John Y. Killen, M.D.,
Director, DAIDS
The meeting, which was held in the Natcher Conference Center on the campus of the National Institutes of Health, was chaired by Dr. Marian R. Neutra, chairperson of the AIDS Research Advisory Committee (ARAC).
Report from the Director — Dr. John Y. Killen
Dr. Killen welcomed three new ARAC members: Dr. Lehrman, Dr. McIntosh, and Mr. Wakefield, and thanked Dr. Neutra for agreeing to serve as Chair. He then discussed the proposed FY1998 NIAID budget and reviewed the status of two trials--the IL2 study and the low dose oral alpha interferon study (LDOAI) . Plans for the IL-2 study are proceeding, while the LDOAI study was closed due to poor enrollment and retention, and lack of data.
Dr. Killen mentioned that advances in treatment, as reflected in the recently drafted DHHS guidelines on use of antiretroviral agents in adults, are having a profound impact on care and also on the conduct of therapeutic clinical trials. As an example, he cited the AIDS Clinical Trials Group (ACTG), which is developing a new approach, called a longitudinal protocol matrix, to designing clinical trials. Guidelines for the use of antiretrovirals in HIV-infected children will be published shortly. Discussion ensued on use of antiretroviral drugs during pregnancy.
In response to the Levine Report, the NIH Office of AIDS Research has created a task force on integration of NIH adult clinical trials networks. NIAID also established a task force to work on the specifics of the peer review and renewal of NIAID’s networks in fiscal year 2000. This task force will focus on shaping the future of the ACTG and Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The parallel task forces will provide each other with information.
Dr. Killen announced several recent appointments: Dr. Mark Grabowsky is the new Chief of the Clinical Development Branch in the Vaccine Prevention Program, and Dr. Dennis Dixon is the new Chief of the Biostatistics Research Branch. Dr. Polly Sager will be on an important temporary assignment serving as Acting Chief of the AIDS Study Section of the Division of Research Grants. Staff departures include Marilyn Kunzweiler, the division’s Administrative Officer, who will become Chief of the NIAID Extramural Administrative Management Branch.
Dr. Killen provided updates on recent grant and contract awards, highlighting the Acute Infection and Early Disease Research Program and the Women and Infants Transmission Study. He also listed: awards made in FY1997 as a result of concepts approved at previous joint committee meetings; and(2) current program announcements. (Refer to information provided below.)
- PAR 96-060: Acute Infection & Early Disease Research Network
- PA96-068: Innovative Drug Discovery Research in AIDS Opportunistic Infections
- PA96-069: Collaborations for Advanced Strategies for Opportunistic Infections
- PA96-072: Mechanisms for AIDS Pathogenesis
- PA96-078: Novel HIV Vaccine
Ongoing program announcements include the following:
- Novel HIV Vaccine Research and Design (FY97-FY99)
- Mechanism of AIDS Pathogenesis (FY97-FY99)
- Drug Discovery Research for Opportunistic Infections (FY97-FY99)
- Collaborations for Advanced Strategies in Opportunistic Infections (FY97-FY99)
- Integrated Preclinical/Clinical Program for AIDS Vaccine Development (NCVDG) (FY98-FY00)
- Pathogenesis Studies in Women’s Interagency HIV Study (FY98-FY00)
- Center for AIDS Research (FY98-FY00)
- Integrated Preclinical/Clinical Program for Novel HIV Therapies in Place of Vaccines (FY98-FY00)
- Feline Immunodeficiency Virus: A Potential Model for AIDS (FY98-FY00)
Dr. Killen announced the staff that received NIH merit awards and thanked outgoing committee members Drs. Janet Butel and Norman Letvin for their contributions.
DAIDS Specimen Repository — Dr. Dale Lawrence
Dr. Lawrence presented an outline of a management plan developed by DAIDS program staff for the AIDS specimen repository. When the committee approved the concept at the previous meeting, it suggested that a management plan be developed to address: (1) selectivity in specimen acquisition and retention, (2) quality assurance monitoring, (3) access to specimens and scientific productivity, and (4) clarification of regulations and responsibilities.
The goal of the repository is to retain specimens with the greatest potential value for future research. In order to achieve this, the repository will accept fewer samples and only retain specimens temporarily. Approaches include the extremes of discarding or limiting retention time for specimens of low potential value, and purchasing additional freezers and expand space as needed. Quality assurance monitoring will involve standard procedures for collection and processing of various types of specimens, bioviability and stability will be spot tested, and a system will be developed for users to report the condition of the specimens.
The committee concurred that this outline captured previous concerns.
AIDS Vaccine Research Committee and Innovation Grant Program:
Update — Dr. Carole Heilman
Dr. Heilman discussed three activities related to the AIDS Vaccine Research Committee (AVRC): the Innovation Grant Program, future AVRC plans, and the Intramural Vaccine Center. The Innovation Grant Program is a simple, fast, targeted funding mechanism, created to encourage the development of innovative vaccine concepts. Its current areas of emphasis are animal models, envelope protein structure, and antigen presentation. One hundred thirty-three (133) applications were submitted to the program; about 30 percent of the applications will be funded as of September 30. While it usually takes 20 months to move a concept to a funded program under the R01 funding mechanism, it only took 7 months in the Innovation Grant Program. This was possible because the procedures for applying were simplified – there was a page limit for applications, reduced paperwork, and a streamlined review system.
