Rifampin and pyrazinamide for latent tuberculosis infection: clinical trials and general practice.

As the prevalence of active tuberculosis decreases in the United States, the focus on treatment of latent tuberculous infection (LTBI) has intensified. However, the standard 6–9-month course of isoniazid has been burdened with suboptimal rates of therapy completion and concerns about hepatotoxicity and infection with isonia-zid-resistant organisms. These issues have spurred interest in alternative, shorter reg-imens [1]. One of these LTBI regimens, a 2-month course of rifampin with pyrazinamide (RZ), has achieved considerable controversy because of serious concerns about its safety. Initially, randomized studies involving HIV-infected individuals indicated that the regimen was safe, with no significant differences in hepatotoxicity, compared with a 6-month course of isoniazid [2, 3]. Gordin et al. [4] found that hep-atotoxicity that was potentially life-threatening or led to treatment discontinuation was less common among patients treated with RZ than among those treated with 12 months of isoniazid. This study had broad inclusion criteria; it enrolled substantial numbers of injection drug users who might have increased risks for hep-atotoxicity, as well as individuals with baseline transaminase levels of up to 5 times the upper limit of normal. This study also reported equal efficacy for both LTBI treatment regimens in HIV-infected individuals. Subsequently, RZ was recommended for treatment of LTBI in HIV-infected individuals, and the recommendation was extended to HIV-uninfected individuals as an acceptable alternative regimen for isoniazid [1]. The ensuing experience with RZ in the HIV-uninfected population raised serious concerns regarding the hepatotoxicity of the regimen. Jasmer et al. [5] found that individuals treated with a 2-month course of RZ developed significantly more elevations in the alanine aminotransferase (ALT) level of grade III or higher (i.e., an ALT level of у250 U/L), compared with patients who were treated with a 6-months course of isoniazid, and RZ recipients were not more likely to complete the regimen. A nonrandomized trial reported significantly more elevations in the aspartate aminotransferase (AST) level of у160 U/ L in patients who were treated with a 2-month course of RZ [6]. There were case reports to the Centers for Disease Control and Prevention that eventually totaled 48 fatalities and hospitalizations associated with RZ, which prompted revised recommendations that limited RZ prescription for treatment of LTBI. These recommendations included provision of no more than 2-week supplies of RZ per visit, exclusion of patients with liver disease or history of significant isoniazid hepatotox-icity, intensified monitoring of liver enzyme levels, and cautious use of RZ for persons …