John Y. Killen, M.D.
Director, Division of AIDS, NIAID
The meeting, which was held in the Natcher Conference Center on the campus of the National Institutes of Health, was chaired by Dr. Gary Nabel, chairman of the AIDS Research Advisory Committee (ARAC).
Report from the Director — Dr. John Y. Killen
Dr. Killen welcomed Committee members and others attending the meeting and thanked them for their participation. He first addressed the NIAID FY 1997 budget, in which pay lines have been raised for both AIDS and non-AIDS research. The President’s budget request for FY 1998 included a 4.4 percent increase for NIAID, the highest of all NIH Institutes, Centers, and Divisions (ICD’s). In comparison, NIH received a 2.6 percent overall increase. NIAID’s high percentage increase is explained by the fact that NIAID projects reflect current priorities, even for non-AIDS research. The AIDS research increase for NIAID is 4.7 percent, higher than AIDS research increases allotted to other ICD’s. Important AIDS initiatives to be pursued in 1998 include the Strategic Program for Innovative Research on AIDS Vaccines, Basic Research on Mucosal Immune Response to HIV Vaccines, Acute Infection and Early Disease Research Program, and International Trials on Prevention of Perinatal HIV Transmission.
Dr. Killen noted that the Congressional budget may allot more funds to NIH, and, if so, the funding plan will be modified.
Dr. Killen mentioned President Clinton’s recent announcement of the goal to achieve an HIV vaccine within 10 years. To help achieve this goal, a vaccine center is being established to consolidate all NIH intramural vaccine research activities. This initiative will bring scientists together who are already working on HIV vaccines. He also indicated that growth in the NIH AIDS budget will be preferentially channeled into vaccine research and development, both extramural as well as intramural research. Some of the 1998 NIAID budget initiatives reflect this.
Dr. Killen congratulated Dr. William Duncan on receiving the Department of Health and Human Services 1997 Secretary’s Award for Distinguished Service from Secretary Shalala.
Dr. Killen reviewed the recent controversy concerning NIH and CDC supported studies of interventions to disrupt perinatal transmission in developing countries. The watchdog group, Public Citizen, criticized these studies as being unethical because they did not include the antiretroviral regimen that was shown to be effective in the 076 study. Dr. Killen stated, however, that Public Citizen is confusing a standard of care issue with an ethical issue and is not considering the reality of health care in the developing world, where simpler interventions are needed. He noted that the countries in question want and need interventions that are easier to administer and less expensive. They, in fact, requested assistance with these trials and have been involved in every aspect of their planning and conduct. Dr. Killen indicated that DAIDS has received many strong letters of support and that the Institute stands behind the trials.
Dr. Killen next provided information on program activities. A factsheet was prepared and widely disseminated to respond to questions about the program announcement for the Centers for AIDS Research (CFAR). Language in the announcement was revised to clarify that two separate CFAR’s can utilize one resource site if there is a demonstrated need.
A working group is being convened to prepare for the recompetition of the AIDS Clinical Trials Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). In keeping with the recommendations of the Levine Report, the working group will examine various options for integrating the efforts of these two clinical trials networks. An NIH task force, consisting of group leadership, independent scientists and NIH staff will define the specifications of an integrated clinical trials system, while NIAID will focus on the renewal of the CPCRA and ACTG and the structure of the RFAs. In addition, the Office of AIDS Research will be creating an overarching therapeutic research advisory group.
Dr. Killen updated the Committee on status of DATRI 002, the low dose oral alpha interferon (LDOAI) study. Although the ARAC recommended that the NIAID undertake this study to obtain reliable data on the effects of LDOAI, the study has not progressed as planned. Low patient accrual, high drop-rates, and problems with data quality have hampered the study. The study team and the Division of AIDS have worked together to try to address these issues, but it is apparent that community interest in the study has waned. The data and safety monitoring board (DSMB) will assess the study’s enrollment and data quality later this month and could recommend closing the study if these problems have not improved.
Dr. Killen thanked outgoing committee members Mr. Ryland Roane and Dr. Gary Nabel for their years of service on the ARAC and their significant contributions. He presented each with a certificate of appreciation..
Vaccine Trials: Status Update — Dr. Patricia Fast
Dr. Fast prefaced her remarks on NIAID vaccine trials by stating that fundamental research underlies all vaccine design and evaluation. She outlined the vaccine design and evaluation process, from preclinical research to parallel animal model research and Phase I/II clinical research (to compare animal and human data) through to the efficacy study. Vaccines are designed to prevent viral entry, prevent viral replication, or destroy infected cells. Multiple vaccine concepts must be carried out because no one approach is known to work best. Concepts being pursued include those for vaccines composed of peptides, subunit envelopes, recombinant particles, whole-killed HIV, DNA, and live-attenuated SIV and HIV.
The AIDS Vaccine Evaluation Group (AVEG) is conducting 25 Phase I trials and 1 Phase II trial, with 15 vaccine candidates, to compare safety and immune responses. The larger HIVNET (HIV Network for Prevention Trials) is conducting trials in the United States and abroad. Dr. Fast summarized the clinical trials being carried out on peptides, envelope proteins, vaccinia/canarypox, prime-boost approach, canarypox, and virus-like particles. Mucosal vaccines are being actively investigated. She noted that researchers are striving to find a vaccine that provides a broad response from which the virus cannot escape.
