Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis |
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| Institution: | 1. Department of Pharmacy Services, Queens University, Belfast, UK;2. Department of Pediatrics, University of Washington, Seattle Children''s Hospital, Seattle, WA, USA;3. Marisco Lung Institute, University of North Carolina, Chapel Hill, NC, USA;4. Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA;1. University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam;2. School of Business and Economics, NUI Galway, Galway, Ireland;3. Professor of Health Economics, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences Queens University Belfast, UK;1. Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, 4 Newark Street, Whitechapel, E1 2AT London, UK;2. Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland;3. MRC Centre for Environment and Health, School of Population Health and Environmental Sciences, King''s College London, UK;1. Division of Respiratory Medicine, University Children''s Hospital of Zurich, Zurich, Switzerland;2. Pediatric Respiratory Medicine, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;3. Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada;4. Pediatric Pulmonology Unit, Department of Pediatrics, CHUV Lausanne, University Hospital of Lausanne, Switzerland;1. Translational Lung Research Center (TLRC), Heidelberg, Germany;2. Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany;3. Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany;4. Department of Pneumology and Critical Care Medicine, Thoraxklinik at the University Hospital Heidelberg, Heidelberg, Germany;5. Division of Pediatric Pulmonology & Allergology and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany;6. Department of Pediatric Pulmonology, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité-Universitätsmedizin Berlin, Berlin, Germany;7. Berlin Institute of Health (BIH), Berlin, Germany;8. German Center for Lung Research (DZL), associated partner site, Berlin, Germany;9. Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR, USA;10. Institute of Medical Microbiology and Hygiene, Technische Universität Dresden, Dresden, Germany |
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| Abstract: | ObjectivesTobacco 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.MethodsA 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.ResultsThe 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).ConclusionTobacco 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. |
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