Tobacco smoke exposure is associated with diminished longitudinal benefit of elexacaftor/tezacaftor/ivacaftor in cystic fibrosis.

Abstract

Background: Tobacco smoke exposure (TSE) is associated with diminished benefit of ivacaftor and tezacaftor/ivacaftor in people with CF (PwCF). This study assessed the association of TSE with clinical benefit from elexacaftor/tezacaftor/ivacaftor (E/T/I), focusing on lung function (ppFEV₁) and pulmonary exacerbations (PEx).

Methods: We conducted a retrospective longitudinal analysis of data from the Cystic Fibrosis Foundation Patient Registry (2019-2021) on PwCF aged ≥ 12 years with documented prescription of E/T/I. TSE was defined by self-report of daily or weekly exposure, including living with a smoker or active smoking. Outcome measures were change in ppFEV₁ and PEx after E/T/I initiation. Mixed effects modeling adjusted for sociodemographic and clinical characteristics quantified the interaction between TSE and E/T/I response.

Results: In 15,005 PwCF (mean age 27.7 years, 51.9 % F508del homozygous), TSE was associated with a 2.7 % lower ppFEV₁ (69.1 % vs 71.8 %, p < 0.001) before E/T/I therapy. After E/T/I initiation, ppFEV₁ increased in both groups, with a similar peak ΔppFEV₁ of 8.5 % at 6 months. However, after 6 months on E/T/I therapy, TSE was associated with an additional 0.03 % monthly decrease in ppFEV₁, resulting in a 3.4 % lower ppFEV₁ (76.3 % vs 79.7 %, p < 0.001) at the end of 2021. Smoke-exposed PwCF on E/T/I had twice the odds of a PEx compared to unexposed counterparts (OR 2.2, p < 0.001).

Conclusion: E/T/I increases ppFEV₁ and decreases PEx in all PwCF, but this benefit is not sustained past 6 months of E/T/I therapy among those with TSE, thus widening long-term disparities in pulmonary outcomes.