Vaccine Education: What Next? — Mr. Steve Wakefield
Mr. Wakefield opened by showing several minutes of an educational videotape, "No Easy Answers," aimed at potential participants in the HIVNET 014/AVEG 202, prime-boost vaccine trial. Several committee members commented on the excellence of the film. He discussed the challenges facing the national community advisory board (CAB), which was established, in part, to facilitate community education, outreach and recruitment efforts.
Mr. Wakefield described six educational tools designed by HIVNET’s Community Education and Media Relations Committee and NIAID for persons considering volunteering for the prime-boost trial: (1) a booklet explaining vaccines, (2) slides describing social harms, (3) top 10 questions and answers, (4) the above-mentioned videotape, (5) NIAID fact sheets, and (6) a guide to informed consent. The committee’s membership includes national staff, site staff, community educators, and community members. Mr. Wakefield noted that community members requested education about the informed consent process.
Mr. Wakefield next listed four important areas for community education to be addressed by the CAB: (1) allowing for different opinions, (2) how to inform the community about avoiding the errors of the Tuskegee study, (3) providing materials appropriate for diverse gender and ethnic groups, and
(4) assessing community readiness for a Phase III trial. Mr. Wakefield remarked that the gay press rarely addresses HIV vaccines.
AIDS Vaccine Research Committee — Dr. Carol Heilman
Dr. Heilman reported on the activities of the AIDS Vaccine Research Committee (AVRC), chaired by David Baltimore, Ph.D. The AVRC was recently established to assist NIH in developing a comprehensive research program to expedite discovery and development of an AIDS vaccine. Its first meeting took place in February 1997.
AVRC is charged with enhancing current NIH AIDS vaccine programs by reviewing scientific opportunities, gaps in knowledge, and future directions of research. Vaccine designs to be reviewed include peptide-based vaccines, protein-based vaccines, vector-based vaccines, DNA vaccines, live-attenuated virus vaccines, and killed virus particles, including virus-like particles. To identify and address needs for vaccine concept development, AVRC will consider structure/function studies of Env protein, antibody response, mucosal immunity, cellular immunity, animal models, and human immunology. The committee is addressing the definition of "vaccine research," availability of primate resources, coordination of U.S. and international efforts, and maximum utilization of the NIH clinical infrastructure to further vaccine development. Empirical research into prime-boost, DNA, and live-attenuated virus vaccines is particularly emphasized. Basic research areas to be stressed are viral pathogenesis, structure/functions, and modes of immune response.
Dr. Heilman described AVRC’s first recommendation, the new INNOVATION Grant Program for Approaches in HIV Vaccine Research. This program was developed by NIAID with input from the scientific community. It supports research projects that may be highly innovative and involve risk. Grant applications were due on May 23.
Discussion areas were the constituency of nationwide focus groups being convened to assist AVRC, the role of AVRC in the NIH infrastructure, and the importance of human clinical studies in vaccine research.
Chemoprophylaxis: Scientific Update and Research Opportunities — Dr. Preston Marx,
Dr. Brooks Jackson, and Dr. Michael Saag
Dr. Killen introduced this section of the program by stating that DAIDS is considering future research initiatives in chemoprophylaxis. Several investigators were invited to address the committee to facilitate a discussion of potential opportunities for concomitant basic research on the biology of HIV infection.
First, Dr. Marx discussed the applicability of a macaque animal model to chemoprophylaxis research. He listed areas where researchers now have choices: multiple routes of exposure (intravenous, mucosal, intramuscular/subcutaneous), varying pathogenicity of infecting stock, varying tropisms of challenge stock, infected cells in different mucosal and lymphoid tissues, and varying outcome/endpoints. A key problem in the use of monkeys is dosage—oral formulations are more available but are not easily adapted to the animal model. Oral dosages must be administered by stomach tube several times daily, which is a strain on the animals and also expensive. Injection formulations are preferred, and subcutaneous injection is the route of choice. Dr. Marx then provided an overview of macaque SIV research that is applicable to HIV chemoprophylaxis research. He described vaginal and rectal transmission models, target cell research (the dendritic cell is thought to be the first target cell), and a penile urethra transmission model. He explained that SIV typically develops more rapidly than HIV. He noted that SIV and HIV have been found to use different T-cell receptors. Several laboratories are studying the unidentified SIV receptor, and results are expected soon.
