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Educational Programs

Barcelona Update

The next Community Consortium event will be a "Report Back from ICAAC" dinner to be held Wednesday evening, October 16, 2002, at the Pacific Campus of the California Pacific Medical Center. ICAAC is a meeting where ongoing clinical trials of antiretroviral agents are updated and early phase studies of new agents are presented.

Stephen O'Brien, M.D., of the East Bay AIDS Center, will moderate the ICAAC Update. The distinguished panelists include Susan Jacobson, M.D., ID Consultant at Kaiser Hayward, Ian McNicholl, Pharm.D., of the UCSF Positive Health Program at San Francisco General Hospital and Paul A. Volberding, M.D., Chief of Medicine at the San Francisco Veteran's Administration Medical Center. Attendees will be eligible for 2.5 hours of Category 1 CME credit.

The next Community Consortium Saturday CME Program, "HIV Treatment Complications: Pathogenesis, Prevalence and Potential Therapies", will be held at California Pacific Medical Center, Pacific Campus on November 2nd, 2002, from 8:00 a.m. to 12:30 p.m.. This program will highlight the pathophysiology, incidence and treatment of some of the more frequently encountered complications of antiretroviral therapy. Presentations will include discussions on the basic science of the metabolic abnormalities, body habitus alterations and potential therapeutic interventions for some of these disorders. In addition, there will be discussions of bone abnormalities in the HAART era and cardiovascular complications. The truly expert pan includes James Weiel, Ph.D., of GlaxoSmithKline, Carl Grunfeld M.D., Ph.D., of the San Francisco Veterans Administration Medical Center, Morris Schambelan, M.D., and Joan Lo, M.D., of San Francisco General Hospital and Dan Klein, M.D., of Kaiser Hayward. This promises to be a most informative and provocative session. We hope to see you there at our final Saturday CME program for 2002.

We are grateful to Merck and GlaxoSmithKline for unrestricted educational grants to assist in this presentation. California Pacific Medical Center is accredited by the California Medical Association to provide continuing medical education activities to physicians. The CPMC Office of Continuing Medical Education certifies that this continuing medical education activity meets the criteria for 3.5 hours of category 1 of the physicians' recognition award of the AMA and the certification program of the California Medical Association. Barcelona Update

On July 24th, the Consortium hosted a "Report Back from Barcelona" post-meeting update dinner following the XIV International AIDS Conference held in Barcelona, Spain. Featured panelists were Richard Cazen, M.D., and William Owen M.D., private practitioners from California Pacific Medical Center, Donald Abrams, M.D., and Diane Havlir, M.D., the new chief of the UCSF Positive Health Program at San Francisco General Hospital. Attendees warmly welcomed Dr. Havlir into the local HIV care provider community!

Donald opened the session with some general impressions of the Barcelona meeting. He noted that this truly is now a global conference. Participants come from all over the world. There is less of a focus and emphasis on U.S.-dominated science and presentations. No major breakthroughs in treatment were reported…or expected; incremental steps forward will continue to be the norm at such meetings for the near future. He suggested that there seemed to be an ongoing tension between those who are supportive of increased prevention efforts worldwide versus those who are demanding increased access to treatments. There was also a groundswell at this meeting suggesting that there is a "right" to an HIV vaccine. Anger and activism appeared to be out in full force at the Barcelona meeting. There were daily demonstrations in the pharmaceutical industry booth area of the meeting that also tended to disrupt the clinical science oral presentations occurring in the same venue. It was interesting to note that the thrust of the activism at this year's meeting was towards making available up to $10 billion for provision of antiretroviral therapy to all of those requiring it in developing nations.

Prior to the conference UNAIDS had released some rather grim global figures that Donald reiterated. Currently there are more than 40 million people infected with HIV. Nine percent of the adults in sub-Saharan Africa carry the virus; that constitutes 28.5 million people. In Botswana, 39% of the adults are HIV positive with a national life expectancy now of less than 40 years. One-third of the adults in Zimbabwe are infected. Of the millions of people in southern Africa with HIV, only 30,000 are currently on antiretroviral therapy; 2.2 million people died there last year from complications of HIV infection. The epidemic is doubling in Asia and Eastern Europe as well. Currently there are 3 million children worldwide under age 15 infected with HIV.

