prescribing AZT for a wider subset of patients than the initial label indications. We hoped that the AZT Database would generate information on how a patient did with therapy. At the same time, it was also clear that many individuals were experimenting with complementary and alternative interventions. The Consortium launched an Alternative Therapies Database, which was ultimately funded by the AmFAR to collect observational information on clinical and laboratory outcomes in patients self-medicating with complementary and alternative therapies.

In addition to these two observational databases, the Consortium also launched two intervention trials in early 1989. Martin Mass, M.D. had suggested that since we had demonstrated the efficacy of PCP prophylaxis, we should now turn to the second most devastating AIDS-related opportunistic infection -- Mycobacterium avium Complex -- and develop prophylaxis for this debilitating infection. He proposed an investigation of clofazimine. The Food and Drug Administration was particularly interested in evaluating prophylaxes for other AIDS opportunistic infections, and it was the Consortium that took this early lead. In addition, Robert Bolan, M.D., spearheaded a placebo-controlled trial of monthly vitamin B12 injections for treatment of AZT-induced anemia, a common problem in the early days when the dosage of AZT was significantly more than currently utilized. Although neither of these trials ultimately produced positive results, they clearly demonstrated that Community Consortium providers could conduct clinical trials based in their own office practices and clinics.

San Francisco has always been rather unique in its response to the AIDS epidemic. Physicians in the San Francisco Bay Area came together in an unprecedented show of cooperation and collaboration to combat AIDS. Although there was interest in duplicating the Community Consortium model in New York City, lack of physician interest in the early days led to a different model of community based clinical trials. Michael Callen of the PWA Coalition established the Community Research Initiative with his private practitioner, Joseph Sonnabend, M.D. The Community Research Initiative (CRI) was instrumental in conducting some safety parameters in patients receiving inhaled pentamidine in a study that ran concurrent to the Community Consortium's PCP prophylaxis trial in San Francisco. The CRI got some public attention following the testimony given to Reagan's Watkins Commission on AIDS. Community activists and PWA's in San Francisco decided that they were interested in establishing a community based clinical trial group modeled after the New York CRI. The Community Research Alliance (CRA) was established as an affiliate of Project Inform in San Francisco. A bit of friction developed between CRA and the CCC. The Consortium providers felt that they were just as representative of the "community" as the CRA founders. In fact, not only were many Community Consortium providers members of the impacted community, a number were also living with HIV infection. These conflicts led to the establishment of an organizational task force of the Consortium, which established membership criteria and established a number of advisory committees. An Executive Advisory Board was created to assist Donald Abrams in making decisions for the group regarding the ultimate direction of the Community Consortium's education, research and advocacy activities. A Scientific Advisory Committee was organized to review proposed research initiatives. In 1989, the Consortium established a Community Advisory Forum, composed of people living with HIV and community activists. This group was established to provide a direct communication link with people with HIV and their advocates, in the hopes that they could provide input into proposed clinical trials. We are proud that our initial Community Advisory Forum was one of the first community advisory groups for an HIV research program, which has been replicated across the country and, in fact, is now mandated for all government-funded groups conducting HIV clinical trials.

In 1989, the CRI and the Community Consortium put on a joint meeting, funded by AmFAR, to discuss the concepts, methodologies and successes of community based clinical trials in HIV. Chaired by Michael Callen and Donald Abrams, the meeting brought together government officials, community members, private funders, and community clinicians in what was an historic coming together. From this meeting emerged the AmFAR Community Based Clinical Trials Network (CBCTN) and the forerunners of the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

In October 1989, the Community Consortium was awarded one of the initial contracts to participate in the NIH-funded community based clinical trials group. We are proud to say that the Community Consortium served as a model for the organization of the CPCRA, as well as the AmFAR CBCTN. Over the ensuing ten years of participation in CPCRA clinical trials, the Consortium has enrolled the largest number of subjects. The CPCRA has made major contributions in the arena of antiretroviral treatment and prophylaxis of opportunistic infections. Currently, the research agenda is focused on answering strategic questions in the use of antiretroviral therapies. Over the years, the Consortium has provided an incredible amount of leadership in CPCRA organizational governance. Carol Brosgart, M.D., Carroll Child, R.N., Becky Perelli, R.N., Clare Rappaport and Donald Abrams have all had significant leadership responsibilities in the CPCRA network.

Despite the fact that a significant amount of Consortium support comes from the CPCRA funding, the Consortium enrollment into CPCRA protocols has been disappointing over the past few years. There are a number of current challenges that make providers less eager to enroll patients into CPCRA strategic trials. In the early days of AIDS clinical research, many patients enrolled in clinical trials to access treatments that were not available from other sources. Today, with 14 approved antiretroviral agents and others in expanded access, there are many treatment options. Patients no longer need to participate in a clinical trial to gain access to a new therapy. Patients are also doing well on their current regimens and are less desperate to enroll in a trial just to access a new treatment. In fact, the current menu of CPCRA studies does not offer new treatments. These strategic, long-term trials are designed to answer questions regarding how to best use the agents that are currently available on the market. Thus, there is little incentive to participate in CPCRA studies. Patients receive a token reimbursement for travel. Providers received variable reimbursements in the past but mainly benefit from having contact with their Community Consortium clinical research nurse. It is understandable that the constraints of managed care make it difficult for providers to fully engage in explaining the Consortium's strategic trials to patients within the confines of a limited patient visit time slot. As well, many Consortium clinician-investigators find it more rewarding to participate in industry-sponsored pharmaceutical studies, which often compete for the same patients who would be eligible for CPCRA strategic trials. Finally, although definitive data are not available to answer many of the long-term strategic questions, many providers in the Bay Area are expert and long-experienced in their care of patients and often do not have equipoise with regards to the clinical question under investigation. They tend to have already determined in their own mind which strategy under investigation is better for any particular patient and are not willing to leave the treatment assignment to randomization.

