COMPLICATIONS OF ANTIRETROVIRAL THERAPY

RELEASE DATE:  September 25, 2002

PA NUMBER: PA-02-172 (see NOT-AI-04-015 and NOT-AI-04-011)

EXPIRATION DATE:  January 3, 2005, unless reissued.

National Institute of Allergy and Infectious Diseases (NIAID)
 (http://www.niaid.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)
National Institute on Drug Abuse (NIDA)
 (http://www.nida.nih.gov)
National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The intent of this program announcement is to encourage research in the 
fundamental biochemical or pathogenic mechanisms of the metabolic 
complications associated with HIV-disease and antiretroviral therapy.

RESEARCH OBJECTIVES

With the advent of potent HIV therapies, the complications associated with 
HIV infection have expanded to include changes in metabolism.  Altered body 
fat distribution or lipodystrophy, insulin resistance, elevated triglycerides 
and cholesterol levels, bone demineralization, and elevated lactate levels 
have been reported in clinical trials and in observational databases.  These 
changes in metabolism may be related to underlying HIV-disease or may be a 
consequence of treatment with antiretroviral agents.  The pathogenic 
mechanisms, including the role of mitochondrial dysfunction, are unknown or 
poorly understood. In addition, the long-term consequences of these metabolic 
changes, including increased risk of cardiovascular disease and central 
nervous system (CNS)complications, have not been determined. However, the 
immediate effects on the quality of life may be substantial.  Although many 
investigators are working to define the syndrome and to assess the short and 
long term consequences, systematic studies examining potential biochemical 
and physiological mechanisms, and genetic contributions are needed.  This 
initiative will encourage researchers to identify those mechanisms as they 
relate to single agents, classes of agents and the combinations of 
antiretroviral agents, as well as to HIV-infection.  Further understanding of 
the fundamental causes of the metabolic complications are likely to improve 
medical management with the existing agents and potentially may lead to the 
design of agents or treatment strategies less likely to produce such 
complications.

Research topics appropriate for this PA include but are not limited to the 
following areas:

o The molecular basis for lipodystrophy, insulin resistance and osteopenia, 
abnormal lipid metabolism, elevated lactate levels
o The relationship between immunologic markers and the metabolic 
complications
o The relationship(s) between mitochondrial function and DNA content of 
tissues affected by the metabolic complications
o The significance of histological and biochemical changes occurring within 
organ tissues affected by the metabolic complication. (i.e. liver, pancreas, 
adipose tissue,bone, and the nervous system)
o Potential genetic predisposition to metabolic complications
o Metabolic, endocrine, and gastrointestinal (MEG) disorders in drug
abusers with complications such as lipid dystrophy, hyperglycemia, insulin 
resistance, pharmacokinetic and pharmacodynamic interactions between 
antiretroviral agents and therapeutics for the treatment of drug addiction

MECHANISM OF SUPPORT 

This PA will use the NIH research project grant (R01) award mechanism and the 
exploratory/developmental research projects grant (R21) award mechanism. 
NIAID,NIDDK, NIDA, and NIMH use R21 grants to provide short-duration support 
for preliminary studies of a highly speculative nature, which are expected to 
yield, within this time frame, sufficient information upon which to base a 
well-planned and rigorous series of further investigations.

R21 grants are non-renewable and limited to 2 years for up to $150,000 in 
direct costs per year. A sound rationale and a well-designed research plan 
with limited preliminary data are required for a R21. The R01 grant supports 
more advanced projects.  As an applicant, you will be solely responsible for 
planning, directing, and executing the proposed project.  

This PA uses just-in-time concepts.  It also uses the modular and non-modular 
budgeting format. (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).   Specifically, if 
you are submitting an R01 application with direct costs in each year of 
$250,000 or less, use the modular format.  Otherwise, follow the standard PHS 
398 application instructions for detailed budgets.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
	
o For-profit or non-profit organization 
o Public or private institution, such as universities, colleges, hospitals, 
and laboratories 
o Unit of State and local governments
o Eligible agency of the Federal government  
o Domestic or foreign
o Faith-based or community based organization 

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

Clinical Studies or Trials

When clinical studies or trials are a component of the research proposed, 
NIAID policy requires that studies be monitored commensurate with the degree 
of potential risk to study subjects and the complexity of the study. AN 
UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is 
available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The 
full policy, including terms and conditions of award, is available at: 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.
  
WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA 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:

Barbara Laughon, Ph.D. 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
Room Number  5110, MSC-7624
6700-B Rockledge Drive
Bethesda, MD 20892-7624 
Telephone: (301) 402-2304 
FAX: (301) 402-3171 
Email: blaughon@niaid.nih.gov

Barbara Linder, M.D., Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases 
National Institute of Diabetes and Digestive and Kidney Diseases
Room Number699, MSC-5460
6707 Democracy Boulevard
Bethesda, MD 20892-5460
Telephone: (301) 594-0021 
FAX: (301) 480-3503 
Email: linderb@extra.niddk.nih.gov

Jag H. Khalsa, Ph.D.
Center on AIDS & Other Medical 
  Consequences of Drug Abuse (CAMCODA)
National Institute on Drug Abuse, NIH
6001 Executive Blvd., Room 5098, MSC 9593
Bethesda, MD 20892-5953
Telephone: (301) 443-1801
Fax: (301) 443-4100, or (301) 594-6566
Email: jk98p@nih.gov
Jeymohan Joseph, Ph.D. 
Center for Mental Health Research on AIDS 
National Institute of Mental Health 
6001 Executive Boulevard, Room 6202, MSC 9619 
Bethesda, MD 20892-9619 
Telephone: (301) 443-6100 
FAX: (301) 443-9719 
Email: jjeymoha@mail.nih.gov 

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

Victoria Connors
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room Number  2121, MSC- 7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-6579 
FAX: (301)  480-3780 
Email: vp14v@nih.gov

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

Gary Fleming, J.D., M.A.
Grants Management Branch
Office of Planning and Resource Management
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301) 443-6710
FAX :  (301) 594-6847
E-mail: gf6s@nih.gov

Brian Albertini 
Grants Management Branch 
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605 
Bethesda, MD 20892-9605
Telephone: (301) 443-0004 
FAX: (301) 443-0219 
Email: albertinib2@mail.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 
http://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.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

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 http://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 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of the NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
	
Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study, 

Obtain agreement from the IC staff that the IC will accept your application 
for consideration for award, and, 
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

Applicants for the R21 grant mechanism may request up to $150,000 (6- $25,000 
modules) direct cost per year and support may not exceed two years.  This 
mechanism provides short-duration support for preliminary studies of a highly 
speculative nature, which are expected to yield sufficient information upon 
which to base a well-planned and rigorous series of further investigations.  
The R21 grants are non-renewable and competitive continuation of projects 
developed under this grant mechanism will be through the R01 research grant 
mechanism.  Funds and time requested should be appropriate for the research 
proposed.

SUPPLEMENTAL INSTRUCTIONS FOR R21 APPLICATIONS: To apply, please follow NIH 
guidelines for submission of an R21 application as listed below: 
1. The description (abstract) must include a brief explanation of the 
proposed activity, and how it is consistent with the exploratory/development 
nature of the R21 mechanism as described in this notice. 
2. Although preliminary data are neither expected nor required for an R21 
application, they may be included. 
3. Sections a-d of the Research Plan may not exceed 10 pages, including 
tables and figures. 
4. Appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan. Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution. The following materials may be included in 
the appendix: 
o Up to five publications, including manuscripts (submitted or accepted for 
publication), abstracts, patents, or other printed materials directly 
relevant to the project. These may be stapled as sets. 
o Surveys, questionnaires, data collection instruments, and clinical 
protocols. These may be stapled as sets. 
o Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included within 
the 10-page limit of items a-d of the research plan. 
Include five collated sets of all appendix material, in the same package with 
the application, following all copies of the application. Identify each item 
with the name of the principal investigator.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, five exact single-sided copies of 
the original application, and five collated sets of appendix materials in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Suite 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  
The CSR will not accept any application in response to this PA 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 a substantial revision of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned to Institutes on the 
basis of established PHS referral guidelines.  An appropriate scientific 
review group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for 
scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by an appropriate 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:

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.

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)

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

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program 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: http://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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete 
copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.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 
http://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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

COMPLIANCE WITH THE NIH GUIDELINES FOR RESEARCH INVOLVING RECOMBINANT 
DNA MOLECULES:  Investigators and institutions are reminded that adherence to 
NIH Guidelines for Research Involving Recombinant DNA Molecules is mandatory.  
For research conducted at or sponsored by an entity receiving any NIH support 
for recombinant DNA research.  These guidelines stipulate biosafety and 
containment measures for recombinant DNA research, delineate critical ethical 
principles, and outline key safety reporting requirements for human gene 
transfer research.  More information can be found at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-052.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

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 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 PA 
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 Catalogue of 
Federal Domestic Assistance in the following citations: No. 93.855, 
Immunology, Allergy, and Transplantation Research, No. 93.856, Microbiology 
and Infectious Diseases Research and No. 93.847, Diabetes, Endocrinology and 
Metabolic Diseases. Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The NIH Grants Policy Statement is available at 
http://grants.nih.gov/grants/policy/policy.htm.  This document includes 
general information about the grant application and review process, 
information on the terms and conditions that apply to NIH Grants and 
cooperative agreements, and a listing of pertinent offices and officials at 
the NIH.

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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