march 2000
Next Meeting: March 15, 2000
Report from the February
AIDS Clinical Grand Rounds
Review of the 7th Conference on Retroviruses and Opportunistic Infections
Committee Reports
Executive Advisory Board
Scientific Advisory Committee Community Advisory Board
Consortium Clinical Trials Open for Enrollment
FIRST
Metabolic Study
Adherence Study
Protease Inhibitor Progression (PIP)
Long-Term Monitoring (LTM)
THC
Just Opened in the Bay Area
Antiretroviral Therapy: HIV Dynamics and Ovulatory Cycles: Nelfinavir, d4T, 3TC
HIV and Hepatitis C Treatment: Pegylated Interferon, Alpha Interferon, Ribavirin
Peripheral Neuropathy: Lamictal
Thought you'd like to know . . .
Avacavir Safety Alert
California Academy of HIV Medicine launched
Donald I. Abrams, MD, Editor
The next meeting of the Community Consortium will be held on Wednesday, March 15, 2000 at 6:00 p.m. at the 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 in the lot.
Following brief announcements, AIDS Clinical Grand Rounds will feature a presentation on "Structured Treatment Interruptions" by Jody Lawrence, MD. Dr. Lawrence is the newest faculty member at the UCSF Positive Health Program at San Francisco General Hospital. Recently joining the faculty from the AIDS Community Research Consortium of Atlanta, Dr. Lawrence is the co-chair of the CPCRA's Multi-Drug Resistance (MDR) protocol, which incorporates a four-month structured treatment interruption (STI) into the trial design. Numerous presentations on STIs at the recent 7th Conference on Retroviruses and Opportunistic Infections were rather inconclusive as to their utility. The CPCRA trial is designed to shed further light onto the potential benefits and possible risks of an STI. The Consortium will be launching the CPCRA MDR protocol very shortly. Please attend our next meeting for what promises to be a most informative session.
The first meeting of what subsequently became the County Community Consortium (CCC) was held in March 1985. A small number of the pioneer physicians initially involved in the care and treatment of patients with AIDS met in the conference room at the San Francisco Medical Society. Since the initial meeting, the Community Consortium has been meeting monthly for the past 15 years. In celebration of the Community Consortium's 15th Anniversary, we are hoping to have a celebration at the April 2000 meeting. Due to a conflict on April 19 with the Passover holiday, the 15th Anniversary Celebration is currently being planned for Wednesday, April 26. Please note this change from the routine third Wednesday of the month meeting on your calendar now so that you will save the April 26th date for the festivity!
This program is sponsored by the University of California at San Francisco (UCSF) School of Medicine. UCSF is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The office of CME designates this continuing medical education activity on an hour-for-hour basis in Category I of the Physicians Recognition Award of the American Medical Association and the Certificate Program of the California Medical Association. In addition, nurses may obtain CEU credits but must keep a record of their own attendance. One hour of credit is available for this meeting.
Review of the 7th Conference on Retroviruses and Opportunistic Infections
The February 2000 AIDS Clinical Grand Rounds featured an update from the 7th Conference on Retroviruses and Opportunistic Infections (CROI). Panelists included Donald Abrams, MD, Steven Deeks, MD, Stephen Follansbee, MD, William Owen, MD, and John James, Editor of AIDS Treatment News. Donald Abrams began by giving an overview of highlights from the meeting. He remarked that because of the rapid pace of major conferences presenting AIDS research updates in the last six months, including ICAAC, IDSA and the CROI, it is unrealistic to expect any major new information to be presented. Treatment advances are being described in incremental fashion as a few weeks or months more additional data for ongoing clinical trials are presented at each conference. He remarked that although "opportunistic infections" is still featured in the title of this major conference, for all intents and purposes, opportunistic infections appear to be absent from both the conference as well as from patients with advanced HIV infection. However, the drug-induced problems of body habitus changes continue and were heavily featured at this year's meeting. New this year were an increasing number of presentations on structured treatment interruptions (STIs), or "drug holidays", both in patients initiating antiretroviral therapy as well as in those who have lost viral suppression. In view of the concerns about the development of body habitus changes and the other metabolic complications, as well as increased interest in structured treatment interruptions, a perennial question that seems to be getting a reprieve is when is the best time to actually begin antiretroviral therapy?
As a professional editor of an AIDS treatment information newsletter, John James felt that it was difficult to get a handle on what exactly was the main thrust of the 7th CROI. He reported that there was, in fact, not a lot of information that clearly stood out. He was predominantly interested in the increasing suggestions that mitochondrial toxicity may be responsible for some of the metabolic alterations in body habitus changes seen in patients on HAART. Increasingly, these toxicities are being blamed on the nucleoside analogs, particularly d4T. Mr. James mentioned that in other areas of medicine, a number of agents have been reported to have protective effects against mitochondrial toxicity. These include carnitine, coenzyme Q and vitamin B2. He suggested that perhaps a study of these agents is warranted in HIV at this time.
Oral Transmission of HIV
From the perspective of the news media, perhaps one of the most widely covered presentations of the meeting focused on the risk of oral transmission of HIV.
