John Y. Killen, M.D., Director, DAIDS
The AIDS Subcommittee of the National Advisory Allergy and Infectious Diseases Council and the AIDS Research Advisory Committee (ARAC) met jointly on January 30, 2001, at the Natcher Building on the National Institutes of Health (NIH) campus in Bethesda, MD. Dr. John Phair chaired the meeting, which was open to the public.
Report from the Director - Dr. Killen
Dr. Killen announced staff changes, noting that the Division of AIDS was almost fully staffed for the first time in many years.
Budget - The budget for FY 2000 brought Congress closer to achieving its goal of doubling NIH's budget by FY 2003. NIH received a 14-percent overall increase, while NIAID's budget increased by 13.7 percent ($2M). Research project grants will receive 68.6 percent of NIAID's funds, and the intramural research budget will receive 11.1 percent. The payline for AIDS and non-AIDS investigator-initiated grants will increase from 20.0 to 22.0, and the bridge award program will expand by $3M to $18M. Noncompeting research grants will receive a 3-percent inflationary increase.
AIDS Vaccine Research Committee (AVRC) - The AVRC met last week to discuss the status of the vaccine candidates NIAID is supporting. They also conferred about the Innovation Grant Program, progress on standardized validated assays for cellular immune responses, the shortage of nonhuman primates for research, and the use of cell substrates for vaccine production.
Research Ethics - A number of organizations are working to clarify ethical issues related to international research. Much of the discussion centers on two issues: the appropriate standard of care for clinical trials and what researchers owe to study participants. Much research is now targeting problems of particular importance in the developing world and is thus increasingly scrutinized with respect to ethics.
NIAID's Global Health Initiative - Dr. Fauci
Infectious and parasitic diseases cause about one-fourth of all deaths worldwide, disproportionately affecting people in their productive years. Dr. Fauci briefed the committee on the increasing Federal emphasis on global health, focusing on how HIV/AIDS can serve as a model for addressing major global health issues. The Institute is applying approaches to AIDS research to other diseases, and examining approaches developed for other diseases for their relevance to enhancing HIV research. Dr. Fauci described NIAID's partnerships with developing nations in establishing Centers of Excellence for research in TB and malaria, for example as a means of addressing critical health problems in those nations. These Centers conduct transnational research and promote infrastructure development and training.
Like other emerging and reemerging infectious diseases, HIV/AIDS has ravaged the economic, political, and public health of many nations important to the United States. As a result, the President, foreign leaders, and major philanthropists now regard AIDS as a national security and foreign policy issue. Resources dedicated to international health have been increasing markedly since 1995, with special attention being given to HIV, malaria, and TB.
Global Initiatives in Vaccine and Prevention Health - Dr. Johnston
The Vaccine Research and Development Program promotes the discovery and development of safe, effective preventive vaccines and other interventions that will stop the spread of HIV/AIDS worldwide. The Program funds fundamental research, preclinical research, and clinical trials. Its multifaceted, sustainable collaborations address the needs of the host countries as they build research capacity and infrastructure.
Dr. Johnston reviewed international programs and concepts being developed for FY 2003. The Program will continue to support innovative fundamental research through unsolicited and solicited programs, foster diverse approaches, support comparative studies and testing in primates, and guide and support promising candidate vaccines and other prevention modalities. The program will also emphasize investigations on how infants can be protected during breastfeeding. Approaches to this research include unsolicited grants and international, multicenter clinical trials.
NIAID is about to launch the Comprehensive International Program for Research on AIDS (CIPRA), which will support fundamental epidemiological, laboratory and clinical studies. CIPRA will also enhance the ability of developing countries to conduct AIDS research relevant to their populations.
Global Initiatives in Therapeutics Research - Dr. Duncan
NIAID is exploring how therapeutic success among HIV/AIDS patients in the industrialized world can be adapted to therapeutic interventions for the developing world. Barriers to this effort include inadequate health care infrastructures, resources, monitoring, and diagnostic capabilities; lack of trained health care professionals; and competing public health priorities. Research is needed on the safety and effectiveness of current antiretroviral regimens; more practical therapeutic approaches, diagnostics, and monitoring tools; incidence of opportunistic infections and other complications; the effects of endemic infections on HIV infection; and the effects of prophylactic and therapeutic interventions and nutritional supplements. This broad research agenda is constrained by limited resources; lack of long-term, stable commitments; and ethical issues. CIPRA will address some of these infrastructural shortcomings, including the need for long-term support for clinical and laboratory studies and inadequate host country capabilities for therapeutic interventions. The committee discussed the tension between trying to provide state-of-the-art care as opposed to affordable and feasible therapeutics.