The AVRC will also provide scientific advice to the new intramural Vaccine Research Center. The center is expected to house both discovery and development components of vaccine research. Its director—currently being recruited—will collaborate with appropriate NIH leaders to configure the center. FY1998 construction funds for the center amount to $26 million; construction funds are specified in the FY1999 budget as well.
HIVNET Post-Exposure Prophylaxis Studies: Update — Dr. Rodney Hoff
Dr. Hoff provided an overview of some recent developments in post-exposure prophylaxis (PEP). At the June 1997 ARAC meeting, the committee discussed the need for more basic and clinical research on the interaction between the host virus and PEP during the period when the drug acts to prevent HIV infection. He noted that a research initiative will be presented later on in the day (the role of pre- and post exposure chemoprophylaxis in the reduction of HIV transmission) that responds to this need.
Dr. Hoff discussed ongoing research related to PEP, some of which is supported by NIAID. These include an acute infection initiative, in vitro screening of antiretroviral drugs, mechanism of pathogenesis studies, animal challenge studies, Phase I-III therapeutic trials (ACTG), and Phase III prevention trials (HIV Network for Prevention Trials [HIVNET]). Two clinical prevention trials of PEP for nonoccupational exposures are just beginning, one in San Francisco and the other a large, multicenter HIVNET study. The HIVNET study is slated to begin in October 1997 with a pilot feasibility study encompassing two treatment groups and a control group.
The AIDS Vaccine Evaluation Group and the HIV Network for Prevention Trials:
Current Status and Future Design — Dr. Patricia Fast
Dr. Fast discussed the Division’s ongoing vaccine research efforts, which are often considered in the context of the vaccine pipeline and vaccine evaluation. Objectives are to study and compare multiple promising candidates and select the best of each class for further evaluation, coordinate primate and clinical studies, conduct intensive laboratory investigation, facilitate efficient progress from Phase I to Phase III, and protect and educate volunteers.
Dr. Fast listed challenges for 1998, which include acquiring additional vaccine candidates for evaluation, better coordination of primate and clinical trials, designing a seamless clinical trials effort, and designs for efficacy trials. Dr. Fast noted both AVEG and HIVNET will be competitively renewed in FY99 and recommendations are now being sought from investigators, community representatives and others on what changes/improvements are needed. She invited input from committee members as well.
FY 1999 Initiatives: Concept Review
The Role of Pre- and Post-Exposure Chemoprophylaxis in Reduction of HIV Transmission: This initiative is designed to encourage investigator-initiated research that addresses the mechanisms of action of chemoprophylaxis in reducing HIV transmission caused by sexual, perinatal, and parenteral exposure. Possible research areas include addressing modes of action of antiretroviral and immunotherapeutic chemoprophylaxis, assessing evidence for abortive infection, and determining safety, tolerance, and acceptability of prophylactic strategies. The committee approved the concept but suggested that efforts be made to encourage applications from the broader scientific community outside of the current clinical cohorts.
Mechanisms and Pathogenesis of Pediatric AIDS: This initiative provides for the continuation of this program, the objective of which is to foster in vivo research on transmission of HIV from mother to infant, acute infection in infants, factors determining the course of infection and long-term survival, and late effects of perinatal interventions. The committee approved the concept but suggested that the scope of relevant research be clarified so that investigators who are not currently associated with NIAID-funded pediatric cohorts recognize the opportunity to apply.
NIAID Tuberculosis Development Support: This initiative provides for continuation of national facilities for rapid screening and development of new candidate antibiotics to combat tuberculosis. Within an overall level budget, three current contracts—one to operate a tuberculosis antimicrobial acquisition and coordinating facility, a second to conduct microbiological screening, and a third to conduct animal models screening—would be continued; a fourth component would be added to facilitate technology transfer. The committee approved the concept.
Multicenter AIDS Cohort Study (MACS) and the Center for Analysis and Management of MACS Data: This initiative provides for the renewal of a multicenter, epidemiologically based study of HIV pathogenesis in homosexual/bisexual men. The program consists of four MACS study centers and the MACS data center. The objective is to study correlates of immunity to disease progression among a large group of well-characterized HIV-infected persons and possible correlates of protection among persons exposed to HIV but who remain uninfected. The committee approved the concept.
MACS Pathogenesis Research: This initiative provides for the continuation of laboratories to study HIV-1 pathogenesis using MACS specimens and data. The laboratories collaborate with investigators at the four MACS study sites and at the MACS data center. The committee approved the concept but suggested that the possibility of funding more than two laboratories be made explicit in the Request for Applications (RFA) and that additional detail be included about whether or not a prior relationship with the MACS is necessary.
Statistical Methods in HIV/AIDS Research: This initiative proposes to stimulate innovative research in statistical methods to advance the study of HIV/AIDS vaccines, therapies, and pathogenesis. New directions in statistical research are needed to address numerous identified gaps and multidisciplinary approaches will be encouraged through this Program Announcement (PA). The committee approved the concept with the modification that the PA contain clear wording for readers from the general research community who do not have a background in statistics.
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