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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 Investigation

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 or died.1,2,4

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.
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.
3. CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000; 49(No. RR-6):1-42.
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

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 applications.

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 laboratory techniques.

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


Released October 2008
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