Abstract 473 presented as a poster by Dillon, et al., from UCSF focused on "Primary HIV infections associated with oral transmission." Investigators evaluated 102 cases of primary HIV infection enrolled in the Options Project at SFGH/UCSF. Subjects were evaluated for their risk of infection. Sixty-nine percent of the cohort reported unprotected receptive anal intercourse, 14 percent unprotected insertive anal intercourse and 18 percent reported that oral sex was their only possible risk behavior. Of those 18 percent where oral sex was the possible transmission risk factor, further investigation yielded eight cases that were probably not oral transmission, three where there was insufficient follow-up and eight where oral sex remained the only possible risk factor. Of these eight cases, one participated only in oral sex, with partner corroboration. One claimed to participate only in oral sex without partner corroboration. In addition, four individuals said that they only had protected anal intercourse, though without partner corroboration. Two reported having unprotected anal intercourse but only with negative partners, who were verified as being HIV negative by the study team. These men were interviewed with regards to their impression of the safety of oral sex without a condom; 85 percent of those questioned felt that this was a low risk activity. The investigators conclude that oral sex may account for up to eight percent of new primary HIV infections. Steve Follansbee pointed out that oral sex certainly transmits other pathogens than HIV. Recently in his practice, he has seen three cases of pharyngeal gonococcal infection.
Opportunistic Infections
Steve Follansbee continued the overview with his impressions, agreeing with Donald that opportunistic infections have definitely taken a diminished role at the conference due to the dramatic change in HIV disease inaugurated by widespread use of highly active antiretroviral therapies. He summarized that posters at one session basically suggested that primary and secondary prophylaxis for Pneumocystis carinii pneumonia, toxoplasmosis, Mycobacterium avium infection, cryptococcosis and other fungal infections can all be discontinued once a patient has achieved an adequate and persistent CD4 cell count increase in response to HAART therapy. The results of the CPCRA048 trial discontinuing prophylaxis for Mycobacterium avium in patients with a past CD4 count less than 50/mm3 who responded to antiretroviral therapy were presented as a poster by Wafaa El-Sadr, M.D. of Harlem Hospital (Abstract 247). Judith Aberg, MD, formerly of the UCSF Positive Health Program at SFGH, and colleagues presented data on discontinuing antifungal therapy in nine patients with previously documented crytococcal infection who had an immunologic response to HAART without evidence of relapse (Abstract 250).
In addition to the immunologic effect of increasing CD4 cells to decrease the frequency of opportunistic infections, Dr. Follansbee discussed an Italian presentation on the suppressive effects of HIV protease inhibitors on in vitro growth of Pneumocystis carinii trophozoites (Abstract 245). In the in vitro culture system, rat Pneumocystis carinii trophozoites were exposed to the currently available protease inhibitors. Trimethoprim/sulfamethoxazole treated and untreated micro-organisms were used as controls. Without any additional drugs, 100 percent growth was the standard. In the presence of TMP-SMX, trophozoite production was reduced to 12 percent of normal. Among protease inhibitors, indinavir reduced trophozoite production to 40 percent of normal, ritonavir 54 percent, nelfinavir 60 percent, saquinavir 64 percent and amprenavir 73 percent. The investigators conclude that these data suggest the possibility that anti-PCP effects of protease inhibitors may be due to the antibiotic effects of the drugs themselves in addition to their effect on HIV and subsequent immunologic restoration.
Pharmacokinetic studies
Bill Owen chose to report on a late-breaking oral presentation on the "Pharmacokinetic interactions between protease inhibitors and selected HMG-CoA reductase inhibitors" (LB6). Safe and effective therapy is needed to treat the hypertriglyceridemia and elevated cholesterol levels seen in patients on HAART therapy. HMG-CoA reductase inhibitors are currently being used. Most of these "statins" are metabolized by the CYP 3A4, as are protease inhibitors. This ACTG study examined statin/PI interactions in 52 normal volunteers. Individuals were all treated with ritonavir/saquinavir at a dose of 400/400 mg bid. The statins investigated were pravastatin, atorvastatin or simvastatin. The statins were dosed at 40 mg a day for four days, followed by 14 days of the ritonavir/saquinavir treatment, followed by four days when the volunteers received both the statin and the protease inhibitor combination therapy. Concentrations of the statins were measured at Day 4 and Day 18. Ten of the subjects discontinued the trial because of protease inhibitor-related toxicities, generally seen days 5 through 8. The PK results demonstrated that the median 24-hour area under the curve (AUC) for pravastatin decreased by 47 percent when taken concurrently with RTV/SQV. The median 24-hour AUC for atorvastatin and two of its metabolites increased threefold and 74 percent, respectively. The median 24-hour AUC for simvastatin increased nearly 27-fold; six patients on the concurrent therapies developed adverse experiences. The investigators conclude that pravastatin is probably safe, atorvastatin should be used with caution and simvastatin should be avoided in patients on ritonavir and saquinavir. A question that remains unanswered is how the statins affect the levels of the protease inhibitors in patients with HIV using HAART therapies.
Metabolic Complications of HAART
Donald Abrams reported that David Cooper from Sydney outlined at the conference the reasons why the metabolic complications of HAART are being recognized with such increased frequency at this time. First of all, there are a large number of drugs in combinations and polypharmacy is common in the treatment of HIV. Secondly, there is little long-term safety data available when drugs are rapidly approved. And, antiretroviral therapies need to be taken indefinitely as survival is extended; hence there is longer exposure to drugs and more time for problems to arise. Lastly, he postulated that hepatitis C co-infection may increase the liver's susceptibility to damage.
Dr. Cooper's Australian lipodystrophy cohort continues to provide much interesting information on the development of body habitus alterations in patients on HAART. A number of Consortium clinicians in the audience lamented that there still remains no consistent definition of the body habitus syndromes, so that comparing various studies becomes difficult. In the Australian lipodystrophy cohort, 1,337 patients have been enrolled, of which the vast majority are men. The median CD4 count is 487/mm3 with 56 percent of the cohort having an HIV RNA level less than 500 copies/ml. Fifty-two percent have asymptomatic HIV infection and 20 percent have a history of a prior opportunistic infection. With regards to use of HAART, 74 percent report current or prior protease inhibitor therapy; 14 percent have been treated with an NNRTI and 12 percent are drug naive. The Australians report a 54 percent prevalence of lipodystrophy overall, 63 percent in patients on protease inhibitors and a remarkable 21 percent in naive individuals. Of those with body habitus alterations, 20 percent have peripheral lipodystrophy alone, 6 percent have central adiposity alone and 28 percent have a mixed phenotype. Severe lipodystrophy was relatively infrequent in the cohort. The investigators note that liver function tests, triglycerides and cholesterol all increase with worsening lipodystrophy. No change can be seen in glucose or lactate levels. Lipodystrophy was also reported to be associated in this review with decreased total testosterone levels. A multivariate analysis of the risk factors for development of lipodystrophy in the Australian cohort shows that lipodystrophy incidence increases with increasing age. Patients with symptomatic disease have a 2-fold increased risk of lipodystrophy. The CD4 cell count is not predictive. As has been clinically noted, patients who develop lipodystrophy appear to be doing quite well on their antiretroviral regimen. Poor viral suppression, that is, a viral load greater than 10,000 copies, decreases the risk of lipodystrophy by 40 percent. In evaluating duration of drug use, greater than 60 months of nucleoside reverse of NRTI therapy yields an odds ratio (OR) of 2.0. Less than 23 months of protease inhibitor therapy yields an OR of 2.0, greater than 23 months yields an OR of 4.0. With regards to the duration of the NNRTI use, no increased risk has been observed to date. A French series also confirmed that lipodystrophy increases with increasing age as well as higher body mass index at baseline. Whereas switching an NNRTI for a protease inhibitor appears to have inconclusive effects on underlying lipodystrophy, one poster demonstrated reversibility on discontinuing d4T therapy.
Neviripine Resistance
Steven Deeks felt that one of the most interesting and important presentations at the conference emanated from a study of pregnant women in Uganda receiving a single dose of nevirapine (200 mg) given at labor to decrease perinatal HIV transmission (Abstract 658). The investigators were interested in determining the presence of nevirapine resistance mutations in treatment-naive Ugandan women following the single dose. Fifteen paired samples were available for analysis, pre- and six weeks post- the dose of nevirapine. Six weeks after the single 200 mg dose, three of the 15 women had developed viruses with the K103N mutation, conferring high level resistance to nevirapine. Dr. Deeks discussed the ramifications of these findings and why he felt that this was such a significant presentation. First, the data raised concerns about the safety of nevirapine prophylaxis during labor. Second, they suggest that NNRTI-related mutations may occur readily in other settings, and that Phase I studies of new NNRTIs giving monotherapy for one to two weeks may be too risky. He also pointed out that in individuals who are fully suppressed and choose to stop their therapy, residual NNRTI plasma levels may be sufficient to select for resistance in view of the half-life of drugs, such as nevirapine and efavirenz. In Dr. Deeks' practice, these observations illustrate to him the risk inherent in using NNRTIs after protease inhibitor failure. In some heavily pre-treated NNRTI-naive patients who have no other effective agents to combine, premature switching to an NNRTI may result in rapid development of resistance to the class. He suggests that some patients may benefit from loose virologic control in which nucleosides and protease inhibitors are continued in the setting of virologic failure, preserving the NNRTI class for the future.
Hydroxyurea
The question of whether or not hydroxyurea is a beneficial adjunct in antiretroviral therapy remains unclear. Steve Follansbee reviewed some of the data that was presented at the 7th CROI. One poster reviewed the rationale for utilizing hydroxyurea and showed a definite drop in intracellular dATP levels in patients treated with hydroxyurea and ddI. A decline in concentration of intracellular precursors for viral replication is the rationale for use of hydroxyurea.
He then described the results from ACTG5025, reported by Diane Havlir from UC San Diego (Abstract 456). In this study, patients who were previously on AZT, 3TC and indinavir with viral suppression for longer than six months, and had a viral load of less than 200 copies/mL and a CD4 count of greater than 200/mm3, were rolled over onto a follow-up trial. Patients had no prior history of ddI, d4T or other protease inhibitors. In each of the three arms, patients remained on indinavir. The patients in the first arm continued their AZT/3TC as well. Patients in the second arm switched to ddI, d4T and hydroxyurea at a dose of 600 mg po bid. In the third arm, patients were given ddI, d4T and hydroxyurea placebo. The endpoint was viral load greater than 200 copies/mL or a treatment limiting toxicity. At baseline, 83 percent of those enrolled had less than 50 copies/mL of HIV RNA, with a median CD4 cell count of 617/mm3. The median duration of prior indinavir was 86 weeks of therapy. The study opened in November of 1998 and was terminated in September 1999 at 40 weeks of follow-up because of increased toxicities seen in the hydroxyurea-containing arm. Twenty-two hydroxyurea-treated patients reached endpoints, including 15 toxicity and 7 viral. Of the patients continuing AZT/3TC, there were only five total endpoints -- two toxicity and three viral. Of the patients whose nucleoside analogs were switched to ddI/d4T alone, there were 12 endpoints, 6 toxic and 6 viral. CD4 counts increased 12/mm3 in patients remaining on AZT/3TC/indinavir, went up 27/mm3 in the patients switching to ddI/d4T and dropped 101 cells/mm3 in the patients on the hydroxyurea-containing regimen. All three deaths in the study were in patients on the hydroxyurea arm. Pancreatitis contributed to death in two of these cases.