UNAIDS reports that 3 million people died worldwide from AIDS in 2001, bringing the cumulative total to 21 million since 1981. There are currently 14 million AIDS orphans, creating a tremendous social and economic burden in heavily impacted nations. The agency predicts that 70 million people will be dead in the next 7 years without significant aid. It has been requested that $7-10 billion/year should be made available to combat the problem by 2005. With such a huge burden of HIV infected people to be treated, it is clear that not all patients can be cared for by infectious disease consultants or HIV physician specialists. A poster presentation from the University of Southern California looked at a comparison of M.D.'s vs non-physician clinicians regarding outcomes of HIV care. Four hundred twenty patients seen in the Los Angeles clinic during April 1999 were evaluated. The mean age of the clients was 39 years, 84% were minority patients and 60% had a prior AIDS-defining diagnosis. M.D.'s treated 203 patients with a baseline CD4+ count of approximately 300/mm3. Fifty-nine percent of the M.D. treated cohort had HIV RNA levels of < 50 copies/mL. Non-physician clinicians, including nurse practitioners and physician assistants, cared for 217 patients whose CD4+ counts averaged 290/mm3. Seventy-one percent of the NPC's clients had undetectable viral loads. This suggests that there was comparable success looking at surrogate marker parameters. It was noted that the NPCs were more likely to utilize dual protease inhibitor regimens. The physicians were more likely to delay the initiation of antiretroviral therapy in their patients.

NEW AGENTS

Bill Owen, M.D., opened his comments with an overview of information presented on new antiretroviral agents. He began with a new class of drugs - the entry inhibitors. He described the various stages of HIV entry into cells and noted that the inhibitors in development actually target different steps in the process. The Roche/Trimeris drug, T-20 (enfuvirtide), is clearly the furthest along in development, and now is available in limited expanded access programs. Bill presented results of the aptly-named TORO (Add T-20 vs Optimized Regimen Only) trials. TORO 1 (conducted in the US and South America) and TORO 2 (conducted in Europe and Australia) both randomized antiretroviral experienced patients with HIV RNA > 5000 copies/mL to T-20 plus optimized background regimen (OB) vs OB alone. Each study included nearly 500 participants with CD4+ counts in the 80-100/mm3 range. In both studies, the OB group sustained a ~0.70 log10 reduction in viral load, while the T-20 arms declined 1.70 and 1.43 logs in TORO 1 and 2, respectively (p<0.0001 in both). T-20 recipients were also more likely to have HIV RNA levels suppressed to undetectable levels using both 400 and 50 copies/mL as threshold values.

The Pfizer UK 427,857 CCR5 inhibitor appears to selectively block the chemokine receptor. Where prior agents in the class had problems with QT interval prolongation on ECGs, this drug is HERG selective. The agent has a very slow rate of dissociation from the receptor and in vitro appears to be additive with nelfinavir, 3TC and efavirenz. In studies to date, a dose effect curve and cross clade activity have been demonstrated. Clinical trials will investigate bid or less frequent dosing.

MediVir, a Swedish company, is developing a new reverse transcriptase inhibitor. FLT (alovudine) is an AZT like drug, being a fluorinated thymidine analog. Its development was abandoned in the early 1990's because of bone marrow toxicity. It is 10 times more potent than AZT in vitro and in monkeys. Once daily dosing is also possible. In the MIV-310 trial, 15 patients with NRTI resistant virus added FLT to their regimen as intensification. The agent was well tolerated. After 4 weeks of treatment, PCR HIV RNA levels decreased 1.88 log in those not on d4T (8/11 < 400 copies/mL) and 0.57 log in those receiving d4T (1/4 < 400 copies m/L). All returned to baseline viral loads on discontinuation of therapy with no new resistance mutations being seen. New NNRTI's include Agouron's capravirine, which had been slowed in development because beagles had developed vasculitis. As there has been no evidence of this complication in humans, trials will resume. TMC 125 is a potent next generation NNRTI developed by Tibotec Virco. It is equipotent in vitro against wild type and virus with resistance mutations. A 2 log decrease in PCR was seen after just 7 days of monotherapy. A small clinical trial substituted TMC 125 for a failing NNRTI in 16 patients, all of whom had 1-4 NNRTI-associated mutations. The mean decrease in HIV RNA was 0.86 log after 8 days. Treatment was generally well tolerated, with diarrhea and headache as the most common side effects.

