NIH GUIDE, Volume 22, Number 3, January 22, 1993

PA NUMBER:  PA-93-44

P.T. 34


  Drugs/Drug Abuse 

  Pulmonary Diseases 

National Institute on Drug Abuse


The purpose of this program announcement (PA) is to encourage

research on the spread of tuberculosis among drug users.  This PA is

critical to the national effort to control the spread of

tuberculosis, which in recent years has again become a significant

public health problem, due in part to the epidemic of human

immunodeficiency virus (HIV).  Historically, drug users have been at

high risk for tuberculosis, and immunocompromised HIV-infected drug

users are at particularly high risk.  Information regarding factors

influencing transmission and treatment of tuberculosis among drug

users and the impact of co-infection with HIV is lacking.  Results

from research studies specifically focused on tuberculosis in drug

users will aid prevention efforts aimed at drug users.


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, The

Spread of Tuberculosis Among Drug Users, is primarily related to the

priority area of HIV infection, immunization, and infectious

diseases.  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 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.

Applications from women and minority investigators are encouraged.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) awards (R29).


Support mechanisms include:  research projects grants (R01), small

grants (R03), and FIRST awards (R29).

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.  However, it is anticipated that the

average amount of an award under the R01 mechanism will be

approximately $300,000 in direct costs.


Background Summary

The incidence of tuberculosis has increased over the last several

years, in direct relationship to the surge in the HIV epidemic.

Immunocompromised persons co-infected with HIV are at high risk for

developing tuberculosis.  In contrast to other opportunistic

infections to which HIV-infected persons are susceptible,

tuberculosis can spread to those uninfected with HIV.  Nationally,

current numbers of cases being reported are in excess of expected

trends, and recent projections suggest that the historical gains in

tuberculosis control are being lost.  According to the Centers for

Disease Control and Prevention, the number of reported cases of

tuberculosis in the United States has increased since 1986, following

many years of steady decline. Between 1985 and 1991, there were

approximately 26,000 reported cases of tuberculosis, an overall

increase of 18.4 percent since 1985.  Urban areas of the United

States such as New York City have shown the most dramatic increases

in tuberculosis incidence since the early 1980s.

Those at high risk of developing tuberculosis include persons with

HIV infection, alcoholics and drug users, close contacts of known

infectious tuberculosis cases, persons with other medical risk

factors that increase the risk of active tuberculosis once infection

has occurred, persons from high prevalence countries, persons who are

medically underserved, and residents of correctional institutions and

other long-term care facilities.  Racial/ethnic groups historically

at high risk for tuberculosis include Blacks and Hispanics, among

whom there were large increases reported in tuberculosis cases

between 1985 and 1991.  Increases in tuberculosis have been reported

in all age groups, including pediatric, with the greatest increase

since 1985 in the 25-44 year age group.

Factors contributing to the spread of tuberculosis include the HIV

epidemic, both in persons with prior tuberculosis infection who are

newly infected with HIV and in persons with prior HIV infection who

are newly infected with tuberculosis; increases in homelessness,

poverty, and substance abuse; deterioration in health care

infrastructure, particularly in urban areas; and the development of

drug resistant strains of tuberculosis.

Recently, there have been reported outbreaks of multi-drug resistant

tuberculosis (MDR-TB), with high case fatality rates. The majority of

cases have occurred in HIV-infected persons, with primary infection

of MDR-TB occurring in several cases.  Factors contributing to

outbreaks include the convergence of highly susceptible, HIV

immunocompromised patients and patients with tuberculosis, as well as

delayed recognition of tuberculosis infection and disease, delayed

recognition of drug resistance, delayed initiation of effective

anti-tuberculosis treatment, and failure of treatment compliance,

resulting in prolonged infectiousness and the development of drug


Historically, tuberculosis has been identified as a prevalent

condition among drug users, with very large reservoirs of latent

infection reported.  Drug users are at high risk for contracting and

spreading tuberculosis, due to high HIV seroprevalence, low

socioeconomic status and poor environmental conditions, and problems

of access to primary health care.  Major areas of concern among drug

users both in- and out-of-treatment are diagnosis and treatment of

tuberculosis infection and disease, identification of strain, control

of transmission, and compliance with therapy.

