November 2000
Next Meeting: November 15, 2000
Migden HIV Transplant Initiative
Committee Reports
Scientific Advisory Committee and Community Advisory Board
Consortium Clinical Trials
Clinical Trials Update
Multi-drug Reistant HIV (MDR)
FIRST
Metabolic Study
Adherence Study
Long-Term Monitoring (LTM)
Just Opened in the Bay Area. . .
Post Exposure Prophylaxis (PEP 2)
Next Meeting
The next meeting of the Community Consortium will be held on Wednesday, November 15, 2000 at 6:00 p.m. at the Davies Campus of the California Pacific Medical Center in the Auditorium located on the B Level of the hospital at Castro and Duboce Streets in San Francisco. Refreshments will be served and free parking is available in the lot. Following brief general announcements, Elisabeth Targ, M.D., from the Complementary Medicine Research Institute at California Pacific Medical Center will discuss "Prayer and Distant Healing in HIV/AIDS."
Dr. Targ is a recipient of NIH funding to study the impact of distant healing and prayer administered by both "healers" and nurses trained in the processes. She is recognized as one of the leading experts in this area. The Community Consortium will assist Dr. Targ's group in identifying patients interested in participating in her recently funded National Center for Complementary and Alternative Medicine trial. This promises to be a most informative, provocative and appropriate meeting for the pre-holiday end-of-the-year final Community Consortium AIDS Clinical Grand Rounds of the year 2000. Immediately following Dr. Targ's presentation, the year-end dinner meeting, to which you were invited under a prior mailing, will occur. Please note that the dinner meeting will commence at 7:30 p.m., immediately following Dr. Targ's presentation, and not 6:30 p.m. as was stated on your invitation. Please R.S.V.P. for the dinner event as soon as possible to assure your attendance. Again, there will be no AIDS Clinical Grand Rounds in December. The next Community Consortium meeting will be held on January 17, 2001. So do make every effort to attend to wish your Consortium colleagues the best for a happy holiday season and a peaceful and prosperous New Year! Migden HIV Transplant Initiative The October 2000 AIDS Clinical Grand Rounds session featured an "Update on the Migden HIV Transplant Initiative at UCSF and Beyond." Tom Coates, Ph.D., Director of the AIDS Research Institute at UCSF, described the heroic efforts of Jeff Getty and Assymblywoman Carol Migden in obtaining support for the newly established initiative to allow patients with HIV to undergo solid organ transplantation. Consortium members in attendance were reminded that theoretical discussions of the possibility and problems of organ transplantation in patients with HIV occurred at an AIDS Clinical Grand Rounds 18 to 24 months ago. Jeff Getty spawned the idea to obtain adequate funding to launch pilot projects. The rationale was that people with HIV were living longer and more of them were dying of liver and kidney failure. Dr. Coates described that through the work of Assemblywoman Migden, Chair of the House Appropriations Committee, a total of $3 million to date has been set aside to cover the costs of patient services so that preliminary research can be conducted. He reported that the NIH is supportive of an initiative that currently involves at least 14-centers in developing a multi-site study to evaluate the safety of kidney and liver transplants in patients with HIV infection. On behalf of the AIDS Research Institute and the Division of Transplant Surgery, Dr. Coates presented a plaque to Carol Migden and Mr. Getty. The plaque will be hung on Ward 86, the UCSF Positive Health Program at San Francisco General Hospital, honoring the work done to establish the Migden HIV Transplant Initiative. Committee Reports
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. 1.5 hours credit is available for this meeting.
Jeff Getty, of Survive AIDS and the recipient of the historic baboon bone marrow transplant, reiterated that if it weren't for Carol Migden, organ transplants in patients with HIV would not be happening. He remarked that Assemblywoman Migden's motivation is humanistic - she has done this because she cares about the people. Mr. Getty related an interesting story. For many years as an AIDS activist, he was demanding access for all to promising therapies. Now that he has been so integral in establishment of the transplant initiative, he suddenly finds himself on the other side of the fence. Telephoned by people who want to stretch the entry criteria to be eligible for transplants, Jeff says that he now finds that his primary goal is to maintain the integrity of the protocol, stating that "This is science and not doing favors for people."
