Full Text PA-97-070
 
UNDERSTANDING AND IMPROVING ANTIRETROVIRAL REGIMEN ADHERENCE
 
NIH GUIDE, Volume 26, Number 21, June 20, 1997
 
PA NUMBER:  PA-97-070
 
P.T. 34

Keywords: 
  AIDS 
  Antivirals 

 
National Institute of Mental Health
National Institute of Nursing Research
 
PURPOSE
 
The introduction of potential new drugs for the treatment of HIV, and
the creation of potent combination medication regimens have restored
a needed sense of optimism and progress in the struggle against AIDS.
The efficacy of these combination regimens is unprecedented in HIV
medicine. Treatment with combination therapies can result in
inhibition of viral replication and reduction of virus load to a
point where viral particles are undetectable in the blood of infected
individuals. Significant and sustained suppression of HIV replication
has been associated with improved clinical outcome.
 
Research has shown that the benefits from combination medication
regimens can be sustained only if rigorous adherence to precise
dosing schedules and other dosing requirements is maintained.
Interruptions in treatment allow the virus to resume rapid
replication, providing the opportunity to generate resistant mutant
strains.  The rigors of treatment adherence are multiple.
Understanding the issues influencing adherence to antiretroviral
medication regimens is of crucial importance, for the individuals
receiving treatment, for those providing treatment, and for public
and private health officials who are responsible for making treatment
available.  Of equal importance are mechanisms of maintaining
adherence to these life-saving drugs.
 
This Program Announcement is sponsored by the National Institute of
Mental Health and the National Institute of Nursing Research to
stimulate investigator initiated research to increase understanding
of the issues influencing adherence and nonadherence, and to identify
methods to improve and assure adherence and compliance to drug
therapy regimens.
 
HEALTHY PEOPLE 2000
 
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 PA,
Understanding and Improving Patients~ Adherence to Antiretroviral
Medication Regimens, is related to the priority area of mental health
and mental disorders.  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 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Eligibility requirements for different funding mechanisms vary.
Applicants are advised to contact program staff listed under
INQUIRIES for additional information and specific application
procedures.
 
Applications may be submitted by foreign and domestic, 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 not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards, research career awards
(K-series) or fellowships (F-series).   Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
The mechanisms available for support by the NIMH and the NINR are:
research project grants (R01), FIRST awards (R29), Mentored Research
Scientist Development Awards (K01), and Individual NRSA Predoctoral
and Postdoctoral Fellowship Awards (F31, F32).
 
FIRST awards, K awards and F awards have special eligibility
requirements (such as citizenship requirements for K and F awards),
application formats, and review criteria.  Refer to the individual
program announcements which describe these grant mechanisms for
further important information.  These announcements are available on
the NIH Website at WWW.NIH.GOV/GRANTS.  In addition, other Institute-
specific mechanisms may be used for research support addressing
issues outlined in this Program Announcement.  Therefore, applicants
are strongly encouraged to consult with program staff listed under
INQUIRIES and to obtain the appropriate additional announcements for
those grant mechanisms.
 
RESEARCH OBJECTIVES
 
Antiretroviral therapy directed against human immunodeficiency virus
(HIV) is just over 10 years old.  Zidovudine (AZT), approved by the
Food and Drug Administration in early 1987, as well as several other
nucleoside analogues subsequently identified, inhibit reverse
transcriptase and have beneficial effects to inhibit HIV replication.
However, these benefits are limited due to their lack of a durable
antiviral effects and the development of viral resistance. The
introduction within the past 2 years of a new category of
medications, protease inhibitors, and the creation of potent
medication regimens that combine these new and old antiretroviral
drugs have restored a needed sense of optimism and progress in the
struggle against AIDS.  The efficacy of these combination regimens is
unprecedented in HIV medicine. Treatment with protease inhibitors and
other anti-HIV drugs can inhibit virus replication and reduce virus
load to undetectable levels. Significant and sustained suppression of
HIV replication is  associated with improved clinical outcomes.
 
