In addition, we have always claimed that our strength is in our numbers. When the Consortium takes a stance on an issue and, for example, writes a letter to an elected official, it behooves us to say that we are an organization of over 200 HIV care providers in the San Francisco Bay Area. Obviously, the larger the number that fills in the blank, the more clout we have. The Community Consortium has much to be proud of. We have been a model for community based clinical trials and provider education in this country for over 15 years. We intend to continue our efforts for as long as they are necessary. We do need and appreciate your support! Please take a moment now to fill out and send back the enclosed membership application if you have not already done so since July. Thanks again for your continued support!

Return to Top

Saturday CME Program

CROI Update

On March 6, the Consortium hosted a Report Back from CROI" post-meeting update dinner following the 9th Conference on Retroviruses and Opportunistic Infections held in Seattle. Information presented was hot off the presses as the meeting had just ended the prior week. Donald Abrams, M.D., moderated the panel which included Virginia Cafaro, M.D., Medical Director, Wellspring Medical Group, Steven Deeks, M.D., Associate Clinical Professor at the UCSF Positive Health Program at SFGH, Harry Lampiris, M.D., Assistant Chief, Infectious Disease Clinic at San Francisco Veterans Administration Medical Center, and Michelle Roland, M.D., Assistant Clinical Professor at the UCSF Positive Health Program at SFGH.

Donald summarized the overriding themes that he perceived at the Seattle Conference. He remarked that it is much more of a conference on retroviruses and their treatments than on opportunistic infections anymore. There were no abstracts or presentations on Pneumocystis carinii pneumonia; there were forty abstracts and presentations on hepatitis C virus. This shift clearly demonstrates changes that we have all appreciated as HIV providers. He expressed concern that AIDS conferences occur at such a rapid rate during the course of the year that it becomes somewhat difficult to fill them with new information. The CROI followed rapidly on the heels of the rescheduled ICAAC and the upcoming international conference in Barcelona in July follows rapidly on the CROI. Details from the same studies are discussed at each of these conferences - the difference being that there may be another twelve weeks of data to present. Clearly progress is currently being measured in small steps as opposed to the giant breakthroughs seen in the past. One of the messages from the 9th CROI was that new drugs are in fact in the pipeline. Harry Lampiris, M.D., summarized some of the new agents that are under investigation. In addition to fusion inhibitors such as T-20 and T-1249, a number of chemokine antagonists are also entering early stages of clinical trials. SCH-C is an oral CCR5 antagonist. Previous studies have demonstrated QT prolongation at higher dosages. A trial reported by Reilly et al. investigated 12 HIV positive patients with CD4+ cell counts greater than 250/mm3 who are not currently on any antiretroviral therapies. HIV RNA decreased 0.5 log after taking SCH-C 25mg PO bid. Two patients were non-responders, 10 of the 12 had at least a 0.5 log response and four had a greater than one log drop in their HIV RNA. Larger scale studies are now in progress.

In contrast to T-20 and T-1249, BMS806 is an orally bioavailable fusion inhibitor. Bristol-Myers Squibb screened 100,000 compounds and ultimately found one with favorable characteristics active against HIV-1. BMS806 has poor brain penetration; however, it is orally bioavailable and animal toxicology studies have been encouraging. Colonno et al. presented early results. Mutants resistant to the drug can be selected in the CD4 binding domain. Early phase clinical studies are now being planned.

Dr. Lampiris then turned to classes of drugs that are already in clinical use and discussed some of the second generation NNRTIs in development. TMC-125 is being developed by TIBOTEC. In a clinical trial reported by Gazzard et al., TMC-125 900mg bid led to a 0.8 log drop in viral load after seven days in patients who were NNRTI experienced. In antiretroviral naïve patients, 900mg bid led to a 2.0 log drop in viral load after seven days of treatment and a CD4+ cell increase of 119/mm3. In the study reported by Lange et al., a comparison five-drug regimen including AZT/3TC/ABC/IDV/NVP led to a similar viral load decline but only a 60/mm3 CD4+ cell increase, not quite as potent as the TIBOTEC NNRTI combination regimen.

DPC083 was a Dupont compound that is now under investigation by Bristol-Myers Squibb. Ruiz et al. reported on 51 patients failing NNRTI containing regimens who were randomized to DPC083 100mg a day or 200mg a day for eight weeks. At the end of the eight weeks, 40% had viral loads less than 400 copies/ml on an intent-to-treat analysis, 70% on an as-treated analysis. The mean drop in HIV RNA was 1.28 logs. Responses did not appear to be dose related. Twenty to thirty percent developed a rash but discontinuation due to adverse experiences was rare. Overall, a better virologic response was appreciated by patients receiving new nucleoside analogs. Further Phase II studies are currently being planned.

