Happy Spring!

The next AIDS Clinical Grand Rounds will be held on Wednesday, May 23rd at 6:00 p.m. at Davies Campus of the California Pacific Medical Center in the auditorium on B Level at Castro and Duboce Streets in San Francisco. Refreshments will be served and free parking is available. This will be the first of our traditional ACGR sessions offered this year. The program will feature a panel on "Continuity of Care for HIV Positive Inmates".

With the HIV population shifts that have been experienced over the past decade, more providers are now caring for individuals making the transition from incarceration to freedom, and vice versa. This panel of experts will address issues unique to the prisoner with HIV and highlight some of the local programs available for their assistance. The panelists include Guy Vandenberg, MSW, RN, Director of Forensic Services, Continuum; Jacqueline Tulsky, M.D., Assistant Clinical Professor, UCSF; and Milton Estes, M.D., Medical Director, Forensic AIDS Project, City and County of San Francisco and Consortium Executive Advisory Board Member. This promises to be a most informative presentation for all. Hope to see you there!

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

With the Community Consortium's new scheduling of educational programs, the publication rate of Synopsis is being adjusted as well. Where in the past dinner meetings and Saturday CME programs had not been summarized in Synopsis, this year we will attempt to feature some of the highlights of these meetings.

Donald opened the discussion by commenting that there was a marked difference between the 8th CROI and the XIIIth International Conference held in Durban, South Africa in July 2000. Whereas social and global HIV issues dominated the July 2000 meeting, perhaps to the expense of science, the CROI opened with two presentations in the first session on the AIDS situation in Africa, but had nothing further to say on the topic throughout the rest of the meeting. He also felt that in contrast to the CROI in previous years, this year seemed more heavily focused on basic science than clinical issues.

Continuing the overview, Steve Follansbee agreed that there was an abundance of basic science but he was impressed that much of it was likely to be eventually translated into therapeutic advances. He reminded those who were not in attendance that they could still attend the meeting virtually by visiting www.retroconference.org. Steve remarked how the early steps of viral attachment to the cell and injection into the cytoplasm are becoming more important. He also remarked that different cells are being highlighted now for their role in HIV infection, such as dendritic cells. He introduced the audience to the concept of DC-sign, present in high concentrations in the rectal mucosa and the vagina and involved in attachment and transportation of the virus. He remarked that he believes that understanding this basic science will ultimately translate into therapeutic advances. With regards to vaccine development, he believes that gp120 and variable loops may be the key to increasing immunogenecity. Simian vaccine models look more encouraging as well.

Regarding antiretroviral therapies, Dr. Follansbee pointed out there was much indirect discussion at the sessions about the new therapeutic guidelines. He felt that the post-exposure prophylaxis issue was important for its economic impact as well as for the need to develop new drugs for new situations. He remarked that advances in viral resistance assays have now allowed for testing down to 5 to 10 copies of virus/mL. However, debate continues regarding how and which assays should be used. He introduced the concept of "virtual phenotypes". Completing his broad overview focusing on OIs and malignancies, Dr. Follansbee mentioned that there really is a diminishing amount of coverage of these previously dominant topics at the CROI. The hepatitis C session attracted much interest. Concluding his opening comments, Steve mentioned the urgent need for prevention and drug treatments in Africa.

Paul Volberding delved deeper into some of the basic science topics that he felt were of major importance. He began by discussing the nef gene and whether or not it would be a new target for therapeutics. Nef is an accessory gene. There has been a long debate over its exact function. Dr. Volberding believes that the more we learn about nef gene function, the more we understand how diabolical HIV actually is. The nef gene downregulates CD4 and MHC-1 proteins on the cell. By decreasing CD4 expression, less CD4 is shown on the surface of the cell. If a cell wants to make more virus, it needs to hide CD4 so that when the virus is released, it doesn't stick to the CD4 on the cells, making it unavailable to infect other cells. Hence, paradoxically, by decreasing CD4 expression, it also increases its output. By decreasing MHC-1, nef decreases immune recognition of the infected cell but it doesn't overdo it, as this would then trigger NK cell killing the cell. All of these maneuvers allow the virus to further its own ends. Hence, nef has become a more attractive drug development target.

