Spring 2003
Next Executive Advisory Board Meeting: Wednesday, October 22 , 2003Educational Offerings
Upcoming Conferences
Employment Opportunities
CROI Update
Consortium Clinical Trials
Marijuana for Cancer Pain
Marijuana for HIV Neuropathy
SMART
ESPRIT
DHEA
Distant Healing
FIRST
LTM
Observational Cohort Study
Next Meeting
The next Community Consortium Executive Advisory Board meeting will be Wednesday, October 22, 2003. Community Consortium 201 Conference Room, 7:30 a.m.
Post Meeting/Dinner CME Program Wednesday CME Program Community Health Program Manager Assistant or Associate Professor
The San Francisco General Hospital Positive Health Program Hematology/Oncology Section of the Department of Medicine of the University of California, San Francisco is seeking applicants at the Assistant or Associate Professor level. The oncology population at SFGH is ethnically and culturally diverse, presenting many challenges as well as opportunities. The applicant should have outstanding clinical and teaching skills for attending in both outpatient and in-patient settings where fellows, house staff and medical students are trained. Board certification in Internal Medicine and Oncology and/or Hematology is required.
Please submit current curriculum vitae and three letters of reference to Donald Abrams, M.D., Chair, Search Committee, Ward 84, 995 Potrero Ave, CA 94110. The University is an Equal Opportunity/Affirmative Action Employer. All qualified applicants are encouraged to apply, including minorities and women. HIV Experienced Physician Sought Research Nurse / Part-Time Multicenter AIDS Cohort Study (MACS)
Incumbent will conduct physical examinations on research participants with special emphasis on identifying HIV-related signs and symptoms; refer subjects for further medical evaluation as needed; and counsel subjects and answer questions about findings from physical exams, blood test results, their HIV status and safe sex practices. No diagnoses or treatments provided.
"Emerging Topics in HIV Infection"
Saturday, June 14th , 2003
8:30 a.m. - 1:00 p.m.
Genentech Hall, UCSF Mission Bay Campus
"Report Back From IAS Conference on HIV Pathogenesis and Treatment"
Wednesday, July 30, 2003
6:00 p.m. - 8:30 p.m.
California Pacific Medical Center
DAVIES Campus Auditorium / Level B
Corner of Castro Street and Duboce
San Francisco
July 13 -16, 20033
For more info: http://www.ias2003.org/
The Community Health Program Manager (CHPG), will be responsible for managing, coordinating and evaluating all outreach, recruitment and subject retention activities for the research groups within the UCSF Positive Health Program (PHP). This position will be responsible for supervising other research staff and efforts; coordinating the program-wide human and material resources of PHP and community resources to ensure timely and efficient target accrual goals; and performing other duties as assigned. The PHP is a pioneer in cutting edge research and clinical practices.
Interested candidates may fax resumes to Julieann Lewis, MSPH, 415-502-5152.
To join primary care practice at 45 Castro Street. Associate sought for clinical and hospital practice.
Contact Stephen Knox, M.D. at 415-863-3366
REQUIRED SKILLS:
Clinical knowledge and skill sufficient to accurately palpate lymph nodes and abdomen, and recognize abnormalities in skin, oral cavity, rectum, genitalia and fat distribution. Require skill and certification in phlebotomy. Prefer knowledge of the course and treatment of HIV disease.
Contact Max Hechter at 310-825-1073 or email: hechtor@ucla.edu
The Community Consortium continued our CME offerings this winter with two successful programs. The Report Back from the 10th CROI dinner was held on February 26 and provided those in attendance with a review of the highlights of this important meeting that had been held in Boston February 10-14th. On March 22nd, our Saturday CME program on HIV Resistance and Fitness: Current Science and Clinical Strategies was presented as our inaugural offering in Genentech Hall at the Genentech Building on the new UCSF Mission Bay Campus. The reviews of the new venue were quite favorable so it is likely that future programs will be utilizing the space. Mark your calendars now for our Report Back from the 2nd IAS Meeting, scheduled for July 30, 2003 at 6:00 p.m. Our next Saturday CME Program will feature Emerging Issues in HIV Infection, on June 14, 2003. Attendees will be eligible for Category 1 CME credit. 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 category 1 of the physicians' recognition award of the AMA and the certification program of the California Medical Association.
Some have said that the 10th Conference for Retroviruses and Opportunistic Infections, although educational, did not generate many groundbreaking findings. Despite that, the Consortium sponsored a highly successful Report Back from the 10th CROI on February 26, 2003, featuring Stephen Follansbee, M.D., Director of Kaiser HIV Services and Steven Deeks, M.D., from the UCSF Positive Health Program at San Francisco General Hospital. The format for the evening was our traditional round robin interchange by the presenters, beginning with Dr. Follansbee who opened the discussion with general praises for President Clinton's address and the moving speech by a member of the performing South African choir, Sinkithemba, an HIV positive ensemble. The Community Consortium has enrolled 37 of our target goal of 50 subjects onto ESPRIT, an international 25-nation 4000 patient trial. The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) recently reached its accrual goal on April 15th, 2003, when the 4000th patient was enrolled. ESPRIT enrollment will end on May 30th, 2003. This study is now accessible for interested participants at the Positive Health Program Research Clinic at 18th and Folsom. A slight divergence from our overall philosophy of taking our clinical trials to the site where participants receive their primary health care was deemed necessary in order to meet our contracted accrual goal. If you know of individuals who may be interested in this IL-2 trial who are not currently cared for in a Community Consortium clinician investigator's practice, they can now be referred for participation in the trial to the PHP research clinic. Donald Abrams, M.D., and the clinic staff will oversee the patients from the trial perspective. Patients randomized to receive IL-2 will have 24/7 access to the study clinicians in case of questions and/or for management of adverse reactions.