Areas of Research Interest

Areas of research interest that examine the factors influencing the

transmission and treatment of tuberculosis among drug abusers that

would be responsive to this announcement include, but are not limited

to, the following:

1.  Epidemiologic investigations which document the occurrence of and

risk factors for tuberculosis infection and disease, including

MDR-TB, among drug users both in- and out-of treatment and in drug

users with and without HIV infection; the prevalence of latent

tuberculosis infection both in- and out-of treatment drug users.

Epidemiologic investigations which utilize DNA fingerprinting

techniques to document the occurrence of specific tuberculosis

strains, changes in strains over time, and transmission patterns

within populations of drug users.  Investigations of drug

susceptibility patterns in populations of drug users.

2.  Research on the interactions of tuberculosis medications with

drugs of abuse, such as cocaine, alcohol, and heroin, and with

methadone treatment.  Investigation of differential effectiveness of

long-term prophylaxis and treatment in relation to substance abuse

and substance abuse treatment.

3.  Studies of the relationship of skin test anergy, PPD tuberculin

reactivity, and active tuberculosis in HIV co-infected drug users.

Longitudinal research on the natural history of and risk for the

development of anergy in HIV co-infected and uninfected drug users;

the impact of repeated tuberculin testing; the incidence of

tuberculin conversions.  Studies of anergy in relation to development

of HIV disease and decline in immune status; studies on the role of

primary infection on risk of developing active tuberculosis in

anergic drug users.

4.  Research on the clinical side effects of tuberculosis preventive

and treatment therapy in HIV-infected and uninfected drug users, such

as studies on combined toxicity of zidovudine and antituberculosis


5.  Investigation of the relationship of tuberculosis prophylaxis and

treatment compliance to the risk of developing active tuberculosis in

drug users, and the risk of developing active disease relative to

tuberculosis therapy and co-infection with HIV; studies of

differences in case rates for active tuberculosis between treated and

partially treated or untreated HIV-infected tuberculin reactors.

Evaluation of the effectiveness of isoniazid prophylaxis in anergic


6.  Development and evaluation of new or innovative antituberculosis

immunization strategies in drug users.

7.  Studies of characteristics of the health care environment which

enhance screening for tuberculosis and promote compliance with

treatment and prophylaxis for in-and out-of treatment drug users.

Studies to expand research on cultural characteristics and gender

differences which influence utilization of health care and

tuberculosis therapy adherence among at-risk drug users.

8.  Studies of the behavioral issues related to compliance with

tuberculosis treatment and prophylaxis regimens; development and

testing of compliance predictor instruments to identify patient

factors associated with poor compliance.

9.  Studies to evaluate the effectiveness of adherence interventions,

such as directly observed therapy, both in the field and in

treatment, incentives, supports, and provision of social and health

care services.

10.  Research on beliefs, attitudes, and knowledge of drug users and

substance abuse treatment staff regarding prevention, appropriate

management, compliance with and adverse reactions to treatment of

tuberculosis, and development and testing of educational strategies

to prevent transmission among treatment staff and drug users.

11.  Evaluation of the effectiveness of linking antituberculosis

therapies and drug abuse treatment in a single setting to enhance

treatment compliance.

12.  Evaluation of the effectiveness of outreach and contact tracing,

e.g., of household contacts of drug users known to be exposed to


13.  Development and evaluation of innovative community-based HIV and

tuberculosis educational and screening programs with linkages to

appropriate treatment or prophylaxis for tuberculosis.

14.  Research on prevention which utilizes epidemiologic studies of

tuberculosis in drug users to target behavioral risk factors for

infection and transmission; development and testing of theory-based

prevention interventions which target the spread of tuberculosis

among drug users.




