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. John Y. Killen, Director, Division of AIDS. Dr. John Modlin participated via telephone for the presentation and discussion concerning the Pediatric AIDS Clinical Trials Group.
Report from the Director: Dr. John Y. Killen
Dr. Killen welcomed everyone to the meeting, particularly two new members of the AIDS Subcommittee, Drs. Koup and Jacobs. He announced that Dr. John C. Martin, who was not able to attend, had also joined the Subcommittee. Several new staff members were also introduced.
Dr. Killen then reviewed the FY 2000 and 2001 budgets. NIH received a 14.2 percent budget increase for FY 2000, and NIAID received a 14.4 percent increase, considerably more than the 2.4 percent increase proposed by the President. The President's proposed budget for FY 2001 gives a 5.6 percent increase to NIH and a 6.1 percent increase to NIAID.
Basic Sciences Program (BSP) -Dr. Carl Dieffenbach
To describe the size and scope of the program, Dr. Dieffenbach noted that about five-eighths of the Institute's $800M in AIDS research money is spent on basic research. He highlighted the richness and diversity of NIH-funded researchers, noting some of their key scientific contributions.
Dr. Dieffenbach cited three important examples in which BSP has facilitated research and development in three major areas:
- coreceptor biology: information on HIV binding and entry is improving researcher's understanding of coreceptor function and facilitating the design of new retrovirals as well as vaccines, microbicides, and therapeutics
- cell-mediated immunity (CMI): studies underscoring the importance of maintaining T-cell immunity, together with the vaccine community's work on the induction of T-cell immunity, suggest a similarity in assay needs and have generated the tools needed to induce immune responses.
- highly active antiretroviral therapy (HAART) therapy and virus reservoirs.
He also discussed the need of researchers for fresh tissue specimens from HIV-infected individuals to investigate a number of important questions, including immune restoration, T-cells dynamics, vial reservoirs, and whether there are anatomical signs of immune reconstitution or various patterns of HIV evolution in tissue. NIAID has contacted the National Disease Research Interchange (NDRI), a group funded by NCRR that identifies, processes, and ships tissues from individuals who are usually identified through organ-procurement organizations. NDRI has agreed to participate in a pilot project to see if the services it provides to the diabetes research community can be adapted for the AIDS research community.
Therapeutics Research Program - Dr. William Duncan
Dr. Duncan discussed the program's progress to date and the state of knowledge in HIV/AIDS therapeutics. Current scientific priorities include the development of drugs and regimens that minimize viral replication and tissue burden; the elucidation of pathogenesis; the study of the immunopathogenesis of opportunistic infections (OIs); the preservation, restoration, and enhancement of HIV- and OI-specific responses; the treatment and prevention of opportunistic and metabolic complications; and the assessment of long-term clinical outcomes. DAIDS is supporting three approaches to preserving and restoring HIV-immune response: intervening during the acute infection phase, therapeutic vaccination during chronic infection, and structured treatment interruptions.
NIAID sponsored a workshop on long-term clinical studies of HIV-1 infection in January. The discussions focused on the best methodological and operational approaches for studies of when to start antiretroviral therapy, when and how to switch therapies, and identifying the long-term consequences of therapy. Workshop participants agreed that large, randomized clinical trials with clinical endpoints are needed to answer the first two questions. Dr. Duncan reviewed the challenges involved in conducting such trials.
Dr. Duncan also updated the committee on the plans for the therapeutics research program, including investigator-initiated studies of new targets, new drugs, and issues related to the pathogenesis of HIV and OIs; preclinical targeted drug discovery programs; preclinical programs for drug screening; animal model studies; chemistry and formulation support for drugs coming out of the pipeline; translational studies; and a clinical trials program.
Concept Review: HIV Disease and Associated Complications in the Hemophilia Population - Dr. William Duncan
This initiative will support investigator-initiated research on the pathogenesis, treatment, and management of HIV infection in people with hemophilia, and the unique complications of HIV infection in this population. This 4-year initiative would make one to four awards totaling $1M in the first year, 2001. About 4,200 hemophiliacs are infected with HIV, up to 90 percent of whom, are also infected with Hepatitis C. As a result many HIV-infected hemophiliacs have difficulty tolerating HAART regimens and will likely develop end-stage liver disease even though their HIV viral replication may have been brought into control.
In October 1999, NIAID convened a task force, chaired by Dr. Phair to discuss issues pertaining to the treatment of HIV among hemophiliacs. The committee recommended that NIH support studies that delineate the long-term outcomes, benefits, and adverse effects of HIV therapy on this population; explore the factors determining the resistance of HIV infection; investigate factors responsible for delayed progression of HIV or its lack of progression; evaluate the interaction between HCV viral load, HIV therapies, the progression of HIV disease, HCV genotype and quasispecies development, and host and HCV immune factors; and evaluate the effects of HIV, HIV therapies, and HIV complications on hemostasis. Dr. Duncan stressed that this RFA is not designed to establish cohorts of HIV-positive hemophiliacs, but to use available cohorts to address these issues.
Related research programs include a trans-NIH Hepatitis C Working Group, which coordinates programs concerned with the treatment of Hepatitis C; the Collaborative Antiviral Study Group, which has studies treating Hepatitis C and is supported by NIAID; and a large hemophilia cohort supported by the NCI. In addition, NIAID's adults therapeutics clinical trials program is conducting trials on the treatment of HIV and HIV/HCV.
Discussion focused on the size and needs of this population and how this initiative could improve our understanding of the biology of chronic, established HIV infection, host resistance, and the biology of co-infection of HCV and HIV. The committee voted to approve the concept.