In ESPRIT, participants on HAART are randomized to receive either interleukin-2 7.5 MIU subcutaneously twice a day for 5 days every 8 weeks or no interleukin-2. ESPRIT data collection only occurs every 4 months. The study is designed to assess clinical benefit of IL-2 and hence will follow 4000 patients worldwide for disease progression events for a minimum of five years. Participants randomized to the IL-2 arm will repeat cycles of therapy to maintain their CD4+ cell counts at twice baseline or above 1000 cells/mm3. If you have patients who may be interested in ESPRIT, please call David MacLeod, R.N., at 415-476-9554, ext 328.
GB virus type C
Dr. Follansbee began the scientific presentation with an overview of GB virus type C (GBV-C), citing its clear significance as it had been reported on in the Sacramento Bee! GBV-C is a single stranded RNA flavivirus, apathogenic that may actually slow the progression of HIV infection, according to a trio of studies and posters presented at the conference. GBV-C has a remarkable genetic similarity to hepatitis C but it does not infect the liver so "hepatitis G" has been dropped from its nomenclature. It is a very common human infection and appears to be benign. It is found in 1.8% of healthy blood donors in the general population. This "friendly" infection stimulates intracellular cytokines that down-regulate the CCR5 co-receptors that HIV favors in entering a cell. It also interferes with some of the mechanisms that HIV uses to take control of a cell once it gains entry.
In a basic science study led by Jack Stapleton, MD, from the University of Iowa, Iowa City, an in vitro PBMC system was infected with GBV-C prior to HIV infection with either CCR5 or CXCR4 trophic strains. In both pre-infected HIV lines there was a decrease in p24 antigen production, i.e., a decrease in the viral burst in HIV, and this burst was neutralized by the presence of an anti-cytokine. A probable mechanism put forth was down-regulation produced intracellularly, where the GBV-C makes the cell produce more of the cytokines RANTES, MIP-1a, and MIP-1b. Cell surface expression of CCR5 is down regulated by these cytokines. The virus also may affect cell apoptosis. The impact of GBV-C declines over time, which could suggest that HIV has a harmful effect on the cellular environment.
Dr. Follansbee reported on a related study from Dr. Carolyn Masters Williams, PhD, of the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, who used stored plasma from 271 gay men in a sub-cohort of the Multicenter AIDS Cohort Study. The stored sera was collected at early/baseline (12-18 months after HIV sero-conversion) visits and at late (5-6 years after HIV sero-conversion) visits from the HIV sero-converters who were still alive (138 samples). The samples were assayed for GBV-C markers (GBV-C RNA and anti-E2 [a marker of past GBV-C infection]). At the early/baseline visit, 39% were GBV-C RNA positive, 46% were anti-E2 positive but negative for GBV-C RNA (indicating that they had cleared the infection) and 14% were negative for both markers. GBV-C status at the early visit was NOT associated with survival. In contrast, GBV-C status at the late visit was associated with survival, which was greatest in those who were GBV-C RNA positive. Interestingly, those who cleared GBV-C RNA between the early and late visits (n=12, 8.7% of the 138 tested) had the highest risk of death, almost six-fold higher than those who were GBV-C RNA positive at both visits (P less than 0.01). Likewise, the rate of CD4+ T lymphocyte decline was highest in those who lost GBV-C RNA - 107 cells/mm3/year versus 26 cells/mm3/year in the persistently RNA positive and 37 cells/mm3/year in those persistently negative. The median duration of follow-up, date of sero-conversion, use of HIV treatment, median log10 HIV RNA levels, and CCR5 delta 32 mutation prevalence did not vary by GBV-C status. One member of the cohort acquired GBV-C during the period studied. Dr. Williams found that 75% of the men who were consistently positive for GBV-C were still alive at the endpoint of the evaluation, some 11 years after sero-conversion. Of men who were never co-infected, 39% were still alive. Of the 12 people who had been infected with GBV-C but had cleared the virus, 16% of them were still alive. "Persistently carrying this virus gives a substantial benefit to the men who carry it," concluded Dr. Williams.
Another study of GBV-C, presented by Dr. Bjorkman from Malmo University in Sweden found that viremia at diagnosis does not predict mortality. In this clinic-based investigation, survival among 230 HIV infected persons was compared according to GBV-C status at baseline and at a later time point in a subset of 163 patients. Baseline was defined as within two years of diagnosis of HIV infection (not HIV seroconversion) and follow-up was for a median of 4.3 years. At baseline, the median age was 35 years, 89% were male, 86% Caucasian, and the median CD4+ cell count was 465 cells/mm3. GBV-C viremia was found in 62 (27%) patients, while anti-E2 was found in 69 (30%). No difference was detected in the incidence of AIDS or overall survival according to baseline GBV-C status. However, 11 of 44 patients who were GBV-C RNA positive at baseline lost GBV-C RNA without developing detectable anti-E2 (the antibody response that is believed to occur when persons clear GBV-C infection), and a marked increased risk of mortality was detected in these 11 patients. Eight of the 11 patients who resolved GBV-C RNA without developing anti-E2 died (P=0.007), 10 developed AIDS (P less than 0.001), and their average CD4+ cell decline was greater (145 cells/mm3/year), compared with those who had repeated GBV-C testing and maintained marker status. These authors concluded that "...the observed loss of GBV-C viremia without anti-E2 sero-conversion in patients with progressive disease supports an interaction between these two viruses. However, the GBV-C status in HIV-1 infection is probably a secondary phenomenon during disease progression rather than an independent prognostic factor".
he presentations on GBV-C and HIV contributed to our understanding of the interaction between these two viruses and raised new questions. The most important new finding was the strong positive association between loss of GBV-C RNA without anti-E2 and progression of HIV infection. This observation is important because it could potentially explain some of the protective effect previously attributed to being GBV-C RNA positive, since the comparison group (those who are negative for all markers) includes both those who lost GBV-C RNA without developing anti-E2 as well as those who were never infected with GBV-C (which is probably a small number). It remains unclear to what extent this could fully explain the apparent protective association of being GBV-C RNA positive since only a small fraction was negative for all markers. In addition, this observation raises the question of why resolution of one virus in an atypical way (that is, without production of anti-E2 as occurs in HIV negative persons) would increase the risk of disease from another virus. Further, although the in vitro work by Stapleton's lab continues to demonstrate clear GBV-C effects on HIV infection, the manner in which GBV-C affects HIV in vivo remains unknown. There are also thoughts that treatment of hepatitis C may result in the clearance of GBV-C. If the beneficial aspects of GBV-C's inhibition of HIV infection are confirmed, that would pose an additional dilemma as to whether to treat HCV in individuals who are co-infected with all three viruses. It would be important to look at long-term non-progressors or slow progressors to evaluate the presence and impact of GBV-C on their disease, in much the same way that researchers examine presence of the CCR5-delta32 mutation that confers resistance to HIV infection and replication.