Among new protease inhibitors in development, atazanavir is attractive as a once-daily, lipid-sparing PI being developed by Bristol-Myers Squibb. Cahn et al. reported on 467 antiretroviral naïve patients receiving a backbone of d4T plus 3TC and randomized to nelfinavir 1200mg bid, atazanavir 400mg qd, or atazanavir 600mg qd. The viral load declined 2.6 logs in all three groups. At 24 weeks 40% of the nelfinavir, 42% atazanavir 400mg and 39% atazanavir 600mg patients had HIV RNA levels less than 50 copies/ml. Grade 3-4 adverse experiences were seen in 11-14% of those treated in each of the three groups. The atazanavir recipients developed dose-proportional hyperbilirubinemia without hepatic transaminase elevations in 42% of the patients. In a study by Piliero et al., 48-week lipid data from the study showed very small increases in cholesterol and triglycerides in the atazanavir 400mg qd patients compared to those receiving nelfinavir bid. Tripanavir is still being investigated for the best dose. A new hard-filled capsule preparation is also being investigated. Tripanavir/HFC is being studies at dosages of 1200mg and 2400mg bid boosted with 100-200mg of ritonavir. Results of a trial in patients who had failed multiple PI regimens should be available in the near future.

Dr. Lampiris noted that there are now increasing options for once daily dosing of antiretroviral therapies. He reviewed the possibilities which include 3TC 300mg qd, tenofovir 300mg qd, d4T-SR 100mg qd, nevirapine 400mg qd, ritonavir 100mg, saquinavir 1600mg qd, lopinavir/ritonavir 800mg/200mg qd. Also, efavirenz will soon be available as a one pill once-a-day dose. Atazanavir, which is completing phase II studies, appears to be an effective qd regimen and trials have also investigated the combination of atazanavir and saquinavir 1200mg qd. Certainly increasing options for once-daily dosing will help deliver effective antiretroviral therapies to patients with adherence issues.

Virginia Cafaro, M.D., reported some information regarding lipodystrophy studies. First of all, she was impressed at attempts to further pin down a universally accepted case definition of lipodystrophy as presented by Andrew Carr, M.D., and his colleagues from Sydney. In the end, however, she reported that there is no real consensus still as to what we are talking about when we discuss this clinical syndrome. The need for a definition exists so that we can determine the prevalence and incidence of lipodystrophy, to increase our understanding of potential risk factors, and to assist in the diagnosis as well as prevention. She described the efforts to define a case definition conducted at 32 sites in North America, Europe, Asia, Australia, pointing out that no sites were located in Africa. Each site contributed 12 cases and 12 controls for the analysis. In mild cases, patients identified that they had lipodystrophy. In moderate cases, the provider was able to pick it up and in severe cases, the lipodystrophy was obvious to anyone. The parameters that were selected for the best model included age > 40 years, female sex, duration of HIV > 4 years, CDC category C, waist-to-hip ratio, wider anion gap, lower HDL cholesterol, higher trunk-to-limb fat ratio, higher intra-abdominal to extra-abdominal fat ratio, and lower leg fat percent. Using a model that fits this definition, the sensitivity of the definition is 78% with a specificity of 80%. In an analysis of 350 patients in the HOPS database, Dr. Cafaro reported that the patients' nadir CD4+ cell count and subsequent rise are useful in predicting whether or not they may get lipoatrophy. A nadir CD4+ cell count of less than 200cell/mm3 with a minimal rise in CD4+ cells yields a greater chance of getting lipoatrophy. In this analysis the time on antiretroviral therapies did not seem to have an impact.

Regarding the treatment of lipodystrophy syndrome, two approaches are being utilized. One approach is to switch the antiretroviral therapy. In the other, attempts are being made to use metabolic treatment agents for the underlying processes associated with lipodystrophy. Dr. Cafaro reported on a study by Fisca et al. that described switching patients from protease inhibitor-containing regimens to either abacavir, nelfinavir or nevirapine. This is an on-going, open-label, randomized study that compares three different PI-sparing regimens in subjects previously exposed to a PI-containing antiretroviral therapy regimen. In a sub-study of 93 patients, evaluation of the effects on metabolic and body composition parameters is being undertaken. In six months, 81 patients have been randomized; 27 to abacavir, 26 to nelfinavir, and 28 to nevirapine. HDL cholesterol, LDL cholesterol, insulin and insulin sensitivity are reported as improved significantly in patients who switch; only in the nevirapine group did triglycerides improve significantly. Interestingly, a late-breaker presentation from Barcelona presented by Martinez et al. evaluated switching PI-based therapy to the same three alternatives with CD4+ cell count and viral load being the primary endpoints. In this study there was similar efficacy in the intent-to-treat analysis with regard to the primary endpoints. However, there were significantly more virologic failures seen in the abacavir arm- most of those patients had been previous recipients of suboptimal serial nucleoside analog therapies. There were more side effects in those switched to the NNRTIs. There was only a small influence overall on clinical lipodystrophy.