A chart review conducted at Johns Hopkins on the incidence of neuropathy in HIV infected patients taking hydroxyurea-containing regimens was also of interest and presented by Dr. Follansbee (Abstract 302). Richard Moore evaluated 1,116 patients amongst which there were 117 cases of peripheral sensory neuropathy. The incidence rate (cases/100 person years follow-up time) and the adjusted relative risk for five different nucleoside regimens are presented below.
RTI RX
Incidence
Relative Risk
ddI
6.8
1.0
d4T
9.8
1.39
ddI+d4T
17.5
3.50
ddI+d4T+HU
28.6
7.8
ddI+HU
8.8
2.35
The authors conclude that the risk of neuropathy is additive, or perhaps even synergistic, for ddI plus d4T plus HU compared to ddI or d4T alone. The combination of ddI plus d4T also increases the risk of neuropathy, but less so than in regimens where hydroxyurea is utilized.
The final hydroxyurea abstract Dr. Follansbee discussed was the PANDA Cohort of Franco Lori, M.D. (Abstract 352). The PANDA patients are a group of nine subjects on ddI/hydroxyurea therapy, which has been previously described. In this uncontrolled trial, Lori and his colleagues performed an eight-week treatment interruption on the nine PANDA patients and compared their outcomes with eight individuals on a protease inhibitor-containing HAART regimen. At baseline, the PANDA patients had a median CD4 count of 495/mm3 and a viral load of 843 copies/mL. After eight weeks, the CD4 count was 500/mm3 and the viral load had almost doubled to 1,596 copies/mL. In contrast, the HAART patients began with a CD4 count of 549/mm3 and a viral load of 97 copies/mL. At eight weeks, the CD4 counts had fallen to 341/mm3 with a median HIV RNA level at week six of 16,863/mL. A week six level is given, as many patients found it necessary to resume therapy at that time. The authors utilize this information to suggest that ddI and hydroxyurea in combination had an immunologic benefit above and beyond that which can be obtained with protease inhibitor-containing HAART regimen. Steve described this as a small, uncontrolled cohort study. He suggested that the PANDA patients may be a group who would be doing well with or without hydroxyurea, in which case it didn't matter whether they were on the treatment or whether it was stopped. This would be in contrast to the patients treated with the PI-containing HAART regimen. Following the 7th CROI, Dr. Follansbee has now begun to eliminate hydroxyurea from treatment regimens in patients who were previously receiving the drug.
Hypersensitivity
The concept of hypersensitivity was discussed at a number of presentations at the 7th CROI. Viruses that had seen nucleosides before but never an NNRTI can actually get a two to tenfold increased sensitivity. The question remains as to whether or not there is any clinical benefit of this hypersensitivity. For example, the 184V mutation enhances the activity of adefovir and tenofivir. The mutation appears to affect the error rate of the reverse transcriptase to make it less error-prone. Because of this, Steve Follansbee reported he is now continuing 3TC in all salvage antiretroviral therapy regimens.
Directly Observed Therapy
Bill Owen presented a study by Margaret Fischl, et al., from Miami on the impact of directly observed therapy (DOT) on outcomes in HIV clinical trials (Abstract 71). In this study, it was demonstrated that DOT was highly successful. As everyone had 100 percent adherence, they were able to achieve 100 percent undetectability. Despite lower CD4 cell counts and higher HIV RNA levels at baseline, the subjects receiving DOT had both a more rapid and greater overall decline in HIV RNA during treatment associated with a greater increase in CD4 cells and less serious toxicities.
NNRTI Rashes
Bill Owen went on to describe some of the interesting studies on NNRTI rashes. A UCSD study noted that in individuals with a history of a sulfa rash, 28 percent developed a rash on NNRTI therapy. In individuals with no history of a prior sulfa rash, the NNRTI rash rate was only 5 percent. Hispanics appeared more prone to developing the rash than Caucasians or African-Americans. Dr. Owen was also interested in a description of dual NNRTI therapy, including emivirine and efavirenz, as he is generally using two NNRTIs in a number of his patients (Abstract 670). This small study of seven patients on dual NNRTI therapy showed that pharmacokinetics were unpredictable. Efavirenz levels tended to be driven down, while emivirine levels went up in combination. Bill stressed the need for pharmacokinetic studies to be conducted as new regimens are concocted.
