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

William T Harris; Elizabeth H Baker; Jennifer S Guimbellot; Joseph M Collaco; Michael S Schechter; Gabriela R Oates

doi:10.1016/j.jcf.2025.05.002

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

J Cyst Fibros. 2025 Jun 11:S1569-1993(25)01471-7. doi: 10.1016/j.jcf.2025.05.002. Online ahead of print.

Authors

William T Harris¹, Elizabeth H Baker², Jennifer S Guimbellot³, Joseph M Collaco⁴, Michael S Schechter⁵, Gabriela R Oates²

Affiliations

¹ University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA. Electronic address: wtharris@uabmc.edu.
² University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
³ University of Arkansas Medical Center, Little Rock, AR, USA.
⁴ Johns Hopkins University, Baltimore, MD, USA.
⁵ Children's Hospital of Richmond, Virginia Commonwealth University, Richmond, VA, USA.

PMID: 40506287
DOI: 10.1016/j.jcf.2025.05.002

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.

Keywords: CFTR modulator; Cystic fibrosis; Elexacaftor/Tezacaftor/Ivacaftor; Health disparities; Secondhand smoke; Smoke exposure; Tobacco.