September 2000

Next Meeting: September 20, 2000

Durban Update

Committee Reports
Executive Advisory Board
Scientific Advisory Committee and Community Advisory Board

Consortium Clinical Trials
IL-2 -- Preliminary Results
Multi-drug Reistant HIV (MDR)
FIRST
Metabolic Study
Adherence Study
Long-Term Monitoring (LTM)

Thought you'd like to know . . .
Abacavir Safety Alert

Donald I. Abrams, MD, Editor

Next Meeting

The next meeting of the Community Consortium will be held on Wednesday, September 20, 2000 at 6:00 p.m. at the Davies Campus of the California Pacific Medical Center in the Auditorium, located on the B Level of the hospital at Castro and Duboce Streets in San Francisco. Refreshments will be served and free parking is available in the lot. This September session will mark the 13th anniversary of Community Consortium's AIDS Clinical Grand Rounds. In a tribute to incredible continuity, the session will feature "Unusual Case Presentations" presented by Stephen Follansbee, MD, Director of HIV Services at San Francisco Kaiser Permanente Medical Center. Steve has been dazzling Consortium clinicians for the past 13 years with informative and state-of-the-art case presentations.

Thirteen years ago, the first AIDS Clinical Grand Rounds informed Consortium clinicians that cryptococcal antigen assays could be performed on blood as well as CSF. Each year since, Steve has presented timely and challenging cases that continue to push the envelope of HIV care. This promises to be a most informative and interesting session. Come and greet your Consortium colleagues after the brief summer break.

Mark your calendars now for the remainder of the Consortium AIDS Clinical Grand Rounds for the year 2000. On October 18, Michelle Roland, MD, from the UCSF Positive Health Program at San Francisco General Hospital, will host a session entitled "Update on the Migden HIV Transplant Initiative at UCSF and Beyond." On November 15, Elisabeth Targ, MD, from the Complementary Medicine Research Institute at California Pacific Medical Center, will discuss her NIH-funded studies involving distant healing and prayer in patients with HIV.

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. One hour of credit is available for this meeting.

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Durban Update

The July 8 Clinical Grand Rounds featured a presentation by Donald I. Abrams, MD, summarizing his impressions of the 13th World AIDS Conference held in Durban, South Africa, July 9 - 14. Please allow me the indulgence of using the first person in discussing of these impressions.

Like many others, I was ambivalent as to whether I wanted to attend the conference in Durban at all. The length of the flight, the Mbeki controversy and the purported paucity of science that was expected were all significant deterrents. However, a number of friends and colleagues said that it would not be viewed in the spirit of solidarity with developing nations to be absent from the meeting. In addition, our marijuana study had been completed at the end of May and a late-breaker abstract had been accepted for a poster presentation, which provided another impetus to attend.

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!

Arriving in Durban, I was struck by the similarities of the city to Miami and its beach. Situated on the coast of the Indian Ocean, Durban is a resort area for residents of South Africa. The buildings are modern. The hotel at which I stayed, essentially in the International Conference Center, was a first rate facility comparable to any conference hotel I have experienced elsewhere. The locals were friendly, helpful and proud. Ultimately, the registration at the meeting was estimated to be 13,000 participants from around the world. There clearly was greater attendance by African delegates than has been seen at prior AIDS meetings.

On the day of the meeting's evening opening session, I had the opportunity to take a brief one-day safari trip to a game park 350 km northeast of Durban. This was an incredible experience that allowed me to see more of the beautiful South African countryside and appreciate a bit more that I had traveled thousands of miles from home than I would have if I had remained in urban Durban the whole trip. We made it back in time from the safari to attend the opening ceremony at the cricket field. This was one of the most entertaining, moving, and well-orchestrated opening ceremonies that I have ever experienced. Of note, all of those in attendance were handed placards that said "ACT UP" on them to raise en masse on cue during the pre-televised section of the opening ceremony festivities. The opening ceremony was broadcast live on South African television, including the speech by President Mbeki. Although the president had stirred up quite a bit of controversy prior to the meeting by aligning himself, in part, with the AIDS denialists who believe that HIV is not the cause of the disease. Once hearing his remarks, it became clear that one of his main points is that HIV/AIDS is certainly a problem in his country, but it is not the main threat to the infrastructure. In fact, poverty, as he pointed out, is their main enemy and the spread of HIV can best be curtailed by impacting on poverty, illiteracy and crime, which run rampant throughout the nation. Although I expected a continuous presence of AIDS denialists at this meeting, aside from two people holding a sign after the opening ceremony, I saw no further evidence of this misdirected school of thought.