With regard to new protease inhibitors, Bill reported on the BMS PI atazanavir, which is moving along the drug development pathway. In the BMS AI424-044 trial, the primary objective was to assess the change in total cholesterol for subjects who switch from nelfinavir to atazanavir 400 mg qd. The study of 346 individuals showed that substitution of nelfinavir 1250 mg bid with ATV 400 mg qd as part of a 3-drug regimen (d4T+3TC) was associated with an improvement in the lipid profile at week 12. Decreases were observed in total and LDL cholesterol as well as triglyceride levels.

The resistance profile of atazanavir appears to differ in naïve and experienced patients. Naïve subjects from a number of nelfinavir vs. atazanavir studies were evaluated for resistance mutations. Of 17 virologic failures, the 8 NFV failures all retained sensitivity to ATV. All of those who failed ATV had the signature I50L mutation, specific to ATV, and from 4-11 additional mutations, often including an A71V. The people failing ATV were susceptible to all other protease inhibitors; in fact, they were most frequently hypersusceptible to all others. Of 8 experienced patients who failed ATV-SQV, the I50L and A71V mutations were absent in all of them. These individuals were resistant to other PI's although they remained susceptible or hypersusceptible to amprenavir. Dr. Owen also reviewed the progress in the development of integrase inhibitors. The original integrase strand transfer inhibitors were diketones. These had poor pharmacokinetics and showed only modest activity. L-870,810 is a potent integrase inhibitor being developed by Merck that has activity even against MDR HIV in cell cultures with good pharmacokinetics in animals. No significant cytochrome p450 interactions are seen. L-870,812, a similar compound, has been studied in rhesus monkeys with impressive early findings. Shionogi is jointly developing an integrase inhibitor with GlaxoSmithKline. S-1360 is a diketo acid integrase inhibitor, which is being studied in a randomized, double-blind, placebo-controlled, escalating, and multiple-dose study in healthy volunteers. No serious adverse events have been seen yet, with headaches being the most common to date. The drug is highly protein bound (98-99.98%) with a half-life that ranged from 7.7 to 16 hours across all doses. Clinical trials in patients with HIV infection are now being planned.

AGENTS IN USE, NEW RESULTS

Diane Havlir, M.D., gave an overall positive impression of the International AIDS Conference, remarking that it provides a very positive potential for networking among the many different sorts of people in attendance. She opened her discussion by reviewing data on tenofovir in various patient populations. The results of Gilead 903, the use of TDF in treatment-naïve patients, were presented as a late-breaker oral session. This phase III, randomized, double-blind, placebo-controlled trial was conducted in 600 patients with viral load > 5000 copies/mL. Patients were randomized to treatment with 3TC and efavirenz with either d4T or TDF. CD4+ count at baseline was 279/mm3, with a VL of 4.9 log10 copies/mL. At baseline, 24% of the subjects were women and 36% were non-white. At 48 weeks all efficacy measures (HIV RNA and CD4+ counts) and safety parameters were comparable in the two arms. The TDF group sustained a change in cholesterol of +25 mg/dl at week 48 compared with +53 mg/dl in the d4T cohort (p<0.001). Dr. Havlir remarked that the long-term toxicity profile of the drug remains unclear at this time.

Gilead 907 was a study of TDF in 550 treatment-experienced patients on stable antiretroviral therapy with viral loads of 400-10,000 copies/mL. The study design was to randomize patients to add TDF 300 mg or placebo (2:1) to their regimen with a crossover of the placebo arm to active drug after week 24. The baseline VL of the participants was 2340 copies/mL with a CD4+ count of ~325/mm3. Fifty percent of the group was on a PI containing regimem, 40% on an NNRTI regimen. At week 24, the VL was unchanged in the placebo group, but had dropped 0.6 log in the TDF recipients. The CD4+ cell increase of +13 cells at week 24 in the TDF group was less robust than what was observed in the naïve cohorts, but better than the 11 cell drop seen in the placebo arm. Dr. Havlir described TDF resistance as a complicated and evolving area. Data from 333 subjects in two TDF trials was presented. In summary, the 41/210 mutation pathway leads to less virologic response to TDF; whereas even with three TAMs sans 41/210 the antiviral response is reasonable.

