Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial.
BACKGROUND
Rifampin and pyrazinamide are recommended for treatment of latent tuberculosis infection in adults without HIV infection, but reports of severe hepatotoxicity have raised concerns about its safety. Clinical trials have not compared this treatment with isoniazid in adults without HIV infection.


OBJECTIVE
To compare the safety and tolerance of a 2-month regimen of rifampin and pyrazinamide with that of a 6-month regimen of isoniazid for treatment of latent tuberculosis infection.


METHODS
Multicenter, prospective, open-label trial.


METHODS
Three urban public health tuberculosis clinics in the United States.


METHODS
589 adults with latent tuberculosis infection who met U.S. criteria for treatment.


METHODS
Patients were assigned in alternate weeks to receive rifampin and pyrazinamide daily for 2 months (n = 307) or isoniazid daily for 6 months (n = 282).


METHODS
Primary end points were hepatotoxicity, other adverse events, and percentage of patients who completed treatment.


RESULTS
Sixteen of 207 (7.7%) patients assigned to rifampin and pyrazinamide developed grade 3 or 4 hepatotoxicity compared with 2 of 204 (1%) patients assigned to isoniazid (odds ratio, 8.46 [95% CI, 1.9 to 76.5]; P = 0.001). The rifampin plus pyrazinamide regimen was more likely than the isoniazid regimen to be discontinued because of hepatotoxicity (odds ratio, 5.19; P = 0.033). The overall percentage of nonhepatotoxic adverse events was 20% in the rifampin-pyrazinamide group and 16% in the isoniazid group. The proportion of patients who completed the study treatment was 61% and 57%, respectively.


CONCLUSIONS
A 2-month regimen of rifampin and pyrazinamide was associated with an increased risk for grade 3 or 4 hepatotoxicity compared with a 6-month regimen of isoniazid. Liver enzymes should be measured routinely during treatment to screen for liver injury and prevent progression to severe toxicity.
Jasmer
Robert M
RM
San Francisco General Hospital Medical Center, University of California, San Francisco, California, USA. rjasmer@itsa.ucsf.edu
Saukkonen
Jussi J
JJ
Blumberg
Henry M
HM
Daley
Charles L
CL
Bernardo
John
J
Vittinghoff
Eric
E
King
Mark D
MD
Kawamura
L Masae
LM
Hopewell
Philip C
PC
D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000009:adverse effects; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage* / Q000009:adverse effects; D008099:Liver / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D011446:Prospective Studies; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000009:adverse effects; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin