Full Text PA-95-026


NIH GUIDE, Volume 24, Number 4, February 3, 1995

PA NUMBER:  PA-95-026

P.T. 34

  Drugs/Drug Abuse 
  Viral Studies (Virology) 

National Institute on Drug Abuse


The purpose of this program announcement is to stimulate research on
the biological and behavioral factors influencing HIV disease
progression in populations of drug users both in and out of drug
abuse treatment, in order to facilitate prevention and treatment
efforts.  Increased understanding of viral, host, and environmental
factors, and their role in vulnerability and resistance to infection
and differential rates of disease progression is sought, as is
identification of additional HIV-related outcomes, assessment of the
impact of available HIV-related interventions on disease course, and
further investigation of the disease in women, adolescents, and


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This program
announcement, HIV Disease Progression in Drug Users, is related to
the priority area of alcohol and other drugs.  Potential applicants
may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).


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.
Foreign institutions are eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.


This program announcement will use the National Institutes of Health
(NIH) individual research project grant (R01), interactive research
project grant (IRPG), small grant (R03), and FIRST (R29) award.
There are special requirements for R29 and R03 mechanisms.  If an
applicant intends to apply utilizing either of these mechanisms, they
should contact the program person listed under INQUIRIES for further
information.  For further information on the IRPG, refer to PA-94-
086, NIH Guide for Grants and Contracts, Vol. 23, No. 28, July 29,
1994.  Because the nature and scope of the research proposed in
response to this program announcement may vary, it is anticipated
that the size of an award will also vary.



Research studies are sought that investigate HIV disease progression
in populations of drug users, with emphasis on integration of
biological and behavioral models in order to enhance understanding of
the unique aspects of the disease in those with a history of active
or past drug use.  The multiple foci of this research program
include:  (1) further characterization of factors determining
vulnerability and resistance to infection and the natural history of
early infection; (2) determination of mechanisms of transmission and
infection, including aspects of the disease that are specific to
women with a history of drug use and/or drug-using sexual partners,
and to pediatric populations with dual drug and HIV exposure; (3)
identification of additional HIV-related outcomes and risk factors
for those outcomes; (4) the impact of interventions on infection, on
the frequency and severity of outcomes, and on progression and
survival; and (5) investigation of the pathogenesis of infection and
disease, addressing virologic, immunologic, genetic, and
environmental factors that may affect differential progression and
survival.  Collaborative efforts and studies associated with well-
characterized samples or cohorts of drug users are encouraged.  Both
generation of new data, including laboratory studies of immune and
virologic parameters, and analyses of existing data and/or biologic
repository specimens will be considered for support.  Studies that
correlate biological data with stage of disease and drug and sexual
behavior are strongly encouraged, as are ancillary studies or
selected sub-studies within larger longitudinal designs.  Where
appropriate, comparison studies in HIV-uninfected drug users are


Since 1986, NIDA has supported a program of longitudinal research on
the natural history of HIV in drug users.  The prospective design has
provided long-term serial follow-up of seroprevalent and seroincident
cohorts to defined outcomes, providing multiple data points for
studies of biologic and behavioral factors related to infection and
subsequent disease progression.  Research in well-characterized
incident and prevalent cohorts has identified many aspects of HIV
infection and disease in drug users, including factors associated
with seroconversion, competing causes of morbidity and mortality,
HIV-related outcomes, markers and prognostic indicators of disease
development, and differential rates of disease progression and
survival.  Further characterization of the disease in drug users in
longitudinal studies provides opportunities for enhanced
multidimensional approaches to research on infection and disease
progression.  Given the high background prevalence of infectious
diseases and abnormalities in immune parameters among drug users,
longitudinal studies in HIV-uninfected drug users have demonstrated
utility in discriminating those factors related to drug use from
those related to HIV infection.  The interval collection of biologic
specimens for assay and repository in the longitudinal context
provides opportunities for selected substudies of HIV pathogenesis.
Additionally, collaborative and meta-analytic efforts utilizing
serial data from multiple cohort studies are particularly productive
in characterizing the many factors affecting disease progression.

Program Description

Examples of areas of research interest that examine the question of
drug use and HIV disease progression include, but are not limited to,
the following.

o  Research on host and viral factors affecting vulnerability and
resistance to infection and the natural history of early infection
during the period when infection is established; the relationship of
route of infection and viral and host factors to establishment of
infection and subsequent disease course; further characterization of
the incubation period and differential rates of disease progression
in studies that link behavioral, immunologic, and virologic factors.

o  Research on the role of drugs in maternal-infant transmission,
e.g., the impact of repeated drug injection on viral load, the impact
of drugs on the placenta; the consequences of dual exposure to HIV
and drugs of abuse on the development of the central nervous system
and the immune system; factors associated with differential rates of
progression and survival in infants; the impact of antiviral
treatment protocols on maternal transmission and disease outcomes in
dually exposed infants.

