This Program Announcement expires on  July 1, 2004, unless reissued.

LIVER AND PANCREATIC DISEASE IN HIV INFECTION

Release Date:  July 17, 2001

PA NUMBER:  PA-01-117

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)
National Institute of  Allergy and Infectious Diseases
 (http://www.niaid.nih.gov)

THIS PA 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, Digestive and Kidney Diseases (NIDDK) and 
the National Institute of Allergy and Infectious Diseases (NIAID) invite 
clinical and basic research applications that focus on the pathogenesis and 
therapeutics of the liver and pancreatic disease associated with coinfections 
that occur in patients with HIV infection or the metabolic complications 
associated with treatment of HIV infection. The coinfections targeted by this 
Program Announcement (PA) specifically include hepatitis B and hepatitis C, 
which are frequent causes of end-stage liver disease, a leading cause of death 
in HIV infected patients.  Metabolic complications, involving the liver and 
pancreas, associated with the treatment of HIV infection include: hepatic drug 
toxicity, hepatic lipid metabolism, nonalcoholic steatohepatitis (NASH) and 
pancreatitis, which are all important causes of morbidity in patients with HIV 
infection.  The proposed studies should advance our understanding of the 
pathogenesis of liver and pancreatic disease in patients with HIV and/or 
metabolic complications of therapy.  These advances should lead to enhanced 
medical management of individuals infected with HIV. 

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 Program Announcement (PA), Title of 
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/.
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 PA will use the National Institutes of Health (NIH) Individual Research 
Project Grant (R01) as well as the Exploratory/Developmental 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 in response to this PA may not exceed five 
years.
Applicants for the R21 grant mechanisms may request up to $ 150,000 direct 
costs 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 competing 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.

RESEARCH OBJECTIVES
Background

The current initiative specifically targets hepatic and pancreatic 
comorbidities in the context of HIV infection, and metabolic complications of 
antiretroviral treatment in support of basic and clinical research that 
addresses the significant emerging clinical issues of disease progression in 
patients with HIV infection. 

Highly active antiretroviral therapy (HAART) has slowed the progression of HIV 
disease and decreased the rate of HIV-associated mortality. In the context of 
enhanced longevity for HIV patients, other comorbidities, such as chronic 
liver disease and pancreatitis, can assume greater importance in the medical 
management of patients. Based on shared routes of transmission, HBV and HCV 
infection are common in HIV-infected patients. HIV infection has a significant 
effect on the natural history of HBV infection with coinfected individuals 
more likely experience severe liver disease. Individuals treated with 
lamivudine as part of their antiretroviral treatment more frequently fail 
treatment, resulting in the emergence of drug resistant strains of HBV. 
Several studies have also documented that HIV diseases modifies the natural 
history of chronic HCV infection leading to an accelerated course of 
progression to end-stage liver disease and death. The accelerated course to 
end-stage liver disease has been suggested to be reduced from the 2-4 decade 
time-frame for HCV mono-infection to as little as 5-6 years in HCV/HIV 
coinfected patients. The result of the common occurrence of hepatitis and HIV 
coinfection and accelerated disease progression is the report that end-stage 
liver disease is now the leading cause of death in hospitalized HIV-infected 
patients.

The etiology and pathogenesis of enhanced progression to end-stage liver 
disease in HIV coinfected patients is unknown.  Recent data have shown that 
hepatitis coinfection results in enhanced liver disease in individuals 
infected with HIV through enhanced severity of fibrosis, a higher frequency of 
cirrhosis and end-stage liver disease as well as increased deaths due to liver 
disease. The role of HCV quasispecies, the effects of immune deficiency on the 
course of hepatitis C, hepatotoxicity due to antiretroviral treatment, chronic 
HBV infection, immune restoration and HBV infection, and development of 
nonalcoholic steatohepatitis (NASH) as a result of lipodystrophy have all been 
hypothesized to play a role in the enhanced liver disease seen in co-infected 
individuals.  Additional research is need to identify the mechanism(s) of 
pathogenesis and to identify therapeutic targets for treatment.