Applications for grants and cooperative agreements that involve human

subjects are required to include minorities and both genders 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 applies

to all research involving human subjects and human materials, and

applies to males and females of all ages.  If one gender and/or

minorities are excluded or are inadequately represented in this

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

compelling rationale for exclusion or inadequate representation

should be provided.  The composition of the proposed study population

must be described in terms of gender and racial/ethnic group,

together with a rationale for its choice.  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.

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., American

Indians or Alaskan Natives, Asians or Pacific Islanders, Blacks,

Hispanics).  Investigators must provide the rationale for studies on

single minority population groups.

Applications for support of research involving human subjects must

employ a study design with minority and/or gender representation (by

age distribution, risk factors, incidence/prevalence, etc.)

appropriate to the scientific objectives of the research.  It is not

an automatic requirement for the study design to provide statistical

power to answer the questions posed for men and women and

racial/ethnic groups separately; however, whenever there are

scientific reasons to anticipate differences between men and women,

and racial/ethnic groups, with regard to the hypothesis under

investigation, applicants should include an evaluation of these

gender and minority group differences in the proposed study.  If

adequate inclusion of one gender and/or minorities is impossible or

inappropriate with respect to the purpose of the research, because of

the health of the subjects, or other reasons, or if in the only study

population available, there is a disproportionate representation of

one gender or minority/majority group, the rationale for the study

population must be well explained and justified.

The NIH funding components will not make awards of grants,

cooperative agreements or contracts which do not comply with this

policy.  For research awards which are covered by this policy,

awardees will report annually on enrollment of women and men, and on

the race and ethnicity of subjects.


Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  The receipt dates for

applications for AIDS-related research are found in the application


Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, Maryland  20892,

telephone 301/496-7441.  The number and title of the announcement

must be typed in item 2a of the face page of the application.

FIRST award applications must include at least three sealed letters

of reference attached to the face page of the original application.

FIRST award applications submitted without the required number of

reference letters will be considered incomplete and will be returned

without review.

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 received under this announcement will be assigned on the

basis of established Public Health Service referral guidelines.

Applications will be reviewed for scientific and technical merit by

initial review groups, in accordance with the standard NIH peer

review procedures.  Following scientific-technical review, the

applications will receive second-level review by the appropriate

national advisory council.  Small grants (R03) applications do not

receive a second-level review.

Criteria for scientific/technical merit of applications will include

the following:

o  Potential significance of the concept

o  Originality of the concept

o  Feasibility of the proposed research


Applications will compete for available funds with all other

applications recommended for further consideration assigned to that

Institute.  The following will be considered in making funding


o  Quality of the proposed project as determined by the peer review;

o  Availability of funds; and

o  Program balance among research areas.


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is


Direct inquiries regarding programmatic issues to:

Katherine Davenny, MPH

Division of Clinical Research

Clinical Medicine Branch

National Institute on Drug Abuse

5600 Fishers Lane, Room 11A-33

Rockville, MD  20857

Telephone:  (301) 443-1801

Direct inquiries regarding fiscal matters to:

Mrs. Shirley A. Denney

Grants Management Branch, OPRM

National Institute on Drug Abuse

5600 Fishers Lane, Room 8A-54

Rockville, MD  20857

Telephone:  (301) 443-6710


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 (42 U.S.C. 241).  Title 42 of

the Code of Federal Regulations (CFR), Part 52, "Grants for Research

Projects," Title 45 CFR Part 74, "Administration of Grants," and 45

CFR Part 92 are applicable to these awards.

Applications submitted in response to this announcement are not

subject to the intergovernmental review requirements of Executive

Order 12372, as implemented through Department of Health and Human

Services regulations at 45 CFR Part 100.  Grants must be administered

in accordance with the PHS Grants Policy Statement, revised October

1, 1990.


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