Full Text DE-94-003 ORAL MANIFESTATIONS OF HIV INFECTION NIH GUIDE, Volume 23, Number 7, February 18, 1994 RFA: DE-94-003 P.T. 34 Keywords: Oral Diseases AIDS National Institute of Dental Research Letter of Intent Receipt Date: April 1, 1994 Application Receipt Date: May 6, 1994 PURPOSE The National Institute of Dental Research (NIDR) invites research grant applications to support research projects on the oral manifestations of Human Immunodeficiency Virus (HIV) infection. These projects encompass multidisciplinary, basic, clinical, epidemiologic, and behavioral research designed to slow the spread of acquired immunodeficiency syndrome (AIDS), to reduce the severity of oral complications of HIV infection, and to minimize the effects of HIV therapy. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Oral Manifestations of HIV Disease, is related to the priority area of oral health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) Award (R29). Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The mechanisms available for support of applications in response to this RFA include research project grants (R01) and FIRST (R29) awards. FUNDS AVAILABLE The NIDR will allocate approximately $2 million to support projects from this RFA during FY 1994. It is anticipated that at least eight awards will be made, provided that applications are of sufficient scientific merit. Applicants may request up to five years of support. Subsequent support will be dependent upon submission by the applicant of a renewal application through established NIH procedures for research grants related to AIDS. Policies that govern research grant programs of the National Institutes of Health will prevail. RESEARCH OBJECTIVES Background The first cases of AIDS in the United States were reported as early as 1981; however, despite sustained efforts by scientists and health care workers along with the commitment of considerable resources, progress in minimizing the spread of this public health menace has been slower than anticipated. Early in 1993, the World Health Organization reported that 611,500 cases from 184 countries had been recorded with over half of them coming from the United States. According to the Centers for Disease Control and Prevention (CDCP), from the time that AIDS was first reported in 1981 through the first half of 1993, a total of 310,680 adult and adolescent AIDS cases and 179,748 deaths from AIDS had been reported in the U.S. During 1992 alone, 47,106 AIDS cases were diagnosed and 29,763 deaths were reported. To date, nearly half of all AIDS cases reported have been either African-Americans or Hispanics, although these groups combined comprise only 21 percent of the U.S. population. In January 1993, the CDCP adopted an expanded definition of AIDS that took into account severe immunodepression, per se, and added recurrent bacterial pneumonias, pulmonary tuberculosis and invasive carcinomas in HIV-seropositive individuals to the long list of AIDS defining conditions. This expanded definition not only will increase the absolute numbers of AIDS cases, but will likewise result in an increase in the relative number of reported AIDS cases in females, as well as in an increase in the number of individuals covered under the expanded AIDS definition. Another factor that will increase the number of AIDS cases is the longer survival time resulting from improved care and management of AIDS patients, which increases the urgency for continuous treatment over longer periods of time. Interest by the NIDR in AIDS, which dates back to shortly after the disease was first identified, is based primarily on the prevalence and severity of oral mucosal and gingival lesions, non-infectious oral lesions, opportunistic infections, the importance of oral fluids as sources of HIV inhibitory factors and as non-invasive diagnostic tests for HIV. In addition, two international workshops, partially supported by the NIDR and devoted exclusively to the oral manifestations of HIV infection, vividly point up the need for continuing broad scale multidisciplinary studies to better understand the natural history of the HIV and its oral manifestations in order to minimize their devastating effects. In the mid-1980s, it was learned that saliva is unlike other fluids such as milk, tears, urine, and blood, in that HIV has rarely been isolated from saliva. NIDR intramural scientists, using saliva from both normal volunteers and HIV patients, reported that in vitro infectivity of monocytes in the presence of saliva was greatly reduced and this finding might be attributed to salivary inhibitory factors. In July 1989, the NIDR issued an RFA (89-DE-2) titled "Human Immunodeficiency Virus Inhibitory Factors in Human Saliva" to confirm findings of the NIDR investigators, and solicit studies to identify, isolate and determine the mechanism of action of the inhibitory factors in saliva. Research resulting from this RFA has shown that inhibitory factors are contained in high and low molecular weight fractions. The factors are specific for HIV, they act rapidly, and their effectiveness falls off when diluted. Further research is needed to expand this information, particularly by determining efficacy and mechanisms of action. Early unpublished findings from other NIDR supported investigations showed that HIV could be detected in gingival crevicular fluid (GCF), particularly in sites with gingival inflammation. The detection of HIV in GCF could be made several months prior to the appearance of HIV antibodies in the serum. The detection of HIV antibodies in the serum is generally regarded as the definitive proof of HIV infection. However, HIV antibodies as well as the virus itself have been demonstrated in limited amounts in saliva as well as in GCF, in many cases before the demonstration of serum antibodies. No studies have determined the specificity, sensitivity and reliability of HIV testing in saliva and GCF versus serum. The earlier the detection of the HIV or its antibodies, the earlier can intervention strategies be begun and the oral complications minimized. Saliva and GCF thus have the potential