This initiative will support basic and clinical research in HIV co-infection 
and metabolic disease related to antiretroviral treatment. Areas of interest 
include but are not limited to:

o The elucidation of biological mechanism(s) that promote enhanced 
progression of liver disease in HIV-infected patients;
o A further elucidation of drug-induced hepatotoxicity associated with 
anti-retroviral treatment regimens;
o The identification of therapeutic targets and/or novel therapies for the 
treatment of liver disease in HIV-infected patients;
o The elucidation of synergy between HIV and HCV, resulting in enhanced 
liver disease;
o Enhanced knowledge of antiviral treatment failures of HBV/HIV 
coinfection and the emergence of HBV drug-resistant strains; 
o Identify underlying liver disease, such as NASH, in combination with HIV 
infection and antiretroviral treatment, that progresses to end-stage 
liver disease;  
o Therapeutics development for the enhanced medical management of patients 
with HBV/HIV or HCV/HIV coinfection or metabolic abnormalities due to 
antiretroviral treatment;
o Altered hepatic lipid metabolism due to antiretroviral treatment;
o HIV-associated pancreatitis and risk factors- hypertriglyceridemia, 
obesity and gallstones;
o The impact of liver transplantation on disease progression in select 
patients with co-infections with Hepatitis B or Hepatitis C.

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 also may 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.

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.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e., as plans for the study are being developed. Furthermore, the application 
must obtain agreement from the IC staff that the IC will accept the 
application for consideration for award. Finally, the applicant must identify, 
in a cover letter sent with the application, the staff member and Institute or 
Center who agreed to accept assignment of the application.
 
This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment. Refer to the NIH Guide 
for Grants and Contracts, March 20, 1998 at  
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

All application instructions outlined in the PHS 398 application kit are to be 
followed, with the following modifications for R21 applications:  

1.  R21 applications will use the “MODULAR GRANT” and “JUST-IN-TIME” concepts, 
with direct costs requested in $25,000 modules, up to the total direct costs 
limit of $150,000 per year. 

2. Although preliminary data are not required for an R21 application, they may 
be included.

3.  Sections a-d of the Research Plan of the R21 application may not exceed 15 
pages, including tables and figures.  

SPECIFIC 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.html is to be used in 
applying for these grants, with modular budget instructions beginning on page 
13 of the application instructions.  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 title and number of the program announcement 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 five 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical merit 
by an appropriate scientific review group convened in accordance with the 
standard NIH peer review procedures.  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 applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the appropriate national 
advisory council or board.

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 method? 
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.

AWARD CRITERIA

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

o Quality of the proposed project as determined by peer review
o availability of funds
o program priority

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Frank Hamilton, M.D., M.P.H. 
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
Building, Room Number
Bethesda, MD 20892
Telephone: (301) 594-8877
FAX: 301  480-8300
Email: fh14e@nih.gov

Thomas Kresina, Ph.D.
Therapeutics Research Program
Division of AIDS
National Institute of Allergy and Infectious Diseases
670OB Rockledge Drive , Room 5229
Bethesda, MARYLAND 20892-7624
Telephone (  301( 435-3762
FAX 301 (301) 402-3171
Email: tk13@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Donita Marconi
Grants Management Branch , Division of Extramural Activities
National Institute of Diabetes, Digestive , and Kidney Diseases 
Democracy 2, 6707 Democracy Boulevard , Room 710
Bethesda, MD 20892- 5450
Telephone: (301) 594-8860
FAX: (301) 480-3504
Email: dm150h@nih.gov


Ms. Linda Shaw
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2125 
6700 B Rockledge Drive MSC 7614
Bethesda, MD 20892-7614
Telephone : (301) 402- 6611
FAX: (301) 480-3780
Email:   ls15k@nih.gov
	
AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance No. 
93.856- Microbiology and Infectious Diseases Research, No. 93.855-Immunology, 
Allergy, and Transplantation Research, No. 93.121-Oral Diseases and Disorders 
Research.  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 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, and 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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