Two studies from Australia also looked at switching antiretroviral therapies. Carr et al. reported on a trial in which patients with lipoatrophy were switched from d4T or AZT to abacavir. Patients underwent a series of laboratory and DEXA evaluations. Progressive improvements in peripheral fat were noted in the arms more than the trunk more than the legs at six months of therapy. A decrease in lactate levels was seen. Only 2% of the patients who were randomized to abacavir developed virologic failure compared to 18% of those randomized to continue on their AZT or d4T regimens. The actual improvement in peripheral fat as assayed by the DEXA scan was 0.4 kilograms after six months. There was no clinically apparent change appreciable. Since the normal limb fat is 7-8 kilograms, it was estimated that it would take years to assess normalization. No changes in abdominal fat were noted. A similar study from the other side of Australia, in Perth, reported on switching patients onto Trizivir versus continuing two nucleosides and a protease inhibitor. Progressive improvements again were reported in peripheral fat; greater after a switch from d4T than from AZT regimens. Again no improvements were seen in abdominal fat and no significant improvements in lipids were appreciated.

Dr. Cafaro went on to summarize three additional treatment studies for lipodystrophy. In the first, a prospective randomized double-blind study, rosiglitazone 8mg versus placebo was prescribed in 30 subjects with lipodystrophy. Subcutaneous fat was measured by MRI scan. There were no significant improvements in BMI, subcutaneous fat, visceral fat, waist-to-hip ratio or lipid levels at the end of 24 weeks. There was a significant improvement in insulin and an increase in triglycerides and cholesterol. The investigators, led by Surrihnen et al., concluded that antiretroviral therapy-associated lipodystrophy is not reversible with rosiglitazone.

Martinez at al. presented a randomized placebo-controlled study conducted in Barcelona where patients received metformin 850mg bid versus gemfibrozil 600mg bid versus placebo. All patients were on HAART and had central adiposity with triglycerides greater than 200mg/dl. Sixty-six subjects were followed every three months for one year. The investigators found no significant differences in lipodystrophy or metabolic abnormalities after one year, again suggesting that the results do not support the use of metformin or gemfibrozil to treat lipodystrophy.

The only study which had some positive findings was a presentation by Jeffrey Fessel, M.D., from the HIV Institute at Kaiser Foundation Hospital San Francisco. In this prospective open label study, 16 patients with central lipoaccumulation received niacin 3000mg immediate release for at least 24 weeks. The median time of follow-up was approximately one year in this observational trial. Patients underwent single cut abdominal CT scan at the level of L2 and fasting lipid evaluations. Intra-abdominal fat decreased in 13 subjects and increased in three. Overall there was a 16.9% decrease; for those who sustained a decrease there was a 26.9% decrease in intra-abdominal fat. The decreased intra-abdominal fat was associated with an increased HDL level and total cholesterol:HDL ratio.

The concern over the lipid abnormalities is the ultimate development of cardiovascular disease. Dr. Cafaro reported on two large studies that seemed to be contradictory with regards to whether an increased incidence in cardiovascular events is being seen in patients with HIV on HAART. Klein et al. presented an analysis reviewing data from 4,159 cases in the Kaiser Permanente group compared to 40,000 controls. The age-adjusted hospitalization rate for cardiovascular disease was higher in all patients with HIV regardless of antiretroviral therapy or no ART compared to HIV negative individuals. Dr. Cafaro pointed out that the data is confounded by the fact that there is an increased incidence of smoking in the HIV positive group compared to the HIV negatives which may be the overriding risk factor. In contrast, Bozette et al. from the US Veterans Administration reported on cardiovascular outcome in 36,766 US veterans on ART with a mean of 8.5 years of follow-up from the VA AIDS service and 7 years additional from National Death Index. Patients followed were on ART for a mean of 40 months. The analysis represented 121,936 patient-years of follow-up. Bozette's data clearly demonstrated that although the use of antiretroviral therapy has increased significantly from 23% in 1993 to 60% in 2001 among the veterans participating in this cohort, cardiovascular admissions and cardiovascular admissions/death have not increased over this time period- if anything, they have declined over the 8 years of follow-up. Death from all causes has decreased from 18 per 100 patient-years to 5.0 in 2001.