An important PK study evaluating the interaction of TDF and ddI-EC was described. This was a classic PK study involving 28 healthy subjects in a 15 day crossover design in both fasting and fed states. Tenofovir PK was unaffected by food and unchanged by ddI-EC. In TDF (fed) and ddI-EC (fasted), a 48% increase in ddI Cmax and AUC was seen. In the TDF - ddI-EC (fed, simultaneous) arm, there was a +64% ddI Cmaz and +60% AUC. This mandates a dose adjustment of ddI when given in conjunction with TDF. Bill Owen offered that he is reducing ddI-EC doses to 250 mg when given with TDF but not altering times of administration. The ACTG 384 trial investigated 3 vs 4 drug regimens in treatment naïve subjects. The objective of the trial was to investigate which is the better strategy for initiation of treatment - to start with an NNRTI, PI or both. The study was a randomized partially blinded study in 980 treatment naïve subjects with HIV RNA > 5000 copies/mL. The study was a 2 x 3 factorial with randomization to ZDV/3TC vs ddI/d4T followed by a second randomization to receive EFV vs NFV vs both. The primary endpoint was the time to failure of two sequential 3-drug regimens or time to failure of a 4-drug regimen. Of the subjects enrolled, 18% were women and 53% were nonwhite. The baseline CD4+ count was 278/mm3 with a viral load of 87,000 copies/mL (41% >100,000). During the trial 396 participants permanently discontinued their study medications (15% non-compliance, 14% complexity, 11% loss to follow-up, 11% toxicity). The bottom line was that there were no real differences in any of these strategies. Trends seemed to favor the ZDV/3TC/EFV regimen, although the confidence intervals overlapped. With regard to time to first regimen failure, EFV with ZDV/3TC appeared superior to NFV. ZDV/3TC appeared superior to the ddI/d4T combination with EFV. The ddI/d4T arm also had a shorter median time to severe or greater toxicity (52 wks) than the ZDV/3TC arm (104 wks). The study appears to have clearly demonstrated that use of both an NNRTI and PI offers no advantage to the use of EFV/ZDV/3TC as first line therapy.

The CLASS study is another treatment naïve trial that is ongoing. Interim results were presented and reviewed by Dr. Havlir. Two hundred ninety-one patients received ABC/3TC and either EFV, APV/r or d4T. Baseline CD4+ count was ~ 300 cells/mm3 with a viral load of 4.9 log10 copies/mL. Interim results at week 48 again showed comparability among all three arms with regard to VL < 400 copies/mL, time to treatment failure and time to virologic failure, CD4+ cell responses and adverse experiences. The NNRTI arm appeared superior in patients with baseline VL >100,000 copies/mL and in the proportion of patients achieving HIV RNA levels of < 50 copies/mL. The study will continue through its planned 96 weeks.

Dr. Havlir reviewed progress in once daily regimens. The d4T XR (extended)/PRC (prolonged) formulation has bioavailability that is not affected by food. A 48-week comparison study looking at EFV/3TC with either d4T XR/PRC or d4T IR demonstrated similar virologic efficacy and adverse event profiles. A phase II trial of ZDV 600 mg qd compared to 300 mg bid in 32 naïve patients with HIV RNA > 7500 copies/mL showed a 0.85 log reduction in the bid arm compared with 0.59 log10 in the qd recipients (p=0.056). A once daily regimen of NVP/ddI/TDF dosed together with breakfast was compared to continuation of the original regimen in a randomized multicenter study of patients with undetectable viral loads for longer than 6 months. At a planned interim analysis, 65 of the 159 participants had completed 24 weeks of study. Viral load remained undetectable in 63 with no change in CD4+ cell counts seen. Triglycerides decreased an average of 61 mg/dl in the qd arm. There was no difference in self-reported adherence between the two groups.