for use as effective non-invasive HIV screening procedures in large populations as well as in remote areas of the U.S.A. and in third world countries. A National Institute of Allergy and Infectious Diseases (NIAID) sponsored national conference on HIV in women, in 1990, suggested differences between males and females in the natural history of HIV infection, including its oral manifestations. However, due to limited participation of women in AIDS clinical trials at that time, it was not possible to confirm or refute this impression. In response, the NIAID organized the Women's Immunodeficiency HIV Study, which is exploring clinical and psychosocial aspects of HIV infection in women. The NIDR is co-funding an oral component of this study to obtain basic information on the oral manifestations of HIV infection in women. This RFA will expand this collaborative effort by investigating the potential role of intrinsic growth factors and hormones in the prevalence, frequency and severity of oral lesions in HIV-infected women. Studies are also sought to examine the long-term, oral side-effects of therapy for HIV infection. Additional investigations could focus on the impact of the mucosal immune system in the transmission of HIV to unborn fetuses and newborns. HIV-infected individuals are reported to have an increased prevalence of periodontal diseases. Both gingivitis, an inflammation of the gums, as well as periodontitis, which causes loss of bone and tissue attachment to the tooth, have unique clinical features in HIV-infected individuals. For example, there are reports of extremely aggressive forms of periodontitis in HIV infected patients that lead to rapid and extensive destruction of the soft tissue and bone exposure. HIV-infected individuals with pre-existing periodontitis tend to experience a higher rate of tooth attachment loss compared with matched controls. Histologically, the lesions in HIV-infected individuals lack at least the CD4+ subsets of T-lymphocytes. The absence of regulatory and effector immune cells may partially explain the rapidly progressive nature of periodontitis in these patients. In contrast to the evidence presented by some laboratories of an increased susceptibility to periodontal disease with HIV infection, there are reports that HIV-infected individuals exhibit healthy periodontia and show no greater prevalence or severity of disease than HIV-negative individuals. Such findings imply that, despite profound immunosuppression, HIV-infected patients have adequate defenses against periodontal diseases. This suggests that CD4+ T-lymphocytes may not be necessary to maintain a healthy periodontium. Studies are needed to explain these apparently contradictory reports. Studies are also needed on the pathogenesis of periodontal diseases in HIV-infected individuals, the host immune response and the unique histological features in these patients. Reports of an increased risk of periodontitis in older persons and women infected with HIV require further investigation and clarification as well. Levels of CD4+ cell counts appear to influence the occurrence and severity of HIV-associated periodontal manifestations. GCF and circulating blood levels of CD4+ cells and their subsets need to be related to the clinical stages seen in HIV infection. The temporal relationship between changes in CD4+ cell counts and clinical manifestations likewise remains to be delineated. Necrotizing gingivitis appears to be more common in HIV-infected patients than in healthy individuals for unknown reasons. Histologic, immunologic, bacteriologic and viral studies, particularly for cytomegalovirus (CMV), are needed to characterize possible risk factors for HIV-associated necrotizing gingivitis. The rate of periodontal attachment loss in HIV-infected persons needs to be established in longitudinal studies. A compromised immune system is the hallmark of HIV infection, AIDS, and the associated opportunistic oral lesions. To reduce the severity of both AIDS and opportunistic oral lesions, it seems logical to preserve and restore the integrity of the immune system. However, from an epidemiologic perspective, the preferred approach to controlling the spread of AIDS is to prevent exposure to the virus. The development of an effective preventive strategy is essential since an effective vaccine is at least ten years away according to the IX International AIDS Conference in Berlin in June 1993. Even after an effective vaccine is developed, preventive strategies will be needed. Prevention programs must rely on solid research including behavioral epidemiological studies of determinants of risk behaviors. Controlled clinical trials of preventive intervention strategies are needed to establish their effectiveness in reducing high-risk behavior and incidence of disease. Further research is needed on community-level interventions, behavior modification programs aimed at prevention, maintenance of behavioral changes, and social and behavioral issues in therapeutic and vaccine trials. Research Areas of Interest Some recommended research topics relevant to this RFA include, but are not limited to: o Studies to fully characterize and determine the molecular mechanisms of action of the HIV salivary inhibitory components. o Analytical studies of early and intermediate salivary markers of HIV infection. o Studies to determine additional immunological factors, along with T-cell defects, that contribute to the severe oral immunopathogenesis associated with AIDS. o Investigation of the molecular events that transform Candida albicans and other oral organisms from non-pathogenic to the pathogenic forms; and the mechanisms of candidal adhesion to oral tissues and to dental instruments. o Epidemiologic studies to determine if individuals who use illicit drugs, alcohol, or tobacco singly, or in combination, have increased susceptibility to oral HIV infection and the mechanisms by which synergism might occur. o Studies of the pathogenesis of HIV-induced gingivitis and periodontitis. o Comparative studies of the microbiota and oral opportunistic lesions of seropositive and seronegative