STI's in Rx Failure
The rationale for treatment interruptions is to improve therapeutic outcomes of a new regimen in patients failing therapy. The hypothesis is that when drug pressure is removed, HIV will lose resistance as the predominant quasi-species revert to wild type (WT). Steven Deeks reported on two trials with dissimilar results that were presented at the 10th CROI. He voiced the general sentiment that there was sparse clinical application within the conference and he felt that the "hot data" of the conference was the treatment interruption data. He praised the UCSF Positive Health Program's Jody Lawrence for her clear and elegant presentation of one of the STI trials - the CPCRA 064 MDR trial.
The CPCRA 064 MDR trial looked at the utility of a 4-month treatment interruption prior to starting a new regimen in patients with multi-drug resistance. The new regimen was selected on the basis of genotypic and phenotypic resistance test results for each participant. This randomized controlled trial enrolled 270 patients with an average CD4+ cell count of 180 cells/mm3 and an average viral load of 100,000 copies/mL. All patients were heavily pre-treated and about 48% had viral isolates resistant to all 3 classes of drugs. Participants were randomized to begin a new regimen either at once or after a 4-month treatment interruption.
During the treatment interruption the STI group experienced a mean 0.3 log10 increase in viral load and 64% of patients isolates reverted to WT. There was no difference in viral load change in the 2 groups after 20 months but there was a greater CD4+ cell increase in the non-STI group. There were more AIDS-associated events reported for the STI group who lost CD4+ cells and did not regain them to the same degree as participants not undergoing an STI. Nor was there was any improvement in the quality of life in the STI group. As no benefits were revealed and indeed possible harm by the STI was shown, the study was closed to further accrual.
The GIGHAART Trial from France was curiously conflicting. Presented by Christine Katlama and in contrast to the CPCRA 064 study, the STI strategy in this trial appeared to be successful. The GIGHAART study was presented at prior conferences with this new data derived from additional follow-up. In this prospective study, 70 patients with multiple treatment failures and very advanced HIV disease (HIV VL > 50,000cps/mL and CD4cells < 200/mm3) were randomized to undergo an immediate treatment interruption of 8 weeks and then receive salvage treatment or to immediately begin a GIGHAART salvage treatment regimen. Therapy consisted of 3-4 NRTIs, one NNRTI and ritonavir (400 mg bid) with amprenavir (600 mg bid) or lopinavir plus a third PI (indinavir 400 mg bid or saquinavir 600 mg bid or nelfinavir 1,250 mg bid) ± hydroxyurea (500 mg bid). Seventy pts were randomized; 68 started study drugs, and 64 were evaluated at week 48. At baseline, median plasma HIV RNA was 5.3 log10 copies/mL, CD4+ cell count 27/mm3; duration of ARV therapy was 6.6 yrs with a median of 11 antiretroviral drugs. By ITT missing equal failure analysis, the percentage of patients with HIV VL decrease > 1 log from baseline was 26% at week 12, 24% at week 24 if immediately salvaged, versus 62% at week 12 and 50% at week 24 in the STI group (p = 0.007 and p = 0.043, respectively). Median decrease in HIV RNA from baseline was -0.37 at week 12, -0.29 at week 24, and -0.37 at week 48 in the immediate group versus -1.91, -1.08, and -0.79 in the STI group (p = 0.008 at week 12, p = 0.013 at week 24). The percentage of participants with HIV RNA < 400 copies/mL was 15% at week 12, 12% at week 24 in immediate salvage vs. 38% and 32% in the STI group (p = 0.053 and p = 0.077, respectively). The median increase in CD4+ cell count from baseline was +7/mm3 at week 24 and week 48 in the immediate salvage group vs. +51/mm3 and +69/mm3 in the STI group. These differences were maintained at 48 weeks. Two subjects died in each arm. Three major factors were associated with virologic success: treatment interruption with reversion of resistance, adequate drug concentration, and the use of lopinavir. Katlama and colleagues concluded that "treatment interruption followed by a multi-drug salvage therapy induces a significant virologic and immunologic benefit up to 48 weeks." An STI of 8 weeks' duration is now part of the French AIDS treatment guidelines in these patients.
Dr. Deeks postulated that the reason for the conflicting results centers around two issues - the duration of treatment interruption and the fact that at week 8, resistant virus converted to wild type. In the second 8 weeks in the CPCRA study, there was a resurgence of wild type with increased replication and increased T-cell turnover, T-cell activation and immunological harm. He therefore believes that 16 weeks is too long of an STI. Data to support this, he says, is found in the OPTIONS study led by Rick Hecht of the UCSF/PHP. This was not an STI study, but looked at predictors of response to HAART. They looked at CD4+ and CD8+ activation, viral load, CD4+ levels, adherence, replication capacity and drug resistance and found that the level of CD4+ activation emerged as most significant. Acute HIV syndrome is similar to a prolonged STI period as there is also increased activation. A question from the audience: Is there an available measure of cell activation? Dr. Deeks answered that in vitro you may see expression of CD38+ receptor expression on CD4+ and CD8+ cells and this is commercially available, some have begun to use this as a marker of when to switch treatment.