Assemblywoman Migden was present at the Consortium meeting and said that she was delighted to have her name, a relatively uncommon one, immortalized on the plaque and in the title of the transplant initiative. She remarked that she felt it was imperative that funding be sought to cover patient care costs, as liver transplants can cost from $200,000 upward. As a member of the state legislature, she is working as a team with the health care providers in providing optimal care for patients with endstage renal and hepatic disease and concomitant HIV. The hope is that with five transplants being successful to date, that third party payers may also now begin covering some of the patient care cost bills, allowing even more procedures to be undertaken.
Following the ceremony, the scientific presentation regarding the HIV transplant initiative was presented by Michelle Roland, M.D., Assistant Clinical Professor at the UCSF Positive Health Program at San Francisco General Hospital and Peter Stock, M.D Associate Professor in Residence in the Department of Surgery. Dr. Stock opened the program by providing some background as to why the timing is now right to consider organ transplantation in patients with HIV. Up until recently, HIV has been considered a relative or absolute contraindication for transplantation at most centers. Prior to now, it didn't make a lot of sense to consider immunosuppression in an immunosuppressed patient population. However, advances in antiretroviral therapy have extended life expectancy in patients with HIV. Increasing numbers of HIV-positive patients are now developing and even dying of endstage organ failure, perhaps even more so than from AIDS-associated opportunistic infections and malignancies. Dr. Stock reported that the pendulum is definitely swinging. Previously a survey of U.S. transplant centers demonstrated that 90 percent of the centers would not transplant an HIV-positive recipient. One hundred percent of the 149 centers responding to the survey reported that HIV testing was required for prospective recipients. Eighty-four percent of the respondents said that a patient who refused HIV testing would not be even considered for transplantation.
Dr. Stock pointed out some of the reasons that the trend is changing at the current time. Epidemiological data show decreased incidence of opportunistic infections and hospitalizations with the use of highly active antiretroviral therapies. HAART in immunosuppressed HIV-positive transplant recipients has been shown to further improve allograft and patient survival. Finally, there is some evidence that the immunosuppressive agents commonly used in transplants have an actual anti-HIV effect. Dr. Stock reviewed a 1993 article in Transplantation by Schwartz, et al., on the effect of cyclosporin on the progression of HIV disease. In this retrospective review of 53 transplant patients with HIV infection secondary to infected perioperative blood transfusions, a difference in outcome was seen in progression to AIDS in five years in those patients treated with cyclosporin-containing regimens. Among 13 patients whose regimen did not contain cyclosporin, 90 percent had rapid progression to AIDS. Among 40 patients who received cyclosporin in their post-transplant regimen, only 31 percent had progressed by five years. This data was collected in the 1980s before all patients transplanted were tested for HIV at a time when there was no highly active antiretroviral therapy. In a more recent publication in Virology, Streblow, et al., suggests that cyclosporin inhibits HIV-1 gag processing. This inhibition results from the binding of cyclosporin A to cyclophilin A. Cyclophilin A may be required for gag conformational changes subsequent to assembly. (Virology 1998; 245:197)
Mycophenolic acid (CellCept) was approved by the FDA in 1993 for renal and liver transplant recipients. Renal transplants are more immunogenic than liver transplants and thus require more immunosuppression. This agent has decreased the rejection rate to less than 20 percent. Mycophenolic acid is a non-nucleoside inhibitor of inosine monophosphate dehydrogenase. It appears to limit the rate of de novo synthesis of guanosine nucleotides in turn blocking the activity of reverse transcriptase. The drug shows strong anti-HIV activity in vitro in both human peripheral CD4-positive lymphocytes and macrophages. There is evidence that CellCept may have anti-HCV qualities as well. (Ichimur and Levy, Virology 1995; 211:554).
Dr. Stock pointed out that these advances, as well as the advances in HIV treatment, have turned the tide in transplanters' enthusiasm to work with HIV-positive patients. The initial historical data of HIV-positive recipients doing poorly was reviewed. A number of articles from the late '80s and early '90s purportedly showed worse outcomes following solid organ transplantation in sero-positive patients. Dr. Stock outlined some of the difficulties in interpreting the data. For the most part, these were small anecdotal experiences with poorly defined outcomes. They also do not take into consideration the advances that have been made in therapies for prophylaxis against opportunistic infections, improved anti-rejection therapies, improved antiretroviral therapies, as well as improved diagnostic testing.