Michelle Roland, M.D., reviewed information on solid organ transplantation that was presented at the conference. Her own poster described a preliminary multi-site experience in liver and kidney transplantation in HIV infected patients. There were 41 eligible subjects including 22 renal transplant recipients and 19 liver transplant recipients. CD4+ cell counts were 455/mm3 (200-1054) in the renal patients and 321/mm3 (103-973) in the liver patients. With a median follow-up of 279 days, there were four deaths including one renal recipient and three liver transplants. The deaths resulted from recurrent hepatitis C, rejection after protease inhibitors stopped, and post-op complications in two patients. Two patients developed opportunistic infections - one each of CMV esophagitis and candida esophagitis. Post-operative CD4+ cell counts remained virtually identical in the renal transplantation group and fell slightly to 296/mm3 (89-590) in the liver recipients. The mean HIV RNA in both cohorts post-operatively was less than 50 copies/ml. One of the liver patients required retransplantation. One kidney graft was lost. Additional rejection was seen in 36% of the kidney and 11% of the liver patients. Overall, 95% of the kidney transplant patients and 84% of liver transplant patients were alive at one year. These numbers are totally compatible with the registry that looks at the survival rates in patients without HIV infection.

Dr. Roland then reviewed a presentation by Ragni et al. from Pittsburgh on antiretroviral therapy and mortality in HIV positive liver transplant recipients. Five centers including Pittsburgh, Miami, Kings College, University of Minnesota, and UCSF were involved in this multi-site study. Twenty-three patients were evaluated overall with a median survival of 15 months (1-49). In this cohort, the 12-month survival was 61% which is lower than the previous report on 19 patients at 279 days. Kings College reported four of eight deaths last year, all in co-infected patients. Dr. Roland pointed out that there are discrepancies between this data and what has been previously reported. All of this emphasizes the need for larger and longer prospective studies.

Dr. Roland also presented some discussion on antiretroviral therapy and treatment in the developing world. She reported that this conference did not have a huge amount of information on such socially relevant topics compared to the International AIDS Conferences. She discussed the presentation on the realities of antiretroviral therapy in Uganda. The country as a whole has an aggressive prevention policy which has led to the prevalence rate of HIV dropping from 25% in 1992 to less than 9% in 2001. There are still 1.2 million HIV positive people in Uganda who require care. Sources of antiretroviral therapy include participation in research studies, obtaining drugs from friends, non-governmental organizations, private companies and pharmacies in Kampala. UNAIDS has a Drug Access Initiative with a goal to treat 10,000 patients by 2001, to decrease prices and to increase access to generics. The result to date is that the drugs have fallen in price from $1200 to $45. There are generics but choices are limited. More than 5,000 patients are on antiretroviral therapy. There are three labs in the whole country able to do CD4+ count and viral loads. The access to treatment is limited predominantly to the capital city Kampala. It has been observed that antiretroviral treatment is difficult to sustain with 15-20% discontinuing treatment in one year due to 1) financial and donor fatigue, 2) the fact that patients start when they are too sick to tolerate therapy, 3) patients stop when they feel better, and 4) because of a variety of cultural beliefs.

Dr. Roland lauded the Elizabeth Glazer Pediatric AIDS Foundation for their programs to prevent mother-to-child transmission. The Glazer Foundation launched a Call to Action in 1999 and since then has funded 30 grants with 17 more under review. Programs currently exist in Thailand, Cameroon, Kenya, Rwanda, South Africa, Uganda, the Congo, Zambia, Zimbabwe, Tanzania, Malawi, and Angola. The program offers a potential to treat 250,000 women in two years if all the projects are fully successful. In general more women are testing and many are getting results but few are using medications. Currently, 50% of the HIV positive women and 31% of babies born to HIV positive women are receiving antiretroviral therapy. Many women who refuse testing are found to be positive. Some programs are actually offering to treat those that refuse testing. The next step will be to offer continued antiretroviral therapy to the mothers beyond childbirth. A problem with using antiretrovirals in developing countries is the lack of access to laboratories. The Drug Access Initiative in the Cote D'Ivore has revealed that the lab tests actually cost more than the medicines ($130USD versus $10-46USD). Only 13 of 56 countries in Africa are equipped to run HIV RNA levels. There is a need to continue to explore low-cost diagnostic tools.

Steven Deeks, M.D. reported that he felt that the focus of the 9th CROI was on basic science and the translational aspects of HIV disease. He felt that the meeting had a markedly reduced clinical focus compared to prior years. The major discussions now are on pathogenesis and how it impacts on clinical practice. If there was a paradigm shift that occurred at this meeting, Dr. Deeks believes that it would be on the importance of genetic characteristics predicting treatment outcomes. He reviewed the concept of major histocompatibility complex and HLA genes. HLA class-1 genes are expressed on antigen presenting cells and present peptides to T-cell receptors on CD4+ cells. HLA class-2 genes are present on all cells and present peptides to TCR on CD8+ cells. Each individual has a unique set of HLA molecules. There are diverse responses to antiretroviral therapy in HAART-treated patients. A recent report indicates that P-glycoprotein expression (MDR1 gene) determines the ability to retain PIs and NNRTIs inside the cell. Individuals with a TT genotype have a low intracellular drug concentration and limited CD4+ T-cell increases.