Occult HBV infections
There were a number of clinical pearls provided by Dr. Follansbee. Hepatitis B has emerged as a significant cause of morbidity and mortality in HIV positive patients in the US. No studies have yet described the prevalence of HBV infection in a nationally representative HIV patient cohort. Investigators led by a team at the University of Cincinnati sought to determine the prevalence of both active HBV and "occult" HBV infection in an Adult AIDS Clinical Trial Group cohort. There is considerable ongoing debate about the significance of occult HBV (anti-HBc+, HBV DNA negative). The researchers randomly selected sample subjects from the cohort for an evaluation of HBV markers that included anti-HBc, anti-HBs, HbsAg, and HBV DNA. The samples were collected before the subjects started anti-HIV therapy. Of the 240 representative samples, 156 (65%) showed evidence of either past hepatitis B exposure or active hepatitis B infection. Of these, 92 samples (38.2%) demonstrated typical markers of HBV infection and clearance (anti-HBs+, anti-HBc+, HBsAg-). These samples were all HBV DNA negative. Seventeen (7.1%) samples were consistent with acute or chronic hepatitis B (anti-HBc+ and HBsAg+); 10 of these were HBV DNA+. Thirty-eight (15.8%) subjects had an "occult" marker pattern characterized by only anti-HBc reactivity. Only one occult sample had detectable HBV. The investigators conclude that the majority of HIV-infected patients in a nationally distributed cohort have evidence of current or past HBV infection. The prevalence of HBV anti-core alone is lower than that seen in European cohorts. Only 2.6% of the US subjects showed any evidence of highly replicative HBV infection.
A question raised was whether these patients needed vaccination, or are they protected by the presence of the core antibody? The general consensus amongst the audience was to vaccinate. A further question was whether it is a false positive core antibody since only 1 of the 38 who were core positive was actually also viremic. These patients were also mostly HCV positive. In addition, eighty percent of the study patients with HCV were also core positive.
Intermittent Therapy
Steven Deeks summarized the findings from two separate trials from Thailand and Spain. The intermittent therapy study performed in Thailand followed the one-week on/one week off model initially piloted by the NIAID Clinical Center group. 74 patients enrolled in the HIV-NAT 0014 trial (1 year of dual NRTI therapy followed by 3 years two NRTIs and a PI) were randomized to three cohorts of approximately 25 patients per group: continuous therapy, short-cycle (1 week on/1 week off) intermittent therapy, or CD4+ cell-count-guided treatment (stop therapy if > 500 cells/mm3, restart at < 350 cells/ mm3). In contrast to the NIAID short-cycle study, the 1week on/1 week off therapy group in this study demonstrated a 40% failure rate; this could be due to their extensive prior treatment histories (and archived drug resistant virus). Conversely, all patients in the CD4+ cell-count-guided therapy group experienced virologic re-suppression upon restarting therapy. At the end of the trial, though, there were no significant clinical or virologic differences between the groups (the CD4+ cell-count-guided group had lower CD4+ cell counts, but this was by design). Excluding the CD4+ cell data CD4+ guided therapy was as effective as continuous therapy. Patients in all 3 arms also had similar lipid, adverse event, and quality-of-life measures. The one big difference is that patients in the continuous therapy group spent 100% of the study's duration on medication; short-cycle intermittent patients spent 59%, and the CD4+ cell-count-guided group only 33%. These results support the general concept of the CPCRA's ongoing SMART trial.
In the Spanish trial, presented by Lidia Ruiz, therapy initiation and interruption were based on CD4+ cell counts and viral load. Treatment was interrupted when CD4+ counts rose to >500 cells/ mm3 and therapy was reinitiated upon a drop in CD4+ cell count to < 350 cells/mm3, or an increase in viral load to > 100,000 copies/mL. By the end of the 48-week trial, 43% of those who stopped therapy remained off therapy. Of the 57% of patients who had to restart therapy, all achieved re-suppression, two thirds of whom were able to re-interrupt therapy. Seventy percent of patients who restarted therapy did so due to an increase in viral load, 6% because of a decline in CD4+ cell count, and 24% for both reasons. It is notable that upon treatment interruption, 10% of patients experienced symptoms consistent with the acute retroviral syndrome.
Dr. Deeks reviewed some of the big picture issues with these trials. The week on/week off strategy did not do well because, though the virus could be re-suppressed, resistance occurred rapidly. He felt it was still unclear how long patients could stay off of treatment on a CD4+ guided interruption strategy, but offered that it might be dependent on the CD4+ nadir.
The ISS-PART study was an Italian prospective randomized multi-center clinical trial of intermittent therapy in suppressed patients presented by Stephano Vella. He reported on the 56 week results of longer cycled interruptions from an Italian cohort. One hundred thirty-seven patients continued therapy, while 136 underwent 1-month on/3 months off cycles. Two-thirds of subjects used NNRTI-based HAART; median CD4+ cell count at entry was 691 cells/ mm3. Due to the long half-life of NNRTIs, the NNRTI was stopped several days before the NRTIs to reduce the chance of NNRTI resistance. While patients on cycled therapy generally suppressed to < 400 copies/ml on re-initiation, a disturbing trend towards increased resistance mutations, particularly NNRTI mutations, in patients undergoing cycling was of concern to Dr. Deeks. No metabolic data was yet available, and given that there is therefore no data to show benefit of this strategy, such cycling should be left to clinical studies. Patients did well in general but resistance emerged at increasing frequency with each subsequent interruption, so Steve Deeks would caution against this approach.