I must confess that I skipped the opening plenary session at the meeting. But I had a great excuse. Instead I visited St. Mary's Hospital in Marionhill, a subdivision of Durban, approximately 15 minutes from the conference center. This hospital is part of the public health network of the city. If they could afford to test people, 60 - 70 percent of the adults in the facility would be found to be HIV-positive, including 60 percent of the pregnant women. The facility was clean and well-organized, with multi-bedded wards filled with people with and without obvious stigmata of HIV/AIDS. One patient was pointed out to me who had been hospitalized with cryptococcal meningitis. I was informed that normally lumbar punctures are performed in the emergency room. If the spinal fluid shows yeast, the patient is sent home to die, as there is no availability of antifungal medications, let alone antiretroviral therapies. The particular patient in the hospital with cryptococcal meningitis had been put on a morphine drip to offer her "freedom from her pain." I was informed by the hospital administrator that when they come in for morning report and hear that four people have died the night before, they have a sense of rejoicing as these people are now released from their pain. To me, the whole situation was very reminiscent of 1983, when all we could do was attempt to treat the opportunistic infections but more often than not, we were involved in palliative and hospice care for hospitalized patients.

Following the visit to St. Mary's Hospital, I had the opportunity to meet with a traditional Zulu healer in her "rondoval" (thatched roof round house). St. Mary's Hospital runs an outreach program for traditional Zulu healers, teaching them basics about HIV/AIDS and how best to avoid infection and transmission. For example, some traditional Zulu healers use razor blades to slit patients' skin and insert herbal remedies. St. Mary's Hospital community outreach program advises the healers not to re-use razor blades. Similarly, trainers have cautioned against the use of stringent enemas for patients with HIV-related diarrheal illnesses. One conundrum is that patients can only be referred to a hospital by first being seen in a district health clinic. For those patients who choose to visit the traditional Zulu healer first, when they are noted to be ill and in need of hospitalization, the healer often refers them to their district hospital. On arrival at the hospital, patients are told that they must first be seen at the district health center. The district health center confirms the Zulu healer's impression that the patient needs to be hospitalized and refers them back to the hospital. This becomes very frustrating for the patient. In addition, the expense of transportation can often be more than trivial for patients needing to visit so many providers before getting the appropriate care.

Ultimately, I did spend some time attending the conference. The meeting was well-organized, although there did appear to be too many concurrent sessions ongoing at any given time. For example, on July 11 in the early afternoon, sessions being held at the same time covered the following topics: antiretroviral therapy in developing countries; mother-to-child transmission; expanding African response; intellectual property laws; adherence to antiretroviral therapy; sexual behavior among students; sex workers and HIV infection; stigma; the role of gender in disease progression; new antivirals; HIV virus diversity; biological determinants of transmission; and natural history of HIV in developing nations. As one can see, there was a definite emphasis on social, economic and geo-political issues.

Although we were somewhat disappointed initially that the marijuana abstract was selected only as a late-breaker poster, reviewing the content of the 29 oral late-breakers presented in Durban provides additional insight into the focus of the meeting. Of these 29 oral late-breaker presentations, 12 were African and 10 emanated from other developing nations. Nine of the late-breakers focused on mother-to-child transmission. Three focused on therapies that were not antiretroviral; three involved treatment interruptions. There were only four trials from the United States that were presented as oral late-breakers. Two of these were retrospective studies. Among the two randomized clinical trials presented, a total of 11 patients were involved.

If one had to choose the dominant theme of this first conference on AIDS held on the African continent, the theme would have to be Africa itself. Some of the statistics emanating from the meeting were truly staggering. The financial realities of the current situation are such that each year African countries spend 15 billion dollars on debt repayment. This is four times more than the amount spent on health and education. It is estimated that Africa would require 3 billion dollars a year for the most basic HIV prevention and care. This is nearly ten times what is being spent today. It is estimated that by the year 2010, 8 percent of Black children of Sub-Saharan Africa will be orphans. This is equivalent to 21.8 million orphans. AIDS will be the cause in 70 percent of these cases.

The conference also highlighted the situation in other developing nations. India -- reportedly with one sixth of the world's population -- has one fifth of the world's HIV infection. The average size of a family in India is five individuals, with 50 percent having only a single earning member. Currently, 50 percent of Indian families live below the poverty line. The proportional food expense in India is 70 percent of the average annual income, which is equivalent to US$350 (1999). A presentation on the affordability of monitoring HIV care in India suggests that 51 percent of individuals with infection can afford a CD4 count at baseline and 24 percent can afford HIV RNA quantification in advance stages. Antiretroviral therapy in symptomatic patients is available for approximately 1 of 3, whereas only 12 percent of asymptomatic patients can afford treatment. In one private clinic where 3,000 eligible patients are seen, only 5 percent were on antiretroviral treatments in 1999.

