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development and clinical trial activities were reduced $29 million, vaccine development and clinical trial activities were reduced $28 million, and studies of the natural history, transmission and risk factors were reduced $21 million.
Question. There has been some interesting news reported regarding progress in the development of AIDS vaccines. To date, only Phase I trials have been undertaken. Has the NIAID made any estimates of what the cost would be of initiating Phase II or III trials of a candidate vaccine and have any plans been made for identifying these resources in a short period of time?
Answer. Presently, the budget is separately developed for Phase I, Phase II, and Phase III Trials. However, we estimate that the dollar figure will be in the millions for Phase II and Phase III testing. The cost for vaccines used in these studies would have to be determined on a case by case basis as some vaccines are more costly to manufacture than others. No vaccine candidate will be tested in large scale efficacy tests until it is proven safe and capable of eliciting a vigorous immune response. We are searching diligently for clues as to what kind of immune response protects individuals against HIV infection--if we find that, we will be able to speed up vaccine development enormously, because we will know how to tailor and how to select the vaccines.
Question. A recent report on a VA study of the value of early intervention with AZT suggests a possible differential impact for minorities with HIV infection. Can you comment on this study and explain what progress the NIAID has made in increasing the demographic diversity of participation in the ACTG trials? How do these statistics compare to enrollment in the Community Program for Clinical Research on AIDS?
Answer. The Veterans Administration (VA) Cooperative Trial #298 looked at early versus late initiation of zidovudine in symptomatic HIV infected but non-AIDS patients. It, as well as the larger ACTG studies 016 and 019, showed a significant benefit of zidovudine in delaying progression to AIDS with early use compared to placebo. In a analysis done retrospectively, the VA investigators did not find an apparent benefit of early versus late therapy for Blacks and Hispanics as compared to Whites.
However, both larger NIAID AIDS Clinical Trial Group (ACTG) studies, each of which enrolled more minority patients than the VA study, showed significant benefit of early zidovudine as compared to placebo in delaying progression to AIDS for Blacks and Hispanics. It is probable that the apparent divergent results stem from differences between the two ACTG studies and the VA study in terms of degree of illness of patients, compliance rates, dropout rates from study, and other confounding factors.
Regarding demographics, in the past three years, the ACTG has made significant strides toward increasing the diversity of participants to reflect better the demographics of HIV-infection in the general population. Currently, Women represent 9.6 percent of the AIDS cases in this country and represent 6.2 percent of the patient caseload of the ACTG. With respect to Blacks and Hispanics, as a percent of AIDS cases, they represent 28.3 percent and 16 percent respectively. Within our ACTG, this same group represents
16.9 percent and 15.1 percent respectively. This is a substantial increase from 1987, when they made up only 7 percent and 11 percent of the patients in trials. We recognize that these figures are not optimum, but we are making every effort to close the gap and create parity between the percent of cases to percent of participation in the ACTG.
Within our Community Program for Clinical Research on AIDS the demographics are more reflective of the populations cited, with Women representing 18 percent of the cases, Blacks 38 percent and Hispanics 16 percent.
Question. There has been growing interest in research into treatments for opportunistic infections in addition to clinical trials of anti-viral treatments. of the estimated 7,500 persons currently in clinical trials funded by the NIAID, how many are participating in anti-viral trials and how many are participating in opportunistic infections treatment trials?
Answer. Cumulatively, 8,685 patients have been enrolled in antiviral studies and 2,914 in opportunistic infections treatment trials in the AIDS Clinical Trials Group. As a result of a heightened emphasis in opportunistic infection (OI) research by NIAID, 1,008 patients have been enrolled into OI trials during the past year.
Question. If additional funds were provided for AIDS research beyond the President's budget request, what areas would you identify as the top priority for expansion?
Answer. The area where funds are most needed would be vaccine research and development. These funds would be used to build the infrastructure necessary for phase II and III efficacy trials.