o  Research that elucidates factors related to differential rates of
progression in drug abusing populations, including behavioral,
genetic, virologic, immunologic and host factors; the identification
of distinct trajectories of progression, including associations among
immunologic, virologic and clinical markers and predictors of disease
course, e.g., infection without immunologic progression, stable
clinical state with prolonged immunosuppression.

o  Research on co-factors for infection and HIV disease progression,
including the pathogenesis of HIV-related malignancies, opportunistic
infections and other diseases associated with drug abuse.

o  Identification of additional HIV-related outcomes, associated
behavioral and biologic factors and their relationship to progression
and survival; studies of the natural history and pathogenesis of
diseases prevalent among drug users, such as hepatitis, tuberculosis,
and other sexually transmitted diseases and the impact of these
diseases on HIV disease course.

o  Characterization of the clinical progression of HIV in the central
nervous system; research on the development of HIV-related neurologic
disease; the impact of drug use and related co-morbid
neuropsychiatric conditions prevalent in drug users on disease
course; studies of clinical, immunologic, and virologic factors that
characterize infection and disease in the brain as distinct from
other organs, and the influence of active drug use on those factors;
studies of the influence of drug use on migration of HIV across the
blood-brain barrier and on establishment of infection and subsequent
disease development in the brain.

o  Immunologic studies that further characterize immune function,
including mucosal immunity, in the context of active drug use and
other co-morbid medical conditions; trajectories of CD4 and CD8 and
other immune parameters and their role in progressive

o  Research that assesses the consequences of repeated inoculation of
virus through drug injection and/or sexual exposure on clinical
course, immune parameters, and on viral factors such as viral
phenotype, genotype and load, and the evolution of viral strain
heterogeneity; the impact of repeated inoculation at different stages
of progression of HIV disease.

o  Studies of interventions and treatments that address long-term
effectiveness (morbidity, clinical disease progression and survival)
in the context of drug use and/or drug abuse treatment; interactions
of licit and illicit drugs with antivirals and the development of
toxicities; the effectiveness of prophylaxis for specific HIV-related
infectious diseases in reducing the incidence of other infections
prevalent among drug users; the impact of active drug use on
adherence to medical treatment protocols and on long-term treatment
effectiveness and the development of viral resistance.

o  Studies of strategies to increase adherence to medical regimens
and their effectiveness in influencing the course of HIV disease and
its associated illnesses.

o  Studies of direct and indirect effects of the lifestyles of drug-
abusing populations on HIV disease course, e.g., poverty, nutrition,
injury, stress, homelessness; studies of indirect effects on
progression via factors affecting access to and utilization of health
services, including issues of financing and linking drug abuse
treatment, acute and primary medical care, mental health care and
public health interventions, e.g., STD and TB screening.

o  Research to develop biostatistical methodologies to enhance the
analysis and interpretation of longitudinal data and the integration
of biological and behavioral factors affecting disease progression;
development of data-driven statistical models to project the effects
of interventions and treatment on disease progression.

All applications should address issues of project feasibility and
collaborative arrangements, study design, sampling procedures,
implementation of interventions, instrumentation and measurement,
data collection, quality control, laboratory assay protocols,
tracking of clients, follow-up, and data analysis, as appropriate.


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted at the AIDS expedited
application deadlines as indicated in the application kit.
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/710-0267.  The title and number of the program announcement must
be typed in Section 2a on the face page of the application.

FIRST applications must include at least three sealed letters of
reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without

Applicants from institutions that 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.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included in
the application.

The completed original application and five legible copies must be
sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**


Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications will be reviewed
for scientific and technical merit in accordance with the standard
NIH peer review procedures.  Following scientific-technical review,
the applications will receive a second-level review by the
appropriate national advisory council.  The small grant (R03) does
not receive second-level review.

Applications that are complete and responsive to the program
announcement will be evaluated for scientific and technical merit by
an appropriate peer 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

Review Criteria

The review criteria are:

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

The initial review group will also examine the provisions for the
protection of human and animal subjects, and safety of the research


Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, availability of funds, and program priority.


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

Direct inquiries regarding programmatic issues to:

Katherine Davenny, M.P.H.
Division of Clinical Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 11A-33
Rockville, MD  20857
Telephone:  (301) 443-1801
FAX:  (301) 443-2317
Email:  kdavenny@aoada.ssw.dhhs.gov

Direct inquiries regarding fiscal matters to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
Email:  gfleming@aoada2.ssw.dhhs.gov

Applications in the area of perinatal or pediatric HIV disease will
be considered for co-funding with the National Institute of Child
Health and Human Development (NICHD).  Direct inquiries to:

Ann Willoughby, M.D.
Pediatrics, Adolescents, and Maternal AIDS Branch
National Institute of Child Health and Human Development 6120
Executive Boulevard, Room 4B11J
Rockville, MD  20892-7510
Telephone:  (310) 496-7339
FAX:  (301) 496-8678
Email:  aw55g@nih.gov


This program is described in the Catalog of Federal Domestic
Assistance No. 93.279.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78- 410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  This
is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.


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