The inequality of distribution of the resource of antiretroviral therapy was quite clear and one of the dominant themes of the meeting. There were some controlled demonstrations against pharmaceutical companies in general occurring sporadically outside of the conference center, as well as an "action" or two against some of the pharmaceutical displays in the exhibition hall. Unfortunately, a number of pharmaceutical companies did not send a full complement of staff to attend the meeting, expressing concerns about safety as well as the ultimate educational value of the conference offerings. In fact, as Brian Gazzard from London said in summing up the clinical tract in his closing rapporteur session, "Sometimes the loudest words are those that are unspoken." Certainly this was quite true for those in attendance at the Durban conference. Much of the impact of being there was essentially being there.

The interaction between big pharmaceutical companies and African nations is a two-way street. There was a session at the conference describing how the Patents Act can be used to bypass being at the mercy of large pharmaceutical companies for obtaining expensive antiretroviral drugs. The New Medicines and Related Substances Amendment Act allows the Health Minister special powers to authorize inexpensive importation of drugs. The Patents Act will be used by the South African government to implement both compulsory licensing and parallel importation. Compulsory licensing allows for the manufacture of a patented agent without permission of the owner in special cases. Parallel importation allows for importation of a product without the authorization of the foreign patent holder where drug is marketed in the patent holder's country at a lower price. Two mechanisms can be used to invoke the Patents Act. The Minister may use it in situations where it is deemed in the national interest. Otherwise, any citizen or organization may compel the Trade and Industry Minister to use the Act on the basis that products under patent are not being used effectively. Despite the percentage of the world's population that it represents, the African market constitutes only one percent of global pharmaceutical spending. The Pharmaceutical Manufacturers Association has stated that they do not object to the use of the Patents Act to obtain less expensive drugs, but the government is not likely to get the same quality medications as has been offered in South Africa for the past three years. The Act would allow the Department of Trade and Industry to grant licenses to other companies to produce less expensive drugs and to import generic products produced overseas. The Act gives the holder the opportunity to ensure that the patent is not being abused.

Following the AIDS conference, it was reported that the U.S. government would offer up to one billion dollars a year in loans for African nations to purchase antiretroviral drugs. This, in fact, seems slightly counter-productive in that it will serve only to increase the debt of African nations. The cause for pardoning debt of these developing nations appears to make a lot of sense, in view of the enormous burden already incurred.

A number of the sessions at the Durban meeting were presented as debates. One debate centered on the question as to whether clinical trials in developing nations should adhere to the same standards of care as those in developed countries. The two speakers were actually not as diametrically opposed in this particular debate as they might have been. One of the discussants was an HIV-positive professor of mathematics from Sao Paulo, Brazil; the other was a professor of medicine from the University of Cape Town in South Africa. The mathematician suggested that trials are conducted in developing countries because of the lower costs, the lower risk of litigation, less stringent ethical review, and the availability of populations prepared to give unquestioning consent. He also suggested that anticipated under-reporting of side effects may also drive pharmaceutical companies to conduct studies in developing nations, in addition to the hopes of developing a larger market. He felt that the promise of future availability of an agent in a poor country is undue inducement to participation in clinical research and, in fact, called it coercive. He also stressed that the clinical trial in a developing nation needs to be relevant to the population there. For example, testing sub-type B vaccine in South Africa is senseless. He questioned whether we would allow testing of a sub-type C vaccine in the United States where that clade of HIV is not seen. This speaker felt that the same studies should be conducted in both developed and developing nations simultaneously.

The South African discussant felt that the use of the term "standards of care" was unfortunate. He said that the only people who speak about "standards of care" are imperialistic people, the underprivileged who desire to change the discussion to access and people who want to protect what has been good in the past but who subsequently, therefore, promote mediocrity. His claim was that, in fact, standards of care in developed countries are mediocre and need to be improved. Turning back to the definition of same "standards of care", he questioned whether one means that the same expenditures should occur, whether there should be identical training of the research teams conducting the trials, whether the same drugs should be used in the studies or that the same quality of hotels should be available for research subjects participating in the clinical trials. He stated that we cannot achieve all of these goals. On the other hand, assuming that only the drugs used constitutes "standard of care" is an arbitrary, selective mindset that reflects the unique attitudes towards drugs in the population. He concluded by urging that trials in developing nations should aim for an even higher standard of care. Researchers need to have knowledge of the local social, political and economic milieu where they are conducting their research. Trials should be of direct relevance to the host country and results should benefit the participating nation. The study should not deflect resources from the country to research but should be constructed such that benefits should flow from the research to the health care setting.

