DRUG ABUSE ASPECTS OF AIDS

NIH GUIDE, Volume 22, Number 24, July 2, 1993



PA NUMBER:  PA-93-098



P.T. 34



Keywords:

  AIDS 

  Drugs/Drug Abuse 



National Institute on Drug Abuse



PURPOSE



The purpose of this program announcement is to stimulate research on

the relationships between drug abuse and associated behaviors and

infection with human immunodeficiency virus (HIV) and progression to

acquired immunodeficiency syndrome (AIDS).  This is a revision of the

January 1990 announcement recognizing the progress made and the

knowledge accumulated regarding these relationships and emphasizing

areas where major gaps exist in this knowledge base.



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 program

announcement, Drug Abuse Aspects of AIDS, is related to the priority

areas of HIV infection and 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).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit and

non- profit, public and private organizations such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.  Women

and minority investigators are encouraged to apply.  Applications are

especially encouraged from State and municipal governments with

research units and/or State and municipal governments collaborating

with university-based research units.  Foreign institutions are not

eligible for First Independent Research Support and Transition

(FIRST) Awards (R29).



MECHANISM OF SUPPORT



This program announcement will use the National Institutes of Health

(NIH) individual research project grant (R01), small grants (R03),

and FIRST awards (R29).  Responsibility for the planning, direction,

and execution of the proposed project will be solely that of the

applicant.  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 vary also.



RESEARCH OBJECTIVES



Background



Between June 1981 and June 30, 1992, 226,281 AIDS cases in the U.S.

were reported to the Centers for Disease Control.  Approximately 30

percent of the AIDS cases are among injecting drug users (IDUs).

Heterosexual IDUs account for 23 percent of AIDS cases, whereas

homosexual and bisexual IDUs account for an additional six percent of

cases.  Nineteen percent of all male cases were heterosexuals who

reported using needles for self-injection of drugs not prescribed by

a physician at least once prior to developing AIDS.  Half of all

females with AIDS reported such a drug use history.



HIV infection and AIDS are not limited to drug abusers who inject

drugs, but have been recently noted to be spreading rapidly among

non-IDUs, such as "crack" smokers.  A survey of five cities

demonstrated an 11 percent HIV infection rate among heterosexual

"crack" users who had never injected drugs.  The multiple sexual

contacts reported by this group of drug users has led to outbreaks of

gonorrhea and syphilis and other sexually transmitted infections,

including HIV infection.



Another facet of the AIDS epidemic is the re-emergence of

tuberculosis (TB) in the U.S.  There are several reasons for the

re-emergence of TB in the U.S., including the HIV epidemic, a failing

public health infrastructure in some districts, increased substance

abuse, poverty and homelessness, and increases in immigrants with TB.



In response to the AIDS pandemic among drug abusers, the National

Institute on Drug Abuse (NIDA) has built a comprehensive research

program, including studies of the effects of drug abuse on the immune

system; epidemiologic studies of seroincidence, seroprevalence, and

progression to disease among drug users (in and out of treatment),

their sexual partners, and their children; and studies to assess

prevention and treatment strategies to reduce behaviors that are

linked to the transmission of HIV and progression to AIDS and other

associated diseases.



To develop a more targeted research program, the NIDA AIDS Office

initiated a planning process addressing four major research areas:

prevention of HIV transmission, drug using and sexual behaviors

associated with HIV transmission, natural history/cofactors of HIV

infection and disease progression, and clinical issues.  Separate

planning processes focused on drug abuse treatment research and

medications development, and aspects of those plans relevant to HIV

were also integrated into the AIDS planning process. The AIDS

five-year plan highlights the priority areas presented below.



Objectives



Priorities have been established, without implication of ranking

importance, in five areas (treatment of drug dependence, prevention

strategies, risk behaviors, etiology and pathogenesis, and clinical

issues).  Three cross-cutting areas include international research,

family issues, and cultural issues.



Treatment of drug dependence:  Treatment of drug dependence is an

important strategy for reducing risky behaviors that are related to

the transmission of HIV.  To that end, NIDA will continue to support

research to improve current treatments and to develop new ones.



