(196) Liver function test abnormalities in people with cystic fibrosis treated with elexacaftor/tezacaftor/ivacaftor.

Background: A high prevalence of abnormalities and fluctuation in liver function tests (LFT) have been reported in people with cystic fibrosis (pwCF), that may represent a potential confounder when monitoring CFTR modulator safety. Triple combination with Elexacaftor, Tezacaftor and Ivacaftor (ETI) can induce generally mild and transient LFT elevation, and, much more rarely, clinically relevant drug-induced liver injury with jaundice and even irreversible decompensation, especially in patients with advanced liver disease. Thus, closer monitoring is recommended and specific thresholds to decrease dosing or to discontinue medication have been recommended. The aim of this study was to characterize the emergence of abnormalities in LFT in pwCF after initiation of ETI and to evaluate those considered clinically relevant.

Methods: After approval in Italy in July 2021, ETI was started in 56 pwCF at the Reference CF Center of the Lombardia region, Italy. LFT were prospectively collected before and 1, 3 and 6 months after starting ETI. Alanine transaminase (ALT), gammaglutamiltransferase (GGT) and total bilirubin (BIL) were measured and expressed as multiple of the upper limit of normality (ULN). Rates (per 100 patient-month) of emergent LFT elevation ( >ULN) were computed in patients with normal pre-treatment LFT, while rates of further increments in LFT were computed among those with abnormal pre-treatment LFT.

Results: Fifty-six patients were included (27 males, 25 F508del homozygous patients, median age: 20 years, range: 13-36); 18 patients had pre-treatment values of ALT, GGT or BIL >ULN, 4 had cirrhosis, associated with portal hypertension in 2. Thirty-eight patients were followed-up for 6 months, 17 patients for at least 3 months and one patient for 1 month. Table 1 reports the number, rates and corresponding 95% confidence intervals (CI) of LFT elevation among patients with normal pre-treatment LFT and increment above pre-treatment values among patients with abnormal pre-treatment LFT. During the follow-up, ALT values > 3 x ULN were observed in 3 patients, GGT > 3 x ULN in 1 patient and BIL > 2 x ULN in 4 patients, all except one with concomitant Gilbert syndrome. None discontinued treatment and 3 patients reduced ETI dose. Most LFT elevations occurred within the first month of treatment and remained above the ULN thereafter.

Conclusions: LFTs elevations after ETI introduction is a relatively frequent adverse event but does not appear to be clinically relevant in most cases, also in patients with advanced liver disease. Longer follow-up is needed to have a clear picture of the safety of ETI.

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