New at the 9th CROI was a suggestion that abacavir hypersensitivity may also be genetically determined. ABC reactions occur in 5% of the population and appear to be decreased in Caucasians relative to other groups. A GlaxoSmithKline study reported on the association of HLA haplotype and abacavir reactions demonstrating that HLA-B57 was present in 39 of 84 (46%) of cases of ABC hypersensitivity versus only 4 of 113 (3.5%) of the controls (p < 0.001). When asked directly, Dr. Deeks said he does not think it is time that we genotype all people prior to beginning abacavir therapy. However, he did suggest that if a patient develops flu-like symptoms on drug, their provider may want to do HLA typing to determine if this is, in fact, someone who may be at greater risk for the hypersensitivity reaction.

Dr. Deeks then turned to a discussion of how HIV causes AIDS- a repeated discussion at many HIV conferences each year. He suggested that there are two camps of belief. David Ho and Alan Perelson are champions of the "accelerated destruction" mechanism. They contend that HIV-mediated cytopathogenicity leads to generalized T-cell activation and activated destruction of CD4+ T-cells. The other camp suggests that HIV causes AIDS by "regenerative failure" caused largely by HIV-mediated thymic dysfunction. In this model, generalized T-cell activation leads to suppression and/or death of naïve T-cells. The central feature here is that the immune system cannot repopulate itself. There is also the possibility that, in truth, the answer might be a combination of both mechanisms. In the T-cell turnover model, HIV infection results in accelerated proliferation of both CD4+ and CD8+ T-cells (approximately a three and eight fold increase compared to HIV negatives). Most of these cells live a short time with the number of long-lived cells reduced. HAART reduces T-cell proliferation/turnover and shifts the population from short-lived T-cells to long-lived T-cells. In the model where the immune system fails to regenerate or keep up because of failure of thymic function, advanced by McCune et al. at the Gladstone Institute of Virology and Immunology at UCSF, thymic growth factors and cytokines which may prolong survival of naïve T-cells are being suggested as possible interventions. IL-2 may be useful in this manner; similarly, recombinant human growth hormone is now being studied as a potential thymic growth factor. Napolitano has demonstrated that growth hormone leads to thymic hyperplasia in the SCIDhu mouse model. There is an increase in thymic size in vivo that is associated with an increase in the number of naïve CD4+ T-cells in five of five subjects studied to date. This preliminary data is leading to a prospective trial to begin evaluating rhGH as a way to augment the immune system.

Dr. Deeks summarized data presented by Peter Hunt, M.D., from UCSF, that includes information from both the SFGH SCOPE cohort and the Community Consortium's Observational Cohort Study. The presentation looked at the baseline CD4+ cell count at the time of HAART initiation and discovered that it is not a major predictor of the change in CD4+ cell count over time. Investigating CD4+ cell count change over 48 weeks in patients who remain with undetectable RNA levels, regardless of the initial CD4+ count, subjects experienced CD4+ cell increases over time. Deeks summarized the clinical implications of the T-cell turnover controversy saying that the predictors of CD4+ outcome and the number of naïve CD4+ T-cells pre-HAART is the strongest predictor of the "delta" CD4+ while on HAART therapy. The other is the number of activated CD8+ T-cells. Hepatitis C co-infection appears to blunt the CD4+ T-cell increase perhaps due to chronic immune system activation. Older age also appears to be associated with a blunted CD4+ T-cell increase perhaps because of reduced naïve T-cells.

Donald interspersed pearls from the CROI throughout the course of the evening. He reviewed data on the baseline characteristics of patients in the ESPRIT cohort investigating interleukin-2 versus no IL-2 in patients on HAART in an international 23-nation trial. Data presented by Labriola et al. reviewed baseline predictors of response to the initial three cycles of IL-2 therapy in the cohort treated to date. CD4+ cell change at eight months was divided into three tertiles: (I: < 212/mm3 ;II: 212-426/mm3 ; III: > 426/mm3). It was found that higher CD4+ cell count at baseline, higher nadir CD4+ cell count and fewer years on antiretroviral therapy translate into the most robust response to IL-2. Overall, patients receiving IL-2 have a mean CD4+ cell count increase after eight months of therapy of approximately 300 cells/mm3 over baseline.

A Spanish study of 189 men in stable clinical condition outlined the associates of sexual dysfunction on HAART therapy. In this cohort study presented by Collazos et al. patients underwent serial analysis of sex hormones as well as symptoms of sexual dysfunction including erectile dysfunction, decreased libido and impaired ejaculation. The CD4+ cell count of the cohort was 451/mm3; 64% of the men had HIV RNA levels that were undetectable. Sexual disturbances were reported by 19% overall. Of patients not on antiretroviral therapy only 3.8% had sexual dysfunction compared to 24.1% on any antiretroviral therapy (p=0.0008). Use of nucleoside analogs and protease inhibitors was associated with sexual disturbances whereas NNRTI use was not. There was no association with the use of substances, hepatitis co-infections, or past AIDS diagnosis. Sexual disturbances were more frequently reported in men who had undetectable viral loads (23.5%) compared to men with detectable viral loads (12.5%, p=0.02) and in men with other metabolic disturbances (25.8%) compared to those without metabolic disturbances (16.6%, p=0.038).