The development of drug-resistant HIV strains can preempt the benefit
of a prescribed treatment protocol.  Research has shown that HIV-
infected persons can benefit from combination medication regimens of
nucleoside analogues and protease inhibitors only if they adhere
rigorously to precise dosing schedules and other dosing requirements.
 Evidence currently indicates that once a person begins treatment
with protease inhibitors, it must continue uninterrupted for a
lifetime in order for it to be effective. Interruptions in treatment
allow the virus to resume its characteristic rapid replication,
providing the opportunity to generate resistant mutant strains no
longer responsive to available antiretroviral drugs. Widespread
transmission of resistant HIV strains is a serious public health
concern, which would threaten to defeat recent advances.
 
The rigors of treatment adherence are multiple.  It is difficult to
adhere to the uninterrupted daily dosing schedule of large numbers of
pills necessary to initiate and maintain treatment and prophylaxis of
HIV-related conditions, and to avoid the emergence of resistant
strains.  In addition, uncertainty remains concerning the development
of side effects, the possibility of drug interactions, and the
unclear long-term benefits and risks of these new treatments.  Added
to these rigors are the physical and emotional distress of having a
chronic disease, the continued daily stigma faced by people living
with HIV, the constant reminders of the fragility of confidentiality
guarantees, the inaccessibility or inadequacy of health care for a
large proportion of infected individuals, and the substance abuse and
poverty in the personal histories and communities of many infected
individuals.  In addition, patients who respond to treatment may find
themselves confronting complicated issues associated with a more
benign course of their disease. They may face re-entering a
professional life or resuming family relationships.  Some individuals
may have exhausted both their emotional and their financial
resources. Those who do not respond to the new medications or develop
side effects or resistance may feel bypassed and isolated.
 
In addition to concerns of individuals, the availability of protease
inhibitors also raises broader social issues.  For instance, protease
inhibitors are difficult to manufacture and combination therapies are
expensive.  Decisions about prescribing protease inhibitors must be
made with the goal of maximizing the possibility of success.
Clinicians will be increasingly required to make accurate predictions
of the likelihood of patients~ adherence to treatment protocols.  In
maintaining patients on these regimens, treatment professionals at
every level will be challenged to make ongoing assessments of
adherence and to work with patients to improve adherence. Negative
assessments of patients~ capacity to adhere or to learn to adhere to
these regimens will, in effect, result in denying them possibly life-
saving medications.  False-positive assessments of patients~ capacity
for adherence may lead to transmission of resistant HIV strains to
uninfected individuals, endangering the public health. Thus it can be
seen that ethical questions and public policy issues are closely
linked to research on adherence.
 
Examples of research that would be an appropriate response to this
Program Announcement include, but are not limited to:
 
o  research to develop and validate measurements of adherence to
medications, including self-reports, clinicians~ observations, and
pill counts;
 
o  research to understand how disease-related factors affect
adherence;
 
o  research to understand sociodemographic characteristics or other
patient-related factors that may contribute to adherence and
nonadherence, such as age, gender, ethnicity, level of education,
occupation, marital status, parental status, socioeconomic status,
religion, cultural beliefs about health, HIV/AIDS, and caregivers,
presence of serious and persistent mental illness such as
schizophrenia, history of childhood sexual abuse or other trauma;
 
o  research on the how the characteristics of medications and
components of medical regimens influence adherence, including adverse
side effects, frequent dosing, large numbers of pills per dose, high
cost, and regimens requiring significant lifestyle changes;
 
o  research to identify variables that are strongly associated with
adherence and nonadherence, such as psychopathology, alcohol and drug
abuse and dependence, and cognitive impairment;
 
o  research to develop and assess the usefulness of clinical profiles
of ~adherers~ and ~nonadherers~ based on patients~ characteristics;
 
o  research to understand how adherence and nonadherence to
medication regimens are correlated with adherence to other desired
behavioral changes, such as practicing safer sex or abstaining from
drug use;
 