He then went on to describe some of the experiences with a few of the patients that have been transplanted who were not know to be HIV-infected at the time of transplant. In one situation, it was clearly demonstrated that the patient was able to reject her transplanted liver, demonstrating that patients with HIV can in fact reject an organ similar to patients without underlying HIV infection. The patient's rejection episode was treated with a steroid bolus. Subsequently, antiretroviral therapy was initiated. Since that time, the patient has had no detectable HIV viral load, negative HBV staining on liver biopsy, no detectable HCV by PCR, no opportunistic infections and normal liver function tests.
Cases such as the one described by Dr. Stock are what crystallized the impetus to establish the current solid organ transplant initiative in HIV positive patients. Dr. Stock reviewed the study aims. The first is to evaluate the impact of kidney and liver transplantation and post-transplant immunosuppression on HIV disease progression and markers of immune function and activity. In addition, the study hopes to evaluate the impact of HIV infection on graft function and survival as well as to describe the pharmacokinetic interactions between immunosuppressive agents and the hepatically metabolized antiretroviral agents.
Michelle Roland, M.D. continued the program with a more detailed review of the current protocol. The initiative is open for both kidney and liver transplantations with some differences in inclusion criteria. The common inclusion/exclusion criteria are that patients meet standard transplant criteria with regards to medical indications, social support and substance use histories. Patients should have no history of opportunistic infection or neoplasm. There are no age limitations. For patients to be eligible for a kidney transplant, they must have CD4 counts > 200/mm3 for six months and a viral load < 50 copies on a stable antiretroviral regimen or a viral load < 50 copies on no antiretroviral therapy as long as they would be willing to go on treatment if HIV RNA becomes detectable. The criteria for liver transplants include CD4 > 100/mm3 for six months and a viral load < 50 copies on a stable antiretroviral regimen. The current additional criteria of a detectable viral load off antiretrovirals but with the ability to predict full suppression following reintroduction of antiviral therapy is currently being re-evaluated and will likely be excluded. A liver transplant is a bloody operation in a blind cavity with a potential for multiple needlesticks. Hence, it is an operation that presents the OR staff with a high risk of exposure. For that reason, the investigators are considering changing the criteria so only patients who are currently undetectable with regards to their HIV RNA will be eligible for transplantation. Once a few procedures have been completed and the safety can be further assessed, the viral load criteria for the liver transplantations may be modified.
Patients participating in the transplant initiative will hopefully be followed for five years, following their organ transplantation. Patients will be seen in follow-up weekly for the first four weeks after transplantation and then every other week for four visits, monthly for two, every eight weeks for four and every twelve weeks for the next two years. For the final two years of the study, patients will be seen every six months. Participants will spend at least six 14-hour stays in the General Clinical Research Center (GCRC) at the University of California ,San Francisco scheduled on weeks one, four, six months and one, two and five years. Additional GCRC visits will also be required when patients change medications.
Dr. Roland described the numerous substudies that are being conducted as part of the HIV solid organ transplant initiative. A multi-disciplinary team has been established to conduct immunology, virology, and pharmacology evaluations. Both HIV-specific and transplant-specific immunology will be investigated. Virology will concentrate on HIV suppression and rebound as well as HCV and HBV levels in tissue and plasma. A collaborative effort with Joel Palefsky, M.D., will investigate cervical/anorectal HPV. Jeff Martin, M.D., will look at HHV8 virus effects.
There are many potential pharmacokinetic interactions that could result from the immunosuppressive and antiretroviral agents taken together post-transplantation. There is a potential for antagonism between CellCept and d4T/AZT in vitro. There is also the possibility that both PIs and NNRTIs may interact with cyclosporin. Patients undergoing transplantation may need to undergo modification of their antiretroviral therapy so as not to antagonize their immunosuppressive agents.
Dr. Roland reviewed some of the mechanics of consenting patients to participate in this transplantation protocol. There is a 10-page informed consent that takes fully 45 minutes to review with an interested participant. Patients sometimes get overwhelmed by the 2-page schedule of events that they are introduced to during the informed consent process. Currently, the study is open predominantly to California residents. The state funding is essentially to cover the clinical costs for California residents who need a transplant and have no other coverage. Money is also available to cover research costs of non-California residents who do have clinical coverage to pay for their transplant. Dr. Roland reports that referrals are coming in currently from all over the country to participate in the program.