Anthony Fauci, MD, Director of the U.S. National Institutes of Allergy and Infectious Diseases (NIAID), discussed the impracticalities of continuous antiretroviral therapy in one of the morning plenary sessions. He stated that prolonged courses (for greater than ten years) of continuous highly active antiretroviral therapy are not viable options for most HIV-positive people. Such courses are associated with toxicities, including metabolic toxicities, damage to organ systems, as well as mitocondrial toxicity. Prolonged therapy will also lead to development of antiretroviral resistance. In addition, the costs of continuous therapy are also enormous, not only for developing nations but also in developed countries. One of the goals, then, of interrupted HIV therapy, according to Fauci, would be to provide regular drug-free periods in order to lessen toxicity, improve adherence, decrease costs, and provide less total time per year on HAART. In addition, a goal of interrupted therapy may be to induce a new permanent immunologic set-point to contain viral replication in the absence of HAART; that is, to induce a state equivalent to that of the long-term non-progressor. He referred to an intramural NIAID study on the effect of a single round of treatment interruption recently published by Davey, et al., in the Proceedings of the National Academy of Sciences. Eighteen fully suppressed individuals were studied. There was robust rebound viremia in all cases noted, including two subjects who had had negative lymph node cultures induced by HAART plus IL-2. These individuals also demonstrated significant rebound in their HIV RNA two to three weeks following a treatment interruption. In all patients resuming therapy, however, undetectable levels were rapidly achieved.

Dr. Fauci then described studies that are being conducted intramurally at NIAID under the clinical coordination of Mark Dybul, MD. In a pilot study of seven days on HAART therapy followed by seven days off, five individuals have been followed for 14 weeks. Dr. Fauci remarked that there is no significant change in viremia. Viral load returns to < 50 copies/ml upon resuming treatment. There is no virus to assay for resistance mutations. He also remarked that there is no change seen in the numbers of CD4+ or CD8+ lymphocytes. HIV specific CD8+ cells return when HIV RNA levels increase and decline again on resumption, but in a delayed fashion.

A second study being conducted at the NIAID is a two-year 70-patient trial comparing structured intermittent therapy (two months on, one month off) to continuous therapy. To be eligible, patients must have CD4 counts > 300/ mm3 and an HIV RNA copy of < 50/ml on antiretroviral therapy. Preliminary data on nine patients was reviewed. There is, again, the expected burst of HIV viremia, which quickly returns to baseline on re-initiation of treatment. There is no evidence of resistance. There is a small decrease in CD4 cells, with no change in CD8 cells. This information was reported as being quite preliminary. In his rapporteur summary of the clinical track presentations, Brian Gazzard of London again questioned "after preaching the sanctity of adherence for so long, how do we now rationalize treatment interruptions to our patients?"

A presentation from the CPCRA Adherence Working Group was made by Gerald Freedland, MD, of Yale. Six hundred thirty-three (633) participants in the FIRST and PIP trials were evaluated. Twenty percent of the participants were women, 52 percent were African-American and 17 percent were injection drug users. The mean CD4 cell count was 212/mm3 with an HIV RNA of 4.9 logs10. There was a strong relationship between adherence to the regimen and obtaining a viral load of < 50 copies/ml. Among those who said that they had 100 percent adherence to their regimen, 67 percent obtained < 50 copies/ml compared to 51 percent among patients reporting 80 to 100 percent adherence, and only 19 percent of those with < 80 percent compliance to their regimen. The data from the CPCRA also demonstrated that the proportion of patients who are 100 percent adherent falls off over time, with 72 percent in this category at month one, 64 percent at month four, and only 60 percent at month 8.

The significance of "blips" in viral loads were described by Diane Havlir, from UC San Diego, reporting on data from ACTG-343, a study of AZT, 3TC and indinavir. Intermittent viremia was described as a viral load of < 50 copies/ml followed by a subsequent measurement > 50 copies/ml and then again < 50 copies/ml. These blips have been suggested to be associated with enhanced rates of viral evolution, slower rates of viral decay, and selection of drug-resistant subpopulations. Two hundred forty-one (241) participants in ACTG-343 were included in this evaluation to assess the frequency, predictors and outcome of "blips." The median CD4 count was 480/mm3 with an HIV RNA of 4.08 log10. Forty percent of those enrolled experienced a rise in viral load to > 50 copies/ml and 20 percent rose above 200 copies/ml. Ten percent had more than one episode of a rise above 50 copies/ml. Thirteen percent had two consecutive episodes of HIV RNA levels > 50 copies/ml. Less than 10 percent (9.3) of those participants who experienced a blip, compared with 13.8 percent of continuously suppressed patients, had subsequent viral rebound (P=0.26). This suggests that, in fact, the occurrence of blips in HIV RNA was not associated with poor outcome.

