(220) Changes in Liver Function Tests and Liver Stiffness Measurements over 12 months in Cystic Fibrosis Patients commenced on Elexacaftor/Tezacaftor/Ivacaftor at a Large Adult Center

Background: Liver function abnormalities have been reported in 7-11% of people with cystic fibrosis (CF) aged over 12 years who received elexacaftor/tezacaftor/ivacaftor in clinical trials. In the majority of cases liver function abnormalities were mild and clinically insignificant, with no interruptions of therapy. However, clinically significant abnormalities have been observed in clinical practice, leaving patients and clinicians with difficult decisions about discontinuation of therapy despite substantial improvements in pulmonary status. Furthermore, there have been case reports of delayed hepatic necrosis in patients after commencing elexacaftor/tezacaftor/ivacaftor and it is unclear whether cystic fibrosis liver disease (CFLD) is a risk factor for hepatotoxicity, especially as people with significant underlying liver disease were excluded from clinical trials.

Methods: All patients prescribed elexacaftor/tezacaftor/ivacaftor at a large, adult CF centre were advised to have liver function tests performed at least quarterly for the first year of therapy. A Friedman test was used to analyse differences over 12 months. Patients with a baseline measurement of liver stiffness (measured by Fibroscan) prior to commencing elexacaftor/tezacaftor/ivacaftor were also offered a follow-up scan after 1 year of therapy and a paired-samples t-test was used to compare differences.

Results: A total of 255/269 CF patients prescribed elexacaftor/tezacaftor/ivacaftor continued therapy for a minimum of 12 months; 78 had pre-existing CFLD as defined by Debray criteria. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin significantly increased from baseline at 3 months (all p < 0.001) and remained above baseline at 6, 9 and 12 months but with no further significant increase. Clinically significant rises in ALT and AST of greater than 3 times the upper limit of normal (ULN) occurred in 8 (3.1%) and 4 (1.6%) people, respectively.

Alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) did not change significantly over the 12-month period, however for those with a raised ALP at baseline there was a significant reduction in ALP over 12 months (-18.5 IU/L) compared to those with a normal ALP at baseline (2.0 IU/L), p = 0.001. There were no significant differences in changes in ALT, AST, ALP, GGT or bilirubin between those with and without CFLD.

Thirty-two patients with a previous baseline Fibroscan result had a follow-up scan (8 with CFLD). There was no significant difference in mean liver stiffness measurement at 12 months (4.92 kPa) compared to baseline (4.95 kPa), p = 0.895. Change in liver stiffness over 12 months was not significantly different between those with and without CFLD (-0.163 vs 0.008, respectively), p = 0.781.

Conclusions: Liver function abnormalities after commencing elexacaftor/tezacaftor/ivacaftor can comprise both rises in transaminases or bilirubin with changes sustained for 12 months. ALP decreased over 12 months for those with a raised ALP at baseline and this may be related to direct effects of elexacaftor/tezacaftor/ivacaftor on CFTR function in cholangiocytes. Changes in liver function tests do not appear to be related to an underlying diagnosis of CFLD. In addition, despite rises in transaminases, liver stiffness measurements do not change significantly after 12 months of therapy, suggesting that this is unlikely to reflect parenchymal damage. CFLD should therefore not be a barrier to treatment or considered a risk factor for hepatotoxicity.

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