Short-Course Rifampin and Pyrazinamide Compared with Isoniazid for Latent Tuberculosis Infection: A Multicenter Clinical Trial

  1. Robert M. Jasmer, MD;
  2. Jussi J. Saukkonen, MD;
  3. Henry M. Blumberg, MD;
  4. Charles L. Daley, MD;
  5. John Bernardo, MD;
  6. Eric Vittinghoff, PhD;
  7. Mark D. King, MD;
  8. L. Masae Kawamura, MD;
  9. Philip C. Hopewell, MD; and
  10. for the Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators*
  1. From San Francisco General Hospital Medical Center, University of California, San Francisco, and Francis J. Curry National Tuberculosis Center, San Francisco, California; Boston University School of Medicine, Boston, Massachusetts; and Emory University School of Medicine and Grady Memorial Hospital, Atlanta, Georgia.

    Abstract

    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.

    Design: Multicenter, prospective, open-label trial.

    Setting: Three urban public health tuberculosis clinics in the United States.

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

    Intervention: 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).

    Measurements: 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.

    *For a list of the Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators, see the Appendix.

    Article and Author Information

    • Grant Support: By the National Institutes of Health (AI 01549, HL 62977, HL 03035, HL 03078, and HL 03057) and the Emory Medical Care Foundation.

    • Potential Financial Conflicts of Interest: None disclosed.

    • Requests for Single Reprints: Robert M. Jasmer, MD, Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, Room 5K-1, 1001 Potrero Avenue, San Francisco, CA 94110; e-mail, rjasmer{at}itsa.ucsf.edu.

    • Current Author Addresses: Drs. Jasmer, Daley, and Hopewell: Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, Room 5K-1, 1001 Potrero Avenue, San Francisco, CA 94110.

    • Drs. Saukkonen and Bernardo: Division of Pulmonary and Critical Care Medicine, Boston University School of Medicine, 80 East Concord Street, Room 304, Boston, MA 02118.

    • Drs. Blumberg and King: Division of Infectious Diseases, Emory University, 69 Butler Street, Atlanta, GA 30303.

    • Dr. Vittinghoff: Department of Epidemiology and Biostatistics, University of California, San Francisco, 74 New Montgomery, Suite 600, San Francisco, CA 94105.

    • Dr. Kawamura: Department of Public Health, Tuberculosis Control Section, 1001 Potrero Avenue, Building 90, Room WD94, San Francisco, CA 94110.

    • Author Contributions: Conception and design: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, C.L. Daley, J. Bernardo, M.D. King, P.C. Hopewell.

    • Analysis and interpretation of the data: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, J. Bernardo, E. Vittinghoff, P.C. Hopewell.

    • Drafting of the article: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, C.L. Daley, J. Bernardo, E. Vittinghoff, M.D. King, P.C. Hopewell.

    • Critical revision of the article for important intellectual content: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, C.L. Daley, J. Bernardo, E. Vittinghoff, M.D. King, L.M. Kawamura, P.C. Hopewell.

    • Final approval of the article: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, C.L. Daley, J. Bernardo, E. Vittinghoff, M.D. King, L.M. Kawamura, P.C. Hopewell.

    • Provision of study materials or patients: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, C.L. Daley, J. Bernardo, M.D. King, L.M. Kawamura.

    • Statistical expertise: R.M. Jasmer, E. Vittinghoff.

    • Obtaining of funding: R.M. Jasmer, H.M. Blumberg, M.D. King, P.C. Hopewell.

    • Administrative, technical, or logistic support: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, J. Bernardo, M.D. King, L.M. Kawamura, P.C. Hopewell.

    • Collection and assembly of data: R.M. Jasmer, J.J. Saukkonen, H.M. Blumberg, J. Bernardo, M.D. King.

    Summary for Patients

    • Summaries for Patients:Short-Course Treatment for Latent Tuberculosis Is Associated with More Frequent Liver Injury Than Long-Course Treatment Is Ann Intern Med October 15, 2002 137:I-32
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    1. Ann Intern Med October 15, 2002 vol. 137 no. 8 640-647
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