Joe Eron from North Carolina presented the results of a study looking at quadruple versus triple therapy. This was a randomized, open label, 64-week trial of combivir, abacavir and amprenavir versus combivir and nelfinavir. Two hundred ninety (290) antiretroviral naive patients were enrolled with CD4 cell counts > 50/mm3 and viral loads > 5,000 copies/ml. The median CD4 cell count at baseline was 350/mm3. Toxicity failure and withdrawal was seen in 16 percent of the patients initially randomized to the triple combination, compared to 31 percent of those on the four drug regimen. Fifty-nine percent had nausea or nausea and vomiting on the four-drug regimen. This is felt to be secondary to a drug-drug interaction leading to increased levels of amprenavir. The CD4 cell responses in the two arms were the same; HIV RNA favored the triple therapy.

Mike Youle from London reported on a Vanguard IL-2 study comparing IL-2 versus no IL-2 in antiretroviral naive subjects who were not taking any HAART therapy. This open label, randomized parallel group study involved 36 subjects. They were randomized to receive either 4.5 MIU bid or 7.5 MIU bid of IL-2 for five days every eight weeks versus no therapy. No patients received antiretroviral therapies even during their cycles of IL-2. At baseline, CD4 counts were 440/mm3 with an HIV RNA level of 4.3 log10. At the end of 24 weeks, CD4 counts rose 148 cells/mm3 compared to baseline in the IL-2 treated patients compared to 25 cells/mm3 in the control group. By 48 weeks, CD4 counts were up 232 cells/mm3 in the treatment group compared to 13 cells/mm3 in the controls. No difference was seen in the area under the curve for change in viral load from baseline in either of the groups.

Another interesting discussion from the United Kingdom involved the use of Viagra. Data was available from 677 gay/bisexual men who had had sex with another man within the past six months. Of these, 100 (15%) had used Viagra. However, 17 had their own prescription for Viagra. Sixty-three combined it with other recreational substances. Among HIV-positive individuals, 29 (27%) reported using Viagra compared to 61 (14%) HIV-negatives. Interestingly, of those who had not been tested, only 10 (7%) reported Viagra use [P < .001]. Among both HIV-positive and HIV-negative men, those who had ever taken Viagra were also more likely to report sero-discordant unprotected anal intercourse, status unknown unprotected anal intercourse, recreational drug use, and anabolic steroid use. These findings are very provocative and suggest that clinicians should be aware of significant unprescribed use of Viagra and its combination with other recreational substances.

The 14th World AIDS Conference will be held in 2002 in Barcelona. Mauro Schecter from Río predicted what might be the hot topics in clinical HIV for the 2002 Barcelona meeting. He felt that by that time, the pendulum will have swung back to later initiation of antiretroviral therapy. He suggests that the definition of failure will be revisited. There will be a greater emphasis on "delta viral load" as proposed Deeks, et al., from UCSF/SFGH. He predicted that CD4 cell counts will return as the most important prognostic predictor, simpler regimens will be the vogue and there will be renewed interest in opportunistic infection prevention. He also felt that structured treatment interruptions would continue to be of interest, due to concerns about toxicity and drug affordability.

Most who attended the Durban conference came away with a sense of invigorated activism. As Pulitzer prize-winning New York Newsday journalist, Laurie Garrett, put it "Yes, the Durban meeting was Woodstock . . . No, more like student mobilization circa 1970: 'We shall levitate the Pentagon!' Now we'll see if the momentum is sustainable." Many came away with a new desire to do whatever they could to help the African situation. At the very least, it is important for AIDS care providers in the U.S. to become familiar with the extent of the ravages of the epidemic in the developing world and to realize the complexities of the socioeconomic and political situations in these nations. Our own Lawrence Goldyn wrote an opinion piece in The New York Times, July 6, entitled "Africa can't just take a pill for AIDS" that nicely outlines many of these issues.

The Consortium is grateful for unrestricted educational grants from Agouron Pharmaceuticals, BTG Pharmaceuticals and CVS Pharmacies that supported the July 19 Durban update dinner meeting.

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Committee Reports

Executive Advisory Board

The next meeting of the Community Consortium Executive Advisory Board will be held on Wednesday, September 27, 2000 at 7:30 a.m. in the Community Consortium conference room.

