Hepatotoxicity from Rifampin Plus Pyrazinamide
Lessons for Policymakers and Messages for Care Providers

WILLIAM J. BURMAN and RANDALL R. REVES

Denver Metro Tuberculosis Clinic, Denver Public Health and the Department of Medicine (Division of Infectious Diseases), University of Colorado Health Sciences Center, Denver, Colorado

	ARTICLE

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This issue of the Journal includes a report from the Centers for Disease Control and Prevention (CDC) of 21 cases of serious hepatotoxicity, including 5 deaths, attributed to treatment of latent tuberculosis with rifampin/pyrazinamide (1). This 2-mo regimen held great promise, particularly in the treatment of difficult-to-reach populations, such as incarcerated or homeless persons, for whom completion rates with 6-9 months of isoniazid are as low as 5-25% (2, 3). Last year's ATS/CDC statement on diagnosis and treatment of latent tuberculosis (4) included the option to use this short-course regimen as standard treatment, and recommended clinical rather than laboratory monitoring for hepatotoxicity (unless other risk factors for hepatic dysfunction were present).

The occurrence of severe or fatal reactions to treatment designed to prevent disease among healthy individuals raises several questions. Do the reported events accurately reflect the number of cases of serious hepatotoxicity? Were the studies indicating that rifampin/pyrazinamide was as safe as isoniazid adequate? Should this regimen be abandoned, or is further study indicated?

The effort CDC devoted to finding and evaluating cases of severe hepatoxicity provides some assurance that the 21 cases are a reasonable estimate of the numerator of the toxicity equation. At first glance, the number of deaths seems high, compared to the annual number of isoniazid-related deaths previously reported to CDC (5). Clearly though, we need the denominator (the number of patients who received the 2-mo regimen) to begin to understand severe hepatotoxicity from the rifampin/pyrazinamide regimen. Increased rates of hepatotoxicity were noted in a preliminary study in HIV-negative patients (6). However, other studies suggested that rifampin/ pyrazinamide would not cause problematic rates of hepatoxicity. There was not an increased rate of hepatoxicity among the approximately 2,000 HIV-infected patients who received rifampin/ pyrazinamide (7). Furthermore, the addition of pyrazinamide to isoniazid and rifampin did not substantially increase hepatotoxicity in trials of treatment of active tuberculosis (11, 12).

To put these events in context, it is instructive to review the history of perceptions about isoniazid hepatotoxicity. The efficacy and safety of isoniazid for treatment of latent tuberculosis was evaluated in placebo-controlled trials involving approximately 100,000 persons (13). Hepatitis was rare in these trials: 0.1% among patients on isoniazid (13). As isoniazid therapy became more widely used, however, there were reports of serious hepatoxicity (14). A surveillance study involving 13,838 patients on isoniazid suggested a higher rate of hepatitis, 1.3%; and there were 8 deaths (later analysis suggests that an outbreak of hepatitis unrelated to isoniazid may have been responsible for most of the deaths) (15). These reports led to pessimism about the advisability of treatment of latent tuberculosis infection. However, recent surveillance reports on isoniazid treatment have suggested rates quite similar to those in the randomized trials: hepatitis - 0.1% (16), fatal hepatitis - 0.001% (17) (a death rate far lower than would be expected if patients were not treated and some progressed to active tuberculosis) (5).

Lessons for Policy Makers

The lesson of this 50-year experience with isoniazid is that we need large, carefully performed studies and cannot draw conclusions from numerator cases. Tuberculosis control programs retained their interest in isoniazid therapy, despite occasional reports of severe hepatotoxicity, because of the size and breadth of the initial studies. The standard for safety of regimens for treatment of latent tuberculosis is clearly higher than for treatment of active disease; active tuberculosis carries a substantial short-term risk of death and serious morbidity, whereas the risk of progression to active tuberculosis is relatively low (5-10%), even among "high-risk" latently infected patients (4). Judged by this standard, rifampin/pyrazinamide has not received sufficient evaluation among HIV-uninfected persons with latent tuberculosis to be routinely recommended.

The concerns about the safety of rifampin/pyrazinamide were carefully noted in the ATS/CDC statement on latent tuberculosis (4), and further research was recommended (and undertaken by CDC and others) to evaluate safety among HIV-uninfected persons. Rather than criticize details of the statement, it is more important to examine the reason the panel had relatively little data with which to formulate guidelines. In recent years clinical trials of treatment of latent infection among HIV-uninfected persons were thought to be unfeasible because of the sample size necessary to evaluate efficacy (the rate of active tuberculosis). Yet the number required, approximately 8,000 for a comparison of two regimens among "high-risk" patients (Sterling, unpublished data), is not a large number when trying to detect and compare rates of hepatotoxicity, and is much smaller than the sample sizes in the clinical trials of isoniazid therapy. Trials of this size have been judged unfeasible because of the small amount of funding available for tuberculosis clinical research, not because of scientific or methodological concerns.

The eventual place of the rifampin/pyrazinamide regimen in treatment of latent tuberculosis is unclear, but the broader concept of short-course treatment of latent infection remains a promising tool for tuberculosis control. The Tuberculosis Trials Consortium is evaluating a short-course, highly-intermittent regimen of rifapentine plus isoniazid in a randomized trial that will enroll 8,000 patients. Rifamycin-alone regimens, such as daily rifampin for 3-4 mo, should also be further evaluated. Finally, there should be a systematic effort to carry out surveillance for severe reactions to antituberculosis therapy. The public health community and ATS must advocate for resources if these exciting possibilities are to be appropriately evaluated.

Messages for Care Providers

The updated guidelines for use of rifampin/pyrazinamide and monitoring during therapy are appropriately cautious, while additional data are being gathered (1). Rifampin/pyrazinamide is suggested as an acceptable alternative for HIV-positive persons and for HIV-uninfected persons who do not use alcohol or other potentially hepatotoxic drugs and are unlikely to finish a longer duration of therapy. No more than a 2-wk supply of medication should be dispensed at a clinic visit, to prevent prolonged unmonitored therapy. The most controversial recommendation is likely to be that monitoring tests (serum AST and bilirubin) be done every two weeks during therapy. These guidelines will, and should, decrease the use of rifampin/pyrazinamide during this time of uncertainty about its safety. They should not lead to its abandonment; the problems of isoniazid treatment remain substantive.

	Footnotes

Correspondence and requests for reprints should be addressed to William J. Burman, M.D., Denver Public Health, 605 Bannock St., Denver, CO 80204. E-mail: bburman{at}dhha.org

	References

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