women. o Studies evaluating the reliability and usefulness of GCF and saliva as potential diagnostic tools for non-invasive assessment of HIV infection. o Epidemiologic studies to determine the extent to which ethnicity, age, gender, education, economic status, access to care, and risk behaviors influence development of oral manifestations of HIV infection. o Knowledge, attitudes, and practices of oral health care personnel on infection control, patient management, ethical issues, and presenting complications of HIV infection. o Studies of neutrophil function in HIV-seropositive and seronegative acute necrotizing ulcerative gingivitis patients. o Investigation of the transmission, or prevention of transmission, of HIV in dental settings. These areas of research are neither prioritized nor meant to be restrictive. Investigators are encouraged to submit scientifically meritorious applications in any area of research responsive to the general research objectives of this RFA. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample site appropriate for the scientific objectives of the study. This information should be included in form PHS 398 (rev. 9/91) in items l-4 of the Research Plan and summarized in item 5, Human Subjects. Applicants are urged to carefully assess the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all such projects to include representation of the full array of United States racial, ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, African Americans, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be deemed nonresponsive. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s), or justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to the NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by April 1, 1994. The letter should include a descriptive title of the proposed research, the name, address and telephone number of the principal investigator, the identities of other key personnel and their participating institution(s), and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains is helpful to the NIDR staff in planning for timely review of applications. It also allows NIDR staff to estimate the potential workload and to avoid possible conflict of interest in review. The letter of intent is to be sent to Dr. Matthew Kinnard at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants are encouraged to consider collaborative arrangement with investigators from other organizations. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director of Principal Investigator should be included with the application. The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301-710-0267; and from the program administrator listed under INQUIRIES. To identify the application as a response to this RFA, check "YES" on item 2a of the face page of the application and enter RFA: DE-94-003, "Oral Manifestations of HIV Infection". The RFA label available in the form PHS 398 must be affixed to the bottom of the face page of the original application. Failure to use this label could result in delayed processing of an application such that it may not reach the review committee in time for review. Submit a signed, typewritten original of the application, including the checklist, and three signed, photocopies, by May 6, 1994 in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must be sent to: H. George Hausch, Ph.D. Extramural Program National Institute of Dental Research Westwood Building, Room 519 Bethesda, MD 20892 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the Division of Research Grants (DRG) for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the program requirements and criteria stated in the RFA is an NIDR program staff function. Applications that are considered non-responsive will be returned by the NIDR, but may be submitted as investigator-initiated research project grants at the next receipt date. Applications that are complete and responsive may be subjected to a triage by a peer review group to determine their scientific merit relative to the other applications received in response to the RFA. The NIH will withdraw from competition those applications judged to be noncompetitive and notify the applicant and institutional business official. Applications judged to be competitive will be further evaluated for scientific/technical merit by a special grants review committee convened by the NIDR Scientific Review Office. Secondary review will be by the National Advisory Dental Research Council. Major factors to be considered in the evaluation of applications include: o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; o availability of resources necessary to perform research; o appropriateness of the proposed budget and duration in relation to the proposed research; AWARD CRITERIA The anticipated date of award is September 30, 1994. Applicants will compete for available funds with all other recommended applications and should be aware that, in addition to scientific merit, program priorities, program balance, the total cost of the proposed project and the availability of funds will be considered by NIDR staff and the Council in making funding recommendations. In addition, the NIDR appreciates the value of complementary funding from other public and private sources including foundations and industrial concerns. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and address the letter of intent to: Dr. Matthew A. Kinnard Oral Soft Tissue Diseases and AIDS Program National Institute of Dental Research Westwood Building, Room 509 Bethesda, MD 20892 Telephone: (301) 594-7641 FAX: (301) 594-9720 Inquiries regarding fiscal matters may be directed to: Ms. Theresa Ringler Grants Management Office National Institute of Dental Research Westwood Building, Room 510 Bethesda, MD 20892 Telephone: (301) 594-7629 FAX: (301) 594-7600 Inquiries regarding review issues may be directed to Dr. George Hausch at the address listed under APPLICATION PROCEDURES. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158,42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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