It is with mixed emotions that the Community Consortium reports that Tom Mitchell, MPH, Community Consortium Program Director, will be leaving his position to assume a different role in the UCSF Positive Health Program (PHP) at San Francisco General Hospital. Tom, who has been with the Consortium for the past 13 years, will become the PHP's first Project Development Specialist. Tom's primary goal will be to increase the number and diversity of investigator-initiated research projects conducted by PHP faculty. He will provide scientific and technical assistance to PHP faculty to enable them to compete successfully for investigator-initiated research projects funded by the National Institutes of Health, other federal and state agencies and private foundations. In the meantime, the Consortium will be losing an outstanding program director and administrator. He has truly been the "behind-the-scenes" force that has kept many of the Consortium's programs, publications and progress on track. We all wish Tom tremendous success in his new endeavor.

The Executive Advisory Board selected a topic for a Fall Saturday CME program. Androgens and anabolic therapies in patients with HIV will be discussed at the upcoming session. The exact date and speakers for the session are still being finalized. Stay tuned for further details as they become available.

The Consortium is about to launch two clinical trials. We have received funding from the National Center for Complementary and Alternative Medicine (NCCAM) to investigate the impact of DHEA in patients with maximally suppressed HIV viremia. This study will evaluate whether there is any additional antiretroviral boost of DHEA. In addition, we will investigate other immunologic changes secondary to DHEA treatment. The study will carefully measure hormone levels and body composition as well. The study will be conducted in the General Clinical Research Center at San Francisco General Hospital. Roz Leiser, RN, Community Consortium Study Coordinator, is working on the final stages of protocol preparation prior to launch. In addition, the Consortium will be collaborating with Elisabeth Targ, MD, from the Complementary Medicine Research Institute at California Pacific Medical Center, in a study of the effects of distant healing on patients with HIV. In this trial, patients will be randomly assigned to distant healing by traditional healers, nurses or to no distant healing. Numerous outcome measures will be investigated. Dr. Targ will do a presentation at the Community Consortium AIDS Clinical Grand Rounds in November to further describe the study. If you have patients who might be interested in participating in either the DHEA or the distant healing trials, please contact Roz Leiser at the Community Consortium, 415.476.9554 extension 21.

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Scientific Advisory Committee and Community Advisory Board

The combined Scientific Advisory Committee and Community Advisory Board will meet on Thursday, October 5 at 12 Noon in the Community Consortium conference room. Lunch will be provided. We will review CPCRA and Community Consortium clinical trials in development. Your input is critical. Please make every effort to attend.

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Consortium Clinical Trials

IL-2 -- Preliminary Results

Preliminary results from CPCRA-059 have been released. An executive summary has been sent to all Consortium investigators who enrolled patients in the trial and participants have received a patient letter outlining the results of the study. Donald Abrams, MD, was the protocol chair for this randomized, open label comparison of intermittent administration of two doses of subcutaneous recombinant IL-2, 4.5 and 7.5 MIU twice daily with control in HIV infected patients taking antiretroviral therapy who had CD4 cell counts greater than or equal to 300 cells/mm3. The primary endpoint of the study was change in viral load between baseline and 12 months. The concern was that IL-2 may lead to increases in HIV RNA levels because of bursts of viremia that had been previously shown to accompany IL-2 therapy in the pre-HAART era. In this study, HIV RNA levels were drawn monthly from IL-2 recipients as well as the controls. Between September of 1988 and July 1999, 511 patients at 15 CPCRA centers were enrolled in this study; 256 patients were randomly assigned to receive IL-2 and 255 to receive no IL-2. Of those assigned to the subcutaneous IL-2 group, 126 were randomized to receive 7.5 MIU and 130 to receive 4.5 MIU both dosed twice daily for five consecutive days. Most participants were men (88.5%), white (69.3%), and had sex with a person of the same sex as their HIV acquisition risk factor (76.7%). The median CD4 cell count at randomization was 536 cells/mm3, with the median nadir CD4 cell count of 299 cells/mm3. Sixty-two percent of patients had an HIV RNA level at baseline that was < 50 copies/ml. The three randomized groups were similar at entry for all of the baseline characteristics considered. All patients were receiving an antiretroviral therapy at randomization as mandated by the protocol. The median duration of antiretroviral therapy was 33 months (range 0 to 153). Fifty-five percent of the patients were on a protease inhibitor containing regimen, 22 percent on a non-nucleoside reverse transcriptase containing regimen, and 12 percent on a regimen that contained both drug classes. Eight percent of those enrolled were on combination nucleoside therapy alone.

