RESEARCH ON ALCOHOL AND HIV/AIDS Release Date: February 16, 2001 RFA: RFA-AA-01-004 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov) Letter of Intent Receipt Date: April 16, 2001 Application Receipt Date: May 14, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) seeks applications to support research to identify and characterize the role of alcohol in the etiology, pathogenesis, prevention, treatment and control of HIV/AIDS. As understanding of the pandemic progresses, and as HIV/AIDS research becomes more focused, it is apparent that the cofactor alcohol consumption is likely to play an important role in sexual transmission, susceptibility to infection, and progression of HIV disease. The purpose of this Request for Applications (RFA) is to encourage multidisciplinary and interdisciplinary studies that focus on a range of population, etiological and intervention issues within HIV and alcohol. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Research on Alcohol and HIV/AIDS, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic 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 not eligible for these grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will support research through the National Institutes of Health (NIH) research project grant (R01) and exploratory/development grant (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for a research project grant (R01) application submitted in response to this RFA may not exceed 5 years. Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000 per year for direct costs. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NIAAA intends to commit approximately $3 million in FY 2001 and FY 2002 to fund up to 10 new and/or competitive continuation grants in response to this RFA. Because the nature and scope of the research proposed might vary, it is anticipated that the size of awards will also vary. Although the financial plans of the NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. BACKGROUND Alcohol abuse and its related consequences together with HIV/AIDS are major public health burdens in many parts of the world. Chronic abusive alcohol use can lead to life threatening organ system damage. Light to moderate consumption can induce organ system changes which may influence HIV pathogenesis. There is overlap between persons at risk for alcohol abuse and individuals at risk for HIV infection. Regardless of the level consumed, alcohol is likely to influence the health status of persons infected with HIV and those whose behaviors place them at risk for acquiring the infective agent. Alcohol has been identified as a cofactor in HIV disease. Alcohol misuse is likely to impact the ability to adhere to complex HIV medication regimens and recent evidence indicated interactive effects of alcohol abuse and HIV infection on brain functioning and cognitive processes. However, carrying out research on the additive or interactive effects of alcohol consumption and more general drinking behaviors on HIV-related health outcomes is challenging. To date, there is no conclusive evidence that acute or chronic alcohol consumption increases susceptibility to HIV infection or accelerates progression to AIDS. However, clinical findings have associated increased levels of chronic alcohol consumption with diminished immune function as evidenced by reduced levels of CD4 and CD8 activity. Strain variations of HIV, individual differences in susceptibility, long incubation time following seroconversion and varying patterns of adherence to HIV medications are some of the difficulties in studying this disease progression. Whether alcohol consumption increases susceptibility to opportunistic infections in HIV+ patients and whether alcohol-induced immunosuppression exacerbates disease pathogenesis are important questions. While effective management of the HIV/AIDS epidemic beyond prevention may be through use of Highly Active Antiretroviral Therapy (HAART), there are significant clinical challenges facing HIV research involving behavioral, pharmacological and biomedical aspects of treatment. However it is of continuing importance to develop and test preventive interventions to reduce the risk of HIV transmission related to alcohol and improve the treatment of HIV infected alcohol abusing and/or alcohol dependent individuals. RESEARCH OBJECTIVES The complex and global nature of unresolved questions surrounding alcohol and HIV/AIDS relationships would suggest multidisciplinary research to be a productive approach. Investigators, representing a broad array of academic disciplines and engaged in cross-cutting fields of science, are encouraged to consider designing hypotheses-driven studies that utilize rigorous methodologies from epidemiological, clinical, and experimental research. Natural History of Alcohol Use and HIV/AIDS: Improved understanding of the epidemiology of alcohol use and abuse in HIV infection and AIDS will help to identify high-risk groups and promote development of effective HIV prevention and treatment efforts including medical management of HIV/AIDS disease. For example, studies are needed to: o Gain insight into the alcohol-HIV/AIDS relationship through population- based research on alcohol consumption patterns of groups at-risk for HIV infection. o Identify and model the impact of alcohol consumption patterns on the spread of HIV infection and associated opportunistic infections over time. o Characterize alcohol use and alcohol use disorders in high-risk groups with HIV/AIDS and co-occurring medical and psychiatric complications. o More fully describe the role of gender, race/ethnicity, cultural and environmental factors in the intersection of alcohol and HIV/AIDS epidemics. Prevention of HIV Risk Behaviors Related to Alcohol: Behavioral, affective, and cognitive factors affect the risk for HIV infection and the efficacy of HIV prevention and treatment among alcohol users and abusers. Models should be developed for interrelating these individual factors with contextual and social factors that influence alcohol misuse, sexual risk-taking, and other HIV risk behaviors. Development and testing of new interventions are needed at various levels, including: individual, dyadic, social network, organizational, community. The following areas are suggested and not inclusive: o Develop community-based interventions, e.g., bar-based server training, altering alcohol availability, and improving linkage of alcohol and HIV preventive services. o Target and retain the highest risk drinkers including those from difficult- to-reach groups in HIV/STD prevention and treatment interventions—including trials for prophylactic vaccines. o Motivate drinkers—including those who perceive themselves to be at low risk for HIV infection—to decrease risky sexual and substance use behaviors. o Assess