Dr. Deeks considers the National Institute of Allergy and Infectious Diseases as the ultimate originators of the idea of cyclic interruptions in antiretroviral therapy. Mark Dybul from NIAID has previously described intermittent therapy protocols according to which HIV positive patients received therapy every other week and successfully maintained virologic control for 32-68 weeks. This approach allowed for successful therapy at half the cost and with fewer side effects (e.g., elevated serum cholesterol and triglyceride levels). The strict timing required by this protocol was deemed difficult to adhere to in practice, however, and success has only been demonstrated under the best possible circumstances, in which patients began therapy with high CD4+ cell counts and no evidence of preexisting HIV drug resistance. In the "Treatment Strategies" session of the conference, Dr. Dybul presented data from a similar, but potentially more practical STI trial at NIAID. In this controlled study of "long-cycle" STI, patients were randomized to receive either continuous or intermittent highly active antiretroviral therapy (HAART). For patients randomized to the STI arm, HAART was administered in cycles of 2 months on therapy/1 month off therapy. Even though there were no statistically significant differences in virologic measures between the intermittent and continuous therapy arms, Dr. Deeks pointed out, the trial was terminated early due to the development of antiretroviral drug resistance in 3 of 8 patients receiving intermittent efavirenz-based regimens. By the end of the second 2-month on-therapy period, none of these patients were able to completely re-suppress viral replication that had rebounded during their initial off-therapy period. This prompted the investigator to proffer re-suppression as an important criterion for continuing with an intermittent therapy approach.
Overall the one-week-on-one-week-off strategy appeared unsuccessful. No evidence of decreased toxicity or improved immune control was reported, at the cost of a striking incidence of virological failure and the appearance of resistance when compared to continuous therapy. The CD4-guided arm appeared to have done well, but the median CD4 count at re-initiation of therapy was 536 cells/mm3, suggesting that therapy was re-initiated after small declines in CD4+ cells. Dr. Deeks felt overall that these studies of treatment interruptions revealed "elegant" virology at work, especially in addressing the question of whether stopping a drug would select for resistance. Some studies were highly predictive- when treatment was interrupted those who developed resistance did so when their viral load was on its way down, usually taking 12 weeks to become undetectable. A hypothesis that is also agreed on by Anthony Fauci of the NIAID is that if one is going to interrupt treatment, it is necessary to shut the virus down. It would be reasonable therefore to do very short interruptions so the virus has no chance to replicate. However, if a short interruption is not chosen, the virus needs to be completely suppressed to undetectable for as long as possible before drugs are discontinued. Otherwise there is genuine risk. "Therefore success depends on time," someone from the audience astutely commented. Structured treatment interruption done in long cycles should only be done in patients with high CD4+ cells, Dr. Deeks added.
The 2NN study
This trial was perhaps one of the most awaited clinical studies presented at the 10th CROI. Steve Follansbee reviewed the results of this open-label, randomized, comparative trial of first-line antiretroviral therapy with regimens containing either efavirenz, nevirapine (dosed either once or twice daily), or both non-nucleoside reverse transcriptase inhibitors simultaneously, along with a nucleoside analog backbone of d4T (stavudine) plus 3TC (lamivudine). The study randomized 1216 individuals, of whom approximately 84% completed 48 weeks. Baseline characteristics were well matched across the groups with a median CD4+ cell count of 190 cells/mm3 and a median viral load of 4.7 log copies/mL.
The proportion of patients who changed off their randomized NNRTI during the course of the study was 20% in the efavirenz group, 29.1% in the nevirapine once-daily group, 22% in the nevirapine twice-daily group, and 34.5% in the dual-NNRTI group. In these 4 respective groups, the proportion of individuals who were considered to experience successful treatment at 48 weeks (that is to say those who completed 48 weeks on their originally assigned regimen with a viral load < 50 copies/mL, and who had not experienced HIV disease progression) was 62.3%, 56.4%, 56.3%, and 46.9%. The only statistical difference in terms in efficacy was seen between the efavirenz and dual-NNRTI group.
An analysis focusing on virologic success and failure rates was also presented at CROI. Virologic failure was defined as the presence of viral load values > 50 copies/mL in patients with previous HIV-1 RNA measurements below this level, or simply the failure to achieve viral suppression to < 50 copies/mL. Based on this negative definition, virologic success was observed in 67.8% of efavirenz recipients, 65% of those randomized to nevirapine once daily, 63.6% of those on nevirapine twice daily, and 61.7% of patients in the dual-NNRTI arm. These differences were not statistically significant for any 2-way analysis. Looking only at individuals who entered the trial with a baseline viral load > 100,000 copies/mL, virologic success was observed in 61.3%, 51.5%, 53.7%, and 57.1% of patients in the respective treatment groups. When considering the on-treatment analysis, no differences were observed between groups, with 86.8%, 88.7%, 81.5%, and 79.5% of patients being classified as treatment successes, respectively. Changes in CD4+ cell count did not differ between groups.
As the treatments are similar in efficacy (although statistical equivalence was not achieved), the focus of interpretation turned to adverse events. Clinical hepatotoxic events were more common in nevirapine recipients, with 1.4% of patients receiving nevirapine once daily and 2.1% of those receiving nevirapine twice daily experiencing at least one grade 3-4 event, compared with 0.3% of efavirenz recipients. When grade 3-4 liver function tests abnormalities were considered, significant differences were observed between the efavirenz and nevirapine once-daily groups. Only 4.5% of efavirenz recipients experienced grade 3-4 AST or ALT elevations (> 5-10 times the upper limits of normal); these changes were seen in 13.2% of nevirapine once daily, 7.8% of nevirapine twice daily, and 8.6% of dual-NNRTI recipients. Grade 3-4 rash was also higher in nevirapine-treated patients (all arms) compared with patients receiving efavirenz. Differences in other laboratory abnormalities were not reported across groups.
CNS effects, such as sleep disturbance, abnormal dreams, and anxiety were reported in 1.8% of patients in the nevirapine once-daily arm, 4.9% of those in the nevirapine twice-daily arm, 6.5% of patients in the efavirenz arm, and 8.1% of patients in the dual-NNRTI arm. The difference between the nevirapine once-daily group and the dual-NNRTI group was statistically significant.
Differences in the percentage of patients in each group who discontinued therapy due to adverse events were also statistically significant (P < .001), with 15.5% of efavirenz patients discontinuing therapy, compared with 24.1%, 21.2%, and 29.7% in the other arms, respectively. Of note, two deaths were attributed to nevirapine: one secondary to fulminant hepatic failure (in the absence of hepatitis co-infection) and one to sepsis following Steven's-Johnson syndrome.
