TREATMENT OF HAART-ASSOCIATED METABOLIC CHANGES IN PATIENTS WITH HIV INFECTION

Release Date:  July 17, 2001

RFA:  RFA-DK-02-006

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)
National Heart, Lung and Blood Institute
 (http://www.nhlbi.nih.gov)

Letter of Intent Receipt Date:  February 21, 2002
Application Receipt Date:       March 21, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  USE THE 
MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 
(REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf.

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) and the National Heart, Lung and Blood Institute (NHLBI) seek 
applications to develop and test strategies for treating the metabolic 
complications associated with anti-retroviral drug therapy in patients 
with HIV infection.

In recent years, the advent of highly active anti-retroviral therapy 
(HAART) has dramatically improved the survival of patients infected 
with HIV. Despite the benefits of the new anti-retroviral therapies, 
HAART has been associated with a variety of metabolic complications -- 
including dyslipidemia, insulin resistance and abnormal distribution of 
body fat (lipodystrophy) -- all of which are major risk factors for the 
development of other serious diseases, such as diabetes and 
cardiovascular disease. Of particular concern for many patients has 
been the problem of lipodystrophy, characterized by increased 
deposition of fat in the abdomen and trunk, and/or loss of fat in the 
face and extremities. Distress over these often disfiguring changes has 
caused some patients to stop taking anti-viral medications.

This RFA solicits clinical studies to 1) test the efficacy, in patients 
infected with HIV, of agents currently approved for the treatment of 
dyslipidemia, insulin resistance or diabetes, and osteoporosis, and 2) 
develop and test novel treatment approaches to HAART-associated 
metabolic changes, including lipodystrophy.

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), Treatment of HAART-Associated Metabolic Changes in 
Patients with HIV, 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 and foreign for-profit and 
nonprofit 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 grant (R01) and the Exploratory/Development Research 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 an R01 application submitted 
in response to this PA may not exceed 5 years.

The R21 awards are to demonstrate feasibility and to obtain preliminary 
data testing innovative ideas that represent clear departure from 
ongoing research interests. These grants are intended to 1) provide 
initial support for new investigators; 2) allow exploration of possible 
innovative new directions for established investigators; and 3) 
stimulate investigators from other areas to lend their expertise to 
research within the scope of this solicitation. Applicants for the R21 
must limit their requests to $150,000 direct costs per year and are 
limited to two years. These R21 grants will not be renewable; 
continuation of projects developed under this program will be through 
the regular research grant (R01) program. 

Applicants from institutions which have a General Clinical Research 
Center (GCRC) funded by the NIH National Center for Research Resources 
may wish to identify the GCRC as a resource for conducting the proposed 
research.   In such a case, a letter of agreement from either the GCRC 
program director or principal investigator should be included with the 
application.  

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.  The anticipated award date is September 30, 2002.

FUNDS AVAILABLE

For fiscal year 2002, the NIDDK intends to commit approximately $2 
million and the NHLBI intends to commit approximately $500,000 to fund 
4-10 grants in response to this RFA. An applicant may request a project 
period of up to 5 years for R01s and up to two years for R21s. Because 
the nature and scope of the research proposed may vary, it is 
anticipated that the size of each award will also vary.  Although the 
financial plans of the NIDDK and the NHLBI 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.  

RESEARCH OBJECTIVES

Background

In recent years, the advent of highly active anti-retroviral therapy 
(HAART) has dramatically improved the survival of patients with HIV 
infection. Despite the clear benefits of the new anti-retroviral 
therapies, HAART has been associated with a variety of metabolic 
complications -- including dyslipidemia, insulin resistance and 
abnormal distribution of body fat (lipodystrophy). These metabolic 
abnormalities represent major risk factors for the development of other 
serious diseases, such as diabetes and cardiovascular disease.  Even 
more recently, reports of clinically significant osteopenia have been 
emerging in HAART-treated patients.

Initial attention focused on protease inhibitors as the cause of these 
metabolic complications; however, the protease inhibitors are 
frequently used in combination with nucleoside and non-nucleoside 
reverse transcriptase inhibitors, making it difficult to pinpoint the 
“offending” agent. In addition, metabolic complications have emerged in 
patients who are not being treated with protease inhibitors.

Lipodystrophy, characterized by increased deposition of fat 
(lipohypertrophy) in the abdomen and trunk, and/or loss of fat 
(lipoatrophy) in the face and extremities, appears to occur commonly in 
patients on HAART. Currently, it is not clear whether abdominal 
lipohypertrophy is simply accompanied by peripheral lipoatrophy, or 
whether these changes constitute two separate entities. The 
lipodystrophic changes have been a particular issue for many affected 
individuals. In addition to concerns over potential long-term health 
implications of these body composition changes, distress over these 
often disfiguring changes has caused some patients to stop taking anti-
viral medications.

 HAART has also been increasingly associated with hyperinsulinemia and 
impaired glucose tolerance; to date, frank diabetes has been reportedly 
less frequently. However, concern about eventual progression to 
diabetes is real, particularly in those patients who also have 
accumulation of abdominal (particularly visceral) fat. 

Patients receiving HAART frequently develop hypertriglyceridemia, which 
can be extreme, as well as hypercholesterolemia. Elevated total and 
LDL-cholesterol levels, which occur following the institution of HAART, 
may be superimposed on low HDL-cholesterol levels, which have been 
described in HIV-infected patients prior to initiating any therapy. In 
non-HIV-infected individuals, co-existence of dyslipidemia and insulin 
resistance/diabetes confers additive risk for the development of 
atherosclerotic heart disease, making these HAART-associated side 
effects a serious potential public health concern. 

Recently, an increasing number of case reports, as well as several 
small clinical studies, have documented the development of osteoporosis 
and osteopenia, often associated with fractures, in patients on HAART.

Large epidemiologic studies are currently ongoing to better describe 
the metabolic changes associated with HAART and understand whether 
particular drugs, or classes of drugs, are the etiologic agent(s) of 
these changes. In addition, a large research effort is aimed at 
understanding the molecular mechanism(s) by which anti-retroviral drugs 
might lead to these metabolic abnormalities. A long-term goal of such 
research might be the development of new, highly active anti-HIV drugs 
that lack these adverse metabolic consequences. 

In the meantime, it is essential to develop strategies to improve lipid 
levels, insulin sensitivity and body fat distribution, and to minimize 
bone loss, in order to enhance patient compliance and decrease the risk 
for future disease. The safety and efficacy of lipid lowering drugs or 
diabetes medications have not been extensively studied in patients 
infected with HIV and/or receiving HAART. It is not known whether 
adverse drug interactions might affect efficacy and safety, or whether 
the underlying infection with HIV (or other opportunistic) infections, 
might affect treatment success. For example, the metabolism and 
clearance of some statins may be affected by concomitant use of 
protease inhibitors. Some available drugs (e.g., metformin, 
thiazolidinediones) will be contraindicated because of co-existing 
renal or liver disease in patients with AIDS. In addition, attention 
must be paid to other risk factors for diabetes and cardiovascular 
disease, such as smoking, physical inactivity, diet and hypertension.

Objectives and Scope

This RFA solicits clinical studies to 1) test the efficacy, in patients 
infected with HIV, of agents currently approved for the treatment of 
dyslipidemia, insulin resistance or diabetes, and 
osteoporosis/osteopenia, and 2) develop and test novel treatment 
approaches to the metabolic consequences of anti-HIV therapy, including 
lipodystrophy.