Dr. Jackson then reviewed chemoprophylaxis research on prevention of perinatal transmission in humans. Perinatal transmission is a serious problem worldwide: half of the 26 million HIV-infected people in the world are women of child-bearing age, and 300,000 to 600,000 HIV-positive children are born each year. Dr. Jackson described research being conducted in Uganda, where seroprevalence rates in women were found to average 31 percent. About 26 percent of HIV-infected mothers passed the virus to their newborn children. Dr. Jackson stressed that many factors can affect calculations of these rates. Routes of viral transmission are intrauterine, intrapartum, and through breast-feeding. The intrapartum route is thought to be the most common. Potential interventions include chemoprophylaxis of pregnant mothers to reduce viral load during the prenatal period, vaginal washing as well as chemoprophylaxis at the time of delivery, and postnatal chemoprophylaxis of the mother and infant. Some methods, particularly use of AZT, have been more successful than others. Several international trials are under way that are modifying AZT regimens. An exciting new effort is investigating chemoprophylaxis of the mother and infant with nevirapine; data are showing powerful antiviral activity. Cost and toxicity aspects of this drug also appear favorable.
Finally, Dr. Saag discussed the possibility of early intervention with chemoprophylaxis to prevent acute HIV infection. His particular interest is the biology of the immune response at the time of initial infection. He described the notion of a "set point"— an equilibrium stage between the immune response to exposure and replication of the virus. When an exposure takes place, a few cells become "activated," enough to initiate an immune response. At this point, however, no major cell replication has started. How the immune system responds to the viral challenge might affect whether infection proceeds.
Dr. Saag then listed several areas of pathogenesis and mechanism of infection to consider for future research: repeated exposure as a risk factor for likelihood of infection, inoculum, natural protection, cell tropism, receptors, and concomitant sexually transmitted diseases. A number of clinical and behavioral issues must also be considered.
Following the three presentations, the Committee discussed the feasibility of tying basic research into ongoing chemoprophylaxis studies to learn about the stage between HIV exposure and infection. Many opportunities were noted, although they also noted several significant logistical, ethical, cost, and technological issues.
IL-2 Update — Dr. H. Clifford Lane and Dr. Lawrence Fox
Dr. Lane provided a brief overview of interleukin-2 (IL-2) therapy for HIV infection. He reviewed recent findings from several trials documenting substantial increases in CD4+ T cells. He listed the main side effects, which include fatigue, malaise, myalgia, and headache. He also presented results comparing subcutaneous and intravenous modes of administration showing that subcutaneous administration is equally effective. In conclusion, he stated that a Phase III efficacy trial is needed to prove that IL-2 yields clinical as well as laboratory benefit in humans.
Dr. Fox reviewed the progress to date on initiating a Phase III trial of IL-2. In January 1997, DAIDS convened a multinational group of investigators interested in exploring the possibility of conducting a Phase III trial. The group reviewed the available Phase II data and agreed that a Phase III clinical efficacy trial of IL-2 for therapy of HIV disease should be developed. Several pilot trials are planned internationally to test the safety and practicality of conducting a Phase III trial at new clinical sites. On May 19, 1997, DAIDS held a meeting of the international Phase III collaborators, where data from ongoing studies were presented. The group formulated a protocol structure and discussed potential accrual issues, including patient retention. Other issues to resolve include logistics, regulation, resources, ethics, and antiretroviral therapy. Meanwhile, European and Canadian investigators are determining the interest of their colleagues in the trial. A protocol executive committee meeting is proposed for July, to be held in Italy. The trial steering committee will meet again to finalize protocol development, no later than September 1997.
In discussion after the IL-2 presentations, Committee members mentioned the toxicity of the drug as well as its potential benefit to patients in early versus more advanced stages of disease.
Concept Review: DAIDS Specimen Repository — Ms. Elaine Matzen
This initiative proposes the continuation of a centralized repository, which stores, catalogs, and retrieves specimens collected from participants in domestic and international clinical research studies sponsored by DAIDS. It provides an infrastructure for delivery of specimens to research groups and individual investigators for collaborative HIV/AIDS studies. Committee members discussed issues related to user access, specimen quality control, and retention procedures. They approved the concept with the modification that a management plan addressing prioritization of specimen collection and storage be developed before issuance of the RFP.
Concept Review: Immunology Quality Assessment Program — Ms. Daniella Livnat
This initiative provides for the continuation of this program, whose objective is to provide a flexible resource for standardization and quality control of immunologic assays used in multisite HIV investigations. The program has accomplished a specific objective of monitoring and certifying laboratories for testing CD4+ T cell and other lymphocyte subsets. Its current objectives are to (a) support comparative evaluations of novel cytometric instruments, methods, and reagents, and (b) facilitate standardization, validation, and quality assessment of immunological assays for implementation in multicenter investigations. The committee approved the concept with the following modifications: an advisory committee should be established; the relationship between the contractor and the immunology investigators should be strengthened to support efficient assay development; an evaluation component should be added; and the contract should have the potential to acquire a broad range of quality control materials, in addition to whole blood.
Concept Review: Research Support Services Contract — Ms. Vaurice Starks
This initiative provides for continuation of operational and logistical support for three large prospective epidemiological cohort studies within DAIDS: the Multicenter AIDS Cohort Study (MACS), Women and Infants Transmission Study (WITS), and Women’s Interagency HIV Study (WIHS). The contract’s objective is to enhance coordination and communication within the three studies through management and administrative support, conference and teleconference support, and provision of research resources. The committee approved the concept. back to top |