HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) CARDIOVASCULAR TOXICITIES 

RELEASE DATE:  March 7, 2002

RFA:  HL-02-028
 
National Heart, Lung, and Blood Institute (NHLBI) 
 (http://www.nhlbi.nih.gov)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov)

LETTER OF INTENT RECEIPT DATES: April 1, 2002 and January 20, 2003

APPLICATION RECEIPT DATES: April 29, 2002 and February 19, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA 

The objective of this RFA is to support basic research to elucidate how 
nucleoside reverse transciptase inhibitors (NRTI), non-nucleoside 
reverse transciptase inhibitors (NNRTI), and/or protease inhibitors 
(PI) affect the development of cardiovascular disease.  Ultimately, 
better understanding of HAART-induced cardiac dysfunction will permit 
development of effective strategies for prevention and treatment.  
Successful applications should address the basic cellular mechanism(s) 
underlying the development of these pathologies.  Studies may include 
any or all of the following: interdisciplinary and collaborative 
research focused on pediatric or adult clinical cardiac complications; 
basic studies using animal models (e.g., rodent, nonhuman primate); in 
vitro mammalian cell; and human tissue studies.  
 
RESEARCH OBJECTIVES

HAART regimens have improved the course of HIV disease.  Patients live 
longer and have a better quality of life.  However, new clinical 
complications have emerged as a result of the therapy, including 
peripheral and coronary arterial diseases, and metabolic disturbances 
seen typically in diabetes.  Throughout the world, patients with HIV 
infection represent one of the most rapidly growing groups of 
individuals with cardiovascular disease.  Significant cardiac morbidity 
from HIV disease is estimated at 6-7% and mortality between 1-6% based 
on US and European data.  

Cardiac abnormalities in patients with HIV-infection range from 
asymptomatic mild dysfunction, which is evident only on 
echocardiographic evaluation, to severe dysfunction with development of 
congestive heart failure (CHF) and dilated cardiomyopathy (DCM).  
Pediatric and adult echocardiographic examination reveal that 15-20% of 
patients having left ventricle dysfunction on echocardiography.  Of 
these patients, 3-5% are symptomatic with CHF or DCM, requiring medical 
treatment to improve cardiac function.  

Antiretroviral drug regimens are strongly suspected as one factor 
responsible for adult and pediatric cardiac dysfunction.  These drugs 
are associated with increases in the incidence of unstable angina, 
myocardial infarction, pulmonary hypertension, right ventricular 
dysfunction, and stroke in HIV-infected adults.  HAART may also be 
associated with development of myocardial dysfunction during fetal 
development, in young children, and teenagers.  Studies in non-infected 
non-human primates with NRTIs demonstrate fetal cardiac morphological, 
biochemical, and genetic abnormalities.  However, clinical pediatric 
studies are still inconclusive; some reports support NRTI-induced 
cardiotoxicity while others show no association between NRTIs and 
cardiac dysfunction. Furthermore, basic research studies have focused 
on the NRTI, zidovudine and not combination therapies.  Thus, the 
contribution of NRTIs and/or combination therapies to the cellular 
mechanisms involved in these pathologies have not been well defined. 
The goal of this program is to encourage research likely to produce a 
better understanding of the mechanisms and/or clinical approaches to 
HAART cardiovascular toxicities.    

Suggested clinical research topics include, but are not limited to:

o Evaluation of cellular functional, metabolic, and structural 
alterations with NRTIs, NNRTIs, and/or PI combinations.  This could 
include evaluating intracellular parameters and correlations with 
clinical presentation in HIV-infected adults and/or children.

o Understanding of the cellular vascular pathology, including 
endocardial involvement of treatment regimens in patients at high risk 
for or with peripheral and coronary arterial diseases.

o Clinical studies using imaging techniques to correlate vascular 
reactivity, endothelial cell function, cellular energetics to clinical 
presentation of ischemic heart disease. 
   
o Determination of the mechanisms and effects of NRTIs, NNRTIs, and/or 
PI combinations in pericardial effusion, endocardial involvement, and 
cardiac arrythmias. 

o Evaluation of the mechanisms and impact of specific treatment 
strategies on cardiovascular function in HIV-infected patients.

o Studies in high-risk patients (hyperlipidemic, hypertension, 
dysmetabolic) dealing with the mechanisms of cardiovascular function, 
coagulation, and inflammatation.

o Studies to evaluate the mechanisms and effects of in utero exposure 
to antiretroviral drugs on the heart, including but not exclusively 
limited to cardiac development, dysfunction, and/or mitochondrial 
abnormalities.

Proposed studies should differentiate between the effects of HIV and 
other co-infections where possible. Populations chosen should be 
carefully defined and characterized as to environmental (e.g. smoking, 
etc.) and other risk factors or diseases.    