Dr. Havlir concluded her remarks by discussing whether HIV DNA may have any role to play in patient management. In this assay, HIV DNA from cells is analyzed via PCR. Interesting data are emerging regarding the utility of the assay as a predictor of HIV disease progression. An oral presentation in Barcelona investigated DNA levels in 130 patients in a hemophilia cohort with 16 years of follow-up. Faster rates of progression to AIDS or death were seen in people with higher DNA levels, the predictive value being independent of HIV RNA measurements. Dr. Havlir then presented some of the work that she reported on in Seville at the Resistance meeting. The research was designed to investigate how viral load really decays. Fourteen patients treated 5-6 years with IDV/EFV with VL < 50 copies were investigated. Each of the patients stayed completely suppressed over the follow-up period, but at different set points, established by 9 months of therapy (2.5-30 copies/mL). Of note, the set point was predicted by pretreatment proviral DNA, not by baseline HIV RNA, CD4+ cell count or time to HIV RNA < 50 copies/mL. The future clinical role of HIV DNA remains to be determined.

TREATMENT COMPLICATIONS

Dr. Cazen began his report back with an overview of Carl Grunfeld's presentation on the Fat Redistribution And Metabolism (FRAM) Study. Dr. Grunfeld will be sharing the data at our November 2nd Saturday CME program. Briefly, FRAM is a cross-sectional analysis of 800 HIV+ men, 350 HIV+ women and 300 controls from the CARDIA study. Individuals undergo BIA and DEXA evaluations and are also assessed for lipodystrophy by questionnaires and examination. In Barcelona, he gave a presentation of data from 357 of the younger males in the study. The median HIV RNA of the HIV+ cohort was <400 copies/mL. Fourteen percent were not on HAART; 53% were on protease inhibitors. Lipoatrophy was more common in the HIV+ participants (40%) compared to the controls (5%). The loss of fat was more pronounced in the lower body, giving an illusion that the individual was bigger in the mid-section. Dorso-cervical fat pads (buffalo humps) were seen more frequently in the HIV negative controls (12% vs 7%). Along the same lines, visceral adipose tissue (VAT) accumulation was less common in the HIV patients than in the controls. There appeared to be no difference in VAT by DEXA scan in HIV+ patients whether they had peripheral lipoatrophy or not. VAT volume increased with age in both cohorts. Most of those in attendance found this information to be quite surprising. For a more in-depth review of the FRAM data, please make sure to attend the November 2nd CME program! Not to be confused, the FRAM study of the Atlantic trial was also presented. This randomized antiretroviral trial utilized a backbone of ddI/d4T with randomization to IDV (21), NVP (22) or 3TC (26) as the third drug. (Numbers refer to those included in the FRAM substudy evaluation, not the entire Atlantic trial.) Substudy participants were enrolled after 72 weeks of treatment and followed with a questionnaire, CT, DEXA, BIA, resting energy expenditure measurements and labs every 24 weeks. Overall, 49.3% developed mild to severe lipoatrophy; 24.6% moderate to severe fat accumulation; or 9.8% both. There were no significant differences among the groups, although IDV compared to each of the other third drugs individually appeared more likely to be associated with changes.

Dr. Cazen then discussed a large Italian study evaluating the incidence of coronary artery disease in HAART patients with or without protease inhibitors. Fifteen hundred fifty-one patients were randomized to receive two NRTIs and either a protease inhibitor (776) or an NNRTI (775). Excluding patients who switched classes or were lost to follow-up, the investigators reported on 587 evaluable PI and 621 NNRTI patients. The PI recipients had markedly elevated triglyceride levels, cholesterol levels and other evidence of metabolic disorder compared to the NNRTI recipients. Ischemic heart disease was defined as the development of angina, non-Q wave myocardial infarction or Q-wave MI. Overall, the risk of developing ischemic heart disease was 9.8 cases/1000 patient years in the PI group compared to 0.8 cases/1000 patient years in the NNRTI group. The fact that events occurred after two years is more suggestive of atherosclerosis as opposed to thrombosis. A number of variables were associated with the risk of developing CAD events including lipodystrophy, dyslipidemias, smoking, gender, therapy, increased fibrinogen and hyperglycemia. These findings are also somewhat divergent from those that will be presented by Dan Klein, M.D. who will review the Kaiser experience at our November 2nd CME program.

