Reply to te Brake et al.: Conflicting Findings on an Intermediate Dose of Rifampicin for Pulmonary Tuberculosis.

From the Authors:

We thank te Brake and colleagues for their interest in the HIRIF (Evaluation of High-Dose Rifampin in Patients with New, Smear-Positive Tuberculosis) trial results (1, 2) and for the PanACEA (Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics) consortium’s ongoing commitment to optimize rifampin dosing for patients with tuberculosis. te Brake and colleagues highlight a perceived difference between the HIRIF findings and those of HIGHRIF2 (PanACEA HIGHRIF study 2) (3). The direction and magnitude of the effects observed in both trials were similar: HIGHRIF2 showed a nonsignificant trend toward a higher hazard of culture conversion in both mycobacteria growth indicator tube and Löwenstein-Jensen medium for the 1,200 mg dose compared with the 600 mg dose, and HIRIF revealed that higher rifampin doses and exposure resulted in modest and statistically significant increases in the rate of sputum culture sterilization (2). Interpretation of the two studies is consistent: rifampin doses up to 20 mg/kg/d, with no additional changes to the regimen, are unlikely to permit treatment shortening.

Similarly to HIGHRIF2, HIRIF found no difference in the secondary efficacy outcome of 8-week culture conversion in Löwenstein-Jensen medium with daily rifampin doses up to 20 mg/kg. Rifampin doses also did not influence the frequency of treatment failure and disease recurrence at 12 months. HIRIF was not powered for these secondary endpoints, which would have required a much larger sample size than was possible for a phase II trial. We are encouraged by the advances the PanACEA consortium has made to date in optimizing doses of rifampin higher than 20 mg/kg/d. We also look forward to improving the statistical power for efficacy and safety evaluations by pooling HIRIF and HIGHRIF2 data through collaboration with the authors of the correspondence. Combined with ongoing trials to optimize the dose of rifampin, pooled individual-level patient data analyses will be critical to influence future treatment guidelines and improve the lives of patients with tuberculosis.