Duffus et al. reported on a comparison of infectious disease consultants to non-infectious disease consultants with regard to how they obtained knowledge about treatment of HIV. Being an oncologist, Donald felt impartial presenting the results of the survey. 310 physicians in Atlanta, Baltimore, Los Angeles, and Miami participated. 148 identified themselves as ID board-eligible or board certified, 90 internal medicine, 50 family practice, 15 general practitioners, and 24 "other." Many aspects of care were similar among all provider groups. Approximately 63% of both the ID and the non-ID providers reported following the published treatment guidelines. Infectious disease consultants were more likely to obtain information about new treatment options at conferences (70% versus 55%, p < 0.01) and from medical journals (80% versus 65%, p < 0.01) than non-ID providers. They were less likely to obtain new medical information from pharmaceutical representatives (28% versus 41%, p = 0.01). Infectious disease physicians were less likely to treat patients who developed diabetes or hypertension (70% versus 95%, p < 0.0001). The ID group was also less likely to discuss condom use (p < 0.01), provide risk reduction counseling (p < 0.05) or query about illicit drug use (p < 0.05). Duffus et al. conclude that there is an "individual care advantage to having an ID physician as your provider; societal protective advantage to having a non-ID physician as your provider."

All in all, despite mixed reviews as to the utility and quantity of information at the conference, the Consortium Report Back from the 9th CROI was a successful evening. We are grateful for support for this update that was generously provided by Abbott Laboratories, Agouron, Boehringer Ingelheim, Bristol-Myers Squid, BTG Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Merck and Co, Ortho Biotech, Roche, Serono, Schering, Vertex Pharmaceuticals, and Virologic, Inc. Stay tuned for information on this summer's update from the International AIDS Conference in Barcelona! +

Return to Top

Committee Reports

Executive Advisory Board

At times in the past the Community Consortium has either been called upon or has decided to take a stance on a public policy issue that impacted on HIV patients and/or their providers. We had a unique "Social Policy and Action" member of the EAB. Lenny Simpson, M.D., and Robert Neger, M.D., have been our prior Board members who expertly handled these functions, keeping us abreast of issues that we might want to address, formulating Community Consortium policies, etc.

Currently, we have no SP&A monitor. We believe that there is no shortage of issues that we should be addressing. For instance, the HIV credentialing debate which is ongoing is certainly one in which the Consortium voice should be heard. What is our feeling? Do we have one?

We are looking for an individual in the community who may be interested in helping us decide which issues to address and helping formulate our position. If this may is something that you might like to deal with in your spare moments, please call us at the Community Consortium office at 415-476-9554 or fax 415-476-6948 and let us know! Thanks!

The Community Consortium Executive Advisory Board will meet on Wednesday, July 24, 2002 at 7:30 a.m.

Return to Top

Consortium Clinical Trials

ESPRIT

Return to Top

DHEA

We have now enrolled 22 of the target 40 patients onto the study of dehydroepiandrosterone (DHEA) to investigate how it impacts on latent HIV replication and host immunity. DHEA has been touted to have a number of beneficial effects in patients with HIV from antiviral to immunomodulatory as well as being an agent to increase lean body mass and improve quality of life. There is some evidence to suggest that DHEA may have potential benefit in purging the latent pool of HIV in resting cells.

To this end, this randomized placebo-controlled trial seeks patients fully suppressed on an antiretroviral regimen. Eligibility criteria include patients with HIV-1 infection who are 18 years or older on stable antiretroviral regimens for at least eight weeks, with HIV RNA < 50 copies/ml. Women must have a normal PAP smear and mammogram within the past year and men are required to have a normal prostate specific antigen level within the past year. Participants are randomized in a 1:1 ratio to receive either DHEA (100 mg po twice daily for males, 50 mg po twice daily for females) or placebo for 12 weeks. All study participants receive DHEA for an additional 12 weeks, for a total study duration of 24 weeks.

Study participants are seen as outpatients at the General Clinical Research Center. They have one screening and one baseline visit prior to starting study drugs. At the baseline visit, they have blood drawn for measurement of HIV RNA, viral DNA, hormone levels, lipid levels, PSA, serum chemistries, and lymphocyte subset analyses for activation antigens and naive and memory T-cell subpopulations. Body weight, height, anthropometric measures as well as body composition measurements by DEXA are obtained, and quality of life assessments are completed. Participants are randomized to either DHEA or placebo for 12 weeks. Follow-up study visits occur at weeks 2, 4, 6, and 12. Visits during the ensuing 12-week open label DHEA treatment occur at weeks 18 and 24. If you have patients who may be interested in participating in this study, please contact Paul Couey at (415) 476-9554, ext. 15.