Despite the Consortium's current lull in enrollments onto CPCRA clinical trials, we are continuing to maintain our leadership role in the community-based clinical trials field. We have diversified beyond CPCRA studies to investigate a number of complementary and alternative medicine interventions. In collaboration with Misha Cohen, O.M.D., LAc, we have investigated Traditional Chinese Medicine interventions for treatment of HIV-related symptoms. The results of the Consortium's collaborative trial of Source Qi in patients with cryptosporidium negative diarrhea is being presented at the 13th World AIDS Conference in Durban next month and will be published in an upcoming issue of Andrew Weil's new journal, Integrative Medicine. Driven by widespread use of smoked marijuana in the community, the Consortium recently completed the study on the short-term effects of cannabinoids in patients with HIV infection. An poster describing the preliminary virologic results of this trial will also be presented as a late breaker to the Durban conference. In view of the continued use of marijuana in the community, the Consortium is now investigating future clinical trials to evaluate the possible therapeutic potential of marijuana in patients with HAART-related nausea as well as painful peripheral neuropathy. We are also about to launch three studies funded by the National Center for Complementary and Alternative Medicine. These include a trial of DHEA in patients with maximally suppressed HIV RNA levels and two collaborative trials being conducted with investigators seeking Consortium referrals for enrollment -- Morris Schambelan's creatine trial and Elizabeth Targ's study of distant healing.

In addition to the tremendous resource that our Community Consortium patients represent as a source of clinical trial participants, Community Consortium physicians have also been the subject of studies over the past decade. Lee Slome, Ph.D., received her doctorate on the basis of a study of Community Consortium physicians' attitudes towards physician-assisted suicide that was published in 1989. A follow-up study published in 1997 revealed that 53 percent of respondents had assisted actual patients in the past. Two other physician surveys spearheaded by Carol Brosgart, M.D., grew into national projects investigating insurance reimbursement for off-label drug products and physician treatment practices and how they relate to treatment guidelines. These studies have served to impact legislation assuring reimbursement for off-label use of drug as well as defining adherence (or lack thereof) to treatment guidelines.

A meeting was held in Washington, D.C. in January 2000 to address what are felt to be some of the most pressing issues today in use of antiretroviral agents. The two major questions that remain unanswered are when to start antiretroviral therapy and when/how to change. The Consortium takes pride in the fact that we attempted to deal with the "when to start" question head-on back in 1992. Working with star-quality biostaticians, Sir Richard Peto and Paul Meier, we created ComPACT1, which was a pilot large simple trial designed to help determine when antiretroviral-naïve patients should start anti-HIV therapy. The pilot was launched in San Francisco and subsequently expanded to Washington, D.C., Los Angeles and New York. The innovative enrollment and follow-up methods that were being tested in the pilot study worked well, but only 86 subjects were enrolled at the end of 18 months, and the study was terminated. Fifty-six of these were enrolled by Robert Scott, M.D., in Oakland, who continues today to be one of the champion enrollers in Community Consortium and CPCRA clinical trials. The Consortium experience with ComPACT1 is helping to define how to revisit this still burning clinical question eight years later. The CPCRA is currently in the process of devising a large simple trial to investigate the "when/how to change antiretroviral therapy" question. More details will be forthcoming.

Donald ended the discussion of community based clinical trials, and particularly the Community Consortium's contributions in this arena by speculating on where we may be going as a group over the next 15 years. Having established an infrastructure for conducting community based research, it would be exciting to expand beyond HIV itself into other related areas. Taking in account the resource of the patient population seen in providers' practices, other issues of gay men's health could also be investigated. Cancer epidemiology, for example, may be worth pursuing. We are also interested in the possibility of more practice-based research as opposed to randomized interventions.

As the sun set over the Pacific on a lovely evening celebrating the Consortium's first 15 years of accomplishment, Donald Abrams thanked all of the current and former Community Consortium staff, Executive Advisory, Scientific Advisory, and Community Advisory Board members, and all of the Consortium clinician investigators for the successes that have been shared. Acknowledging the losses of patients, friends, lovers and colleagues over the past 15 years (visit the Community Consortium bench in the AIDS Memorial Grove), Donald reminded all present that, as a group, we still have much to be proud of and much to celebrate . . .

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Committee Reports

Executive Advisory Board

The next meeting of the Community Consortium Executive Advisory Board will be held on Wednesday, July 26, 2000 at 7:30 am in the Community Consortium Conference Room.

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