The results of the Serono STARS study of recombinant human growth hormone for the treatment of HAART associated visceral fat accumulation were presented in a late-breaker session. Dr. Cazen reviewed the study design, which randomized 239 patients to receive either rhGH 4mg subcutaneously daily (78), every other day alternating with placebo (82) or placebo (79). After the initial 12 weeks, placebo recipients received daily rhGH, the alternate day group continued the same schema, and the daily group was randomized to continue daily therapy or receive placebo injections. The co-primary endpoints were change in distribution of adipose tissue at week 12 as measured by abdominal CT scan for visceral adipose tissue and trunk:limb fat ratio measured by DEXA scan. Statistically significant benefits in both measurements were seen in the daily dose > alternate day dose groups compared to placebo recipients. Improvements in total cholesterol and non-HDL cholesterol were seen only in the daily dosing group.

Dr. Cazen presented some pearls related to hepatitis co-infection. HIV/HCV co-infected patients have more rapid rates of fibrosis progression and higher inflammatory grades compared to HCV infected patients. Progression to cirrhosis is also estimated to be more rapid (21 years compared to 38 years). Two studies reported on the comparison of pegylated-interferon alfa-2B plus ribavirin versus interferon alfa 2-B plus ribavirin. In both trials, PEG-IFN was found to be superior with response rates at 48 weeks of 44% vs 27%. He cautioned, however, that one should not use ddI or d4T with ribavirin because of an increased risk of pancreatitis that could be fatal. Regarding hepatitis B, Dr. Cazen mentioned a trial where tenofovir was added to 3TC in HIV/HBV co-infected patients with detectable HBV DNA. There was a median 2.89 log10 (0.71-4.70) drop by week 12 to 24 with one person losing HBsAg by week 48.

BARCELONA PAELLA

Donald continued his impressionistic overview by commenting on a number of studies evaluating treatment complications. He shared a quotation from Abigail Zuber, M.D., that had appeared in the July 9 New York Times - "Half the world is determined to put as many patients as possible on medication, while the other half is trying to take as many patients as possible off." A study conducted in two centers in Buenos Aires randomized patients to continue therapy or stop for 48 weeks. Eligible patients were those on ARV treatment for more than 6 months who met prior but not current recommendations for therapy, i.e., CD4+ > 350/mm3, VL < 60,000 copies/mL. Study endpoints are CD4+ < 350/mm3 on two measurements, a one log increase in viral load, the development of symptoms or an AIDS-defining diagnosis. Very preliminary data was reported as only 13 people had reached week 48. Of the 36 enrolled, 20 were randomized to the treatment interruption and 16 to continue therapy. The CD4+ cell counts range from 600-630/mm3 on average with an approximate nadir of 450/mm3. Most had been on treatment for about three years with pre-therapy viral loads 24,000-36,000 copies/mL. Viral load had risen to pre-treatment levels by 4 weeks in the group interrupting therapy. The net CD4+ cell loss was only 14 cells/mm3. Interestingly hemoglobin increased from 13.3 gm/dl to 15.1 in the STI group. A cost estimate suggested that the annual expense in the interrupted group is $870 compared with $4000 in those continuing therapy. The investigators concluded that it is safe to discontinue treatment in "prematurely treated" patients. Joel Gallant, M.D., from Johns Hopkins, came to a similar conclusion from a treatment interruption observational database that enrolled 75 subjects at the time they stopped therapy. Prior to HAART, the group had an average CD4+ count of 426/mm3 and a viral load of 27,000 copies; at the time of interruption these values were 677/mm3 and 263, respectively. One third of the cohort had undetectable HIV RNA at discontinuation. Twenty-three individuals resumed therapy at a mean of 30 weeks after interruption. Their CD4+ cells had dropped 258/mm3 to a total of 258/mm3 prior to resumption. The viral load rose to 160,000 copies prior to resuming therapy. The majority (52) of the patients remained on the TI for an average of 69 weeks. They had experienced a similar magnitude of CD4+ decline, but only reached 508/mm3 with HIV RNA of 22,000 copies/mL. Metabolic abnormalities and body habitus alterations appeared to improve in the treatment interruption group. Dr. Gallant concluded, "people who didn't need therapy then, don't now" and reminds us that treatment should be initiated based on CD4+ cell count, not HIV RNA levels. Christine Katlama, M.D., from Paris, presented data from her study of STI followed by GIGHAART in salvage. This trial compared immediate versus deferred GIGHAART (3-4 NRTIs, one NNRTI, 3 PIs and HU) in 70 patients with baseline CD4+ counts of 26/mm3 and HIV RNA of 5.2 log10. Participants had been exposed to an average 11 drugs over 6-7 years of antiretroviral therapy. Thirty-four evaluable patients were randomized to an 8-week treatment interruption prior to commencing GIGHAART and 34 to immediate GIGHAART. During the STI, CD4+ cells declined 10 cells (40%) and HIV RNA increased 0.16 log. The STI group had statistically significant greater declines in HIV RNA compared to the GIGHAART group both at week 12 (-1.91 log vs -0.37 , p=0.008) and at week 24 (-1.08 log vs -0.29). Twice as many of the STI group experienced more than one log reductions and a greater proportion (32% vs 12%) were able to achieve suppression to < 400 copies/mL. The delayed GIGHAART group also had a more robust CD4+ cell increase of 51 cells compared to 8 in the immediate group. Donald contrasted this data to the preliminary findings of the CPCRA 064 MDR trial that has recently closed to new accrual (see below). In the CPCRA trial, which that investigated a 4-month treatment interruption and did not specify a particular salvage regimen, the STI group had more clinical events and an inferior CD4+ cell response compared to the no STI group. Patients are continuing to be followed for clinical events in the CPCRA study and further analysis details will be forthcoming.