There are many special challenges facing this program. The high risk of HCV co-infection may be problematic. HCV liver transplant patients generally do not do well. HCV may also have an impact on the outcome in patients undergoing kidney transplants. To date, many of the patients that have been screened appear to have a history of anogenital warts. Some dysplasia is now also being seen. Hence, the substudy being conducted in collaboration with Joel Palefsky may be quite important. The overlapping drug toxicities and potential for drug-drug interactions have already been described. In addition, Dr. Roland reported that elevated triglycerides and the risk of diabetes are high from both protease inhibitors as well as immunosuppressive therapies.
The Migden HIV Transplant Initiative is just a first step and allows UCSF and California to lead the nation in gaining experience in solid organ transplantation in patients with concurrent HIV infection. A multi-site study is being planned that will involve at least 14 centers using a common protocol and data collection tools. Centralized data management and statistical support is currently being developed for this study, which will be submitted for full NIH funding. Dr. Roland expects that nearly 100 transplants will be conducted across the country over the next year and a half.
Dr. Stock concluded the presentation by reviewing the CD4 cell and HIV RNA responses in five subjects who have been transplanted at UCSF to date. He mentioned that the average wait time for a Type O renal transplant recipient is five to seven years. HIV-positive recipients may have a little advantage because in general they are willing to use high risk donors. Organs are refused by all centers because of high risk behavior of the donor, including injection drug use, multiple sexual partners, or incarceration. To date, such organs used at UCSF have been HIV and HCV negative. Three of the four kidney transplant patients have done quite well and the fourth has not experienced any HIV-related complications. There is an even more severe shortage of livers for transplantation. Dr. Stock reported that this is being managed by using living donors. In this situation, the donor gives a lobe of the liver, which usually regenerates within about a month's time back to the normal size.
If you have patients who might be interested in participating in the solid organ transplantation program, the referral and screening process is complicated but ultimately doable. All referrals should be directed initially to the study coordinator, Laurie Carlson. Ms. Carlson is best contacted directly by her pager at (415) 719-0729 or via e-mail at CarlsonL@surgery.ucsf.edu. If the patient meets the initial HIV eligibility screen, Ms. Carlson will direct the referring clinician to either the kidney transplant coordinator, Linda Moczkowski, or to the hepatologist on call. All patients who appear to meet clinical (liver or kidney), HIV and financial eligibility criteria will be seen by both Dr. Roland for HIV screening and by the kidney or liver transplant teams. For non-patient related information about the local or national studies, contact Dr. Michelle Roland at mroland@php.ucsf.edu.
Scientific Advisory Committee and Community Advisory Board
A special year-end holiday luncheon session of the Scientific Advisory Committee and Community Advisory Board will be held on Thursday, November 16, 2000 at 12 Noon in the Community Consortium conference room. Please note this divergence from the normal first Thursday of the month meeting time. This will serve as our November/December meeting and will be the last SAC/CAB meeting of the year 2000.
Consortium Clinical Trials
The Consortium is in the process of gearing up to launch three new clinical trials in the Bay Area. In preparation for this increase in clinical activity, we have brought aboard a new research associate. Mr. Paul Couey has joined the Consortium and will be involved in the distant healing and DHEA projects. Mr. Couey comes to us from the AIDS Research Consortium of Atlanta. Please welcome Mr. Couey when he calls on your clinical site.
At the November AIDS Clinical Grand Rounds, we will hear more about the study of prayer and distant healing by nurses and healers "as an adjunctive intervention in AIDS" from Elisabeth Targ, M.D., principal investigator. Dr. Targ has received NIH funding to conduct this clinical trial. Two preliminary double blind studies conducted by Dr. Targ found significantly improved psychological and medical outcomes in patients with advanced AIDS who had received distant healing attempts by a diverse selection of professional "healers". While provocative, conclusions from these studies are limited by the small study size (N=20 and N=40), by the fact that patients were being treated in a variety of different clinics and by collection of medical data by retrospective chart review. For these reasons, replication is warranted. The purpose of the study which is about to commence enrolling is to extend the preliminary work by studying a larger sample, examining additional biological markers of disease progression and following medical and quality of life outcomes for a longer period. In addition, the study will compare distant healing efforts by professional "healers" with distant healing efforts by professional nurses with no previous training.
