Comparison of three linezolid management strategies for peripheral neuropathy in multidrug- or rifampicin-resistant tuberculosis treatment: a target trial emulation

BACKGROUND

Peripheral neuropathy frequently leads to linezolid dose reductions or interruptions during multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) treatment. The implications of these modifications on treatment success are uncertain.

METHODS

We conducted a target trial emulation using the endTB Observational Study among individuals who developed non-severe peripheral neuropathy while receiving linezolid 600 mg daily within 6 months of initiating an individualized MDR/RR-TB regimen. We examined three linezolid management strategies: immediate change (i.e., dose reduction, temporary interruption, discontinuation) within Weeks 1–7 after peripheral neuropathy onset, deferred change within Weeks 8–26, and no change (i.e., continuing linezolid 600 mg daily) during Weeks 1–26. To emulate the per-protocol analysis of a trial, we used an approach involving cloning and censoring participant data, and applying inverse probability of censoring weights.

RESULTS

Among 303 eligible participants from 12 countries, peripheral neuropathy occurred a median of 11 weeks (interquartile range: 4–18) after treatment initiation. Weighted, standardized probabilities of treatment success were 84.7% (95% CI: 69.2%, 92.9%) for immediate change, 78.9% (95% CI: 65.9%, 87.1%) for deferred change, and 85.2% (95% CI: 80.5%, 89.1%) for no change. Compared with no change, treatment success ratios were 0.99 (95% CI: 0.83, 1.11) for immediate change and 0.93 (95% CI: 0.78, 1.01) for deferred change.

CONCLUSIONS

We did not find evidence of a substantial negative impact of immediate modification to linezolid on MDR/RR-TB treatment success. Our results support the clinical practice of cautiously adjusting linezolid when needed to manage non-severe peripheral neuropathy.