A number of presentations covered results of non-occupational post-exposure prophylaxis (nPEP) registries. The CDC presented data on their 424-person nPEP Surveillance Registry comprised predominantly of participants in Boston and San Francisco. The majority of the participants were men (71%) with a source patient being known in 215 cases. In 124 instances the source was known to be HIV+. Anal receptive intercourse was the most common risk behavior (44%). NPEP was provided to 99% of the cohort, 97% taking treatment for 4 weeks. Fifty-three percent took three drugs and 43% took two. Combivir (39%) and CMB/NLF were the most frequent regimens. Three-quarters completed 4 weeks of treatment; of the discontinuations, 55% were because of symptoms. Of 160 evaluable, there was only one seroconversion in an exposed partner who had had unprotected insertive anal intercourse with an HIV+ source patient with >100,000 copies/mL of HIV RNA. The presentation was extremely well complemented by the discussion of the 901 case European nPEP registry, although there were more seeking treatment for heterosexual exposures. The providers considered all but 48 of these exposures low risk, but 60% of the 901 were treated and 80% received a three-drug regimen. Again, there was only one documented seroconversion in a gay German who had insertive anal intercourse with an HIV+ source and experienced a broken condom.

A very provocative presentation on PEP for sexual violence in the Congo was given by a physician from the Medecins Sans Frontiéres (Doctors Without Borders) group. War refugees returned home to problems of malnutrition and rape. MSF intervened with a feeding center and support for victims of sexual violence in Brazzaville. From 1999 -2002, 1555 people were admitted to the program. Individual data is available on 329 people, of whom 99% are women, ages 2-55, with many under 16 years of age. Vaginal rape was reported in 49% of the cases, 53% with multiple aggressors and 51% with government aggressors. Thirty-one percent of the women were pregnant at the initial visit and 4% were HIV positive at baseline. Care was provided within 72 hours to 132 women, including morning after contraception (52%), STD prevention (88%) and HIV prophylaxis (84%). Initially ZDV monotherapy for 28 days was used; more recently CMB has been provided. No seroconversions have occurred to date but there is a very high (68%) rate of lost to follow-up. PEP has been well tolerated with only 3 minor side effects of therapy reported. The MSF physician reminded all in attendance that caring for the victims of such tragedy is a universal responsibility of all health care providers.