Concept Review: Pediatric AIDS Clinical Trial Group - Dr. Jim McNamara and Dr. Fred Batzold
Dr. McNamara gave an overview of the NIAID's HIV/AIDS pediatric HIV research program, which includes the Pediatric AIDS Clinical Trials Group (PACTG), the HIV Vaccine and Prevention Trials Networks and the Women and Infant Transmission Study (WIHS). These groups work on various aspects of the pediatric HIV research agenda, overlapping but also complementing one another.
Globally, the number of cases of HIV transmitted from mother to child has been steadily increasing since the early 1980s, and more than 50 percent of the adult infections are in adolescents and young adults (under 24 years of age). However, in the United States, the incidence of pediatric AIDS is decreasing due to improved prophylaxis, combination therapies, and HAART regimens. However, with regard to adolescents, a population that is particularly difficult to reach and engage in long-term health care, there is no evidence to suggest that the epidemic is slowing. Infections in this age group are increasingly in women and minorities.
Dr. McNamara reviewed some of the many significant accomplishments of the PACTG. In addition to PACTG 076, which demonstrated that the use of AZT reduces the risk of perinatal transmission by two-thirds, the PACTG also defined the standard of care for treating HIV-infected children, provided pivotal data leading to FDA approval of therapies for children, and provided long-term follow-up of infants exposed to antiretroviral therapies. The priorities for the PACTG renewal are consistent with those identified by the Office of AIDS Research (OAR) Working Group to Review NIH Perinatal, Pediatric, and Adolescent HIV Research Guidelines, which was convened in June 1999. These include the further reduction of maternal-infant transmission; identification of optimal treatment strategies for children and adolescents; a broader research agenda that more fully addresses the special issues around adolescents and HIV infection; and long-term follow-up of children (infected and uninfected) exposed to antiviral therapy.
Dr. Batzold continued the presentation of the PACTG describing how the group would be structured under the new RFA. There would be a core award, encompassing the group's scientific leadership, laboratory resources, operations center, and statistical and data management center, and awards to the clinical sites. This is a competitive renewal for 5 years beginning in 2002, with the first-year funding remaining at $36M for a single network.
The discussion focused on the unquestionable success of the PACTG, the importance of and difficulties involved with expanding adolescent research, and global issues. Dr. McNamara clarified that studies are categorized as domestic or international according to where the work will be done and that the PACTG is already collaborating with sites in several countries.
The committee approved the initiative with the following modifications:
- A substantial emphasis in adolescent-specific treatment research, and a detailed program for outreach to that population.
- A perinatal research effort targeting specific issues remaining problematic in totally preventing mother-to-child transmission (e.g., new drug studies, and pregnant women who are identified very late in pregnancy)
- Long-term follow-up of children, including those who are infected, and those who were exposed in utero but remain uninfected
- The possibility that "unaffiliated" sites may apply for funding, regardless of whether they are part of the group application.
Concept Review: Follow-up of Pediatric Enrollees from WITS - Dr. Rod Hoff
The Women and Infants Transmission Study (WITS) is an integral part of the Division's pediatric AIDS research program. It complements the clinical trials of the Pediatric ACTG and provides an opportunity to answer important pathogenesis-related questions. This RFA will renew the existing program for 5 years at a cost of $2M for four awards. The WITS cohort is representative of the general population. The mother-infant observations date back to pregnancy, standardized growth and neurodevelopment assessments of the children are available, standardized clinical and laboratory procedures and treatment history and abstraction enable systematic assessment, and the repository of samples from the patients enable continued pathogenesis studies.
Future research priorities of the WITS include: 1) the long-term effects of ART on the progression and pathogenesis of HIV in pregnant women and their infected children; 2) the long-term effects of exposure to HIV and antiretroviral drugs on the uninfected children born to HIV-infected mothers; and 3) antiretroviral resistance and compliance as factors of perinatal HIV and the progression of HIV disease. The RFA requires a comprehensive research plan from the six clinical sites and the data center; the sites will then apply individually for support to implement their individual, site-specific plans.
It was noted that this is a unique opportunity to follow both infected and non-infected infants and children who were exposed to HIV during pregnancy and the first 6 weeks of life, particularly with regard to tumor and mitochondrial toxicity. The committee approved the proposal.
Concept Reviews: Innovation Grant Program, HIV Vaccine Research and Design, and Integrated Preclinical/Clinical AIDS Vaccine Development Program - Dr. Margaret Johnston and Dr. Steve Bende
Dr. Johnston explained the context for these initiatives, reviewing the overall framework of NIAID's HIV vaccine and development program. The program is designed to provide investigators and sponsors with many opportunities to enter the research and development pipeline.
Dr. Bende described the Innovation Grant Program, which uses R21 grants to facilitate the entrance of novel, high-risk, high-impact approaches into the pipeline, and encourage young new investigators to become engaged in AIDS vaccine research. Awards are limited to $150,000 per year for 2 years. NIAID seeks to fund about 35 of these awards each year, with a cost of $8.4M in the first year. During this program's six rounds to date, NIH has made awards to 191 of the 350 applicants. These programs do not target specific scientific areas, although the Innovation Grant Program does try to fund research that presents a particular opportunity for advancement or fills gaps in the portfolio.
The HIV Vaccine Research and Design (HIVRAD) program utilizes program project grants to support consortia of investigators from various fields in academia and industry pursuing concepts that are more advanced, but not yet ready for translation into the clinic. The Division hopes to make 10 awards in the first year totaling approximately $13 million.
The Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD) promotes the refinement and movement of vaccine concepts into the clinic. The Division hopes to fund five of the awards totaling $8 million each year.
All three concepts were considered to be of very high importance. The committee voted to approve all three back to top |