The objective of drug abuse treatment research related to AIDS is to

improve the efficacy of psychosocial/behavioral and pharmacological

drug dependence treatment interventions; to improve the effectiveness

of drug abuse treatment programs and modalities; to develop effective

new psychosocial treatments and medications to treat drug dependence;

to potentiate the efficacy of drug abuse treatment through optimal

integration of psychosocial/behavioral treatments and medications.

Specific examples of research priorities include:



o  Systematic evaluation and replication of promising

psychosocial/behavioral therapies and promotion of the acceptance and

utilization of those therapies that show efficacy for differing

patient populations including women, particularly pregnant women,

those with mental illness, and crack users.

o  Continue large scale, multi-program treatment evaluation research

to provide current information on the effectiveness of treatment

modalities for differing client populations.

o  Studies of treatment engagement and retention in order to address

the problem of client attrition early in treatment by developing

strategies to increase time in treatment.



Prevention strategies:  Although treatment for drug dependence is

considered the optimal intervention, other HIV prevention strategies

are needed for drug users who are not in treatment or whose treatment

is not totally effective in eliminating their use of drugs and for

others at risk of infection through drug abuse such as sex partners

and children of drug abusers.  In addition, for drug users who are

already infected with the HIV, strategies to slow progression of AIDS

illnesses are needed.



Attention needs to be placed on research that not only evaluates

outcomes of specific risk reduction programs, but does so in a manner

that contributes toward a generalizable understanding of the factors

and processes that contribute to risk behavior and behavior change.

Furthermore, there is a need to develop and evaluate prevention

efforts that are integrated with other public health programs that

address the myriad health and safety issues that make HIV a less

salient concern for many persons at risk.  A special focus is needed

on alternative strategies for women.  Specific areas of research

attention might be:



o  Multi-site AIDS community-based outreach/intervention research

designed to:  recruit drug abusers into drug abuse treatment and HIV

counseling programs, study the duration of behavior change following

intervention, and develop booster programs to ensure long term

behavior change and prevent relapses to risk-taking behaviors.

o  Assess prevention strategies that alter the progression of disease

among seropositive drug abusers.

o  Assess intervention models that focus on sexual risk behaviors.

o  Clarify the efficacy (risks and benefits) and cost-effectiveness

of harm reduction strategies, such as needle/syringe exchange

programs and the use of bleach as a disinfectant.  Studies are

encouraged that examine the impact of these programs on patterns of

drug use practices, including needle-related practices with potential

impact on the transmission of blood-borne diseases, e.g., HIV,

Hepatitis B.  The development of biological measures of infectivity

and multiple use patterns are encouraged.

o  Develop and evaluate prevention strategies for areas of "low

prevalence" of AIDS/HIV infection, including use of other "markers"

of risk such as HTLV-I/II and hepatitis viruses.

o  Assess the risks and benefits of HIV testing and counseling.  Give

special emphasis to interventions designed to improve behavior change

for clients who test HIV negative.

o  Studies of the diffusion of innovations comparing characteristics

of communities that adapt early, later, or fail to adopt innovative

preventive strategies.  Such studies should also examine the impact

on HIV risk behaviors.



Risk behaviors:  Drug using behaviors and sexual behaviors associated

with drug use account for a major portion of the AIDS cases reported

in the United States.  Studies have focused on behaviors of

individual drug users, particularly in relation to injection drug

practices and their use of sex as a mechanism for obtaining drugs.