Appropriate topics for investigation under this RFA would include but 
are not limited to:

o Studies to examine the effects of currently available 
pharmacotherapies for the treatment of insulin resistance or diabetes, 
hypercholesterolemia and/or hypertriglyceridemia, and osteoporosis in 
the metabolic syndromes associated with HAART;

o Studies to identify potential drug interactions between HAART and 
current pharmacotherapies for the treatment of insulin resistance or 
diabetes, hypercholesterolemia and/or hypertriglyceridemia, and 
osteoporosis;

o Studies to test agents that affect fat deposition and/or metabolism 
for the treatment of HAART-associated lipodystrophy;

o Studies to identify and test new therapies to prevent or reverse the 
metabolic complications associated with HAART; 

o Studies to evaluate the efficacy of diet and exercise alone, or in 
combination with medication, in reversing dyslipidemia and insulin 
resistance/diabetes in patients on HAART;

o Studies to evaluate whether switching anti-HIV drugs is an effective 
approach to the treatment of metabolic changes.

SPECIAL REQUIREMENTS

Upon initiation of this program, the NIDDK and the NHLBI plan to hold 
annual meetings to encourage exchange of information among 
investigators who participate in this program. A goal of these meetings 
would be to foster collaborative efforts among program grantees, 
including the sharing of resources to enhance productivity. Applicants 
must budget for travel funds that will allow principal investigators 
and other key research scientists to participate in these one-day 
meetings in Bethesda, Maryland. Applicants should also include a 
statement in their applications indicating their willingness to 
participate in such meetings.

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 sub-populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are 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 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 may also 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.

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.  This policy announcement is found 
in the NIH Guide for Grants and Contracts Announcement dated June 5, 
2000, at the following website:  
http://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:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA 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.

LETTER OF INTENT 

Prospective applicants are asked to submit, by February 21, 2002, 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 NIDDK staff to estimate the potential review 
workload and plan the review.

The letter of intent is to be sent to:

Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 
5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used 
in applying for these grants. This version of PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using 
the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, 
however, the NIH will return applications that are not submitted on the 
5/2001 version.  For further assistance contact GrantsInfo, Telephone 
301/435-0714, Email: GrantsInfo@nih.gov.

STEP-BY-STEP 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 NIH staff.  The research grant 
application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in 
applying for these grants, with the modifications noted below.  
Applicants are permitted, however, to use the 4/1998 revision of the 
PHS 398 for scheduled application receipt dates until January 9, 2002.  
If you are preparing an application using the 4/1998 version, please 
refer to the step-by-step instructions for Modular Grants available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

The RFA label available in the PHS 398 (rev. 5/2001) application form 
(http://grants.nih.gov/grants/funding/phs398/labels.pdf) 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.

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 time of submission, two additional copies of the application must be 
sent to:

Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)

Applications must be received by the application receipt date listed in 
the heading of the RFA.  If an application is received after that date, 
it will be returned to the applicant without review. Supplemental 
documents containing significant revision or additions will not be 
accepted, unless applicants are notified by the Scientific Review 
Administrator.  

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 previously 
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 NIDDK.  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 NIDDK in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will receive a written critique and undergo a process in 
which only those applications deemed to have the highest scientific 
merit, generally the top half of the applications under review, will be 
discussed, assigned a priority score, and receive a second level review 
by the NIDDK and the NHLBI Advisory Councils.

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 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 to the 
proposed research.

o The adequacy of the proposed protection of humans, animals, or the 
environment, to the extent that they may be adversely affected by the 
project proposed in the application.

o Availability of special opportunities for furthering research 
programs through the use of unusual talent resources, populations, or 
environmental conditions in other countries which are not readily 
available in the United States or which provide augmentation of 
existing U.S. resources.

Schedule

Letter of Intent Receipt Date:    February 21, 2002
Application Receipt Date:         March 21, 2002
Peer Review Date:                 July 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002

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:

Barbara Linder, M.D, Ph.D. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 699 MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
E-mail:  bl99n@nih.gov

Deborah Applebaum-Bowden, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10184, MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550
FAX: 301/480-2858
Email: da40q@nih.gov

Direct inquiries regarding fiscal matters to:

Charlette Kenley
Division of Extramural Activities
Grants Management Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 723 MSC 5456
Bethesda, MD 20892-5456
Telephone:  (301) 594-8847 
FAX:  (301) 480-3504
E-mail: ck128k@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847 and 93.837. Awards are 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 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 and contract 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.


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.