Isoniazid (INH) has been the mainstay of treatment of
latent tuberculosis infection for almost 50 years. The currently recommended preferred regimen is 9 months daily self-administered INH (9H); this has efficacy of more than 90% if completed properly. Unfortunately, INH is associated with serious adverse events, including hepatotoxicity. Although risk factors for this complication are well established, allowing for better selection of candidates for
therapy, this complication still occurs, and is occasionally fatal. Hence close follow up of patients is necessary, increasing the cost and complexity of treatment. This problem, plus the lengthy duration, results in poor acceptance by patients and providers, and poor adherence by patients. As a result, many preventable cases of
tuberculosis continue to occur, and the public health impact of
latent tuberculosis infection treatment is suboptimal. These problems have spurred interest in finding shorter, safer and cheaper alternative regimens, with similar efficacy. Of the many regimens that have been examined, 2 months of
rifampin and
pyrazinamide has excellent efficacy-in experimental studies in mice and randomized trials, largely in HIV-infected persons. However, while the safety of 2 months of
rifampin and
pyrazinamide appears acceptable in HIV-infected persons and children, in non-HIV-infected adults this regimen is associated with an unacceptably high rate of severe liver toxicity. Three to four months of INH and
rifampin has had equivalent effectiveness
as 6 months INH in several randomized trials. However, completion of
therapy and toxicity has been the same as with INH-possibly because two drugs are taken rather than one. The fourth commonly studied regimen is 4 months
rifampin. This has been found to have significantly better completion than 9H, with significantly less toxicity, especially hepatotoxicity. However, only one trial has evaluated efficacy and effectiveness of mono-
rifampin therapy. In this trial, 3 months
rifampin had somewhat better efficacy than either 3 months of
isoniazid and
rifampin (3HR) or 6 months
isoniazid. Two large scale trials are ongoing; one is comparing efficacy and effectiveness of 9H with 4 months
rifampin (both daily and self-administered), while the second, which is nearing completion, compares daily self-administered 9H with 3 months directly observed once weekly INH combined with
rifapentine. The results of these two trials will likely shape future recommendations substantially.