Acceptability and safety of one versus three months of rifapentine and isoniazid to prevent tuberculosis in people exposed in the household or workplace in Brazil: The Ultra-Curto randomized controlled trial

Background Short-course tuberculosis preventive therapy with isoniazid and rifapentine (HP) is widely recommended, but the acceptability and safety of one month of daily HP (1HP) compared to three months of weekly HP (3HP) is uncertain. We compared treatment with these two regimens in people with a positive latent tuberculosis infection test and without HIV infection. We hypothesized that 1HP would have greater treatment completion and fewer targeted safety events than 3HP. Methods and findings We conducted a Phase 4 randomized trial of 1HP versus 3HP in adolescents and adults without HIV infection with recent tuberculosis exposure and a positive latent tuberculosis infection test in two sites in Brazil. The primary outcomes were successful completion of >90% of medication as ascertained by self-report, pill counts, and pharmacologic monitoring, and safety. Treatment safety was defined as occurrence of Grade > 2 targeted events or discontinuation of treatment for side effects. We randomized 500 individuals to 1HP (249) and 3HP (251); 193 males and 307 females, with a median age of 39 years. Treatment completion was 89.6% for 1HP recipients versus 84.1% for 3HP recipients (site-adjusted risk difference 5.2%, 95% CI: [−0.1%, 11.2%, p = 0.10). Targeted > Grade 2 adverse safety events or treatment discontinuation occurred in 16.1% of 1HP recipients and 10.4% of 3HP recipients (site-adjusted risk difference 6.1%, 95%CI: [−0.04%, 12.3%, p = 0.05). The proportions who discontinued treatment for any side effect were 7.2% for 1HP and 4.4% for 3HP. The risk difference for the primary safety outcome adjusted for site and baseline demographic and clinical covariates was 3.4% (95% CI −2.3,9.1%, p = 0.24). The trial was not designed to ascertain efficacy. Conclusion Both 1HP and 3HP had high rates of treatment success. Participants assigned to 1HP had more targeted safety events, mostly low-grade. Neither regimen was superior to the other. These results will inform global guidelines for tuberculosis preventive therapy. NCT04703075 ( clinicaltrials.gov ).