Infectious Disease
Comparative Effectiveness of Three Linezolid Management Strategies for Peripheral Neuropathy During Multidrug- or Rifampicin-Resistant Tuberculosis Treatment: A Target Trial Emulation Matthew Romo* Matthew Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Romo Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA
Linezolid is a key component of multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) regimens, but peripheral neuropathy (PN) is a frequent, treatment-limiting toxicity. Clinicians often suspend linezolid or reduce the dose, but the impact of these changes on treatment success is uncertain. We emulated a target trial using data from the endTB Observational Study, a prospective cohort of people with MDR/RR‑TB treated with 18–24-month individualized regimens. Eligible participants had an adverse event of grade 1–2 PN while on linezolid 600 mg daily within 6 months of treatment initiation. We compared three strategies from PN onset (time zero): (1) early linezolid change (suspension or dose reduction) within 0–48 days; (2) late change within 49–181 days; and (3) no change within 0–181 days. Using a clone–censor–weight approach, we estimated the per‑protocol effect on end‑of‑treatment success, standardized for baseline confounders including site, weeks on linezolid at PN onset, and measures of TB disease severity and regimen strength. Among 281 participants from 12 countries, PN occurred a median (IQR) of 13 (6–18) weeks after treatment start. Weighted, standardized probabilities of treatment success were 84% (95% CI: 71%, 93%) for early change, 78% (65%, 87%) for late change, and 85% (79%, 89%) for no change. Compared with no change, treatment success ratios were close to the null value of 1 for both the early change (1.00, 95% CI: 0.83, 1.11) and late change (0.92; 95% CI: 0.75, 1.05) strategies. Modifications to linezolid in the first six months of individualized regimens for MDR/RR-TB were associated with similar probabilities of treatment success compared with continuing linezolid 600 mg daily among people who developed mild or moderate PN. These findings support the clinical practice of cautiously adjusting linezolid when needed to manage PN during MDR/RR-TB treatment.