Basic research studies should be translatable to human studies.  Thus, 
in animal and mammalian cell experiments, the drug combinations and 
amounts should be pharmacologically relevant and animal models chosen 
should exhibit similar systemic pharmacokinetics and pharmacodynamics 
as humans. Appropriate basic research topics to respond to this RFA 
include but are not limited to:

o Studies to examine the pathological effects of NRTIs, NNRTIs, and/or 
PI combinations in adult or pediatric (including in utero) animal 
models for either heart, peripheral vascular, and/or coronary arterial 
diseases.

o Studies in vitro with NRTIs, NNRTIs, and/or PI combinations and 
mammalian cells or tissues associated with the cardiovascular system 
that could contribute to the etiology of these diseases, such as 
vascular endothelial, myocardial, and/or adipocyte cells.

o Studies to evaluate the mechanisms and effects of NRTIs, NNRTIs, 
and/or PI combinations in any of the following animal or in vitro 
models: interferences with ion pumps or exchange mechanisms, 
mitochondrial damage and enzymatic dysfunction, premature truncation of 
genes, oxidative stress, apoptosis, nucleoside imbalances, 
phosphorylation, and post-transcriptional changes in glycosylation, and 
how these genetic, biochemical, and/or morphological changes contribute 
to the etiology of cardiovascular diseases.

MECHANISM OF SUPPORT
 
This RFA will use the NIH R01 award mechanism.  The applicant will be 
solely responsible for planning, directing, and executing the proposed 
project.  There will be two receipt dates: April 29, 2002 and February 
19, 2003.  Applicants who submit to the first receipt date and are not 
funded may revise and submit an amended application for the second 
receipt date. Future unsolicited, competing-continuation applications 
based on this project will compete with all investigator-initiated 
applications and will be reviewed according to the customary peer 
review procedures. The anticipated award dates are September 30, 2002 
and 2003, respectively.  

This RFA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
https://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.

FUNDS AVAILABLE
 
NHLBI intends to commit approximately $5.0 million in FY 2002 and 
another $2.0 million in FY 2003 to fund 10 to 20 new and/or competitive 
continuation grants in response to this RFA. NICHD intends to commit 
$500,000 to fund 2 new applications relevant to studies in children in 
2003.  Because the nature and scope of the proposed research will vary 
from application to application, it is anticipated that the size and 
duration of each award will also vary.  An applicant may request a 
project period of up to five years.  Although the financial plans of 
the IC(s) 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. 
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   
 
SPECIAL REQUIREMENTS 

The Principal Investigators of grants funded under this RFA will be 
expected to participate in yearly grantee meetings to present findings 
of the research supported and suggest future research directions.  
Funds for travel to such meetings must be incorporated in the 
development of the budget.
 
Applications focused on the development of metabolic complications
(hypercholesterolemia, hyperinsulinemia, lipoatrophy) will not be 
considered responsive to this RFA.     
 
WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
two areas:  scientific/research and financial or grants management 
issues:

o Direct your questions about scientific/research issues to:

Mariana Gerschenson, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 9180
MSC 7940
6701 Rockledge Drive
Bethesda, MD  20892-7940
Phone: 301-435-0515
FAX: 301-480-1336
Email: gerschem@nhlbi.nih.gov

Lynne M. Mofenson, M.D. 
Pediatric, Adolescent and Maternal AIDS Branch 
Center for Research for Mothers and Children 
National Institute of Child Health and Human Development 
National Institutes of Health 
6100 Executive Boulevard, Room 4B11 
Rockville, MD 20852 
Telephone:  301-435-6870 
Fax:  301-496-8678 
Email:  LM65D@nih.gov

o Direct your questions about peer review issues to:

Anne Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7178 (MSC 7924)
Bethesda, MD 20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
FAX:  (301) 480-0730
Email: ClarkA@nhlbi.nih.gov

o Direct your questions about financial or grants management matters 
to:

Kevin Keating
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Suite 7159, MSC 7926
Bethesda, MD  20892-7926
Telephone: (301) 435-0185
FAX:  (301) 480-3310
Email: KeatingK@nhlbi.nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Anne Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7178 (MSC 7924)
Bethesda, MD 20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
FAX:  (301) 480-0730
Email: ClarkA@nhlbi.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) 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 RFA 
label is also available at: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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 as 
well as six collated sets of appendix material must be sent to:
 
Anne Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7178 (MSC 7924)
Bethesda, MD 20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
FAX:  (301) 480-3541
Email: ClarkA@nhlbi.nih.gov
 
APPLICATION PROCESSING: 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.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NHLBI.  

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 the (IC) in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the National Heart, Lung, and Blood 
Advisory Council and the National Child Health and Human Development 
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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you 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 your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  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 INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

o BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Dates: April 1, 2002 and January 20, 2003
Application Receipt Dates: April 29, 2002 and February 19, 2003
Peer Review Dates: July, 2002 and June, 2003
Council Reviews: September 5, 2002 and September 4, 2003
Earliest Anticipated Start Dates: September 30, 2002 and September 30,
2003

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.
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research 
components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
https://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy 
of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating 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 clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_20
01.htm.   The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must 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) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a 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 Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
https://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for research 
involving human subjects.  You will find this policy announcement in the 
NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom of 
Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

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.   Furthermore, we caution reviewers that their anonymity 
may be compromised when they directly access an Internet site.

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 RFA 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.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.837 and 98.865 and is not subject to 
the intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  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 described 
at https://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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