Three months of weekly rifapentine and isoniazid versus four months of rifampicin for tuberculosis infection: a randomised controlled trial

Background Treatment of tuberculosis infection (TBI) is a key pillar of the WHO End TB Strategy. Two short-course rifamycin-based regimens-weekly isoniazid plus rifapentine for 12 weeks (3HP) and daily rifampicin for 16 weeks (4RIF)-are widely recommended; however, they have not previously been directly compared in a randomised controlled trial. We compared treatment completion between 3HP and 4RIF among individuals with TBI. Methods We conducted a multicentre, open-label, parallel-group randomised controlled trial across seven tuberculosis clinics in Sydney, Australia, between July 2019 and June 2024. Participants of any age with TBI were randomised 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 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%) compared with the 4RIF group (65.4%; relative risk 1.30, 95% CI 1.22-1.38; p Conclusion 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 optimise adherence and outcomes in TBI programs.