The 2NN investigators conclude that there was no significant difference between the 3 single-NNRTI approaches, but that the dual-NNRTI approach was inferior to efavirenz-based therapy, due mostly to the increased discontinuation rate observed in the dual-NNRTI arm. There was also a positive influence on treatment success in all groups with regards to individuals commencing therapy with viral loads > 100,000 copies/mL.
For practical purposes, there is something here for fans of both drugs. Whether it will change practice is another question. Nevirapine does well from an efficacy standpoint, but efavirenz is not surpassed, and appears numerically better. Efavirenz has the CNS side effects, and nevirapine is associated with more serious rash and hepatobiliary events. Ultimately, if efficacy is similar for both drugs, physicians and patients are left with the task of determining with which adverse-event profile they feel more comfortable.
Partial treatment interruption
Partial treatment interruption - in which inactive components of combination therapy are discontinued, while the rest of the regimen is maintained with no additional drugs added - may be a useful therapeutic strategy for some patients with HIV. Steven Deeks himself advanced this provocative idea, presenting in the final plenary session of the 10th CROI.
He reviewed how drug-resistant virus is unable to replicate as well as wild-type virus and produces less T-cell activation. When therapy is interrupted, "a shift [occurs] in the virus population from drug-resistant to wild-type," said Dr. Deeks. "It is hard for the virus to become both highly resistant [to a drug] and highly fit" in terms of replicative capacity.
"The wild type virus emerges because it is more fit, in the absence of drug, than the resistant variant." This emergence results in "a rapid and dramatic drop in T-cell count and a dramatic rapid increase in T-cell activation and turnover." This relationship between viral fitness and T-cell turnover is widely acknowledged as a key feature of HIV pathogenesis.
From this foundation, Dr. Deeks formulated a hypothesis that in highly treatment-experienced patients who have developed resistance to one class of antiretroviral drugs in a combination regimen, and cannot suppress viremia to undetectable levels, the sustained use of the remaining active agents alone might exert sufficient pressure to maintain the current resistant virus and keep wild-type virus from emerging. This could potentially improve the patient's risk-benefit ratio, Dr. Deeks said. "The goal of treatment in these patients is not to treat the resistant virus, it is to ignore the resistant virus and use those drugs which are able to prevent the rebound of the more virulent, more fit wild-type form," he explained. "Because the major benefit to patients was reduction of toxicity, the decision was made not to randomize patients but to interrupt the therapeutic drug class to which the patient was having the most toxicity."
Twenty subjects were studied in this non-randomized, open-label pilot analysis. Subjects actually chose which drug class they would interrupt. The median baseline viral load was 3.9 log [8,000] copies/mL and the median CD4+ T cell count was 336 cells/mm3. Fifteen volunteers interrupted all of their PIs and continued all of their NRTIs; 5 other volunteers interrupted NRTI therapy and continued PI therapy. In the individuals who stopped just their PIs and continued their NRTI's, through one year of follow-up, the level of viremia has remained absolutely stable. In patients stopping protease inhibitors and remaining on a stable regimen of nucleoside analogs, no shift in the dominant virus population was observed through the first 24 weeks. There was no rebound in wild type, and no shift in the resistance profile it was stable in the absence of the PI. In contrast, those who stayed on PI's and discontinued their NRTI's experienced a viral load increase of 1 log10 suggesting that NRTI's have continued activity against the virus even if resistance is present. However, after week 24, gradual changes in the resistance profile were seen in patients who stopped NRTI's and stayed on PI's. For example M184V reverted to WT after 24 weeks and became M184M, but resistance to other drugs remained stable. A conclusion that may be drawn is that M184V, for example, may have a big impact on viral fitness, i.e., the ability to replicate.
In earlier work Dr. Deeks had found that mutant virus reverts to wild type somewhere between week 2 and week 16 depending on the individual, when all therapy is stopped. This suggests that nucleoside analogs continue to have direct activity against resistant virus. This is not surprising to virologists, as many studies have suggested the maintenance of RT mutations results in a virus that grows more slowly, and that this may confer a clinical benefit. Of note, three of the 5 subjects interrupting NRTI therapy exhibited a delayed loss of M184V, which was temporally associated with a rise in viremia. Dr. Deeks said they are looking very carefully at partial treatment interruption as "a bridge therapy as we wait for the next big thing." He saw multiple benefits in interrupting PI therapy in patients with multi-drug resistant HIV: reduced toxicity, cost, and "no forward evolution of the virus in terms of protease inhibitors." Partial treatment interruptions may be appropriate for maintaining partial virologic responses in persons with limited treatment options. A noteworthy observation about these conclusions is the specific patient population in whom this clinical strategy might be considered. The patients in this study all had preserved CD4 counts (366/mm3) and many PI and RT mutations. Such a tactic is unlikely to work without a virus significantly impaired by MDR mutations and without a partially intact immune response. Question from the audience: What about the possibility of using a partial dose of a drug as a "suppressant"? Dr. Deeks informed us that the French are carrying out such a study using full and half doses of NVP and 3TC.
TDF/3TC in HBV
Steve Follansbee summarized 48-week interim results of the trial entitled Tenofovir and Lamivudine Combination Therapy Compared to Lamivudine Alone for HBV in Therapy-naive HIV/HBV Co-infected Patients. Tenofovir DF (TDF) shows strong activity against both wild type and lamivudine 3TC-resistant hepatitis B virus (HBV). Study 903 is an ongoing, randomized, double-blind, active-controlled 144-wk trial of TDF 300 mg qd vs. stavudine 40 mg bid in combination with efavirenz 600 mg qd and 3TC 150 mg bid in 600 HIV treatment-naive adults. Stavudine and efavirenz have no reported anti-HBV activity. Eleven HIV/HBV co-infected patients from Study 903 (5 TDF + 3TC and 6 3TC) with baseline serum HBV DNA = 6 log10 copies/mL and with wk 48 data were included in this as-treated analysis. Baseline mean characteristics: age 38; plasma HIV RNA 4.8 log10 copies/mL; CD4 count 204 cells/mm3; serum HBV DNA 8.6 log10 copies/mL; serum ALT 86 IU/L (2.0 x ULN). There were no significant differences in baseline characteristics. Ten patients were HBeAg+. Sera HBV from pts with detectable (> 1000 copies/mL) HBV DNA at wk 48 were genotypically analyzed for the development of 3TC-resistance mutations. The 4 pts who developed the 3TC resistance mutations showed a mean increase in HBV DNA of 2.3 log10 from their response nadir. The investigators concluded that, "The combination of TDF + 3TC appears to more effectively suppress both HBV replication and 3TC resistance development compared to 3TC alone. Further study will be needed to clarify the role of TDF + 3TC combination anti-HBV therapy in HIV/HBV co-infected patients."
Dr. Follansbee also gave an overview of the French study looking at the use of Tenofovir in 3TC resistant chronic hepatitis B in HIV co-infected patients. Long- term use of lamivudine often results in the development of YMDD mutations in the hepatitis B virus. This, in turn is associated with the progression of liver disease and clinical decline. The incidence of the YMDD mutations in HIV/HBV co-infected patients may be as high as 91% after four years of treatment with Epivir-HBV. Tenofovir is active against both HIV and HBV. The current small study explored whether TDF might be an effective alternative therapy for HIV/HBV co-infected patients with lamivudine-resistant HBV infection. Ten HIV/HBV co-infected patients treated with lamivudine and HAART added TDF to their regimen, and then were monitored on a monthly basis for the first 3 months and every 3 months thereafter for HIV and HBV viral load, transaminases and CD4 T cell count. After 12 months of treatment, there was no significant change in HIV viral load or transaminase levels, but there was a dramatic mean decrease in HBV viral load (4.55 +/- 1.21 log). TDF treatment was not associated with any HIV or HBV specific resistance mutations. These encouraging results suggest that TDF is an effective alternative therapy for lamivudine-resistant HBV in HIV/HBV co-infected patients who are on an effective antiretroviral regimen.
Dr. Follansbee next gave a summary of a pharmacokinetic study showing the interaction between didanosine and tenofovir. There are currently 17 approved antiretroviral medications, five of them with a QD indication (ddI, efavirenz, tenofovir, 3TC and d4T-ER). Two more drugs (abacavir and nevirapine) have good data supporting a QD dosing, and three more (atazanavir, 908 and FTC) are in the advanced stage of development. One of the most curious PK dynamics between these agents is the unexpected pharmacokinetic interaction between ddI (didanosine, Videx) and tenofovir DF (TDF, Viread). Didanosine is to be taken on an empty stomach, while TDF was released with a light meal restriction. Previous studies have shown that taking ddI with food reduces the area under the curve (AUC) by 18-27 percent. However, early Gilead data showed that TDF could increase ddI levels by almost 40 percent. So what happens when both drugs are taken in combination was of some interest. To answer that question, a formal study, presented last year in Barcelona, was conducted. In that study the PK of both ddI (400 mg EC) and TDF (300 mg) was measured when both drugs were taken simultaneously with a light meal. The ddI AUC increased by 60 percent (with a range of 43-78). There were no alterations in the PK of TDF. This new information prompted many clinicians to dose reduce ddI-EC to 250 mg when co-administrated with TDF. In this study, presented by Brian Kearney from Gilead, a formal assessment of that dose reduction was performed. He also compared the PK interactions after co-administering TDF 300 mg and ddI-EC 250 mg with a light meal, in a fasted state, and when both are administered staggered as per current label recommendations. The results of the study showed that a staggered administration, per current label (using ddI-EC 400 mg), resulted in an AUC equivalent to the administration of ddI-EC 400 alone. The simultaneous co-administration of TDF and ddI-EC 250 mg in fasted state resulted in an increase of ddI Cmax of 14 percent, while co-administration in a fed state resulted in a decrease of ddI AUC of 11 percent. Interestingly, the administration of ddI-EC 250 mg with TDF staggered or simultaneously with or without a meal resulted in similar drug exposure to ddI-EC 400 mg alone (as calculated by the geometric means relative to the 400 mg alone dose, with values within the 90% confidence interval). No information was reported on the TDF levels in this study on fed and fasted states. Although TDF was approved with a light meal restriction, in the future, Dr. Follansbee would like to see more information on the TDF levels in a fasted state when used in combinations with other RTs.
Fusion Inhibitors
Steven Deeks rounded off the evening with a brief presentation on fusion inhibitors. Fuzeon (enfuvirtide, T-20) is the first entry inhibitor to be FDA approved for the treatment of HIV infection. Fuzeon, and a similar peptide, T-1249, act by inhibiting the interaction of gp41 with the human cell, blocking viral fusion with the cell and entry into the cell. Since Fuzeon will be used initially in patients with high levels of resistance to currently available antiretrovirals and few treatment options, a significant number of Fuzeon-treated patients are likely to eventually develop Fuzeon resistance. These patients will need subsequent treatment, and the potential for sequencing patients failing Fuzeon to T-1249 was explored in a trial presented at the 10th CROI. In the study, 54 patients failing a Fuzeon-containing antiretroviral regimen, as reflected by two consecutive plasma viral loads between 5,000 and 500,000 copies/mL, discontinued Fuzeon and substituted T-1249 (192 mg per day) for 10 days. The median baseline viral load and duration of prior Fuzeon treatment were 5.0 log10 copies/mL and 70 weeks, respectively. Of the 25 patients that were reported, 24 patients had resistance testing available and all demonstrated Fuzeon-resistance mutations and/or decreased phenotypic susceptibility. After 10 days of T-1249 therapy, the median decrease in viral load from baseline at day 11 was 1.12 log10 copies/mL, with 63% of patients achieving at least a 1.0 log10 copies/mL decrease in viral load. The patients who had been on a failing Fuzeon regimen for <48 weeks had a better response than those who had been failing for >48 weeks (-1.6 vs. -0.94 log10 copies/mL). Finally, T-1249 was well tolerated and there were no serious adverse events attributed to T-1249. The authors themselves concluded, "The results of this interim analysis suggest that T-1249 demonstrates potent short-term suppression of plasma HIV RNA in most patients who harbor ENF-resistant viruses."