Return to Top

Distant Healing

One hundred twenty-eight of the target 159 participants have now been enrolled in this clinical trial being conducted in collaboration with Elisabeth Targ, M.D., principal investigator of this NIH-funded study to investigate distant healing by nurses and healers as an adjunctive intervention in AIDS. On the basis of provocative preliminary data, this larger study is being conducted to further evaluate the impact of these interventions. The study is enrolled in cohorts of 15 patients. In each cohort, five patients are randomized to receive DH attempts by professional "healers", five patients receive DH attempts by nurses, and five patients receive no special intervention beyond usual medical treatments. The study is double-blind so that neither patients nor their doctors nor the researchers know who is receiving the healing treatments. Outcome measures include the clinical course, psychological course, utilization of medications as well as HIV RNA, CD4+/CD8+, NK cell function, metabolic measures and antiretroviral therapy toxicity. Eligible individuals must be HIV sero-positive between the ages of 18 and 65 with a history of having had a CD4+ cell count < 200/mm3. Patients who are not English-speaking, unable or unwilling to fill out questionnaires or who have a history of non-HIV related life-threatening disease are excluded. Study procedures are conducted at the California Pacific Medical Center site. Participants return after their baseline evaluation to this study site at six months and one year for follow-up questionnaires and blood work. The research assistant will extract the remainder of the data from clinic charts. We are especially eager to complete enrollment of the remaining participants in this trial as Elisabeth Targ is currently battling a glioblastoma (www.etarg.org). Please direct an intention for health and wellbeing in Elisabeth's direction and patients who may be interested in enrolling to Paul Couey at (415) 476-9554, ext. 15.

Return to Top

MDR

The Community Consortium has enrolled 21 patients of the 259 accrued throughout the CPCRA. Jody Lawrence, M.D., from our unit is the protocol chair for this study, which is now the largest randomized STI trial accrued to date. The Data Safety Monitoring Board (DSMB) of the NIAID recently reviewed the study. The DSMB commended the study team for the design of this very important study and found no safety concerns that would warrant early termination of the trial.

This study of an 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 initiate the salvage regimen based on information generated from both genotypic and phenotypic resistance testing that is provided as part of the protocol.

Four hundred and eighty subjects will be randomized in the trial. Participants are followed monthly for the first 8 months, and then every 4 months. Should CD4+ cell counts drop below threshold levels, prophylaxis for opportunistic infections is resumed. This study will provide much information on the kinetics 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 include age > 13 years with HIV RNA >5000 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 the 103M 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 the 215Y/F mutation. Any patient previously exposed to at least two PIs and either a) three nucleosides/nucleotides or b) at least one NNRTI, 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!

Return to Top

FIRST

The CPCRA's Flexible Initial Retroviral Suppressive Therapies (FIRST) trial, the entry point into the CPCRA's menu of strategic antiretroviral studies for naïve patients, closed to further enrollment on January 13, 2002. The study surpassed its target enrollment and will now continue to follow subjects already accrued. The Consortium contributed 49 of the 1397 patients randomized in the study. Stay tuned for further information to be made available as the study matures. Thanks to all who referred participants to the study and especially to Robert Scott, M.D., who enrolled 29 with the able assistance of the Consortium's Paula Pell, R.N.!!! .

Return to Top

Marijuana for HIV Neuropathy

We are delighted to report that our pilot trial of smoked marijuana in patients with HIV-related peripheral neuropathy has enrolled the first four of its 16 target subjects. The 9 day in-patient study is conducted in the General Clinical Research Unit at San Francisco General Hospital. Eligible subjects must have neuropathy with persistent measurable pain confirmed by Cheryl Jay, M.D., our neurologist co-investigator. Subjects also undergo an experimental pain model using heat and capsaicin that will hopefully provide increased information on the mechanism of cannabinoid-induced anesthesia. It is expected that the results of this small pilot will allow us to calculate the sample size for a follow-on randomized placebo-controlled trial. Participants must have smoked marijuana at least six times previously in their life and need to discontinue marijuana smoking for at least 30 days prior to enrollment. If you have patients with neuropathy who may be interested in participating, please contact Hector Vizoso, R.N., at 415-476-9554, ext. 21.

Return to Top

Adherence Study

How to ensure that our patients can best adhere to the complicated HAART regimens that we prescribe is a most important question. 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." Future patients enrolled onto the MDR 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 - the medication managers and a timer alarm. The ultimate goal will be to evaluate which intervention produces the best HIV RNA results as well as self-reported adherence. The Community Consortium has enrolled 22 of the 1103 participants being followed by the CPCRA overall.