Structured Treatment Interruptions
Steve Deeks attempted to put some sense to the numerous structured treatment interruption (STI) studies that were presented at the 7th CROI. He reported that there were approximately 20 studies in which individuals who were undetectable stopped treatment for the "autovaccination" effect. All of the presentations were small. Conflicting results were reported. The best that he could conclude from the studies was that STIs in patients who were maximally suppressed probably does not lead to the emergence of viral resistance. He then reviewed his own data on stopping treatment in patients who were failing drugs with a lot of pre-existing resistance (Abstract LB10). In this randomized trial, individuals on a protease inhibitor for more than 12 months who had a viral load greater than 2500 copies/ml were assigned to a structured treatment interruption versus continuation of their therapy. They were seen every week for 12 weeks then every four weeks. Dr. Deeks reported on 18 patients who had been randomized to the STI arm of the trial. The CD4 count was 245/mm3 with the median HIV RNA of 4.6 log10. Patients had 36 months of prior protease inhibitor therapy. The average decrease in susceptibility to their protease inhibitor at baseline was 56-fold. After 12 weeks of STI, CD4 cells declined an average of 94/mm3 and the viral load increased 0.82 logs. Sixteen of 17 patients, however, became susceptible to their prior protease inhibitor. It took 6 to 11 weeks of being off drug to revert to susceptibility. Low level AZT-resistance persisted in seven patients. There was an abrupt and rapid loss of resistance seen at one to two weeks. Resistance was lost to all drugs at the same time. Prior to this shift, there had been a slower increase in HIV RNA, which accelerated once the shift occurred. There was an accelerated CD4 cell count decline following the shift as well. Increased viral fitness was observed after the shift to wild type. Despite the shift to wild type seen in the plasma, Dr. Deeks reported that his group was able to culture resistant virus in long-lived peripheral blood mononuclear cells. In addition, other studies reported at the conference demonstrated the ability to culture resistant virus from lymph nodes and cerebrospinal fluid in patients undergoing STIs.
Superinfection
The Consortium recently had an AIDS Clinical Grand Rounds devoted to the question of superinfection. A late-breaker at the conference described a single case report that is said to have now documented HIV superinfection and acceleration of disease progression in a previously stable individual (Abstract LB2). This report from Ottawa, Canada described Patient A who had been a long-term non-progressor, and was antiretroviral naive with CD4 cells of greater than 600/mm3. The patient had sexual contact with Patient B, a rapid progressor who had been on multiple HAART regimens. Following the sexual encounter, Patient A's CD4 count dropped precipitously with a rapidly increasing viral load. Phylogenetic analysis was performed. HIV strains from Patient B in 1998 were homologous to patient A. Homology was present in the reverse transcriptase in PI genes. The authors conclude that "the fact that HIV-I infection does not necessarily result in resistance to subsequent infection has significant public health and epidemiological implications and emphasizes the importance of safer sexual practices between HIV-infected persons."
New Drugs
The session ended with the review of new drugs in development. There are at least seven new protease inhibitors currently being tested. The furthest along includes ABT-378/r, the Abbott protease inhibitor that is ten times more potent than ritonavir. The drug was designed for decreased interaction of codon-82 amino acid. There is marked pharmacokinetic enhancement when taken with ritonavir. It is hoped that a QD dose may ultimately be possible. The drug is currently available in expanded access.
Tipranavir is a drug that was designed by Pharmacia and Upjohn, and is now currently being further developed by Boeringer Ingleheim. It has broad activity against a number of protease inhibitor-resistant viruses. Ninety percent of 107 highly resistant strains were susceptible. Some, in fact, were hypersensitive. The drug itself yields a modest 1.0 to 1.5 log decline in HIV RNA at a dose of 1500 mg tid. Unfortunately, it is currently formulated in 150 mg tablets, requiring 30 pills a day. The tipranavir level is increased 7 to 40-fold by concomitant ritonavir. Significant protein binding is also a problem.
BMS-232, 632 is a Bristol-Myers Squibb protease inhibitor that has potent in vitro activity and is now being evaluated in Phase II trials. Once daily dosing is hoped for with this agent, which also has a possible unique pathway to resistance.
New NNRTIs in development include capravirine (AG1549), the Agouron protease inhibitor where high level mutation requires more than one codon change. The drug is active against 103N mutants. A 5-fold increase in the concentration levels was seen when taken with nelfinavir. Dupont 961 is a highly potent efavirenz derivative. The drug is troubled by having cytochrome P450 interactions and high protein binding.
Other reverse transcriptase inhibitors that are moving along in development are DAPD, a novel nucleoside analog that is deaminated by ADA to DXG. The drug is also active against RTI-resistant HIV as well as hepatitis B. It is hoped that BID or even QD dosing of DAPD may be available. Mutants with K103N are possibly hypersensitive to the drug; codon 151 mutations lead to resistance. Tenofovir (bis-POC PMPA) is a nucleotide analog that is active against SIV, HIV and hepatitis B. Once daily dosing is possible with this long half-life agent. 3TC resistant strains may have increased susceptibility similar to the situation with adefovir.
In addition to new drugs in the three currently available classes, new targets for inhibition are also being evaluated. Blockade of chemokine receptors CCR5 and CXCR4 is being attempted. Updates on the activity of the T-20 fusion inhibitor were presented at the conference, with some evidence of possible persistent antiviral effect. The next generation of fusion inhibitor, T-1249, is also entering clinical trials. Information was also presented on integrase inhibitors. Merck has two candidate diketo acid drugs, L-708, 906 and L-731, 988, under evaluation.
Committee Reports
The next meeting of the Community Consortium Executive Advisory Board will be held on Wednesday, March 29, 2000 at 7:30 a.m. in the Community Consortium Conference Room. The Executive Advisory Board will continue to discuss diversification of the Consortium's areas of investigation as well as planning for the Spring Saturday half-day CME program.
