Can elexacaftor/tezacaftor/ivacaftor cause liver damage in adults with cystic fibrosis?

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) rarely results in severe drug-induced liver injury among adults with cystic fibrosis, as shown in a study presented at AASLD 2023. Moreover, serum markers of fibrosis have increased but remain within normal range.

On the other hand, “transient elastography (TE) values decreased, a potentially encouraging finding suggesting improvement in liver fibrosis,” according to the authors, led by Olivia Portolese from the Liver Unit, Centre hospitalier de l’Université de Montréal in Montreal, Canada.

Portolese and her team conducted this retrospective descriptive cohort study to determine the short- and long-term effects of ETI on liver outcomes in adults with cystic fibrosis currently treated by the Respirology Division of the Centre hospitalier de lUniversité de Montréal. They collected clinical data prior to treatment initiation and during therapy.

TE was used to assess liver fibrosis, with 6.8 kPa used as threshold to define cystic fibrosis liver disease (CFLD) based on previous findings. Standard formulas were used to calculate Fibrosis-4 (Fib-4) and aspartate aminotransferase to platelet ratio index (APRI) scores for each patient: values 1.3 and 0.7 were respectively used as thresholds for increased fibrosis.

A total of 154 patients (mean age at treatment initiation 37 years, 51.3 percent male) were included in this study. Of the patients, one had a prior liver transplant, four (2.6 percent) had imaging findings compatible with cirrhosis, three (2 percent) had thrombopenia, and eight (5 percent) had splenomegaly.

Prior to ETI initiation, baseline liver tests were within normal limits in most patients, except for six who presented with an alanine transaminase (ALT) >1.5 times the upper limit of normal and only case of elevated bilirubin. [AASLD 2023, abstract 1708-A]

Pretreatment TE measurement was available in 31 patients, with an average measure of 6.8 kPa (range, 3.3‒24.2 kPa). Twenty-nine percent of patients were deemed to have CFLD, while five had elevated Fib-4 score and only one had heightened APRI score.

Over a mean follow-up of 9 months, 26 patients (16.8 percent) presented with at least one episode of ALT >1.5 times the upper limit of normal and four with increased bilirubin (unconjugated in all cases). Treatment interruptions occurred in three patients due to liver-related causes, with one successful therapy resumption. One patient died due to a nonliver-related cause.

Furthermore, the average APRI score rose from 0.20 to 0.32 (p=0.0001) and Fib-4 from 0.62 to 0.72 (p=0.07). The APRI score remained significant on paired analysis (Wilcoxon test <0.0001). Average TE significantly dropped from 6.8 to 6.1 kPa (p=0.01) in 15 patients with paired measures and improved by 1.3 kPa in those with a baseline elevated TE score.

“Additional long-term follow-up is required to determine trends in TE and explain the discrepancy with serological markers of fibrosis,” said Portolese and colleagues.

“Cystic fibrosis is a genetic disease caused by a mutation in the CFTR gene, the most common being F508del,” the investigators said. “ETI modulates the F508del mutated protein and improves respiratory outcomes.”