One hundred fifty subjects with advanced AIDS will be enrolled in the study and randomized to one of three study arms. The study will be completed in ten cohorts of 15 patients. In each cohort, five patients will be randomized to receive DH attempts by professional "healers", five patients will receive DH attempts by nurses, and five patients will receive no special intervention beyond usual medical treatments. The study will be double-blinded so that neither patients nor their doctors nor the researchers will know who is receiving the healing treatments. Outcome measures include the clinical course, psychological course, utilization of medications as well as HIV RNA, CD4/CD8, NK cell function, and metabolic measures and antiretroviral therapy toxicity. Inclusion criteria are HIV sero-positive between the ages of 8 and 65 with a history of having had a CD4 cell count < 200/mm3. Patients who are not English-speaking, unable or unwilling to fill out questionnaires or who have a history of non-HIV related life-threatening disease are excluded. Study procedures will be conducted at the California Pacific Medical Center site. Participants will be required to return after their baseline evaluation to this study site at six months and one year for follow-up questionnaires and blood work. The remainder of the data will be extracted from clinic charts by the research assistant. If you are interested in enrolling eligible patients for the distance healing study, please contact Paul Couey at (415) 476-9554, ext. 15.
We are about to launch a study of dehydroepidrosterone (DHEA) to investigate how it impacts on latent HIV-1 replication and host community. DHEA has been touted to have a number of beneficial effects in patients with HIV ranging from antiviral, immunomodulatory as well as being an agent to increase lean body mass and improve quality of life. There is some evidence to suggest that DHEA may have some potential benefit in purging the latent pool of HIV in resting cells. To this end, this randomized placebo-controlled trial will be open to patients fully suppressed on an antiretroviral regimen. Eligibility criteria include patients with HIV-I infection who are 18 years old or older on stable antiretroviral regimens for at least eight weeks, with HIV RNA < 50 copies/ml. Women should have a normal PAP smear and mammogram within the past year and men are required to have a normal prostate specific antigen level within the past year. Participants will be randomized in a 1:1 ratio to receive either DHEA (100 mg po twice daily for males, 50 mg po twice daily for females) or placebo for 12 weeks. All study participants will then receive DHEA for an additional 12 weeks, for a total study duration of 24 weeks. Study participants will be seen as outpatients at the General Clinical Research Center. They will have one screening and one baseline visit prior to starting study drugs. At the baseline visit, they will have blood drawn for measurement of HIV RNA, for viral DNA, hormone levels, lipid levels, PSA, serum chemistries, levels of circulating IL-2 and lymphocyte subset analyses for activation antigens and naive and memory T-cell subpopulations. Body weight, height, anthropometric measures as well as body composition measurements by DEXA will be obtained. Quality of life assessments will be completed. Participants will then be randomized to either DHEA or placebo for 12 weeks. Follow-up study visits will occur at weeks 2, 4, 6, and 12. Follow-up visits during the ensuing 12 week open label DHEA treatment will occur at weeks 18 and 24. If you have patients who may be interested in participating in this study, please contact Paul Couey at (415) 476-9550, ext. 15.
The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is the follow-on study of the CPCRA IL-2 trial which recently terminated. CPCRA 059 patients are being rolled over onto the ESPRIT study for an anticipated four to five additional years of follow-up for clinical endpoints and survival. In addition, we are working now to make the protocol available to further patients with CD4 cell counts > 300/mm3 who are on or initiating antiretroviral therapy. The randomization in ESPRIT would be to receive subcutaneous recombinant IL-2 at a dose of 7.5 MIU bid for five days every eight weeks for at least three cycles and then subsequently to maintain the CD4+ cell count at twice baseline or > 1000 cells/mm3. If this study demonstrates that IL-2 is of clinical benefit, all patients will subsequently be offered therapy for some period of time. If you would like to enroll patients onto the ESPRIT trial, please contact Carroll Child, RN, at the Community Consortium at (415) 476-9554, ext. 22.
Thanks to Michael Jones, RN, Community Consortium Clinical Research Nurse, and the provider at Castro-Mission Health Center for their continued enthusiasm for the CPCRA MDR trial. To date, we have enrolled six patients of the 52 accrued nationwide. This study of a structured treatment interruption (STI) in patients with multi-drug resistent (MDR) HIV is a randomized clinical endpoint study to determine whether a prescribed four-month STI will delay clinical disease progression and death compared with a strategy of immediately initiating a new antiretroviral regimen in patients with MDR virus. Subjects will initiate the salvage regimen based on information generated from both genotypic and phenotypic resistance testing that is provided as part of the protocol. As there is little existing information on the optimal amount of time to wait before resuming therapy following an STI, the first 150 participants in the CPCRA trial will have point mutation assays performed. These are more sensitive than routine resistance assays. These initial patients will also undergo more frequent HIV RNA testing, which should enable the investigators to know early in the course of the trial whether four months is too long or too short of an STI.
