Full Text PA-95-026 HIV DISEASE PROGRESSION IN DRUG USERS NIH GUIDE, Volume 24, Number 4, February 3, 1995 PA NUMBER: PA-95-026 P.T. 34 Keywords: AIDS Drugs/Drug Abuse 0765034 Viral Studies (Virology) National Institute on Drug Abuse PURPOSE The purpose of this program announcement is to stimulate research on the biological and behavioral factors influencing HIV disease progression in populations of drug users both in and out of drug abuse treatment, in order to facilitate prevention and treatment efforts. Increased understanding of viral, host, and environmental factors, and their role in vulnerability and resistance to infection and differential rates of disease progression is sought, as is identification of additional HIV-related outcomes, assessment of the impact of available HIV-related interventions on disease course, and further investigation of the disease in women, adolescents, and children. 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 program announcement, HIV Disease Progression in Drug Users, is related to the priority area of alcohol and other drugs. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or 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, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This program announcement will use the National Institutes of Health (NIH) individual research project grant (R01), interactive research project grant (IRPG), small grant (R03), and FIRST (R29) award. There are special requirements for R29 and R03 mechanisms. If an applicant intends to apply utilizing either of these mechanisms, they should contact the program person listed under INQUIRIES for further information. For further information on the IRPG, refer to PA-94- 086, NIH Guide for Grants and Contracts, Vol. 23, No. 28, July 29, 1994. Because the nature and scope of the research proposed in response to this program announcement may vary, it is anticipated that the size of an award will also vary. RESEARCH OBJECTIVES Summary Research studies are sought that investigate HIV disease progression in populations of drug users, with emphasis on integration of biological and behavioral models in order to enhance understanding of the unique aspects of the disease in those with a history of active or past drug use. The multiple foci of this research program include: (1) further characterization of factors determining vulnerability and resistance to infection and the natural history of early infection; (2) determination of mechanisms of transmission and infection, including aspects of the disease that are specific to women with a history of drug use and/or drug-using sexual partners, and to pediatric populations with dual drug and HIV exposure; (3) identification of additional HIV-related outcomes and risk factors for those outcomes; (4) the impact of interventions on infection, on the frequency and severity of outcomes, and on progression and survival; and (5) investigation of the pathogenesis of infection and disease, addressing virologic, immunologic, genetic, and environmental factors that may affect differential progression and survival. Collaborative efforts and studies associated with well- characterized samples or cohorts of drug users are encouraged. Both generation of new data, including laboratory studies of immune and virologic parameters, and analyses of existing data and/or biologic repository specimens will be considered for support. Studies that correlate biological data with stage of disease and drug and sexual behavior are strongly encouraged, as are ancillary studies or selected sub-studies within larger longitudinal designs. Where appropriate, comparison studies in HIV-uninfected drug users are encouraged. Background Since 1986, NIDA has supported a program of longitudinal research on the natural history of HIV in drug users. The prospective design has provided long-term serial follow-up of seroprevalent and seroincident cohorts to defined outcomes, providing multiple data points for studies of biologic and behavioral factors related to infection and subsequent disease progression. Research in well-characterized incident and prevalent cohorts has identified many aspects of HIV infection and disease in drug users, including factors associated with seroconversion, competing causes of morbidity and mortality, HIV-related outcomes, markers and prognostic indicators of disease development, and differential rates of disease progression and survival. Further characterization of the disease in drug users in longitudinal studies provides opportunities for enhanced multidimensional approaches to research on infection and disease progression. Given the high background prevalence of infectious diseases and abnormalities in immune parameters among drug users, longitudinal studies in HIV-uninfected drug users have demonstrated utility in discriminating those factors related to drug use from those related to HIV infection. The interval collection of biologic specimens for assay and repository in the longitudinal context provides opportunities for selected substudies of HIV pathogenesis. Additionally, collaborative and meta-analytic efforts utilizing serial data from multiple cohort studies are particularly productive in characterizing the many factors affecting disease progression. Program Description Examples of areas of research interest that examine the question of drug use and HIV disease progression include, but are not limited to, the following. o Research on host and viral factors affecting vulnerability and resistance to infection and the natural history of early infection during the period when infection is established; the relationship of route of infection and viral and host factors to establishment of infection and subsequent disease course; further characterization of the incubation period and differential rates of disease progression in studies that link behavioral, immunologic, and virologic factors. o Research on the role of drugs in maternal-infant transmission, e.g., the impact of repeated drug injection on viral load, the impact of drugs on the placenta; the consequences of dual exposure to HIV and drugs of abuse on the development of the central