When to Start Antiretroviral Therapy - Drs. Duncan, Wheeler, and Benson
Dr. Duncan continued the ongoing discussion of a possible study to explore when to start antiretroviral therapy. At a workshop on this issue, the participants agreed that a randomized clinical trial would provide the clearest answer this question. However, it is unclear whether such a study would be feasible or whether it would yield useful results. NIAID is therefore continuing to explore options.
Dr. Wheeler offered a primary care clinician's perspective on such a trial. He stressed the importance of ensuring that people with HIV/AIDS understand every aspect of their illness, the medications, and monitoring before initiating therapy. He discussed the indications that a patient is ready for antiretroviral therapy and how to identify patients suitable for a clinical trial.
Dr. Benson discussed the controversies surrounding one trial proposed by the AACTG. She outlined the protocol and the mixed sentiments it provokes, from agreement that the question is important, to concern over randomization, whether the study is feasible, and whether it will be able to answer the question. She reviewed the rationale for both early and late initiation of therapy and the need to accommodate the needs of individual patients. Finally, she summarized an alternative approach involving a prospective observational study and both prospective and retrospective meta-analyses.
Committee members raised many questions, including whether the study is feasible, whether it should be done, and what information is available that can help answer this question today. Yvette Delph of the AIDS Treatment Action Group presented the preliminary results of a community survey conducted at the National AIDS Treatment Advocates Forum in November. Those surveyed agreed about the importance of this question, but were divided over whether a large, randomized trial should be conducted to resolve it. She suggested that a pilot be conducted to see if the study is feasible.
The committee also discussed the possibility of combining several approaches, including a small, focused randomized study, a prospective meta-analysis of patients randomly assigned to their antiretroviral therapy; current natural history studies and databases; and, perhaps, a new prospective study. Committee members named numerous sources of data as possibilities for meta-analysis. They agreed that the research community should organize itself to collect data continually and prospectively. They would especially like to have information on patients before they are ready to begin therapy, long-term toxicity data, and information on irreversible immune dysfunction. They noted that statistical methodology and expertise to address this question were in short supply.
Future Directions in Basic Sciences - Dr. Dieffenbach
Dr. Dieffenbach highlighted recent scientific developments, reviewed upcoming challenges with respect to the basic research portfolio, and discussed initiatives for FY2003. In the past few years, researchers have learned a great deal about HIV binding and entry, information that has led to the development of novel therapeutics and topical microbicides. HIV trafficking is now emerging as a key to binding and entry, as well as the initiation and maintenance of HIV infection. He explained the role of DC-Sign, a molecule on dendritic cells that initially stabilizes the virus and promotes the infection of the T-cell. Some drugs in clinical trials are attempting to disrupt this process. Innovation Grants for AIDS research and for research in human immunology would support investigations of such state-of-the-art concepts. These Innovation Grants would target specific areas.
Concept Review: Pathogenesis Studies in the WIHS - Dr. P. Miotti
This concept provides for the 3-year renewal of a program announcement promoting investigator-initiated R01 funded research for the study of fundamental mechanisms of HIV infection and its progression in women. The program will cost $1M in its first year. The reviewers endorsed the need for these further studies in gender-specific areas of HIV disease, and the committee approved the concept.
Concept Review: Statistical Methods in HIV/AIDS Research - Dr. D. Dixon
New methods of data analysis are needed to deal with the large variety of data now being collected and the complexity of the questions being addressed. This concept would renew a program supporting statistical innovation. The first year will cost $700,000 and would likely cover four awards. The reviewers found the initiative highly relevant, and said it should be supported. Several committee members questioned whether the initiative had adequate resources and whether a training component or another means of attracting people to the field should be added. The reviewers supported the concept, and the committee approved it.
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