New Consortium Website Launched
Tom Mitchell, MPH, Community Consortium Program Director, reports that the new Community Consortium web page is now up and running. Please check out the site at http://www.communityconsortium.org. The website includes a number of features of interest to Consortium members. For example, you can check out the calendar for the topics, dates and locations of upcoming Consortium educational programs, and register on-line for our Saturday morning CME programs. You can also find previous issues of Synopsis, or use a handy index to find the discussion of an AIDS Clinical Grand Round topic presented at a past meeting. And, Consortium members can easily create their own homepages and have them posted on the site. Please visit the site and provide us with feedback.
Consortium Studies of DHEA and Creatine Funded by NIH
We have recently been informed that the National Center for Complementary and Alternative Medicine (NCCAM) is interested in funding a study of the immunologic and virologic effects of DHEA and a study to evaluate the ergogenic effects of creatine supplementation in HIV-associated wasting -- two of the four clinical protocols submitted last year as part of the Community Consortium's application to become a Center for Complementary and Alternative Medicine in HIV/AIDS. Particularly Donald Abrams, MD, is the principal investigator of the DHEA study and Morris Schambelan, MD, is the principal investigator of the creatine trial. Once details of the awards are known, we will work on completing the protocols and begin enrollment. Stay tuned for further information.
Continued Funding Recommended for CPCRA
The National Institute of Allergy and Infectious Disease (NIAID) Advisory Council met on February 17 to discuss future funding for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). CPCRA funding has been critical to the Community Consortium's ability over the past 10 years to conduct community-based clinical trials. An application was submitted in January 1999 to continue our funding for the next five years. The word from Council is that the CPCRA should be re-funded. Further details regarding the exact arrangements regarding future funding will be forthcoming. In any event, we are delighted that we will be able to continue the work that is currently ongoing, as well as plan future studies.
Scientific Advisory Committee Community Advisory Board
The next combined meeting of the Community Consortium SAC and CAB will be held on Thursday, March 9, 2000 at 12 Noon in the Community Consortium conference room. Lunch will be provided. Please note this alteration from the usually scheduled meeting on the first Thursday of the month due to travel conflicts. At this meeting, two CAB members will make presentations of clinical trials that they suggest the Consortium consider undertaking. We will also update the groups on grant applications that are being submitted for future Community Consortium research. We need your input. Come join us at this important SAC/CAB meeting and let your voice be heard!
Consortium Clinical Trials Open for Enrollment
The CPCRA Flexible Initial Retroviral Suppressive Therapies (FIRST) trial is the entry point into the CPCRA menu of strategic antiretroviral trials. FIRST is open to patients who are antiretroviral naive. The question being asked is "What constitutes the best initial regimen for patients beginning antiviral therapies?" Patients will be randomized to one of three arms. One arm will include two nucleoside analogs and a protease inhibitor, a second arm will include two nucleoside analogs and a non-nucleoside reverse transcriptase inhibitor (NNRTI), and a third arm will include at least one nucleoside analog plus an NNRTI and a protease inhibitor. Clinicians who so desire will have free reign to choose all of the drugs that the patient begins within the classes to which patients have been randomized. If providers have equipoise among the various protease inhibitors and NNRTIs, patients may undergo a second randomization to specific drugs within the class. With the increasing untoward consequences that are being seen from highly active antiretroviral therapies and the increasing number of agents available in our antiretroviral armamentarium, the FIRST study is poised to answer a very timely and pertinent question. Patients are eligible regardless of their CD4+ cell counts or their HIV RNA levels. In this strategic trial, no drugs are provided; drugs are all currently available by prescription. When a patient is randomized, the provider will write a prescription for the appropriate regimen. The endpoint in the study will be the time to second virologic failure. This endpoint takes into account the fact that it is likely that all of the regimens may be nearly equivalent in their initial ability to suppress HIV RNA. The real differences may appear when switching patients to a second regimen once patients have progressed. Thus, the FIRST trial has a rather unique clinical endpoint. It is hoped that all patients enrolled will also be co-enrolled in the CPCRA long-term monitoring protocol, which is still in development. This will allow us to collect further information on clinical status of the patients.
A perplexing question that baffles all HIV care providers is the etiology of the body habitus alterations and metabolic consequences of highly active antiretroviral therapies. Are these changes related to protease inhibitors alone? Are the same consequences seen in patients who being therapy with an NNRTI-containing HAART regimen? To answer this study, the CPCRA has launched the Metabolic Trial as a substudy of FIRST. The trial is designed to capture information from patients as they enroll onto the CPCRA FIRST trial. Patients will undergo serial metabolic evaluations, including laboratory testing and anthropomorphic measurements. By co-enrolling patients from the FIRST trial, we hope to be able to get answers to the question as to whether changes in body habitus alterations and metabolic abnormalities being seen in patients on HAART are related to protease inhibitor therapy or are seen with equal frequency in patients commencing an NNRTI-containing regimen. Patients enrolled in the metabolic study will undergo measurements of glucose, insulin, cholesterol and triglyceride levels. In addition, body composition measurements (e.g., BIA, skinfold measurements and body circumference measurements) will also be obtained. This trial promises to contribute much valuable information on risks and rates for developing metabolic and body habitus alterations after initiating HAART.
How to ensure that our patients can best adhere to the complicated HAART regimens that we prescribe is a most important question. Among the FIRST family of accompanying clinical trials, the CPCRA Adherence Study is now open for enrollment. Unlike most CPCRA studies where the individual patient is randomized to one intervention or another, the adherence study has randomized the entire Community Consortium to an adherence intervention that utilizes the services of "medication managers." Patients co-enrolled onto a CPCRA strategic antiretroviral trial who choose to participant in the adherence substudy will have interactions with our trained medication managers. These Consortium clinical research nurses will do everything per protocol to ensure that patients are reminded to adhere to their prescribed regimens. Two different interventions are being evaluated in a two-by-two factorial design involving CPCRA units randomized to different arms across the national network. The ultimate goal will be to evaluate which intervention produces the best HIV RNA results as well as self-reported adherence.
