Real-World Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis: A 24-Month Italian National Registry Study.

Background

The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) has transformed cystic fibrosis (CF) care, but national-level real-world data on long-term effectiveness, durability of response, and treatment de-escalation remain limited.

Methods

We conducted a nationwide longitudinal study using the Italian Cystic Fibrosis Registry. People with CF aged ≥6 years who initiated ETI between October 2019 and December 2022 and received ≥3 months of continuous therapy were included. Lung function (percent predicted FEV1, ppFEV1), nutritional status (BMI or BMI z-score), hospital days, complications, microbiology, and chronic treatments were assessed during the two years before and up to two years after ETI initiation. Longitudinal changes were analyzed using generalized estimating equations with multiple imputation for missing data.

Results

The cohort included 2276 individuals (mean age 27.9 ± 13.3 years; 49% female). Mean ppFEV1 declined during the pre-ETI period but increased by 9.9 percentage points at 12 months after ETI initiation (p < 0.001) and remained 6.8 percentage points above baseline at 24 months. A decline between 12 and 24 months was observed overall, except in individuals with severe baseline lung disease (ppFEV1 < 40%), who maintained stable improvements. Mean annual hospital days decreased by approximately 65% and remained low throughout follow-up. Nutritional status improved, with a mean BMI increase of approximately 1.05 kg/m2 compared with immediate pre-treatment in adults and a BMI z-score increase of 0.2 SD compared with pre-treatment timepoints in children. Use of most standard CF therapies declined substantially, particularly among individuals with ppFEV1 ≥ 40%. The prevalence of allergic bronchopulmonary aspergillosis decreased, while liver disease prevalence increased modestly, largely reflecting transient elevations in liver enzymes.

Conclusions

In this nationwide real-world cohort, ETI was associated with sustained improvements in lung function, nutritional status, and hospitalization burden. The attenuation of lung function gains after the first year, particularly in less severe disease, supports the need for individualized monitoring and cautious treatment de-escalation in the ETI era.