The median follow-up was 16.2 months. Among patients randomized to the 7.5 MIU and 4.5 MIU doses of IL-2, 82.5 percent and 80.8 percent respectively completed at least three cycles in the first 12 months of follow-up. Thirty-seven percent of the patients in the 7.5 MIU group and 51 percent of the patients in the 4.5 MIU group completed the first three cycles without an interruption or dose reduction. With regard to the primary endpoint, at month 12, 64.4 percent of the patients assigned to the IL-2 group and 61.7 percent assigned to the control group had undetectable HIV RNA levels. Based on a repeated measure analysis, there was no difference between the treatment groups with respect to the proportion of patients with viral load < 50 copies/ml at each monthly visit. Using multiple metrics to assess differences in HIV RNA levels between the treatment groups, none showed any significant variation.

As has been demonstrated in numerous prior clinical trials, there was a significant difference in CD4 cell counts at 12 months between individuals receiving subcutaneous IL-2 and the control group. The CD4 cell count difference was 217 cells/mm3 at the 12-month time point. At 12 months, 31 percent of the IL-2 recipients compared to three percent of patients assigned to the control group had a CD4 cell count > 1,000 cells/mm3. CD4 cell count response was greater for the 7.5 MIU dose group than for the 4.5 MIU dose group; however, none of the differences between those groups are statistically significant over the 12 months of the study. As one might have expected, there were increased toxicities in the higher dose group; however, severe adverse events and death were more common in the group receiving 4.5 MIU.

Patients enrolled in CPCRA-059 will hopefully all be rolled over into the longer, larger clinical endpoint ESPRIT clinical trial. ESPRIT is an international study that will investigate clinical outcomes, including progression of disease and survival in 4,000 patients followed for a minimum of five years to ascertain whether the CD4 increases obtained with IL-2 therapy translate into clinical benefit. It is hoped that ESPRIT will be available for patient enrollment in the Bay Area through the Community Consortium. We are trying to determine how much interest there would be in the ESPRIT protocol. If you have patients who you think would enroll, please contact Roz Leiser at the Community Consortium, 415.476.9554 extension 21.

Thanks to all Community Consortium providers who enrolled patients in CPCRA-059 as well as to the participants themselves.

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Multi-drug Reistant HIV (MDR)

Congratulations to Michael Jones, RN, Community Consortium Clinical Research Nurse, and the providers at the Castro-Mission Health Center, who have already screened 12 patients for eligibility into the newest CPCRA clinical trial, which just opened for enrollment. This study of a structured treatment interruption (STI) in patients with multi-drug resistant (MDR) HIV is a randomized clinical endpoint study to determine whether a prescribed four-month STI will delay clinical disease progression and death compared with a strategy of immediately initiating a new antiretroviral regimen in patients with MDR virus. Subjects will initiate the salvage regimen based on information generated from both genotypic and phenotypic resistance testing that is provided as part of the protocol. As there is little existing information on the optimal amount of time to wait before resuming therapy following an STI, the first 150 participants in the CPCRA trial will have point mutation assays performed. These are more sensitive than routine resistance assays. These initial patients will also undergo more frequent HIV RNA testing, which should enable the investigators to know early in the course of the trial whether four months is too long or too short of an STI.

Four-hundred-eighty subjects will be randomized in the trial over a 12-month accrual period. This will make this, by far, the largest STI trial conducted to date. Participants will be followed monthly for the first 8 months, and then every 4 months. Should CD4 cell counts drop below threshold levels, prophylaxis for opportunistic infections will be resumed. This study will provide much information on the kinetics or the return of CD4 cells following the reinstatement of an antiviral regimen, as well as much clinical information over its planned two years of follow-up. Entry criteria includes age > 13 years with HIV RNA >10,000 copies/ml.

The potential subject must have demonstrated a multi-drug-resistant HIV strain on genotypic antiviral resistance testing (GART), with evidence of broad PI resistance combined with broad NNRTI and/or broad NRTI resistance. The patient and provider must have the intention of initiating a new regimen and should be able to accept the potential timing of this change as specified in the protocol. Individuals should be on a stable antiretroviral regimen for at least 14 days prior to the qualifying GART test and randomization. Broad PI resistance is defined as having at least two major resistance mutations against PIs. Broad NNRTI resistance would include B103M mutation or a combination of two other NNRTI mutations. Broad resistance to nucleosides is defined as the presence of 151M/69S mutation or a combination of mutations including B215Y/S mutation. Any patient previously exposed to three nucleosides, one NNRTI and two PIs, is also eligible for screening and will have GART performed if they meet the remaining entry criteria. If you have any individuals who may be interested in participating in the CPCRA MDR trial, please let your Community Consortium clinical research nurse know!

