IMPACT OF HAART ON HIV/CNS DISEASE Release Date: December 15, 1999 RFA: MH-00-003 National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Institute on Deafness and Other Communication Disorders Letter of Intent Receipt Date: February 10, 2000 Application Receipt Date: March 10, 2000 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE Recent advances in therapy for HIV disease, particularly the use of combinations of antiretroviral drugs including nucleoside analogs, protease inhibitors and reverse transcriptase inhibitors, collectively termed highly active anti- retroviral therapy (HAART) have resulted in a dramatic improvement in health status for a large number of HIV-infected individuals. Although many of the drugs used in these drug regimens do not readily or efficiently cross the blood- brain barrier, many individuals show improvement in associated CNS disease following treatment with HAART. However, research to study the long-term impact of treatment on HIV/CNS disease is needed to better understand the mechanisms underlying improvement in the CNS manifestations of HIV disease, as well as reasons for unresponsiveness, with attention to the potential role of the CNS as a viral reservoir. In addition, the interaction of potent antiretrovirals with other drugs used to treat the mental health complications of HIV infection, such as anti-depressant or anti-anxiety medications has not been studied. This RFA solicits applications to study the effects of HAART on HIV/CNS disease with respect to the clinical, neurological, neuropsychological, virological, immunological, and neuropathological response to the drugs. This solicitation also includes studies to develop drug formulations with improved ability to cross the blood-brain barrier, studies to develop improved methods of delivering drugs to the CNS, and the interaction of anti-retrovirals with psychotropic drugs. 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), Impact of HAART on HIV/CNS Disease, is related to the priority areas of Mental Health and HIV-induced CNS disease. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/ 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Research Project Grants (R01) mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years for an R01 application. This RFA is 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. The anticipated award date is September 2000. For all competing R01 applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being undertaken at NIH. More detailed information about modular grant applications, including a sample budget narrative justification pages and a sample biographical sketch, is available via the Internet at: http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. FUNDS AVAILABLE The NIMH intends to commit approximately $1,200,000 in FY 2000 to fund up to six new and/or competitive continuation grants in response to this RFA. The NINDS intends to commit approximately $1,000,000 in FY 2000 to fund three to four new and/or competitive continuation grants in response to this RFA. The NIDCD intends to commit approximately $200,000 in FY 2000 to fund one new grant in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. It is expected that the direct costs will be awarded in modules of $25,000, however, program and grants management adjustments may be necessary prior to award. Although the financial plans of the Institutes 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 applications of outstanding scientific and technical merit. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. RESEARCH OBJECTIVES One of the most serious clinical consequences of HIV infection stems from its assault on the nervous system. HIV can infect cells of the CNS, such as astrocytes and microglial cells, and it is not clear if the CNS provides a protected immune environment for virus because of the blood-brain barrier. HIV infection can lead to a spectrum of CNS complications, which includes neuropsychological defects collectively referred to as HIV-associated dementia (HAD). These complications can be relatively mild in earlier stages of the infection, however frequently advanced stages are marked by global cognitive impairment, mutism, and paraplegia, among other devastating symptoms. Serious neuropsychological impairment may predict poor survival. Patients with severe symptoms are unable to be productive, to maintain their independence, and to adhere to complex medication regimens. HAART, potent anti-retroviral drugs given in combination therapeutic regimes, has been successful in interrupting the disease process in HIV-infected individuals, resulting in a decrease in viral load to sometimes undetectable levels, and an increase in CD4 cells and immune function. Reports indicate that, at least in some patients, viral load in the CNS, reflected by measured viral load in the CSF, also decreases in response to treatment with HAART, with an associated improvement in HAD, despite the fact that the drugs show limited ability to cross the blood-brain barrier. Although much is known about the effects of HIV in the CNS, the mechanisms responsible for HAD are unclear, and cannot be accounted for by high CNS viral load. Although there is evidence that the incidence of HAD is declining, there is also some evidence that the prevalence of HAD in adults may be increasing. This may be the result of enhanced patient survival due to remarkable progress with combination therapies. As more patients live longer, they may confront enhanced risk of neuropsychological dysfunction. The nervous system remains vulnerable to reservoirs of HIV-infected cells, located in the periphery and in the central nervous system. Research to study the long-term impact of treatment with HAART on HIV/CNS disease is needed to better understand the mechanisms underlying improvement in the CNS manifestations of HIV disease, as well as reasons for unresponsiveness, with attention to the potential role of the CNS as a viral reservoir. In