Protease Inhibitor Progression (PIP)
The revised version of the PIP protocol is now open for enrollment. The study is now more clearly presented as four concurrent companion trials under one master protocol. Two strategies are being evaluated. In patients progressing on a FIRST protease inhibitor-containing regimen, who still have adequate nucleoside analog options from which to choose, the strategy question will be one of intervening with immediate versus differed non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy. Patients will be randomized to begin two protease inhibitors or two protease inhibitors and an NNRTI. The specification of the actual drugs to be used, which was found in the initial version of PIP, has now been removed to allow providers to choose among protease inhibitors and NNRTIs. This study is open to patients progressing either on nelfinavir/ amprenavir or indinavir/ritonavir as their initial protease inhibitor treatments. For those patients progressing with limited options of nucleoside reverse transcriptase inhibitors to employ in their next regimen, the strategic question will be whether one or two protease inhibitors in conjunction with an NNRTI is the best salvage regimen. In these studies of PIP, patients progressing on their initial protease inhibitor regimen will be randomized to switch to one or two protease inhibitors and all patients will receive an NNRTI.
Patients must have a viral load >500 copies/ml. All patients will receive baseline genotypic resistance testing and the results will be returned as soon as available to the provider. There is no CD4 cell restriction. The question of how to best manage patients progressing on their first protease inhibitor-containing regimen is still largely unanswered. A survey of the Science Planning Committee of the CPCRA at the recent September meeting revealed that the options available in PIP correlate with the regimens that providers are offering to their patients off protocol. PIP is one of the first randomized trials looking at the question. In this CPCRA strategic trial, no drugs are being offered to the patient. Once the patient is randomized, the drugs will be obtained through provider prescription. We are quite eager to enroll as many of your progressing patients onto this protocol as possible.
The CPCRA is committed to long-term evaluation of patients enrolled on randomized clinical trials. Where a number of our trials have intermediate surrogate marker endpoints, co-enrolling patients onto the LTM protocol will ensure that we are able to capture long-term disease progression and survival information on patients who may not have already reached a clinical endpoint. Our goal is to enroll all patients on the CPCRA core protocols (FIRST and PIP) onto LTM. In this way, even if and when patients reach the endpoint of a clinical trial, they will continue to be followed for disease progression and survival, adding further information to the large CPCRA database. There are no specific laboratory tests. There are no specific laboratory tests required in the LTM trial. Patients are followed at every four-month intervals and CD4 cell and HIV RNA levels that have been drawn as part of their routine clinical care will be collected and reported. Your Consortium clinical research nurse will be making every effort possible to enroll all of your eligible patients onto long-term monitoring.
In addition to patients participating in CPCRA trials, LTM is also open for two other subsets of patients of interest. If you have an antiretroviral naive patient who is offered enrollment onto the CPCRA FIRST trial but who declines to participate in the randomized trial, we are interested in capturing their outcome information by enrolling them onto LTM. Similarly, antiretroviral naive patients who are choosing to remain antiretroviral naive are also being offered enrollment onto the LTM study. In this way, we will be able to amass a significant amount of standardized information on the cohort of patients who remain antiretroviral naive. Enrollment of these patients onto LTM will also facilitate subsequent enrollment onto other CPCRA intervention clinical trials.
Fifty-nine patients have now been enrolled in the Consortium study of short-term effects of cannabinoids in patients with HIV infection. The target sample size has now increased to 67 because of some patients dropped out of the protocol prior to reaching the critical Day 14 evaluations. However, only eight more participants are needed to complete the trial. We hope that the study will be ready for analysis by mid-2000 The goal of the study is to determine whether there is any pharmacokinetic interaction between cannabinoids (oral or smoked) and protease inhibitors, specifically indinavir and nelfinavir. We are hoping to enroll 32 patients on each of these protease inhibitors. We are almost at our target for nelfinavir. Additional indinavir patients are needed. In addition, the majority of patients enrolled to date have been men. It is important for us to be able to investigate these potential interactions in women as well. Therefore if you have any patients on indinavir or any women who may interested in participating in the trial, please have them call the number below for more information.
During the 25-day in-patient evaluation at the GCRC, patients will be randomized to smoke THC three times daily or to oral marinol three times daily or to marinol placebo. Immune parameters, HIV RNA levels, testosterone levels, body composition and pharmacokinetic measure- ments will be obtained. Patients will receive up to $1,000 for completion of the study. They will also be contributing important information that will help to provide some data for the current debate regarding the safety and medical utility of smoked marijuana. Eligibility criteria include prior history of use of marijuana (none in the month prior to randomization), stable viral load and stable antiretroviral regimen (including either indinavir or nelfinavir as the sole PI) for at least eight weeks. Patients who are tobacco smokers, on methadone maintenance, taking anabolic steroids or who are pregnant will be excluded. If you have patients who are interested in participating in the trial and who appear to meet the eligibility criteria, please have them call (415) 502-5705 for further information.
