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TB Notes 1, 2003
Updates from the Surveillance and Epidemiology Branch
Update on Rifampin and Pyrazinamide (RZ)
Treatment for Latent Tuberculosis Infection (LTBI) Patient Cohort
From October 2000 through December 2002, a total of 44 cases of
severe liver injury associated with treatment of latent tuberculosis
infection (LTBI) with the drug combination rifampin and pyrazinamide
(RZ) were reported to DTBE, of which 10 were fatal. A case was defined
as liver injury in a person who was taking RZ for LTBI and was hospitalized
On August 31, 2001, DTBE issued new guidance regarding RZ, indicating
that the 9-month regimen of isoniazid (INH) is preferred for treatment
of LTBI for patients who have indications for treatment, and that
4 months of daily rifampin is an acceptable alternative.1,3 Daily
RZ regimens for 2 months or twice-weekly RZ regimens for 2 or 3
months should be used with caution, especially in patients taking
other medications associated with liver injury, and in those with
alcoholism, even if alcohol is discontinued during treatment. RZ
is not recommended for persons with underlying liver disease, or
for those who have had INH-associated liver injury. If RZ is prescribed,
evaluation of patients should include symptom screening as well
as tests of serum aminotransferase (AT) and bilirubin at baseline
and at 2, 4, and 6 weeks of treatment. No more than a 2-week supply
of RZ should be dispensed at a time (with a pyrazinamide dose of
< 20 mg/kg/d and a maximum of 2 gm/d).1,4 Since publication of
the new recommendations, CDC has received no reports of deaths in
patients undergoing RZ therapy.
In order to determine an estimate of the incidence rate of severe
liver injury in persons receiving RZ, and to determine the presence
of factors associated with adverse effects due to RZ, DTBE is currently
investigating cohorts of patients who received this regimen. In
December 2001, a short questionnaire was e-mailed to state/city
TB controllers to identify programs and providers prescribing RZ.
In February 2002, follow-up phone calls were made to the programs
and providers using RZ to confirm its use. TB controllers from all
50 states completed the 2001 e-mail questionnaire; 41 (82%) states
reported RZ use. Cohorts include patients from TB clinics, correctional
facilities, and homeless shelters.
On September 24, 2002, a four-page RZ Patient Cohort Enumeration
survey was mailed to 139 health care providers identified as prescribers
of RZ, asking for general characteristics of cohorts; no patient-specific
data are being collected. Survey questions included the number of
patients who were eligible for treatment of LTBI; number who initiated
RZ therapy; number who stopped RZ because of elevated serum AT,
symptoms of hepatitis, or other adverse effects; number who completed
RZ therapy; and number taking RZ who were hospitalized or died with
liver injury. The survey also included questions about reasons for
RZ use and frequency of serum AT monitoring.
Through December 2002, only 59 (42%) of these surveys have been
received. DTBE continues to contact health care providers who have
not yet responded to the survey. We request that those persons who
received the survey and have not yet responded please do so as soon
as possible, but no later than February 28, 2003. Data collected
from these surveys are crucial to estimating the incidence of severe
liver injury associated with the use of RZ for treatment of LTBI.
Analysis of the survey data will help CDC formulate future recommendations
related to the use of this regimen.
DTBE encourages providers to report possible cases
of severe liver injury associated with RZ or any regimen for treatment
of LTBI to DTBE at (404) 639-8442. You may also call this number
if you have questions about the Patient Cohort Enumeration survey.
Possible cases of severe liver injury should also be reported to
the state health department or local TB control program.
-Reported by Lauren A. Lambert, MPH
Div of TB Elimination
1. CDC. Update: Fatal and severe liver injuries associated with
rifampin and pyrazinamide for latent tuberculosis infection, and
revisions in American Thoracic Society/CDC recommendations, 2001.