relationship of alcohol consumption, alcohol-related sexual expectancies, social norms, and decision-making on HIV risk behaviors for different at-risk groups. o Elucidate social dynamics and environmental characteristics of high-risk alcohol-related settings, bars, parties, “wet” neighborhoods and the impact of alcohol regulations and policies on HIV transmission. o Improve methods for assessing and analyzing complex relationships between alcohol use and abuse, specific situations and settings, and HIV-related risk behaviors. o Assess family and peer group dynamics as they may influence alcohol use, unsafe behavior and exposure to co-occurring risks such as violence, poor health care and disease. Alcohol Use and Treatment Among HIV-Positive Individuals: Alcohol use may be a key determinant in adherence to therapeutic regimens. Research is needed on interventions to improve treatment adherence and to ameliorate negative physical, behavioral, affective, cognitive, and social consequences of HIV infection in alcohol-using and -abusing populations. Research efforts are needed to: o Integrate HIV risk reduction goals into alcohol abuse treatment settings— including psychosocial and pharmacological interventions. o Better understanding of the dynamics between alcohol use and abuse, and adherence to HIV therapeutic regimens. o Improve medication adherence in alcohol-using and alcohol-abusing HIV+ patients. o Prevent alcohol relapse and related HIV risk behaviors among HIV+ individuals. o Develop and test interventions to improve quality of life for alcohol-using and –abusing HIV-infected persons (e.g., ameliorating the interaction of alcohol use and medical sequelae of AIDS progression). o Better understand the relationship between alcohol use and abuse, access to care, and delivery and cost of services for infected persons. o Enhance linkage of primary medical care with alcohol prevention and treatment services for HIV-infected alcohol abusers. o Characterize and assess strategies to improve health care delivery for hard-to-reach populations exposed to HIV risks and alcohol. o Determine and evaluate the existing and potential roles for collaborative community-based programs to contribute to all phases of alcohol and HIV/AIDS prevention, intervention and treatment. Biomedical Research on Alcohol and HIV/AIDS: Lack of knowledge on the influence of alcohol on HIV infectivity and viral replication is a major impediment to understanding HIV-related morbidity and mortality. Therefore, research that provides detailed knowledge of how alcohol and HIV, each in its own way or acting in concert, usurp host defense mechanisms and co-opt vital cellular machinery to enhance viral replicative success, is urgently needed. Biomedical research that delineates the multiple dimensions of alcohol and HIV on host defense mechanisms will provide a rational basis for the development of new methods of therapeutic interdiction. The following topics serve to illustrate the types of research that would be responsive to this RFA: o Effects of alcohol on viral burden, immune function, and organ system pathogenesis in HIV infected individuals or appropriate animal models. o Determine organ system changes at the cellular, molecular and tissue levels that may influence infectivity, viral load, disease progression and/or therapeutic response. o Effects of alcohol consumption on seroconversion and progression of disease in defined cohorts including biological endpoints which relate to both alcohol abusing populations (e.g., MCV, CDT, liver function enzymes) and AIDS-specific measures (e.g., viral load, CD4+ and CD8+ levels). o Mechanisms by which alcohol consumption affects liver disease progression in individuals with HIV or coinfected with hepatitis C (HCV). o Drug-drug interactions between alcohol and antiretroviral drugs including altered pharmacology and toxicity due to chronic or acute alcohol consumption. o Animal models of alcohol consumption and AIDS to explore cellular changes and immune state dynamics. o Alcohol-related host defense impairment and opportunistic infection caused by pathogens such as M. tuberculosis, S. pneumoniae, P. carinii and HCV. o HIV-specific complications including neuropathogenesis and pathogenic processes involved in HIV wasting, neuropathy, encephalopathy, and enteropathy. 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 policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, 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 allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: RFA: AA-01-004 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 (Rockville, MD 20852 for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date listed. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, E-mail: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000. (Applications that request more than $250,000 in direct costs for any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: RFA: AA-01-004 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by the NIAAA. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAAA in accordance with the review criteria stated below. As part of the initial merit review, all applications 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council on Alcohol Abuse and Alcoholism. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share data, if appropriate. Additional consideration pertinent to the review of Exploratory/Developmental Grant (R21) applications: Pilot/feasibility studies may contain little or no preliminary data. Review should focus on whether the rationale for the study is well developed and whether the proposed research is likely to generate data that will lead to a regular research project grant or full-scale clinical trial. Adequate justification for the proposed work may be provided through literature citations, data from other sources, or investigator-generated data. Schedule: Letter of Intent Receipt Date: April 16, 2001 Application Receipt Date: May 14, 2001 Peer Review Date: July/August, 2001 Council Review: September 19, 2001 Earliest Anticipated Start Date: September 28, 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review), o availability of funds, and o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding applications under this RFA to: Kendall Bryant, Ph.D. Scientific Director Alcohol and HIV/AIDS Research Office of Collaborative Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-8820 or (301) 402-9389 FAX: (301) 443-8774 Email: kbryant@niaaa.nih.gov Direct inquiries regarding fiscal matters to: Linda Hilley Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0915 FAX: (301) 443-3891 Email: lhilley@niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.273. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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