Efficacy, safety, and completion of modified short-course rifapentine and isoniazid for latent tuberculosis infection in patients with high-risk rheumatic disease: a multicentre, open-label, randomized, non-inferiority trial

Background Patients with rheumatic diseases are at high risk for latent tuberculosis infection (LTBI) reactivation. We aimed to evaluate whether a modified 3-month regimen (3HP-PUMCH) was non-inferior to the standard 9-month isoniazid regimen (9H) for tuberculosis preventive treatment in this vulnerable population. Methods We conducted a multicenter, open-label, randomized, non-inferiority trial at nine tertiary general hospitals in China. Eligible participants were adults (18-70 years) with high-risk rheumatic diseases and LTBI undergoing immunosuppressive therapy. Patients were randomized (1:1) to receive either the 3HP-PUMCH regimen (twice-weekly rifapentine 450 mg plus daily isoniazid 300 mg) or the 9H regimen (daily isoniazid 300 mg). The primary endpoint was the occurrence of tuberculosis, with a non-inferiority margin of 1.4 percentage points. Analysis used the modified intention-to-treat population. The trial was registered with Chinese Clinical Trial Registry ChiCTR1800018242. Findings Between 19 September 2018 and 18 August 2021, 536 patients with rheumatic diseases were enrolled. The cumulative rate of tuberculosis was 0.00% (0 of 249, 95% CI 0.00-1.47) in the 3HP-PUMCH group, compared with 1.15% (3 of 260, 95% CI 0.24-3.34) in the 9H group, with a rate difference of -1.15 percentage points (95% CI -2.4 to 0.14). Drug discontinuation rates due to serious adverse events or tuberculosis occurrence were 2.8% (7 of 249) in the 3HP-PUMCH group and 1.9% (5 of 260) in the 9H group (p = 0.509). Adverse drug reactions occurred in 24 (9.6%) of 249 patients versus 39 (15.0%) of 260 (p = 0.066), with hepatotoxicity in 11 (4.4%) of 249 versus 27 (10.4%) of 260 (p = 0.010). 223 (89.6%) of 249 patients completed treatment in the 3HP-PUMCH and 237 (91.2%) of 260 in the 9H group (p = 0.54). Interpretation The short-course 3HP-PUMCH regimen was non-inferior to the 9H regimen in preventing tuberculosis and demonstrated a favorable safety profile, with high treatment completion in LTBI patients with rheumatic diseases. This regimen might be more suitable for patients with underlying diseases and those on concomitant medications. Funding National Natural Science Foundation of China.