One-Month Rifapentine–Isoniazid Regimen Versus Six-Month Isoniazid Monotherapy for Latent Tuberculosis: Experience from a Reference Center

<i>Background and Objectives</i>: Isoniazid monotherapy has been the most widely used treatment for latent tuberculosis infection (LTBI). Although effective, it has been associated with poor adherence and a higher incidence of adverse events. The shorter duration of rifamycin-based regimens has become increasingly preferable. The one month of daily rifapentine plus isoniazid (1HP) has demonstrated low toxicity and higher completion rates in HIV-infected populations. This study aims to compare the completion rate and adverse events between the 1HP and daily isoniazid for 6 months (6H) regimens in the non-HIV adult population. <i>Materials and Methods</i>: Retrospective, observational, longitudinal study, followed at the National Reference Center for Tuberculosis (Lisbon, Portugal), from January 2024 to January 2025. Treatment-related symptoms and liver function were assessed throughout the treatment. Relevant hepatic toxicity was defined as aspartate transaminase (AST) and/or alanine transaminase (ALT) > 1.5 times the upper limit of normal (ULN). <i>Results</i>: A total of 90 and 74 patients were assigned to the 1HP and 6H groups, respectively. No significant differences were observed in the frequency of reported adverse symptoms between the 1HP and 6H groups (28.9% vs. 23.0%, <i>p</i> = 0.4). The 1HP regimen was associated with a significantly lower risk of relevant hepatic toxicity (4.6% vs. 32.9%, <i>p</i> < 0.001) and a higher rate of treatment completion (97.8% vs. 67.6%, <i>p</i> < 0.001). Adverse drug reactions were the leading cause of treatment discontinuation in both groups, with hepatic toxicity and gastrointestinal intolerance being the most frequent events. A therapeutic switch to rifampicin was required in 16.2% of patients receiving the 6H regimen, whereas no switch was needed in the 1HP group. <i>Conclusions</i>: The 1HP regimen was associated with a higher rate of treatment completion and lower hepatic toxicity with no significant differences in the reported adverse symptoms.