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. 2021 Jul;20(4):612-617.
doi: 10.1016/j.jcf.2020.09.011. Epub 2020 Oct 3.

Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis

Elizabeth Baker  1 , William T Harris  1 , Steven M Rowe  1 , Sarah B Rutland  1 , Gabriela R Oates  2
Affiliations

Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis

Elizabeth Baker et al. J Cyst Fibros. 2021 Jul.

Abstract

Objectives: Tobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years.

Methods: A retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016-2018) compared the slope of change in lung function (GLI FEV1% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling.

Results: The sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV1 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV1 and experienced a greater lung function decline. Over two years, the difference in ppFEV1 by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV1 among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively).

Conclusion: Tobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12-20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.

Keywords: CFTR modulators; Secondhand smoke; Smoke exposure; Tezacaftor/ivacaftor; Tobacco.

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Conflict of interest statement

Declaration of Competing Interest WTH and SMR have received support through their institution (UAB) from Vertex Pharmaceuticals to conduct and oversee CFTR modulator clinical trials.

Figures

Figure 2.
Figure 2.. Mean ppFEV1 of tezacaftor-ivacaftor1 users, by tobacco smoke exposure (TSE)
1 FDA-approved in February, 2018. *Statistical significance of the increased difference in ppFEV1 by TSE from 2016 to 2018.
Figure 3.
Figure 3.
ppFEV1 estimates from mixed effects regression
See this image and copyright information in PMC

Comment in

  • Speaking of pandemics..
    Schechter MS. Schechter MS. J Cyst Fibros. 2021 Jul;20(4):564-565. doi: 10.1016/j.jcf.2021.04.017. Epub 2021 Jun 5. J Cyst Fibros. 2021. PMID: 34103249 Free PMC article. No abstract available.

References

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    1. Oates GR, Baker E, Rowe SM, et al.Tobacco Smoke Exposure and Socioeconomic Factors Are Independent Predictors of Pulmonary Decline in Pediatric Cystic Fibrosis. J Cyst Fibros. 2020. - PMC - PubMed

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