MMWR 2001:50(34):733-35. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5034a1.htm
2. CDC. Fatal and severe hepatitis associated with rifampin and
pyrazinamide for the treatment of latent tuberculosis infection,
New York and Georgia, 2000. MMWR 2001:50(15)289-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5015a3.htm
3. CDC. Targeted tuberculin testing and treatment of latent tuberculosis
infection. MMWR 2000; 49(No. RR-6):1-42. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4906a1.htm
4. CDC. Public Health Dispatch: Fatal and Severe Liver Injuries
Associated with Rifampin and Pyrazinamide Treatment for Latent Tuberculosis
Infection. MMWR 2002;51(44): 998-999 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5144a4.htm
The Biotechnology Engagement Program
Background. The Biotechnology Engagement Program (BTEP) is a U.S.
government initiative which is designed to form partnerships between
U.S. scientists and former Soviet Union (FSU) bioweapons specialists.
The U.S. government continues to be deeply concerned about the risk
of proliferation of weapons of mass destruction and the ease with
which former Soviet expertise in bioweapons development could be
transferred to rogue states and terrorists. To address these concerns,
HHS has agreed to work with the Department of State and the Department
of Defense in efforts to redirect this expertise (and resources)
from military to civilian research. BTEP provides funding for cooperative
research projects, with the objective of encouraging former Soviet
bioweapons scientists (also known as biodefense workers or BDWs)
to stay in their home state and develop new civilian-oriented research
skills. It is hoped that this work will eventually help to develop
and expand commercial production of drugs, vaccines, biologic test
kits, and other quality products and technologies designed to meet
current public health needs in Russia and the region.
BTEP provides 12 to 36 months of financial support to the research
collaborators. The program encourages joint teams of former Soviet
BDWs and U.S. experts to apply for support and cooperation in areas
of research and development that address urgent public health concerns
in Russia and the northern Eurasian region. The primary source of
proposed projects is through matchmaking and targeted requests for
Armenia/Georgia BTEP Project. Independent since 1991, the Republic
of Armenia experienced a three-fold increase in TB morbidity, from
282 reported case-patients in 1991 (14 of whom were children) to
896 reported case-patients in 2001 (38 of whom were children). These
data come from Armenia’s Sanitary Epidemiologic Services (SES).
The sharp rise in TB cases among children is of grave concern and
indicates significant ongoing transmission of TB disease in Armenia.
However, there are disparities in the epidemiologic data because
Armenia has two independent TB reporting systems: the SES and the
TB hospitals. The TB hospital data show an even greater number of
overall TB case-patients, from 724 reported in 1991 to 1343 reported
in 2001. Concomitant with this increase in absolute numbers of TB
case-patients in the past 10 years was a dramatic drop in the population
from about 3.8 million in 1991 to about 2.5 million in 2001, owing
in large part to emigration to other countries (e.g., Russia and
the United States). But despite this drop, the 1991 demographic
data are still used to calculate the official Armenian Ministry
of Health (AMOH) TB rates, which are clearly understated. Further,
the rise in drug-resistant M. tuberculosis has reached significant
levels; 20%-25% of all M. tuberculosis isolates are resistant to
at least one antibiotic. The exact levels of drug-resistant TB are
difficult to ascertain because of the paper-based system of laboratory
information at the Armenian National TB Reference Laboratory. AMOH
officials attribute rising drug-resistant TB rates to poor compliance
and follow-up of diagnosed TB case-patients and the increasing incidence
of TB in the prison system.
Consistent with World Health Organization (WHO) recommendations,
the AMOH plans to determine the incidence of drug-resistant TB and
to assess the current TB program activities in order to conceive,
develop, and implement a National Armenia TB Program (NATBP). This
NATBP would include a comprehensive reorganization and decentralization
of local TB control services and activities to account for DOTS
implementation. It would also include the strengthening, unification,
and computerization of all TB case-patient management, laboratory,
epidemiologic and investigative, and reporting activities. Finally,
the NATBP would include a new national TB training program for postgraduate
medical officers and advanced laboratory training in the latest
If successful, this BTEP proposal would finance the applied research
and program assessment necessary to conceive, develop, and implement
the first phases of the NATBP. This proposal also includes a regional
collaboration with the Ministry of Health, Republic of Georgia TB
Program. This collaboration would include funding for additional
support for the Republic of Georgia TB Program and for regional
TB conferences, workshops, and joint training activities.
There are currently two BTEP projects underway in the division,
the one described above and another in Russia. The second project
will be described in the next issue of TB Notes.
-Reported by Scott J.N. McNabb, Ph.D., M.S.
Div of Tuberculosis Elimination