Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons?
BACKGROUND
In 2000, results of a multinational trial demonstrated that a 2-month course of rifampin and pyrazinamide (RZ) was as effective as isoniazid (INH) in reducing tuberculosis in human immunodeficiency virus (HIV)-infected individuals with latent tuberculosis infection (LTBI). After the release of new guidelines, the Centers for Disease Control and Prevention received reports of severe hepatotoxicity associated with the use of the RZ regimen for the treatment of LTBI in the general population. To better understand the occurrence of hepatotoxicity in an HIV-infected population, we conducted a more detailed analysis of the liver function test results obtained in the multinational trial of RZ.


METHODS
At study entry, patients were required to have a bilirubin level of < or =2.5 mg/dL and both an aspartate aminotransferase (AST) level and an alkaline phosphatase level of < or =5 times the upper limit of normal. Patients with acute hepatitis were excluded. At months 1 and 2 of the study, all patients had bilirubin and AST levels measured.


RESULTS
There was no difference between the RZ and INH groups with regard to AST level or bilirubin level at baseline. An increase in the AST level of > or =40 U/L was associated with the use of INH and older age; and an increase in the bilirubin level of > or =0.5 mg/dL was associated with the use of RZ, male sex, and nonwhite race (P<.05). An absolute AST level of >250 U/L occurred in 12 of 745 INH recipients and in 15 of 721 RZ recipients (P=.56), and an absolute bilirubin level of >2.5 mg/dL occurred in 5 of 743 INH recipients and 13 of 718 RZ recipients (P=.06).


CONCLUSIONS
These data demonstrate very little liver injury associated with either INH or RZ in the HIV-infected subjects, leaving unclear the reasons for serious RZ-related liver damage in the general population.
Gordin
Fred M
FM
Infectious Diseases Section, Veterans Affairs Medical Center and George Washington University, Washington, DC 20422, USA. Fred.Gordin@med.va.gov
Cohn
David L
DL
Matts
John P
JP
Chaisson
Richard E
RE
O'Brien
Richard J
RJ
D000293:Adolescent; D000328:Adult; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology*; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D015999:Multivariate Analysis; D011718:Pyrazinamide / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D012293:Rifampin / Q000009:adverse effects* / Q000627:therapeutic use; D014376:Tuberculosis / Q000097:blood / Q000150:complications / Q000188:drug therapy*
D011718:Pyrazinamide; D001219:Aspartate Aminotransferases; D001663:Bilirubin; D007538:Isoniazid; D012293:Rifampin