The Community Consortium is grateful for the generous support from Abbott Laboratories, Agouron, Bristol-Myers Squibb, Boehringer Ingelheim, BTG, Gilead, GlaxoSmithKline, Merck & Co., Ortho Biotech, Roche, and ViroLogic, Inc. that made this Report Back From the 10th CROI possible.
We recently completed enrollment of our study of dehydroepiandrosterone (DHEA) and its effects on latent HIV replication and host immunity; follow-up continues through November 2003. DHEA has been touted to have beneficial effects in patients with HIV - antiviral and immunomodulatory, as well as metabolic (increasing lean body mass) and psychological (improving mood and quality of life). There is some evidence to suggest that DHEA may aid in purging the latent pool of HIV in resting cells. To investigate this concept, this randomized, placebo-controlled trial enrolled 41 patients who were fully suppressed on an antiretroviral regimen. Participants were required to be HIV-positive, 18 years of age or older, and on a stable antiretroviral regimen for at least 8 weeks with HIV RNA <50 copies/mL. Women needed to have had a normal PAP smear and mammogram within the past year; men were required to have had a normal prostate specific antigen level within the last year. Participants were randomized in a 1:1 ration 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 patients receive DHEA for an additional 12 weeks, for a total study duration of 24 weeks. Participants are seen in the General Clinical Research Center at SFGH as outpatients. Each patient had one screening visit and one baseline visit prior to starting study drug. At the baseline visit blood was drawn for HIV RNA and viral DNA levels, hormone levels, lipid levels, PSA, serum chemistries, and lymphocyte subset analyses for activation antigens and naive and memory T-cell populations. Body weight and height were obtained, as well as anthropometric measurements and body composition measurements by DEXA, and quality of life assessments were completed. Follow-up visits in the placebo-controlled portion of the study occur at weeks 2, 4, 6, and 12; visits in the ensuing open-label portion occur at weeks 18 and 24. Thanks to everyone who referred participants for this trial!
The study of distant healing and HIV, in which the Consortium continues to assist our collaborators at CPMC, was closed to enrollment in December 2002. The study was enrolled in cohorts of 15 patients, each randomized to one of 3 arms. In each cohort, five patients receive DH efforts 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: neither the patients nor their doctors nor the researchers know who is receiving the healing treatments. Outcomes include clinical course, psychological course, and medication use; HIV RNA, CD4/CD8 cell, and NK cell levels; metabolic measures and antiretroviral toxicities. The study enrolled a total of 155 HIV-positive individuals, each on a stable antiretroviral regimen and each with a history of having had a CD4+ cell count <200/mm3. Patients who did not speak English or were unable or unwilling to fill out questionnaires were excluded, as were patients with non-HIV related life-threatening disease. Study procedures take place at CPMC. Following their baseline evaluations, patients return for month 6 and month 12 visits, which include follow-up questionnaires and blood work. The research assistant extracts the remaining data from clinic charts. Patient follow-up in this trial will continue until November 2003.
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. Stay tuned for further information to be made available as the study matures.
Venturing for the first time into non-HIV territory, the Community Consortium has launched a new study investigating the effects of smoked marijauna in patients with cancer pain. The study, supported by funding from the University of California San Diego Center for Medicinal Cannabis Research (www.cmcr.ucsd.edu) investigates the interaction of smoked marijuana and oral morphine sulfate. Eligible patients must have persistent cancer pain despite any analgesic medication containing regimen. The study will evaluate the potential synergistic analgesic affect of the cannabis and opioids, whether cannabis decreases opioid side effects and the pharmacokinetic interaction between smoked marijuana and oral morphine sulfate. Initially we will conduct a 16 patient pilot followed by a randomized controlled study. If you know of patients who may be interested in participating in this trial, please have them contact Hector Vizoso, R.N., at 415-476-9554, ext. 366.
With the successful completion of the pilot study, the Community Consortium is now enrolling eligible patients into the second phase of this study, the Randomized, Double-Blind, Placebo-Controlled Trial (RCT). Screening is now open to obtain a target goal of 50 patients. Eligible participants must be: HIV positive, 18 or older, diagnosed with HIV-related painful neuropathy, taking either a stable antiretroviral therapy or no antiretroviral therapy for at least 8 weeks, cease smoking marijuana for 30 days prior to entering the study, and not be a cigarette or cigar smoker. Eligible participants will spend 7 days and nights in a clinical research center at San Francisco General Hospital, have blood tests and other measurements done, smoke either medicinal marijuana or placebo three times daily, and keep a pain diary for 7 days pre and post hospitalization to track neuropathy related pain. If you have patients with neuropathy who may be interested in participating in the upcoming placebo-controlled trial, please contact Hector Vizoso, R.N., at 415-476-9554, ext. 366.
16TDo you have patients who have chosen to remain antiviral naïve or who have been long-term non-progressors? The CPCRA Long Term Monitoring team is looking to enrich follow-up of such patients in the LTM database. If you have individuals who may be interested to contributing to the general knowledgebase regarding naïve and LTNP patients and you are currently a collaborating Consortium clinician/investigator, please let your clinical research nurse know. Such individuals are often eager to participate in observational studies so that their experience can be counted! 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.
TThe 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. We are delighted to report that we have successfully competed for continued funding to support the analyses of the Observational Cohort Study and are thankful to the University wide AIDS Research Program (UARP) for their continued support.
A special thank you to William Owen, M.D., and Carl Stein, PA, for achieving 100% followup on all patients enrolled. Patient # 59 was randomized on April 4, 2003. 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+ 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 250/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 healthcare utilization and resulting costs. In addition, Consortium participants may participate in an HIV transmission risk behavior substudy. Here subjects complete a confidential risk behavior self-report describing condom use and needle-sharing behavior. In addition, biological testing for subjects in the substudy 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. 333, for further information.
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