Dr. Volberding went on to discuss that HIV interactions with co-receptors were becoming more complex and more interesting. He discussed the role of dendritic cells. HIV gp-120 binds to lectin (DC-sign and others) on dendritic cells which then present the virus to CD4 cells. This is an important step in how the virus establishes infection and is a key step in moving the virus to the lymph nodes from mucosal surfaces. The level of DC-sign will affect the ease of transmission, the rate of disease progression, as well as maternal-infant transmission.

Another basic science area that Paul felt was important for future drug development was the increasing knowledge being obtained about drug transport. P-glycoprotein (p-gp) is found in many of the same tissues as cytochrome p-450 CYP 3A4 (the enterocyte, hepatocyte, proximal renal tubular and blood:brain barrier). P-gp pumps drugs out from the gut lumen, bile, urine and blood vs CSF. P-gp expression is controlled by the MDR-1 gene, which has a high frequency of polymorphisms. This implies a wide inter-patient variability in pharmacokinetics. MDR-1 related multidrug resistance is common with cancer chemotherapy. There is now an active ongoing search for p-gp inhibitors.

Steven Deeks began his review of the 8th CROI by discussing therapeutic drug monitoring (TDM). The French conducted the PharmADAPT study. In this trial, 256 patients on antiretroviral therapy with HIV RNA levels greater than 2,000 copies/mL were randomized to receive genotype information with or without TDM. The patients were all treated with a PI-based salvage regimen. A four-week trough level was obtained and the dose of the protease inhibitor was adjusted to achieve a trough greater than fourfold more than the wild type IC-50. The dose adjustment was made at week 8. In the TDM arm, 22% of the participants modified their PI dose on the basis of the trough level. At 12 weeks, those patients employing genotypic information alone had a 2.6 log decline of their HIV RNA compared to a 2.3 log decline in those patients using genotypic information plus TDM. Dr. Deeks concluded that this was a negative study for the clinical utility of therapeutic drug monitoring and suggested that more evidence is needed before it becomes standard of care.

Bill Owen began his discussion by describing a case of viral evolution after transmitted resistance. The patient presented was a 32-year-old Asian gentleman presenting with fever, rash, myalgias, lymphadenopathy and oral ulcers consistent with an evolving HIV Western blot. The patient deferred therapy. At the time of infection, he had multiple mutations in both the RT and protease gene with phenotypic resistance being demonstrated for all NRTIs except dDI and dDC, all NNRTIs, and all PIs except saquinavir. After five months of follow-up, the patient experienced a tenfold increase in HIV RNA level at which time the genotype of the predominant virus no longer had any of the major RTI or PI mutations noted since baseline. Dr. Owen queried whether we should genotype all new seroconverters. The U.S. military now tests all active duty personnel for HIV infection every one to three years. Most of those found to be newly seropositive also get genotypic testing. In an analysis of 103 individuals tested, 21 had intermediate or resistant Vircogen-1 at baseline. In the cohort of patients, initial therapy was begun without knowledge of their genotypic testing. There was no difference in the treatment offered those who had resistance versus those who were sensitive. At six months, those who had baseline resistance mutations had increased CD4 cell counts and decreased HIV RNA levels on triple therapy. The investigators postulate that baseline resistance mutations may decrease viral fitness or cause hypersusceptibility.

Donald summarized the information from the vanguard interleuken-2 studies conducted in Thailand, Argentina and Houston. These three studies all compared dosages of subcutaneous rIL-2 to no treatment. The doses investigated were 1.5 MIU bid, 4.5 MIU bid, and 7.5 MIU bid. There were significant differences in both higher dosages when compared to the 1.5 MIU bid dose with regard to CD4+ T lymphocyte increases at both six and twelve months. At six months, patients receiving 4.5 MIU bid had 271 more CD4+ T cells than the 1.5 MIU bid group. At six months, the group receiving 7.5 MIU bid had 478 more CD4+ T cells than the 1.5 MIU bid cohort. This information has led to the selection 7.5 MIU bid for the larger, longer ESPRIT clinic endpoint trial. Even when comparing the 4.5 and 7.5 MIU doses, the higher dose group had 194 more CD4+ T cells at six months than the 4.5 MIU bid group (P=0.042). However, by twelve months, the difference between these two dosages was not significant. This is probably because patients may not have continued the cycle to maintain their CD4+ T cells at target levels.