The transactional and dynamic aspects governing these high risk

behaviors have been less well explicated.  Specific examples of

research priorities include:



o  Identification of factors associated with the transition from

non-injecting to injecting drug use, including the role of drug and

needle sharing in injection initiation.

o  Studies of factors that support the maintenance of or relapse to

drug injecting behaviors and that play a role in user decisions to

adopt and maintain safer injecting procedures, including social and

situational determinants (e.g., drug choices, availability of drugs,

social networks, social support, and gender roles) of sharing and

other high risk practices.

o  Studies of the determinants of sexual behavior of IDUs and their

sexual partners, how risk taking behavior is mediated by the dyadic

relationship, peer group influences, social networks, gender

differences, and patterns of non-injected and injected drug use.

o  Investigations of the relationship between non-injected drug use

and high risk sexual behaviors in gay and bisexual males and other

groups potentially at risk.

o  Development of statistical methodologies for analysis of behavior

in context and for measuring multiple risk behaviors.

o  Studies to model the prevalence of AIDS and AIDS risk behaviors

balancing theory and data, in special subpopulations of drug abusers

(the homeless, adolescents, the highly sexually active, gays and

bisexuals).



Etiology and pathogenesis (Cofactors):  It is hypothesized that the

transmission/progression of infection may be influenced by non-HIV

related factors.  These "cofactors" may include the use of drugs or

alcohol (e.g., quantity) as well as the use of specific substances

(e.g., nitrite inhalants).



The overall objective of this area is to stimulate research on the

pathogenesis of HIV in drug users and their offspring and the impact

of co-factors which may operate in conjunction with HIV to influence

susceptibility to infection, disease progression, and the various

clinical manifestations observed in drug users.  Examples of research

areas include:



o  Studies of drug receptors in psychoneuroimmune systems including

the basic mechanisms of psychoneuroimmune pathways, the mechanisms of

action of different cytokines and drugs on these receptors and how

drugs might be modified to intervene in these actions to assist the

development of new treatment drugs that do not impinge on immune

function or that may enhance immune response.

o  Studies of the role of stress and how drugs of abuse modulate the

immune function and the progression of disease, as well as the

biochemical and immunologic mechanisms in the pathogenesis of

drug-modulated encephalopathy in the absence or presence of HIV or

other infections.

o  Studies in prevalent positives of clinical staging of HIV-related

disorders, decline in CD4, and onset of other infectious diseases

(e.g., hepatitis B and C, pyogenic bacterial infections, syphilis,

tuberculosis); medical sequelae of AIDS-related disorders, e.g., M.

tuberculosis, pulmonary and central nervous system infections,

mycobacteria, T. gondii, Kaposi's sarcoma, C. neoformans).

o  The extent to which drug use and/or co-infection with other

pathogens affects vulnerability to HIV infection and the rate of

disease progression in incident seroconverters; the impact of drug

use and co-infection on immune function and rate of decline in CD4;

the interactions of HIV with drugs of abuse and the effects of

combinations of cofactors on susceptibility to infection and disease

course.

o  The immunosuppressive role of drugs of abuse such as opiates,

cocaine, marijuana, and nitrites on progressive immune dysfunction

and disease progression; association of drug use with variable

expression of HIV manifestations in drug users as distinct from other

groups, e.g., the association of nitrite use with Kaposi's sarcoma.

o  The interaction of drug treatment medications, e.g., methadone,

LAAM, and buprenorphine, HIV-related therapeutics, and drugs of abuse

and the impact on HIV disease progression.

o  HIV transmission and disease development in special populations,

e.g., women, infants and children prenatally drug-exposed, and

adolescents.

o  Studies that examine factors in drug abusing populations that

predict, protect against, contribute to, or limit the progression of

complications of HIV infections related to the nervous system, e.g.,

HIV dementia.



Clinical issues:  Important clinical issues include drug abuse

relapse prevention, case management, HIV testing, and linkages

between the drug treatment and primary health care systems.  These

issues are particularly complex in that drug abuse treatment has been

managed outside the mainstream of health care practice.  Within this

context, the following are examples of research initiatives:



o  Assess strategies to link drug abuse services with primary health

care, public health, and mental health services.

o  Assess the ability of drug abuse treatment staff to resist burnout

and to enhance skills, and explore their attitudes toward

HIV-positive and substance abusing clients.

o  Evaluate a variety of comprehensive case management models that

include health and social services for drug abusers who are infected

with HIV and for those who have progressed to AIDS.

o  Study the impact on the lives of the families of seropositive drug

abusers and drug abusers with AIDS including their service needs and

patterns of help-seeking.



