Update: Fatal and Severe Liver Injuries Associated With Rifampin and Pyrazinamide for Latent Tuberculosis Infection, and Revisions in American Thoracic Society/CDC Recommendations - United States, 2001 [Am J Respir Care Med 2001;164:1319] ]: This document represents the official recommendations of the American Thoracic Society and the CDC with endorsement by the IDSA for the use of the two month rifampin-pyrazinamide regimen in patients with latent tuberculosis. Twenty-one cases of liver injury associated with this regimen reported to the CDC. Cases were defined as "severe" if there was hepatic injury requiring hospitalization or causing death. None of the patients were known to have HIV infection, one had hepatitis C, three had prior INH hepatotoxicity, and five died with this complication. All deaths occurred in the second month of treatment. None of the patients had concurrent active viral hepatitis. Autopsies were performed on two of the patients, both of whom had acute hepatic necrosis. Details are summarized below:

Analysis of Hepatotoxicity with RIF+PZA for Latent TB: 21 cases
Median age	44 years
Gender	12/21 male
Jaundice	15/18 (83%)
HIV positive	0/11
HCV infection	1 (5%)
Prior INH hepatotoxicity	3 (14%)
Death	5 (24%)

As a result of these observations, recommendations for the management of latent tuberculosis have been revised, as summarized below.

Recommendations for 2-Month PZA-RIF Regimen (ATS, CDC, IDSA, 11/01)

• Use with caution especially with concurrent use of other hepatotoxic drugs, alcoholism or history of alcoholism
• Avoid with prior INH hepatotoxicity
• If used, warn patient of hepatotoxicity
• The 9 month INH regimen is preferred for those without HIV infection; RIF x 4 month is an appropriate alternative to INH
• PZA + INH is appropriate for: 1) patients with HIV, 2) patients without HIV who are unlikely to complete treatment requiring > 2 months
• If PZA-RIF used:
  1. Prescribe only a 2 week supply using PZA dose <20 mg/kg/d and maximum of 2 gm/d
  2. Assessment by provider at 2, 4 and 6 weeks; document completed course at 8 weeks. At each assessment determine if the patient is experiencing abdominal pain, emesis, jaundice or other symptoms of hepatitis
  3. Obtain ALT and bilirubin at baseline, 2, 4 and 6 weeks
  4. Discontinue treatment if: a) ALT is >5x ULN in asymptomatic patient, b) any elevation of ALT in symptomatic patient, or c) elevated bilirubin.

Comment: There were two settings in which the 2-month PZA-RIF regimen was recommended: For patients with HIV infection and patients without HIV infection who were considered unlikely to complete more than a two month course of treatment. There are rather stringent rules for monitoring therapy, which include clinical observation at two week intervals and measurement of ALT plus bilirubin at baseline, 2, 4 and 6 weeks. Cases of severe liver injury leading to hospitalization or death should be reported to the Division of Tuberculosis Elimination at 404-639-8116.
posted 12/18/2001

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