On the other end of the exposure prophylaxis spectrum is the concept of pre-exposure prophylaxis (PrEP). In some developing nations, for example, it is suggested that sex workers may need to continue to work to ensure their livelihood. To protect them from acquiring HIV, PrEP may be an option. A group at Johns Hopkins has evaluated three low doses of nevirapine as potential PrEP in high-risk populations. To date, a small safety and PK study has been conducted evaluating NVP 200 mg weekly, twice weekly or every other day. Of the 33 subjects enrolled, 9 did not complete the 12-week treatment course and 8 are lost to follow-up. Trough NVP levels were > 100 ng/ml in all groups with stable levels except in the high dose group where enzyme induction was seen. In general, therapy was well tolerated, with no rashes or jaundice seen although higher LFTs were appreciated at the higher doses, especially in HCV co-infected patients. Tenofovir has also been suggested as a potential agent to study for pre-exposure prophylaxis in high-risk populations. Expect to hear more about this intriguing concept as the lines between prevention and treatment continue to merge in this truly global pandemic. The Community Consortium is grateful to our friends and colleagues at Abbott Laboratories, Agouron, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Merck & Co., Serono, Roche and ViroLogic, Inc. for the generous support for this educational program.

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Committee Reports

Executive Advisory Board Report

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, October 30, 2002 at 7:30 a.m.

Welcome New Consortiumites

Congratulations to Starley Shade, M.P.H., Consortium biostatistician par excellence, on the arrival of Elizabeth Pearl, born July 6, 2002. Starley is the first Community Consortiumite to deliver while a staff member in our 1 year history! We are delighted to report that the mothers, Starley and partner Lynn Wenger, M.S.W., M.P.H., and baby are doing fine and that Elizabeth has consented to allow Starley to return to work sometime in the very near future!

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Clinical Trials Update

ESPRIT

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DHEA

We have now enrolled 29 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.

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Distant Healing

We are deeply saddened by the untimely death of Elisabeth Targ, M.D., principal investigator of the NIH-funded Distant Healing study and highly respected psychiatrist at the Pacific Campus of the California Pacific Medical Center. Elisabeth succumbed after a short battle with her glioblastoma that had been recently diagnosed. She will be deeply missed by all those whose lives she has touched. The 143 participants enrolled in the clinical trial are undergoing continued follow-up. The study will enroll 30 more patients, each of whom is randomized to receive distant healing attempts by professional "healers", distant healing attempts by nurses, or no special intervention beyond the usual medical treatment. Eligible patients must be HIV seropositive between the ages of 18 and 65 with a history of having had a CD4+ < 200/mm³. Patients who are not English speaking, who are unable or unwilling to fill out questionnaires or who have a history of non-HIV related life threatening illnesses are excluded. Participants are seen at baseline, 6 months and one year. Please direct any interested patients to Paul Couey at 415-476-9554 x 15.

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MDR

The Data Safety Monitoring Board (DSMB) of the NIAID recently reviewed the Multi-Drug Resistant HIV study and recommended that it be closed to further accrual and that all enrolled participants be followed for an additional two years. This study of an STI in patients with MDR is the largest randomized treatment interruption trial conducted to date. Jody Lawrence, M.D., of the Community Consortium and the UCSF Positive Health Program at SFGH, is the protocol chair. The trial 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. The study was terminated for further enrollment by the DSMB because of more clinical events seen in the STI group compared to the no-STI group as well as evidence of depressed immune recovery in the STI group. An Executive Summary reporting more details of the trial is forthcoming. If you would like a copy, please call the Consortium office at 415-476-9554.

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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. .

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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 eleven 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-up 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.

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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. 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.

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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 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.

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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!

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SMART

The Strategies for Management of Antiretroviral Therapy (SMART) study was launched on January 2nd. The Community Consortium has randomized 41 of our first year target of 50 patients onto the Strategies for Management of Antiretroviral Therapy (SMART) study. Congratulations to our super enrollers- the providers of Castro Mission Health Center (15) with Michael Jones, R.N., and Bill Owen M.D., and Carl Stein, P.A., (11) with Pierre Crouch, R.N. 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. Three-thousand 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 is participating in a quality of life/healthcare utilization substudy where the VS and DC groups are compared for QOL and symptom severity as well as

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