Steve Follansbee, ever the infectious disease consultant, felt obligated to discuss at least one treatment for an opportunistic infection. He presented information on the results of a 21-day continuous infusion of topotecan for PML. Ten patients were treated. Three out of ten improved with better MRI scans. The median overall survival was 16.5 weeks. Toxicity, however, was high. Nine out of ten experienced grade 3 or 4 toxicities with hematologic side effects predominating. In an open label non-randomized ACTG trial of cidofovir for PML, 24 patients were treated with a mean survival of 7.5 weeks. It was felt that this was no better than no treatment. Steve remarked that there have been some cases discussed of PML occurring very early in HIV disease. He suggests that these cases may be the result of immune reconstitution disease in patients beginning highly active antiretroviral therapies.

The DHHS released new guidelines for antiretroviral therapy coincident with the Chicago meeting. Paul Volberding chose to review some of the presentations on the issue of timing of HIV therapy. He remarked that the rationale for very early treatment of established infection is to maintain immune integrity and prevent viral evolution. The rationale, on the other hand, for treatment deferral is that deferred therapy (but not beyond a drop to below 200/mm³ CD4 cells) restores "safe" levels of immune function while delaying drug toxicity, cost, and the emergence of resistance. He reminded those in attendance that starting therapy before the patient is able to commit to adhere to a regimen is never appropriate.

Although the answer to the question when to begin therapy remains elusive, Dr. Volberding felt that data presented at the 8th CROI mostly supported the new CD4 guidelines but left some room for debate with regard to viral load thresholds. He remarked that designing a clinical trial to resolve this issue would be expensive and would likely take years to complete. On the other hand, he cautioned that data from cohort studies, usually retrospective, add heat but little light to the question. Reviewing studies reported in Chicago, Paul noted that the CDC study suggested some benefit in treating patients with CD4+ T cells in the 200-350/mm³ range, little benefit with CD4+ T cells greater than 350/mm³, and most benefit in those with CD4+ cells less than 200/mm³. The Swiss cohort, on the other hand, suggested benefit in patients with CD4+ cells greater than 350/mm³. A Johns Hopkins cohort study demonstrated benefit only with CD4 less than 200/mm³. Both the MACS and WIHS cohorts show low one-year progression rates for individuals with CD4+ T cells greater than 200/mm³ unless the viral load is very high. The bottom line distillation of these studies is, as per Dr. Volberding's interpretation, that therapy should be started above 200/mm³ but beyond that, there is little firm ground.

The CDC Adult and Adolescent Spectrum of Disease (ASD) cohorts presented by Kaplan involved ten sites across the U.S., where charts were extracted every six months. 5,100 subjects were included with no prior antiretroviral therapy. The baseline CD4 was one that was abstracted within 12 months of beginning antiretroviral therapy. Patients were enrolled after 1994. Hence, some patients were begun on two-drug therapy and others on three. There were 902 deaths in the cohort during the follow-up period. Mortality was evaluated as a function of baseline of CD4+ cell counts. Most of the deaths occurred in those whose CD4+ cells were less than 50/mm³ at baseline. There were essentially no events at two years follow-up in those patients who began therapy with CD4+ greater than 350/mm³. There was some decreased mortality noted in the cohort of patients who began therapy with CD4+ T cells in the 200-350/mm³ range that was almost statistically significant. Use of two drugs compared to three drugs led to a 50% increase in mortality.