QUESTIONS SUBMITTTED BY SENATOR HARRY REID
CHRONIC FATIGUE SYNDROME
Question. How many full-time staff are working on chronic fatigue syndrome research activities at the NIAID? Will any staff be added for these activities soon?
Answer. We do not have any staff assigned full-time to the study of chronic fatigue syndrome (CFS), however, within our Intramural program, two physicians and two nurses devote substantial portions of their time to clinical studies of CFS. They are assisted by research fellows as they rotate through the infectious diseases program. Two doctorate-level researchers also are involved in laboratory studies in addition to two scientists who are conducting contracted laboratory research activities for the Institute. Three doctorate-level scientists are involved in the administration and stimulation of extramural research. We have no plans to hire additional personnel in the immediate future.
Question. What types of research is the NIAID pursuing on chronic fatigue syndrome?
Answer. The NIAID's broadly-based intramural research includes studies of Human Herpesvirus-6 and -7, enteroviruses and retroviruses, immunologic competence, sleep disorder, neuropsychiatric and neuroendocrine function, patient-care regimens, and therapies.
The extramural CFS program includes studies of prevalence, risk factors, natural history, role of viral reactivation, immunologic markers and psychoneurologic correlates. Relevant viral and immunological studies being conducted at present include:
A recently funded study of enterovirus-induced polymyositis in mice provides an animal model that could yield insights about the pathogenesis of CFS.
Ongoing studies of the effects of acute viral infection involving white blood cells on immunological function, activation and suppression are providing invaluable data with which to compare immunological parameters in CFS.
Studies of the molecular basis of reactivation of latent viruses continue to build the foundation for our understanding and ultimate control of this important process which may contribute to the morbidity in CFS.
The NIAID supports major research efforts on mechanisms of immunologic diseases and on the biology of the immune system. These studies should lead to a better understanding of the immune mechanisms and/or dysfunctions which may underlie the complex CFS syndrome.
Question. Which Institutes of the NIH are involved in chronic fatigue syndrome research? Which are cooperating in this research?
Answer. The NIAID is the only institute with a chronic fatigue syndrome research program, but NIAMS has a program of intramural and extramural research in fibromyalgia, a closely related illness. Investigators at the NIAID are collaborating with investigators at the NINDS and NCI at the NIH and also with colleagues at the NIMH. They also are providing advice to and collaborating with extramural scientists.
Question. What additional extramural research on chronic fatigue syndrome will be conducted by the NIAID in the future?
Answer. The NIAID recently solicited applications for a cooperative research center for multidisciplinary studies and expects to make at least one award in FY 1991. A program announcement of interest in receiving applications concerned with natural history and etiology also is planned.
Question. Dr. Fauci, you have reported to the Congress that chronic fatigue syndrome is triggered by an infectious agent. The CDC has reported that this illness sometimes appears in "clusters," such as we have had in the Lake Tahoe area. What research is the NIAID doing to help identify agents that might cause this type of "cluster?"
Answer. The epidemic reported in Lake Tahoe was studied by the Center for Infectious Diseases, CDC. In addition, specimens from that outbreak and from others reported in North Carolina and Ohio have been examined for retroviruses and human herpesvirus 6 (HHV-6) by scientists at NCI and studies of HHV-7 have recently been undertaken in NIAID. NIAID extramural scientist, Anthony Komaroff, also has been involved in studies of the Lake Tahoe outbreak.
Question. At the University of Nevada Medical School, scientists have been studying chronic fatigue syndrome for years. Does the NIAID have any plans for university-affiliated centers for research on this illness?
Answer. The NIAID plans to expand its university-based CFS research by the addition of at least one center for multidisciplinary research in FY 1991. A solicitation for applications for cooperative CFS research centers was advertised in the NIH Guide for Grants and Contracts on February 8, 1991.
Question. At the University of Nevada Medical School, hundreds of serological samples from chronic fatigue syndrome patients in northwest Nevada have been stored for years. Is the NIAID cooperating in studies of these samples? Does the NIAID have plans to fund studies of these samples? Does the NIAID have funding for this type of work?
