Three Months of Weekly Rifapentine and Isoniazid Versus Four Months of Daily Rifampicin for Tuberculosis Infection: A Randomized Controlled Trial

Abstract Background Treatment of tuberculosis infection (TBI) is a key pillar of the World Health Organization End TB Strategy. Two short-course rifamycin-based regimens—3 months of weekly isoniazid plus rifapentine (3HP) and 4 months of daily rifampicin (4RIF)—are widely recommended; however, they have not previously been directly compared in a randomized controlled trial. We compared treatment completion between 3HP and 4RIF among individuals with TBI. Methods We conducted a multicenter, open-label, parallel-group randomized controlled trial across 7 tuberculosis clinics in Sydney, Australia, between July 2019 and June 2024. Participants of any age with TBI were randomized 1:1, stratified by site, to receive either weekly 3HP or daily 4RIF. All doses were self-administered. Participants in the 3HP group received weekly Short Message Service (SMS) adherence reminders; both groups received standard clinic follow-up. The primary outcome was treatment completion, defined as ingestion of ≥90% of prescribed doses. Analyses were conducted on an intention-to-treat basis. Results A total of 210 participants were enrolled (106 assigned to 3HP and 104 to 4RIF). Treatment completion was significantly higher in the 3HP group (84.9%) than in the 4RIF group (65.4%; relative risk, 1.30 [95% confidence interval, 1.22–1.38]; P < .001). Adverse events of any grade occurred in 24.5% of participants receiving 3HP and 20.2% receiving 4RIF. No treatment-related deaths were reported. Conclusions Weekly 3HP supported by SMS reminders achieved significantly higher treatment completion than daily 4RIF, with similar safety. These findings support broader implementation of 3HP to optimize adherence and outcomes in TBI treatment programs. Clinical Trials Registration Australian New Zealand Clinical Trials Registry (ACTRN12618001672246).