A Johns Hopkins cohort reported by Sterling, et al., compared 530 individuals who began HAART therapy compared to 484 who did not. The HAART group had a higher proportion of individuals with less than 200 cells/mm³ (54% versus 25% at baseline). No impact of baseline viral load (i.e., less than 20,000/mL versus greater than 100,000/mL) was noted on ultimate outcomes. HAART was noted to delay disease progression in the cohort of patients with CD4+ cells less than 200/mm³. There was no effect on progression of disease in those with CD4+ T cells in the 200-350/mm³ range or greater than 350/mm³ at baseline. No gender differences were noted.

The only presentation that differed from these observations came as a late breaker from the Swiss cohort. The data was collected in a retrospective chart review of 11,200 patients; 6,550 enrolled after 1996, in the HAART era. The patients who were treated were compared to those who declined treatment. If patients began therapy, they were then removed from the cohort. Mean follow-up in the treatment group was 2.3 years compared to 1.3 years in those declining therapy. Patients were followed for progression to clinical AIDS, which included bacterial pneumonia as well as tuberculosis. More rapid progression was seen in the untreated group with CD4+ cell counts greater than 350/mm³ (17%) compared to the treated group (4.5%). However, there was a high rate of drug discontinuation (30%) and switches for toxicity in the group beginning treatment. The authors suggest that this demonstrates a benefit for earlier therapy. However, one concern is the very high apparent rate of disease progression in the untreated cohort (17% over 1.3 years in people with greater than 350/mm³ at baseline).

At the other end of the spectrum, Dr. Deeks chose to discuss the question of when to stop antiretroviral therapy. He pointed out that there are thousands of patients to evaluate with regard to the "when to start" question; however, most of the data presented at the AIDS CROI on the "when to stop" question came from much, much smaller cohorts. In fact, his own study of 22 individuals was almost twice as large as any of the other five studies presented at the Structured Treatment Interruption Symposium. He began by reviewing updates of studies where treatment interruption is being used as an immunotherapy, particularly among patients with primary infection. Bruce Walker now has 14 individuals who were initially treated early after seroconversion. These patients were treated for about a year with antiretrovirals and then discontinued treatment until their viral load rose to more than 5,000 copies/mL on three occasions or more than 50,000/mL copies once. Successful therapy was defined as an HIV RNA level less than 5,000 copies/mL off therapy. Seven of the 14 individuals have been "successful" to date. In the Aaron Diamond cohort reported by Markowitz, et al., patients had begun HAART a median 65 days after initial infection. Most had sustained prolonged plasma suppression on drugs for approximately three years. After a first treatment interruption, three of 15 maintained a viral load less than 500 copies/mL with a mean follow-up of 100 days. Five viral loads rebounded to 5,000-20,000 copies/mL range and seven with greater than 20,000 copies/mL

A case control study of structured treatment interruption in chronically infected patients was reported by Garcia, et al., from Barcelona. The EARTH study looked at 30 chronically infected patients with CD4+ T cell counts greater than 500/mm³ and viral loads greater than 5,000 copies/mL. Twelve individuals received more than one year of HAART and then underwent repeated cycles of structured treatment interruptions defined as four weeks off therapy followed by six months on. The viral load doubling time tended to increase after each treatment interruption. The mean viral load after one year of treatment interruptions was 10,000 copies/mL in individuals who had undergone three STIs versus 50,000 copies/mL in individuals who had no treatment interruptions.

The Swiss-Spanish intermittent trial of 132 patients with CD4+ counts of greater than 350/mm³ is perhaps the largest of the studies. Patients were treated two weeks off therapy followed by eight weeks on therapy. After four cycles, 21 of 99 had durable HIV RNA levels less than 5,000 copies/mL. A low pre-therapy viral load predicted positive outcome.

Bill Owen reported on the NIAID study of short cycle intermittent HAART that was described by Dybul, et al. This study enrolled nine patients who had baseline CD4+ T cells greater than 300/mm³ and viral loads less than 500 copies/mL for five months and less than 50 copies/mL at screening. Patients were treated with seven days of d4T/3TC, ritonavir and indinavir followed by seven days off therapy. Failure was defined as viral load greater than 500 copies/mL twice or a drop in CD4+ counts. All nine patients remained below the level of quantification after three to eleven months on short cycle intermittent HAART.