Just Opened in the Bay Area
Antiretroviral Therapy: HIV Dynamics and Ovulatory Cycles: Nelfinavir, d4T, 3TC
This study will look to see what differences there are in the time it takes HIV to be reduced in the bloodstream in two groups of women and one group of men who are starting HAART. Women beginning their menstrual cycle will call the study coordinator to have a vaginal ultrasound performed. If the ultrasound shows that women are ovulating, they will be randomized to the early follicular group or to the midluteal group. A second ultrasound will be done two weeks later to confirm ovulation. Women in the early follicular group will be admitted to the research clinic for one day after the first vaginal ultrasound, while those in the midluteal group will be admitted after the second ultrasound. Men will be admitted at any time. Once admitted, patients will begin taking nelfinavir, d4T and 3TC, then have HIV RNA levels checked every two hours for six hours, then every six hours for 18 hours, then once a day for six days. T-cell counts will also be done and women will have reproductive hormone levels done the same day as ultrasounds. The study lasts about one month. Women will be paid $235 for completing the study and men will receive $205. Men and women can earn an additional $50 if they participate in a substudy of the pharmacokinetics of nelfinavir. The substudy will last 13 hours and take place on the last day that the viral load testing is done and will include nine blood draws. Patients must be between 18 and 45 years old and have more than 10,000 copies/mL of HIV RNA. Women must have regualr menstrual cycles. Prior use of any protease inhibitors, use of any NRTIs within the past year, or women using contraceptives are not allowed. Call Sarah Ellison, RN at the Women's Interagency HIV Studies (415) 502-8056.
HIV and Hepatitis C Treatment: Pegylated Interferon, Alpha Interferon, Ribavirin
This study will compare pegylated interferon (a long-acting form of interferon) alone vs. pegylated interferon plus ribavirin vs. alpha interferon plus ribavirin. Patients are randomized to one of three groups. The first group will take pegylated interferon (PEG Intron) plus ribavirin placebo. The second group will take PEG Intron plus ribavirin. The third group takes alpha interferon plus ribavirin. PEG Intron is given by injection under the skin once a week. Alpha interferon is given by injection under the skin three times a week. Patients assigned to take PEG Intron will not know if they are taking ribavirin or placebo until the study is completed. Treatment lasts 48 weeks and study visits are every two weeks for the first two months, at Week 12, then every six weeks. Patients must have at least 200 T-cells with any viral load or between 100 and 199 T-cells with a viral load less than 5,000 copies/mL. Patients must have detectable hepatitis C virus (more than 1,000 copies/mL). Patients on HAART must be on stable therapy or patients who have not been on HAART for at least eight weeks must be willing to delay starting HAART for at least six weeks. Pregnancy, male partners of pregnant women, active OIs or OMs, prior use of interferon or ribavirin, or any other chronic liver diseases other than hepatitis C are not allowed. Please call Jay Lalezari, MD at Quest Clinical Research, San Francisco (415) 353-0800.
Peripheral Neuropathy: Lamictal
This study will see if Lamictal helps relieve the pain of peripheral neuropathy and improves the quality of life in HIV-infected patients. Patients are assigned by chance to receive Lamictal or placebo. Both are pills. Neither patients nor providers will know which they are taking until the study is completed. There are six study visits and the study lasts 11 weeks. Patients will have the option to continue taking open label Lamictal for three months. Patients will be paid for each study visit they attend. Patients must be between 18 and 65 years old and have moderate to severe peripheral neuropathy diagnosed by a neurologist. Patients taking ddI, ddC or d4T must be on stable doses for at least eight weeks prior to study entry. Pregnancy, active OIs or prior use of Lamictal are not allowed. Please call Naomi Schoenfeld at the UCSF Department of Neurology (415) 502-5064.
Thought you'd like to know . . .
The Ziagen (abacavir sulfate) drug label has carried a warning about fatal hypersensitivity reactions since the drug was approved in December 1998. Recently GlaxoWellcome sent a "Dear Investigator" letter to physicians nationwide which included revised product labeling and a revised warning describing the role that respiratory symptoms play in the diagnosis of these hypersensitivity reactions. A newly recognized component of the abacavir hypersensitivity reaction that includes cough, dyspnea and pharyngitis has been seen in approximately 20 percent of patients who experience the hypersensitivity reaction. Fatalities have been reported in patients whose initial presentation included respiratory symptoms as part of the hypersensitivity reaction.
The warning box in the package insert has been revised to reflect this new information. In addition, the adverse reaction section of the revised abacavir package insert includes the statement: "The diagnosis of hypersensitivity reaction should be carefully considered for patients with symptoms of acute onset respiratory diseases, even if alternative respiratory diseases (pneumonia, bronchitis, pharyngitis or flu-like illness) are possible."
California Academy of HIV Medicine launched
The California Academy of HIV Medicine (CAHM) will be holding its founding membership meeting and dinner for HIV physicians in the West Bay region, which includes practices and clinics in Sonoma, Marin, San Francisco, San Mateo, Santa Clara, Santa Cruz and Monterey counties. The Academy is an organization of physicians dedicated to promoting excellence in HIV care.
On a national level, CAHM's parent organization, the American Academy of HIV Medicine, plans to be involved in the education and credentialing of HIV specialists. On a state level, CAHM will support quality care for patients with HIV.
There will be no charge to physicians for the dinner, which has been funded by a grant from Bristol-Myers Squibb, but please RSVP when you receive your invitation in the mail. For more information call Bill Owen, MD, at (415) 861-2400 or email Bill@owenmed.com.
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