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
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.
Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of
Health and Human Services.References to non-CDC sites on the Internet are
provided as a service to MMWR readers and do not constitute or imply
endorsement of these organizations or their programs by CDC or the U.S.
Department of Health and Human Services. CDC is not responsible for the content
of pages found at these sites. URL addresses listed in MMWR were current as of
the date of publication.
All MMWR HTML versions of articles are electronic conversions from ASCII text
into HTML. This conversion may have resulted in character translation or format errors in the HTML version.
Users should not rely on this HTML document, but are referred to the electronic PDF version and/or
the original MMWR paper copy for the official text, figures, and tables.
An original paper copy of this issue can be obtained from the Superintendent of Documents,
U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800.
Contact GPO for current prices.
**Questions or messages regarding errors in formatting should be addressed to