Answer. Yes, the NIH has been cooperating in studies of clinical specimens from the Nevada outbreak. Specimens from Lake Tahoe have been examined for retroviruses and human herpesvirus 6 (HHV-6) by scientists at NCI and studies of HHV-7 also have recently been undertaken in the NIAID. The NIAID-supported extramural scientists have coordinated additional studies of those specimens.
In the absence of persuasive new etiologic clues, the NIH has no plan for additional studies of these specimens at this time. It should be noted that the Lake Tahoe outbreak was studied by the Centers for Disease Control and the results have been published.
As in the past, NIH investigators are prepared to assist extramural scientists in the follow-up of promising leads when appropriate specimens are available. The NIAID accepts applications for funding of research proposals designed to examine the infectious disease etiology of CFS.
QUESTIONS SUBMITTTED BY SENATOR ARLEN SPECTER
AIDS PROJECTS--WOMEN AND CHILDREN
Dr Fauci, please provide for the Subcommittee answers to the following questions concerning AIDS projects by Institute (NCI, NIAID, and NICHD) which focus exclusively on mothers and/or children:
Question. How many children have been enrolled or are currently enrolled in HIV related clinical trials? How many clinical trial units do you fund to conduct HIV-related therapeutic trials exclusively in children or pregnant women?
Answer. The AIDS Clinical Trials Group (ACTG) within the National Institute of Allergy and Infectious Diseases (NIAID) has enrolled 891 children as of March 15, 1991. Of the 47 total AIDS Clinical Trials Units, 27 conduct HIV-related clinical trials exclusively in children or pregnant women.
The National Institute of Child Health and Human Development (NICHD) currently supports 28 clinical trials units around the country which focus their therapeutic research activities exclusively on HIV-related research in pregnant women and children. Some of these units are located in regions--such as Puerto Rico and Atlanta--which have no other pediatric or maternal clinical trial units. NICHD has enrolled 547 children into HIV-related clinical trials. Considerable progress has been made toward the functional integration of the NICHD clinical trial units with those of the NIAID in order to avoid duplication or overlap of pediatric and maternal clinical trial activities.
The National Cancer Institute (NCI) has enrolled 198 children in HIV related clinical trials. In FY 1990 10 of their 29 HIV related trials, or approximately 35 percent, were pediatric trials.
Question. Have any RFAS been released by NIH institutes which focus on HIV-related research specifically focused on mothers and children? If so, how many and from which Institutes? How many grants are being supported as a result of these RFAs?
Answer. The NIAID has released four Request for Applications (RFAs) in FY 1990 in the area of women and children with HIV. treatment research, the NIAID released the Pediatric Expansion of the AIDS Clinical Trials Units RFA resulting in 12 awards. Three RFAs in basic research are soliciting applications for research in these areas: Development of Models for Pediatric AIDS; Development of Models for Placental and Pediatric Metabolism; Toxicity, and Transport of Anti-HIV Drugs; and HIV in Mothers and Infants: Immunity and Early Diagnosis. In addition, the NIAID released a program announcement in Mechanisms of HIV Pathogenesis in Pediatric Populations.
The NICHD has released two RFAs focused on HIV-related research
in pregnant women and children. The first one was released in early 1989 and solicited research grants which focused on improved methods of early diagnosis in neonates, infants, and children. Six grants were awarded to major medical centers around the country as a result of this RFA, totalling approximately $2 million, The second RFA was released in the fall of 1989 and solicited proposals focusing on the role the placenta in the transmission of HIV and anti-HIV agents from mother to fetus. Three awards in this area of research were made as a result of this RFA totalling over $500,000 of research support. In addition, NICHD is a co-sponsor with the National Institute of Mental Health and other NIH Institutes of a Program Announcement focused on HIV-related research in the pediatric population.
The NCI has not released any RFAs which focus on HIV-related research specifically focused on mothers and children.