o  research on the physician/caregiver-patient alliance and how these
relationships affect adherence to complicated medication regimens and
to identify the ~active ingredients~ of effective alliances;
 
o  research to understand patients~ confidentiality concerns as a
factor in adherence and nonadherence, and the threat to
confidentiality posed by protease inhibitors;
 
o  research on the effectiveness of improving adherence through
patient education using a variety of health-related informational
modules, a variety of modalities (including groups involving
families, friends, significant others), repetition of information,
and follow-up educational sessions, computers, etc.;
 
o  research on the effectiveness of various forms of peer support in
increasing adherence to antiretroviral medications;
 
o  research to determine the effectiveness of increasing patient
involvement in treatment decisions as a way of improving adherence;
 
o  research to understand individual characteristics that may
contribute to adherence and nonadherence to medication regimens, such
as personality traits (e.g., fearfulness, hostility,
conscientiousness), social attitudes, and self-esteem;
 
o  research on the effectiveness of staff training in patient
education in improving adherence;
 
o  research to understand how integrated service delivery systems
contribute to  effective patient adherence;
 
o  research on the effectiveness of various types of mental health
treatments and substance abuse treatments in improving adherence.
 
o  research to understand the role of cost in the decision to
prescribe protease inhibitors, the use of various resources to pay
for them, and the relationships between these factors and adherence.
 
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 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.
 
APPLICATION PROCEDURES
 
Applications for R01, R29, and K01 grants are to be submitted on the
grant application form PHS 398 (rev. 5/95) and will be accepted at
the AIDS-related application deadlines indicated in the application
kit.  The F31 and F32  applications are to be submitted on grant
application form PHS 416-1 (rev. 8/95) on the dates specified
therein.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910,
telephone (301) 435-0714; fax: (301) 480-0525; Email:
ASKNIH@ODROCK1.OD.NIH.GOV.  They are also available on the NIMH Home
Page.  The title and number of the program announcement must be typed
in Section 2 on the face page of the application.
 
Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.  Applications for F series
awards must include reference letters as noted in the application
kits.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight mail service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete 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 board, when
applicable.
 
Review Criteria for research grant applications (R01 and R29):
 
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 review, comments on the following aspects of the application
will be made 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
the assignment of the overall score.
 
(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, the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research will be reviewed.  Plans for the recruitment
and retention of subjects will also be evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications assigned to NIMH or NINR.  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
 
Inquiries are encouraged.  We welcome the opportunity to clarify any
issues or questions from potential applicants.
 
Direct inquiries regarding NIMH programmatic issues to:
 
Dianne Rausch, PhD
Office on AIDS
National Institute of Mental Health
Parklawn Building, Room 10-75
Rockville, MD  20857
Telephone:  (301) 443-6100
FAX:  (301) 443-7274
E-mail: dr89b@nih.gov
 
Direct inquiries regarding NINR programmatic issues to:
 
June R. Lunney, Ph.D., R.N.
Division of Extramural Activities
National Institute of Nursing Research
Building 45, Room 3AN-12
Bethesda, MD 20892-6300
Telephone: (301) 594-6908
FAX: (301) 480-8260
E-mail: jlunney@ep.ninr.nih.gov
 
Direct inquiries regarding NIMH fiscal matters to:
 
Diana S. Trunnell
Assistant Chief, Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov
 
Direct inquiries regarding NINR fiscal matters to:
 
Mr. Jeff Carow
Grants Management Officer
National Institute of Nursing Research
Building 45, Room 3AN-12
Bethesda, MD 20892-6300
Telephone: (301) 594-5974
FAX: (301) 480-8260
E-mail: jcarow@ep.ninr.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.242, 93.281 and 93.282 (NIMH), and 93.361 (NINR).
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 66, and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems Agency review.  Awards
will be administered under PHS grants policy as stated in the Public
Health Service Grants Policy Statement (April 1, 1994).
 
PHS strongly encourages all grant and contract recipients to provide
a smoke-free workplace and promote the nonuse 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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