High rate of successful outcomes treating highly resistant TB in the ZeNix study of pretomanid, bedaquiline and alternative doses and durations of linezolid


BACKGROUND: In the Nix-TB trial, a 6-month BPaL regimen, starting with 1200 mg linezolid daily, resulted in 89% durable cure at 24 months post therapy follow-up, but a high rate of linezolid-related adverse events. The subsequent ZeNix trial enrolled patients with highly resistant TB in South Africa, Russia, Georgia and Moldova and treated them for 6 months with bedaquiline (B), pretomanid (Pa) and varying doses and durations of linezolid (L), with follow up to the primary endpoint 6 months after completion of treatment.
METHODS: Patients were treated for 6 months with bedaquiline (200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks), pretomanid (200 mg daily) and were equally randomized, dose-blinded, to daily linezolid starting at 1200 mg for 6 months (1200L6M), 1200 mg for 2 months (1200L2M), 600 mg for 6 months (600L6M), or 600 mg for 2 months (600L2M). Clinical, laboratory and sputum liquid culture evaluations were performed at baseline, weekly for 8 weeks and then every 2-4 weeks through the end of treatment, monthly for 3 months, and at the primary endpoint 6 months after completion of treatment.
RESULTS: 181 participants with highly resistant TB were enrolled, including 36 (19.9%) who were HIV positive. A high success rate at the primary endpoint, similar to Nix-TB, was observed: 93% in 1200L6M, 89% in 1200L2M, 91% in 600L6M and 84% in 600L2M. Patients in the 1200L6M arm had higher rates of adverse events of peripheral neuropathy and myelosuppression, as manifest as anemia: 38% and 22% in 1200L6M, 24% and 17% in 1200L2M, 24% and 2% in 600L6M, and 13% and 7% in 600L2M, respectively. Four patients had optic neuropathy that reversed, all in the 1200L6M arm. More patients in the 1200L6M arm required linezolid dose modification (reduction, interruption, or discontinuation): 51% in 1200L6M, 30% in 1200L2M, 18% in 600L6M, and 18% in 600L2M.
CONCLUSIONS: The ZeNix trial confirms the high relapse-free cure rate for the BPaL regimen in highly resistant TB and suggests that reduced doses and/or shorter durations of linezolid than 1200 mg for 6 months have similar efficacy and improved safety.