(260) CFTR Modulator-Associated Liver Inflammation in Pediatric Cystic Fibrosis

Background: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene and affects 70,000 people worldwide. The impaired CFTR protein leads to abnormal ion transport and consequential multiorgan dysfunction involving the pulmonary, gastrointestinal, pancreatic, and hepatic systems. CFTR modulators are a novel class of medications that target the root cause of CF by altering the CFTR protein function.

There are currently four CFTR modulators with proven clinical efficacy in the CF population: Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), Symdeko (tezacaftor/ivacaftor), and Trikafta (elexacaftor/tezacaftor/ivacaftor). Due to reports of liver enzyme elevation in clinical trials of ivacaftor, a component of all four modulators, the manufacturer recommends monitoring liver function tests (LFTs) prior to modulator initiation, every three months during the first year of therapy, and annually thereafter.

The study objective is to evaluate effects of the CFTR modulators on liver inflammation in pediatric CF patients.

Methods: This study was a single-center, retrospective chart review of patients aged 4 months to 21 years diagnosed with cystic fibrosis and initiated on CFTR modulator therapy for at least 1 month between January 2012 and October 2021. All patients are followed by the Rady Children’s/UC San Diego Cystic Fibrosis Center. Collected data included clinical characteristics and markers of liver inflammation (ALT, AST, GGT, and total bilirubin) at baseline and within 12 months after modulator initiation.

Wilcoxon paired signed ranks tests, Mann-Whitney U tests, and Kruskal-Wallis tests were utilized for data analysis.

Results: Of the 99 modulator trials found within the study period, only 65 initial trials were included to avoid the potential confounding effects of previous modulator therapy on each patient. There were 14 patients started on Kalydeco, 33 on Orkambi, 5 on Symdeko, and 13 on Trikafta.

In comparing the LFTs at baseline and at maximum within 12 months after modulator initiation, there were significant differences identified in ALT and AST within the Orkambi group (p 0.016, p 0.038) and in total bilirubin within the Kalydeco and Trikafta groups (p 0.011, p 0.002).

When analyzing the measured difference between baseline and maximum LFT values across all four modulator groups, significance was only achieved in total bilirubin, in contrast with ALT, AST, and GGT. Within the total bilirubin analysis, significant differences were identified between Kalydeco and Orkambi (p 0.028), Kalydeco and Trikafta (p 0.003), and Trikafta and Orkambi (p < 0.001).

Conclusions: Liver inflammation was observed via LFT elevations in all modulator groups except Symdeko. In comparing the effects of all four CFTR modulators, the most notable marker of altered liver function was total bilirubin, with significant differences between the Kalydeco, Orkambi, and Trikafta groups. Given the restricted number of patients per modulator group, particularly with Symdeko, there is limited generalizability beyond this clinic population. Further research with more robust sample sizes may aid the goal of understanding whether certain modulators are associated with increased liver inflammation, which can inform clinical decisions when CF patients are eligible for multiple CFTR modulators.

Acknowledgements: Zaineb Boulil, Data Analyst; Janelle Celso, Research Coordinator; Michelle Chau, PharmD Candidate; Andrew Defante, Data Analyst

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