Perhaps if antiretroviral therapies were more convenient to take, there would be less interest in interrupting the treatments. Bill, the consummate clinician, reported on currently available or pipeline medications that have a once-a-day dosing potential. Among the NRTIs, lamivudine, didanosine, abacavir, emtricitabine (FTC) and stavudine-SR are all qd candidates. Tenofovir is a nucleotide reverse transcriptase inhibitor with once-a-day dosing schedules. Among the NNRTIs, nevirapine and efavirenz may both be dosed once daily. Ritonavir boosting has led to the investigation of once daily combination with saquinavir, indinavir, amprenavir and lopinavir (Kaletra). Bill reported on two Italian studies looking at ddI, 3TC and efavirenz or ddI, FTC and efavirenz in antiretroviral naive patients. Both had excellent success with regard to surrogate marker outcomes using once daily dosing. Another study switched patients who had participated in a study amprenavir, abacavir, and 3TC onto a ritonavir-containing regimen that allowed for once daily dosing of amprenavir. Only minimal GI-related side effects were noted. Again, in this small study with 12-weeks of follow-up, surrogate marker responses were excellent.

Steve Follansbee reported on some of the information regarding hepatitis C (HCV) co-infection in patients with HIV. Whereas all agree that HIV affects the course of HCV infection, the question remains as to whether or not there is an affect of HCV on the course of HIV. A study from Johns Hopkins looked at 1,700 patients, half of whom had HCV. The only factor that was associated with risk of progression to HIV was lack of HIV suppression to less than 400 copies/mL. The use of HAART reduced the risk of progression to 0.3, irrespective of the HCV status. A cross-sectional study from Madrid evaluated a cohort where 70% were co-infected with HCV. It was found that those with HCV and HIV generally had lower CD4+ T cell counts and higher HIV RNA levels. Adherence to antiretroviral regimens was felt to be equivalent in the HCV positive and HCV negative cohorts. The CD4+ cell increase was greater in those who did not have HCV co-infection. Similarly, a greater decline in viral load in association with HAART was seen in those who were HCV negative. Steve also pointed out that both efavirenz and nevirapine were equally efficacious in patients with chronic hepatitis B or HCV. HAART-related hepatotoxicity appears greater in patients who sustained greater CD4+ T cell increases on initiation of therapy.

Steve then went on to describe some new terminology and technology in resistance testing and drug monitoring. He described the "virtual phenotype". Virco has taught computers how to correlate phenotypes with a genotypic pattern. After programming hundreds and thousands of genotypes into a computer and correlating them with phenotype, the "virtual phenotype" can be predicted based on genotypic information.

Dr. Deeks reported that there was not a whole lot of progress apparent in the metabolic complications of antiretroviral therapy or resultant body habitus alterations. There were a number of posters regarding avascular necrosis, many of which had conflicting results. A number of the panelists wondered how the reviewers allowed posters to be presented that contradict each other so blatantly. The question remains as to whether avascular necrosis is, in fact, a complication of highly active antiretroviral therapy or of HIV disease itself. Dr. Deeks pointed out that one study suggested that alcohol use and prior prednisone therapy may contribute to the development of avascular necrosis. In a pediatric study, increased osteoporosis in children appeared to be related to the duration of HIV infection and not necessarily to any particular antiviral therapy.

Bill Owen concluded the evening's presentations by discussing some new therapies in the pipeline. Of particular interest was a Schering CCR5 antagonist, SCH C. HIV that utilizes CCR5 is preferentially transmitted. Some long-term non-progressors have been noted to be heterozygous for CCR5 deletion. SCH C blocks RANTES to CCR without any effect on CXCR4. Early studies demonstrate that the drug inhibits HIV, including antiretroviral resistant virus, for up to 25 hours. The compound causes a 2.5 log10 reduction in viral load in SCID-HU mice. The compound appears synergistic with agents that have other mechanisms of action. Single dose studies have been conducted in men using 25-600 mg per dose. QTc prolongation has been noted in one human volunteer at the highest dose to date. CCR5 inhibitors are also under development at a number of other pharmaceutical companies.