nervous system and the immune system; factors associated with differential rates of progression and survival in infants; the impact of antiviral treatment protocols on maternal transmission and disease outcomes in dually exposed infants. o Research that elucidates factors related to differential rates of progression in drug abusing populations, including behavioral, genetic, virologic, immunologic and host factors; the identification of distinct trajectories of progression, including associations among immunologic, virologic and clinical markers and predictors of disease course, e.g., infection without immunologic progression, stable clinical state with prolonged immunosuppression. o Research on co-factors for infection and HIV disease progression, including the pathogenesis of HIV-related malignancies, opportunistic infections and other diseases associated with drug abuse. o Identification of additional HIV-related outcomes, associated behavioral and biologic factors and their relationship to progression and survival; studies of the natural history and pathogenesis of diseases prevalent among drug users, such as hepatitis, tuberculosis, and other sexually transmitted diseases and the impact of these diseases on HIV disease course. o Characterization of the clinical progression of HIV in the central nervous system; research on the development of HIV-related neurologic disease; the impact of drug use and related co-morbid neuropsychiatric conditions prevalent in drug users on disease course; studies of clinical, immunologic, and virologic factors that characterize infection and disease in the brain as distinct from other organs, and the influence of active drug use on those factors; studies of the influence of drug use on migration of HIV across the blood-brain barrier and on establishment of infection and subsequent disease development in the brain. o Immunologic studies that further characterize immune function, including mucosal immunity, in the context of active drug use and other co-morbid medical conditions; trajectories of CD4 and CD8 and other immune parameters and their role in progressive immunodeficiency. o Research that assesses the consequences of repeated inoculation of virus through drug injection and/or sexual exposure on clinical course, immune parameters, and on viral factors such as viral phenotype, genotype and load, and the evolution of viral strain heterogeneity; the impact of repeated inoculation at different stages of progression of HIV disease. o Studies of interventions and treatments that address long-term effectiveness (morbidity, clinical disease progression and survival) in the context of drug use and/or drug abuse treatment; interactions of licit and illicit drugs with antivirals and the development of toxicities; the effectiveness of prophylaxis for specific HIV-related infectious diseases in reducing the incidence of other infections prevalent among drug users; the impact of active drug use on adherence to medical treatment protocols and on long-term treatment effectiveness and the development of viral resistance. o Studies of strategies to increase adherence to medical regimens and their effectiveness in influencing the course of HIV disease and its associated illnesses. o Studies of direct and indirect effects of the lifestyles of drug- abusing populations on HIV disease course, e.g., poverty, nutrition, injury, stress, homelessness; studies of indirect effects on progression via factors affecting access to and utilization of health services, including issues of financing and linking drug abuse treatment, acute and primary medical care, mental health care and public health interventions, e.g., STD and TB screening. o Research to develop biostatistical methodologies to enhance the analysis and interpretation of longitudinal data and the integration of biological and behavioral factors affecting disease progression; development of data-driven statistical models to project the effects of interventions and treatment on disease progression. All applications should address issues of project feasibility and collaborative arrangements, study design, sampling procedures, implementation of interventions, instrumentation and measurement, data collection, quality control, laboratory assay protocols, tracking of clients, follow-up, and data analysis, as appropriate. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the AIDS expedited application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The title and number of the program announcement must be typed in Section 2a on the face page of the application. FIRST applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. 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 or principal investigator could be included in the application. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. The small grant (R03) does not receive second-level review. Applications that are complete and responsive to the program announcement will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The review criteria are: 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 the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, and safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Katherine Davenny, M.P.H. Division of Clinical Research National Institute on Drug Abuse 5600 Fishers Lane, Room 11A-33 Rockville, MD 20857 Telephone: (301) 443-1801 FAX: (301) 443-2317 Email: kdavenny@aoada.ssw.dhhs.gov Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 Email: gfleming@aoada2.ssw.dhhs.gov Applications in the area of perinatal or pediatric HIV disease will be considered for co-funding with the National Institute of Child Health and Human Development (NICHD). Direct inquiries to: Ann Willoughby, M.D. Pediatrics, Adolescents, and Maternal AIDS Branch National Institute of Child Health and Human Development 6120 Executive Boulevard, Room 4B11J Rockville, MD 20892-7510 Telephone: (310) 496-7339 FAX: (301) 496-8678 Email: aw55g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. 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. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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