Return to Top

Long-Term Monitoring (LTM)

The CPCRA is committed to long-term evaluation of patients enrolled on randomized clinical trials. Where a number of our studies 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. Currently, we are working to enroll all patients from CPCRA randomized interventional trials onto LTM. The Consortium has a goal of 100% co-enrollment onto the LTM protocol for eligible patients. To date, 3,180 patients are being followed on the LTM nationwide, including 153 from our site.

Return to Top

Observational Cohort Study

The Consortium continues to follow nearly 900 subjects enrolled on the Observational Cohort Study. Funded by the Universitywide AIDS Research Program (UARP), the OCS has focused on an analysis of how Bay Area patients with HIV are treated compared to the DHHS published treatment guidelines. The OCS has recently pooled data with the SCOPE cohort of Steven Deeks, M.D. at San Francisco General Hospital leading to increased power to make observations. Our observational studies have been analyzed by our able biostatistican, Starley Shade, MPH, who is about to go on maternity leave in conjunction with the upcoming birth of her daughter in July. Please join us in wishing Starley the best. We hope to be able to share with you results from her analyses of the OCS in a special version of synopsis to be produced post-partum!

Return to Top

SMART

The Strategies for Management of Antiretroviral Therapy (SMART) study was launched on January 2nd. The Community Consortium has enrolled 17 of our target 50 patients to be randomized in year one. Congratulations to Nilda Alverio, M.D., of Castro Mission Health Center and Michael Jones, R.N., for enrolling the Consortium's first SMART participant! The trial is open to subjects with CD4+ cell counts greater than 350/mm3 currently on or naïve to antiretroviral therapy. There are two strategies to which patients are randomized to in the study. In the Viral Suppression (VS) arm the goal is to use antiretroviral therapy to maintain viral load as low as possible throughout the anticipated six to nine years of study follow-up. In the Drug Conservation (DC) strategy arm, antiretroviral therapy is stopped (or deferred) until the CD4+ positive T-cell count drops to less than 250/mm3 at which time episodic antiretroviral therapy is initiated to increase the CD4+ cell count to greater than 350/mm3. 3000 participants are required per arm for a total target sample size of 6000.

A participant randomized to the VS group who is already receiving antiretroviral therapy will, if fully suppressed, just continue their current regimen. If there is a detectable HIV RNA level, the regimen should be modified to achieve viral suppression. Naïve individuals not on therapy at the time of randomization to the VS arm will begin HIV therapy - again with the goal of maintaining the HIV RNA level as low as possible for as long as possible.

For participants randomized to the DC arm who are on HAART at the time of randomization, antiretroviral therapy will be stopped until the CD4+ cell count drops under 350/mm3, verified on repeat testing. Once that threshold is reached, the provider is instructed to "hit hard" to restore the CD4+ cell count to greater than 350/mm3. For naïve patients randomized to the DC arm, HAART is deferred until the CD4+ cell count drops to less than 250/mm3. The goal of the DC arm is to conserve anti-HIV agents until the risk of HIV disease increases. Clinical judgment prevails over the protocol guidelines throughout, such that if a patient becomes symptomatic or if the provider prefers to use, for example, a cutoff of less than 15% CD4+ cells, therapy can be initiated. Once treatment restores CD4+ cell counts back to greater than 350/mm3 (verified on at least two measurements), it is then discontinued again until the 250/mm3 CD4+ cell threshold is reached. Hence individuals randomized into the DC arm will oscillate with CD4+ cell counts held roughly between 250-350/mm3, a zone with very low risk of HIV disease progression during the course of the entire study.

Once a subject is enrolled on the SMART study, follow-up visits will be scheduled at months one and two, and then every two months in the first year. Subsequent visits are every four months until the end of the trial. It is anticipated that the VS group will have a CD4+ cell advantage for the first few years of the study. Whether that advantage persists over the ensuing years and which strategy provides a clinical benefit are the questions being asked in the trial. With a multi-year 6000 participant trial, it would be silly not to ask additional questions. Hence a number of substudies are being conducted as part of SMART. The Community Consortium will participate in a quality of life/healthcare utilization substudy where the VS and DC groups will be compared for QOL and symptom severity as well as healthcare utilization and resulting costs. In addition, Consortium participants will be able to participate in an HIV transmission risk behavior substudy. Here subjects will complete a confidential risk behavior self-report describing condom use and needle-sharing behavior. In addition, biological testing for subjects in the substudy will include syphilis serology and urine testing for Neisseria gonorrhea and Chlamydia trachomatis. If you or your patients might be interested in participating in the SMART study, please contact Pierre Crouch, R.N., at (415) 476-9554, ext. 23, for further information.

Return to Top

New in the Bay Area . . .

Positive Partners Study

Return to Top

Women's Interagency HIV Study (WIHS)

Return to Top

Stay Tuned for Vorologic, Inc. Replication Capacity Assay