Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis

Abstract

Background: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.

Methods: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.

Results: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.

Conclusions: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

Figure 1.. Screening, Randomization, Treatment, and Follow-up.

Figure 2.. Time to an Unfavorable Outcome and Time to a Linezolid Dose Modification.

Panel A shows the time to an unfavorable outcome in the modified intention-to-treat population (i.e., the participants in the intention-to-treat population, with the exception of those who were lost to follow-up after successful treatment or who died from a cause that was adjudicated to be unrelated to tuberculosis). The intention-to-treat population was defined as all participants who underwent randomization, with the exception of those who were excluded after the randomization period either because of protocol violations that occurred before randomization (and were detected after randomization) or because they did not have drug-resistant tuberculosis that was confirmed on the basis of a sputum sample obtained within 3 months before screening. There were no exclusions from the intention-to-treat population. An unfavorable outcome was defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. In participants with bacteriologic failure, a negative culture status for Mycobacterium tuberculosis was not attained or maintained during treatment. In those with relapse, negative culture conversion status was not maintained during follow-up, and a positive culture of an M. tuberculosis strain was confirmed as being genetically identical to that at baseline. Clinical treatment failure was defined as a change from the protocol-specified tuberculosis treatment as a result of a lack of clinical efficacy, retreatment for tuberculosis, or tuberculosis-related death. Panel B shows the time to a linezolid dose modification (i.e., the first of interruption, reduction, or discontinuation) in the intention-to-treat population through the last dose of linezolid. The vertical lines represent the time of the last active linezolid dose.