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FIRST

The CPCRA's Flexible Initial Retroviral Suppressive Therapies (FIRST) trial is the entry point into the CPCRA's menu of strategic antiretroviral trials. FIRST is open to patients who are antiretroviral naive. As of mid-August, the CPCRA has enrolled 743 of the target 1,410 participants. Accrual is expected to close at the end of March 2001. To date, the Consortium has enrolled 32 patients onto the study. The question being asked is "What constitutes the best initial regimen for patients beginning antiviral therapies?" Patients are randomized to one of three arms. One arm includes two nucleoside analogs and a protease inhibitor, a second arm includes two nucleoside analogs and a non-nucleoside reverse transcriptase inhibitor (NNRTI), and a third arm includes at least one nucleoside analog plus an NNRTI and a protease inhibitor. Clinicians who so desire have free reign to choose all of the drugs that the patient begins within the classes to which patients have been randomized. If providers have equipoise among the various protease inhibitors and NNRTIs, patients may undergo a second randomization to specific drugs within the class. With the increasing untoward consequences that are being seen from highly active antiretroviral therapies and the increasing number of agents available in our antiretroviral armamentarium, the FIRST study is poised to answer a very timely and pertinent question. Patients are eligible regardless of their CD4+ cell counts or their HIV RNA levels. In this strategic trial, no drugs are provided; drugs are all currently available by prescription. When a patient is randomized, the provider will write a prescription for the appropriate regimen. The endpoint in the study will be the time to second virologic failure. This endpoint takes into account the fact that it is likely that all of the regimens may be nearly equivalent in their initial ability to suppress HIV RNA. The real differences may appear when switching patients to a second regimen once patients have progressed. Thus, the FIRST trial has a rather unique clinical endpoint. It is hoped that all patients enrolled will also be co-enrolled in the CPCRA long-term monitoring protocol, which is still in development. This will allow us to collect further information on clinical status of the patients.

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Metabolic Study

A perplexing question that baffles all HIV care providers is the etiology of the body habitus alterations and metabolic consequences of highly active antiretroviral therapies. Are these changes related to protease inhibitors alone? Are the same consequences seen in patients who being therapy with an NNRTI-containing HAART regimen? To answer this study, the CPCRA has launched the Metabolic Trial as a substudy of FIRST. The trial is designed to capture information from patients as they enroll onto the CPCRA FIRST trial. Patients will undergo serial metabolic evaluations, including laboratory testing and anthropomorphic measurements. By co-enrolling patients from the FIRST trial, we hope to be able to get answers to the question as to whether changes in body habitus alterations and metabolic abnormalities being seen in patients on HAART are related to protease inhibitor therapy or are seen with equal frequency in patients commencing an NNRTI-containing regimen. Patients enrolled in the metabolic study will undergo measurements of glucose, insulin, cholesterol and triglyceride levels. In addition, body composition measurements (e.g., BIA, skinfold measurements and body circumference measurements) will also be obtained. This trial promises to contribute much valuable information on risks and rates for developing metabolic and body habitus alterations after initiating HAART. The CPCRA has enrolled 270 of the 360 patient target onto this protocol as of the end of August.

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Adherence Study

How to ensure that our patients can best adhere to the complicated HAART regimens that we prescribe is a most important question. Among the FIRST family of accompanying clinical trials, the CPCRA Adherence Study is now open for enrollment. Unlike most CPCRA studies where the individual patient is randomized to one intervention or another, the adherence study has randomized the entire Community Consortium to an adherence intervention that utilizes the services of "medication managers." Patients co-enrolled onto a CPCRA strategic antiretroviral trial who choose to participant in the adherence substudy will have interactions with our trained medication managers. These Consortium clinical research nurses will do everything per protocol to ensure that patients are reminded to adhere to their prescribed regimens. Two different interventions are being evaluated in a two-by-two factorial design involving CPCRA units randomized to different arms across the national network. The ultimate goal will be to evaluate which intervention produces the best HIV RNA results as well as self-reported adherence. The CPCRA has enrolled 363 of the target 592 patients from FIRST onto the adherence protocol.

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Long Term Monitoring (LTM)

The CPCRA is committed to long-term evaluation of patients enrolled on randomized clinical trials. Where a number of our trials have intermediate surrogate marker endpoints, co-enrolling patients onto the Long-term Monitoring (LTM) protocol will ensure that we are able to capture long-term disease progression and survival information on patients who may not have already reached a clinical endpoint. Our goal is to enroll all patients on the CPCRA core protocols (FIRST and PIP) onto LTM. As of mid-August, the CPCRA has enrolled 1863 patients onto LTM.

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Thought You'd Like to Know . . .

Abacavir Safety Alert

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