Cystic fibrosis liver disease progression in the era of elexacaftor–tezacaftor–ivacaftor

Abstract

Background & Aims

The effect of elexacaftor–tezacaftor–ivacaftor (ETI) on cystic fibrosis liver disease (CFLD) outcomes remains unknown. Thus, we investigated the association between the ETI rollout and trends in CFLD progression in a nationwide cohort.

Methods

Using the French National Hospital Discharge Database (2014–2023), we measured the incidence of CFLD progression (decompensated cirrhosis, gastroesophageal variceal bleeding, primary liver cancer, or liver transplantation) before and after ETI became available (December 2019) in patients with cystic fibrosis (pwCF) aged ≥12 years. Death without CFLD progression and lung transplantation were treated as competing events. Incidence rates were compared across ETI calendar eras in both the full cohort and a 1:1 propensity score-matched sample. Analyses used Kaplan–Meier curves, Fine–Gray competing risk models, and adjusted incidence rate ratios (aIRRs).

Results

The cohort included 10,083 pwCF (median age: 19 years [IQR 14–29]; 52.6% male), with 24.6% censored pre-ETI and 75.4% post-ETI. The overall incidence of CFLD progression was 3.7 per 1,000 person-years: 25.4 pre-ETI versus 1.2 post-ETI (p <0.001). The incidence of all CFLD outcomes, including non-bleeding varices, declined post-ETI (p <0.001). In matched analyses, pwCF censored during the ETI era had a lower incidence of CFLD progression (aIRR 0.28, 95% CI: 0.18–0.43; p <0.001). In addition, deaths in pwCF occurred at an older age during the ETI era.

Conclusions

The incidence of CFLD progression declined during the ETI rollout. While these findings suggest an association between ETI availability and improved liver outcomes, unmeasured confounders and concurrent changes in management might have also contributed. Thus, further studies are needed to confirm causality and understand underlying mechanisms.

Impact and implications

In this nationwide French cohort study of over 10,000 people with cystic fibrosis, we observed a significant decline in the incidence of cystic fibrosis liver disease outcomes following the rollout of elexacaftor–tezacaftor–ivacaftor (ETI) in December 2019. The rate dropped from 25.4 to 1.2 per 1,000 person-years post-ETI. Matched analyses confirmed a reduced risk of liver disease progression, with an adjusted incidence rate ratio of 0.28. Although the findings suggest ETI may improve liver outcomes in people with cystic fibrosis, potential confounding factors necessitate further research to establish causality and understand the underlying biological mechanisms.