The Impact of Elexacaftor‐Tezacaftor‐Ivacaftor on Biochemical Surrogates of Cystic Fibrosis Hepatobiliary Involvement: A Retrospective Cohort Study

Background Elexacaftor‐tezacaftor‐ivacaftor (ETI) has significantly improved lung function and growth in people with cystic fibrosis (pwCF). However, its impact on cystic fibrosis hepatobiliary involvement (CFHBI) remains unclear. This study aims to investigate the impact of ETI on biochemical surrogates of CFHBI using a large population database. Methods This 1:1 retrospective cohort study utilized TriNetX, a de‐identified multicenter database, and included people aged 6–21 years with ICD‐10 diagnostic codes for cystic fibrosis who were prescribed pancreatic enzyme replacement therapy. ETI group (pwCF on ETI seen from 1/1/2020 to 1/1/2024) and non‐ETI group (pwCF not on ETI seen from 1/1/2014 to 1/1/2018) were analyzed. Groups were matched using propensity scores, and statistical analyses were performed on TriNetX (significance set at p = 0.05). Results There were 533 children with CF (CwCF) aged 6–12 years and 1177 adolescents and young adults with CF aged 13–21 years in each cohort. In CwCF, the ETI group had significantly lower ALT (33 ± 44 U/L vs. 45 ± 57 U/L, p = 0.003) and GGT levels (18 ± 20 U/L vs. 28 ± 51 U/L, p = 0.004), as well as improved albumin and PT/INR compared to non‐ETI group. In pwCF (13–21), the ETI group had significantly lower GGT (21 ± 26 U/L vs. 32 ± 63 U/L, p = 0.002), and improved albumin and PT compared to non‐ETI group; however, indirect bilirubin was higher (0.7 ± 0.5 mg/dL vs. 0.3 ± 0.4 mg/dL, p < 0.001). Conclusion Our findings suggest that earlier ETI use in children with CF is associated with improved liver enzymes, offering reassurance against widespread drug‐induced liver injury. Long‐term follow‐up including imaging and biopsy when available, pre‐ and post‐ETI, is needed to better assess the impact of ETI on CFHBI and advanced CF liver disease.