addition, the interaction of potent antiretrovirals with other drugs used to treat the mental health complications of HIV infection, such as anti-depressant or anti-anxiety medications must be studied. This RFA solicits applications to study the effects of HAART on HIV/CNS disease. Examples of research include but are not limited to the following: o correlative studies between clinical findings and HAD, both short-term and long-term, o neuropathological effects due to the use of HAART, with particular emphasis on correlations with clinical status, o Impact of HAART on neuropsychological, virological and immunological aspects of infection as they relate to the CNS. o Epidemiology of CNS infections in light of current therapies. o Research using state of the art imaging technique (MRI, fMRI, MRS, PET and SPECT) to correlate structural, metabolic and functional changes following HAART therapy. o studies to develop drug formulations with improved ability to cross the blood-brain barrier, o studies to develop improved methods of delivering drugs to the CNS, o pharmacokinetic studies in animals and in clinical settings, o studies on the interaction of anti-retrovirals with psychotropic drugs, o studies to examine the development and incidence of auditory, vestibular, olfactory and gustatory disorders in patients in various stages of HIV infection, including those treated with HAART. 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). It is also NIH policy 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 Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html 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 the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 Institute staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Dianne Rausch, at the address listed under INQUIRIES, by February 10, 2000. 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) 710-0267, Email: [email protected]. The application is also available at http://grants.nih.gov/grants/funding/phs398/phs398.html SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS 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 per year. (Applications that request more than $250,000 direct costs in 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 FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) 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. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget tables on page 5 of the PHS 398 (rev. 4/98) Form. It is not required nor will it be accepted at the time of 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 key 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 key 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 and must display the RFA number MH-00-003. The RFA number must be typed on the label as well. A sample modified mailing label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in pdf format. 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, Impact of HAART on HIV/CNS Disease, MH-00-003, must be typed on line 2 of the face page of the application form and the YES box must be marked. 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: Dianne Rausch, Ph.D. Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Blvd., Room 6209, MSC 9619 Bethesda, MD 20892-9619 Applications must be received by March 10, 2000. 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 CSR and responsiveness by the NIMH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NIMH in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which 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 Institute’s National Advisory Council. 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 methods? 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. Schedule Letter of Intent Receipt Date: February 10, 2000 Application Receipt Date: March 10, 2000 Peer Review Date: April 2000 Council Review: September 2000 Earliest Anticipated Start Date: September 29, 2000 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 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 programmatic issues to: Dianne Rausch, Ph.D. Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Boulevard., Room 6209, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-7281 FAX: (301) 443-9719 Email: [email protected] A. P. Kerza-Kwiatecki, Ph.D. Neural Environment Team National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2115 MSC 9521 Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: [email protected] Thomas M. Johnson, Ph.D. Division of Extramural Research National Institute on Deafness and other Communication Disorders Executive Plaza South-400C 6120 Executive Blvd. Bethesda, MD 20892-7180 Telephone: 301-402-3461 FAX: 301-402-6251 E-mail: [email protected] Direct inquiries regarding fiscal matters to: Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: [email protected] Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3261 MSC 9619 Bethesda, MD 20992-9619 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: [email protected] Meigs Ranney Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-B, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 FAX: (301) 402-1758 E-mail: meigs [email protected] Although not participating in the preliminary activities that led to this RFA, the National Institute on Drug Abuse has a strong interest in supporting studies on the role of drugs of abuse and the medications used to treat drug abuse on the effects of HAART on HIV/CNS disease, e.g., pharmacokinetic and pharmacodynamic issues, and adherence issues for drug abusers. For futher information, contact Katherine Davenny, M.P.H., Center on AIDS and Other Medical Consequences of Drug Abuse, National Institute on Drug Abuse, telephone: (301) 443-1801, E-mail: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.242 (NIMH), 93.853 (NINDS), and 93.171 (NIDCD). 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. 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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