Cross-Cutting Issues:  Three cross-cutting issues have been

identified: international studies, family issues, and, cultural

issues.



Applications are encouraged especially from countries that have

access to data which are unavailable in the U.S. and which are

important to U.S. interests in the area of drug abuse and AIDS in any

of the areas mentioned above.



Interrelationships among drug abuse, HIV infection, and family

functioning, utilizing a broad definition of family functioning to

include biological and non-biological networks.  The focus of this

research is the design effective prevention strategies and to enhance

treatment efforts.



Studies of special target populations are encouraged that focus on

cultural factors that impact injecting and high risk sexual behavior;

female drug users and female sexual partners of IDUs; high risk

adolescents (e.g., homeless and gay youth, and youth living in areas

with high rates of HIV infection and/or injection drug use); gay and

bisexual males, including injecting and non- injecting drug users;

and institutionalized populations such as prisoners.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be required to include minorities and

women in study populations so that research findings can be of

benefit to all persons at risk of the disease, disorder or condition

under study; special emphasis should be placed on the need for

inclusion of minorities and women in studies of diseases, disorders

and conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should be provided.   The composition of the

proposed study population must be described in terms of gender and

racial/ethnic group.  In addition, gender and racial/ethnic issues

should be addressed in developing a research design and sample size

appropriate for the scientific objectives of the study.  This

information should be included in the form PHS 398 in Sections 1-4 of

the Research Plan AND summarized in Section 5, Human Subjects.



Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However,

NIH recognizes that it may not be feasible or appropriate in all

research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).



The rationale for studies on single minority population groups should

be provided.



For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the application will be returned.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the receipt dates for

AIDS-related research found in the form PHS 398 instructions.

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 240, Bethesda, MD 20892, telephone

301/710-0267).  The title and number of the announcement must be

typed in Item 2a on the face page of the application form PHS 398.



Applications 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

with the application.



REVIEW CONSIDERATIONS



The Division of Research Grants, NIH, serves as a central point for

receipt of applications for most discretionary DHHS grant programs.

Applications received under this announcement will be assigned to an

initial review group (IRG) in accordance with established PHS

referral guidelines.  The IRGs, consisting primarily of non-Federal

scientific and technical experts, will review the applications for

scientific and technical merit in accordance with the standard NIH

peer review procedures.  Notification of the review recommendations

will be sent to the applicant after the initial review.  Applications

will receive a second-level review by an appropriate National

Advisory Council, whose review may be based on policy considerations

as well as scientific merit.  Only applications recommended for

further consideration by the Council may be considered for funding.



AWARD CRITERIA



Applications recommended for further consideration by an appropriate

National Advisory Council will be considered for funding on the basis

of overall scientific, clinical and technical merit of the proposal

as determined by peer review, appropriateness of budget estimates,

program needs and balance, policy considerations, adequacy of

provisions for the protection of human subjects, and availability of

funds.



INQUIRIES



Written and telephone inquiries to clarify any issues or questions

from potential applicants are welcome.  Direct inquiries regarding

programmatic issues to:



Harry W. Haverkos, M.D.

National Institute on Drug Abuse

5600 Fishers Lane, Room 10A-38

Rockville, MD  20857

Telephone:  (301) 443-6697



Direct inquiries regarding fiscal matters to:



Chief, Grants Management Branch

National Institute on Drug Abuse

5600 Fishers Lane, Room 8A-54

Rockville, MD  20857

Telephone:  (301) 443-6710



AUTHORITY AND REGULATIONS



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, Section 301, and administered under PHS

grants policies and Federal Regulations at Title 42 CFR 52 "Grants

for Research Projects", Title 45 CFR Part 74 & 92, "Administration of

Grants" and 45 CFR Part 46, "Protection of Human Subjects".  Title 42

CFR Part 2, "Confidentiality of Alcohol and Drug Abuse Patient

Records" may also be applicable to these awards.  This program is not

subject to the intergovernmental review requirements of Executive

Order 12372 of Health Systems Agency review.



.

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