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) 435-0714, Email: 
GrantsInfo@nih.gov.  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: dr89b@nih.gov 

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:  ak45w@nih.gov

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: tj56y@nih.gov

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:  Diana_Trunnell@nih.gov 

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:  dj35j@nih.gov

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 ranney@nih.gov

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: kdavenny@mail.nih.gov 

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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