Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis

**Background:** Cystic fibrosis (CF) is caused by mutations in the CFTR gene, leading to multi-organ disease. While CFTR modulator therapies like lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve pulmonary outcomes, their impact on liver disease—a major cause of morbidity and mortality in CF—remains unclear. This study aimed to evaluate whether these modulators affect serum biomarkers of liver fibrosis in children and adolescents with CF.

**Methods:** This retrospective, single-center analysis included patients from a tertiary care Pediatric CF Center treated with lumacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor for ≥6 months, with available liver function tests and platelets before and during treatment. Patients were categorized as having “liver involvement” (APRI ≥0.345 or GPR ≥0.403 on ≥2 occasions ≥3 months apart) or “no liver involvement” prior to starting therapy. Laboratory values (AST, ALT, GGT, platelets) were collected, and APRI and GPR were calculated. Paired comparisons were made using Wilcoxon signed-rank tests. A subanalysis examined seven patients who received lumacaftor/ivacaftor followed by elexacaftor/tezacaftor/ivacaftor, controlling for treatment duration (~12 months each).

**Key Results:** Of 84 patients analyzed, 35 received lumacaftor/ivacaftor (13 with liver involvement) and 49 received elexacaftor/tezacaftor/ivacaftor (15 with liver involvement). In patients with liver involvement on lumacaftor/ivacaftor (mean treatment 33.3±12.2 months), significant decreases were observed in GGT (p=0.002), APRI (p=0.042), and GPR (p=0.002). No significant changes were seen in AST, ALT, or platelets. In patients without liver involvement on lumacaftor/ivacaftor, no significant differences were found. For elexacaftor/tezacaftor/ivacaftor (mean treatment 14.1±4.9 months for those with liver involvement), patients with liver involvement showed an increase in ALT (p=0.048) and a decrease in platelets (p=0.010), with no significant changes in AST, GGT, APRI, or GPR. In those without liver involvement on elexacaftor/tezacaftor/ivacaftor, ALT, APRI, and GPR increased (p=0.005, 0.027, 0.023 respectively) and platelets decreased (p=0.002). In the subanalysis of seven patients with liver involvement who switched from lumacaftor/ivacaftor to elexacaftor/tezacaftor/ivacaftor, improvements in AST, ALT, GGT, and GPR were seen on lumacaftor/ivacaftor but not further improved on elexacaftor/tezacaftor/ivacaftor; ALT actually worsened on the latter.

**Clinical Implications:** This study provides the first evidence that lumacaftor/ivacaftor may improve liver fibrosis markers in children and adolescents with CF and pre-existing liver involvement, suggesting a potential role in treating CF-associated liver disease. The lack of similar improvement with elexacaftor/tezacaftor/ivacaftor may be due to prior normalization of biomarkers by lumacaftor/ivacaftor or shorter treatment duration. These findings highlight the need for larger, multicenter studies with imaging or histology to confirm these results and to understand the differential effects of CFTR modulators on liver health. The study also underscores the importance of considering prior modulator exposure in future research.