A Phase II controlled trial of T-20 was presented by Jay Lalezari, et al. 71 patients with prior protease inhibitor experience, but naive to NNRTIs, were randomized to receive abacavir, ritonavir-boosted amprenavir, efavirenz and T-20 at doses of 0, 50, 75 or 100 mg subcutaneously b.i.d. Baseline CD4+ T cell count was 232/mm³ with a viral load of 4.27 logs10. At week 16, the median change in HIV RNA was -2.16 logs in the control, -2.2 logs in the group receiving 50 mg b.i.d., -2.3 logs in the group receiving 75 mg b.i.d. and -2.8 logs in the group at the 100 mg b.i.d dosage. The main side effect was local pain, redness and swelling at the injection site in 65% of those receiving T-20. Eighteen patients discontinued the study early; 10 of these for injection site reactions. Eron, et al., presented information on the newest fusion inhibitor, T-1249, a close relative of T-20 but felt to be 2 to 100 times more potent and highly active against T-20 resistant virus. Once daily dosing is being trialed with this subcutaneous agent. Preliminary findings from a Phase I dose-finding trial that enrolled 72 subjects were presented. Further information will certainly be forthcoming at the next antiretroviral conference to be held in Buenos Aires, Argentina in July 8-11, 2001.

The Consortium is extremely grateful to our colleagues at Agouron, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co., Vertex Pharmaceuticals and Virologic, Inc. for educational funding provided for this dinner update.

We look forward to holding our next dinner conference update following the First International AIDS Society Conference on HIV Pathogenesis and Treatment, to be held in Buenos Aires, Argentina. The event is currently scheduled for July 18. Please mark your calendars now!

The Community Consortium Executive Advisory Board will meet on Wednesday, June 6, 2001 at 7:30 a.m. in the Community Consortium conference room. Please note this alteration from our normally scheduled meeting date. Having the meeting on June 6 will allow us to return from the CPCRA group meeting to be held in Washington, D.C. earlier that week. It will give the EAB an opportunity to discuss the Community Consortium's future involvement in this group. At this point in time, it looks like the CPCRA's proposed Strategic Management of Antiretroviral Therapy (SMART) protocol is being favorably reviewed by the Division of AIDS. It is likely that the SMART study will be piloted by the current CPCRA to assess the feasibility of the trial. More information on SMART will be forthcoming in the coming months.

The Community Consortium will become a National Trial Coordinating Center (NTCC) of the ESPRIT trial. The Evaluation of Subcutaneous Proleukin in a Randomized International Trial is very similar to CPCRA 059, the evaluation of two different dosages of interleukin-2. However, in ESPRIT, participants will only be randomized to receive either interleukin-2 7.5 MIU subcutaneously twice a day for 5 days every 8 weeks or no treatment. As well, instead of monthly visits as in the CPCRA study, ESPRIT data collection only occurs every 4 months. We hope that this study will be open for enrollment for interested patients sometime in the very near future. The study is designed to assess clinical benefit of IL-2 and hence will enroll 4000 patients worldwide and follow them 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+ T cell counts at twice baseline or above 1000 cells/mm³. If you have patients who may be interested in ESPRIT, stay tuned for further information concerning the launch of the study.

The University of California Center for Medicinal Cannabis Research (CMCR) has approved its first set of proposals for the study of cannabis as treatment for specific medical conditions. Four proposals out of 13 submitted from various California research institutions were recommended for funding by the CMCR's independent Scientific Review Board following rigorous scientific review. A study submitted by Donald Abrams and collaborators at the UCSF Pain Clinical Research Center to evaluate the effect of marijuana on HIV-related peripheral neuropathy is one of the four studies to be funded in this initial grant cycle. It is anticipated that this will be a short General Clinical Research Center inpatient trial. Additional information will be available as the study gets closer to launch. The other three studies will be conducted at the University of California San Diego. These will include another outpatient study in patients with painful HIV neuropathy, a study of the effect of marijuana on spasticity in multiple sclerosis, and an evaluation of the impact of repeated cannabis treatments on driving abilities.

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