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Public Health Dispatch:
Update: Fatal and Severe Liver Injuries Associated with Rifampin and Pyrazinamide Treatment for Latent Tuberculosis Infection

Reports of fatal and severe liver injury associated with treatment of latent tuberculosis infection (LTBI) with the drug combination rifampin and pyrazinamide (RZ) prompted CDC to issue revised guidelines for the use of this regimen on August 31, 2001 (1). To determine if these revised guidelines were effective in reducing morbidity and mortality, CDC has continued to collect reports on adverse effects associated with this regimen. This update summarizes the results of this ongoing investigation.

A case of severe liver injury was defined as a hospital admission or death of a patient being treated for LTBI with RZ (1,2). As of September 25, 2002, a total of 40 cases (eight fatal) were reported, of which 23 (five fatal) have been described (1,2). Of the 17 cases (three fatal) that have not been described in previous reports, two occurred in patients who started RZ after publication of the revised guidelines. Both patients survived. One patient had contraindications for RZ (i.e., hepatitis and alcoholism). The other did not have contraindications for RZ and received RZ twice a week by directly observed therapy (DOT). According to information collected during DOT visits, the patient did not complain of any symptoms until the last week of the regimen. However, because the patient did not speak English, comprehension might have been a barrier. The patient missed two scheduled clinic appointments; serum aminotransferase and bilirubin levels were measured before treatment, but no biweekly tests were performed while the patient was on RZ, as is recommended in the revised guidelines. Physicians who choose to administer RZ instead of the preferred INH should follow the revised guidelines.

Summary of Revised Guidelines

The 9-month regimen of isoniazid (INH) remains the preferred treatment for patients who have LTBI and indications for treatment (1,3). Daily RZ for 2 months or twice-weekly RZ 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 tests of serum aminotransferase and bilirubin at baseline and at 2, 4, and 6 weeks of treatment. No more than a 2-week supply of RZ (with a pyrazinamide dose of <20 mg/kg/d and a maximum of 2 gm/d) should be dispensed at a time.

CDC continues to collect data on reports of severe liver injury leading to hospital admission or death in persons receiving any treatment for LTBI. To determine the incidence of and risk factors for this problem, CDC is investigating cohorts of patients who received RZ. Health-care providers should report possible cases to CDC's Division of Tuberculosis Elimination, telephone 404-639-8442.

Reported by: State and territorial health depts. Lambert L, MPH, Div of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, CDC.


  1. CDC. Update: Fatal and severe liver injuries associated with rifampin and pyrazinmaide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations, 2001. MMWR 2001:50:733--5.
  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;50:289--91.
  3. CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-6).

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