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.
The potential subject must have demonstrated a multi-drug-resistant HIV strain on genotypic antiviral resistance testing (GART), with evidence of broad PI resistance combined with broad NNRTI and/or broad NRTI resistance. The patient and provider must have the intention of initiating a new regimen and should be able to accept the potential timing of this change as specified in the protocol. Individuals should be on a stable antiretroviral regimen for at least 14 days prior to the qualifying GART test and randomization. Broad PI resistance is defined as having at least two major resistance mutations against PIs. Broad NNRTI resistance would include B103M mutation or a combination of two other NNRTI mutations. Broad resistance to nucleosides is defined as the presence of 151M/69S mutation or a combination of mutations including B215Y/S mutation. Any patient previously exposed to three nucleosides, one NNRTI and two PIs, is also eligible for screening and will have GART performed if they meet the remaining entry criteria. If you have any individuals who may be interested in participating in the CPCRA MDR trial, please let your Community Consortium clinical research nurse know!
The CPCRA's Flexible Initial Retroviral Suppressive Therapies (FIRST) trial is the entry point into the CPCRA's menu of strategic antiretroviral trials. FIRST is open to patients who are antiretroviral naive. As of mid-October, the CPCRA has enrolled 817 of the target 1,410 participants. Accrual is expected to close at the end of March 2001. To date, the Consortium has enrolled 34 patients onto the study. The question being asked is "What constitutes the best initial regimen for patients beginning antiviral therapies?" Patients are randomized to one of three arms. One arm includes two nucleoside analogs and a protease inhibitor, a second arm includes two nucleoside analogs and a non-nucleoside reverse transcriptase inhibitor (NNRTI), and a third arm includes at least one nucleoside analog plus an NNRTI and a protease inhibitor. Clinicians who so desire 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. The CPCRA has enrolled 304 of the 360 patient target onto this protocol as of the mid-October.
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. The CPCRA has enrolled 411 of the target 592 patients from FIRST onto the adherence protocol.
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 on the CPCRA CORE protocols (FIRST and PIP) onto LTM as well as patients now being randomized on MDR. In addition, patients on the original IL-II protocol are also being asked to co-enroll onto LTM. The Consortium has a goal of 100% co-enrollment onto the LTM protocol for eligible patients by November 15. To date, we have enrolled 85 of the 2000 participants nationwide. Please assist your Community Consortium clinical research nurse in explaining to patients participating on eligible trials why the long-term monitoring protocol is essential.
Just Opened in the Bay Area . . .
Post Exposure Prophylaxis (PEP 2)
David Townley, Project Coordinator of the PEP Program, attended the October Community Consortium meeting to update providers on the status of non-occupational services in San Francisco. The initial study of non-occupational post-exposure prevention (PEP 1) conducted at San Francisco General Hospital and at the City Clinic, closed to new enrollments over a year ago. This study was designed to describe the demographic and risk behavior characteristics of those seeking PEP, their adherence to their medications, the incidents of toxicities, and to assess the feasibility of offering antiretroviral medications following high risk HIV exposure. Results of this study have been presented at national and international meetings and have recently been accepted for publication.
Since PEP 1 closed, PEP Services (415-514-4PEP) have been provided at the UCSF Positive Health Program at San Francisco General Hospital and at the San Francisco City Clinic. Recently the CDC opened a non-occupational PEP Registry.
The Registry was established to describe (1) the characteristics of the exposures for which PEP is prescribed, (2) adherence to medications and the impact of side effects and adverse events, (3) differences in PEP practice in different clinical settings, and (4) a comparison of HIV infection rates between those who sustain exposures and are treated with PEP and those who are exposed but untreated. For information about the CDC PEP Registry, visit the website at www.hivpepregistry.org or call David Townley, CDC National PEP Registry Coordinator in the San Francisco Bay Area at (415) 476-9296, ext. 334. If you provide PEP in your office, staff is available to assist you. For further information on call Mr. Townley.
Mr. Townley also reported that PEP 2 is scheduled to begin enrolling partici-pants in mid-February 2001. PEP 2 is a randomized trial to compare the effect of standard (two sessions) versus enhanced (five sessions) risk reduction counseling on risk behavior incidents in individuals receiving PEP. All services will be provided free of charge. Stay tuned for more details.
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