Cystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosis

Abstract

BACKGROUND Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol. AIM To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF. METHODS A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups. RESULTS A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients ( P = 0.05), patients on Ursodiol ( P < 0.001), and patients on dual therapy ( P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients ( P < 0.001) or patients on Ursodiol and CFTR modulators ( P = 0.01). CONCLUSION CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

Increased aminotransferases do not necessarily mean hepatotoxicity of CFTR modulator therapy

“…However, in the long term observation CFTR modulators may have a beneficial effect on liver function [ 11 ] and it may improve markers of liver fibrosis [ 12 ]. It is speculated that CFTR modulator treatment may lower the rate of patients progressing to liver cirrhosis in comparison with no treatment or single UDCA therapy [ 13 ]. For that reason liver function monitoring is an important aspect of CFTR modulator therapy.…”

Risk factors for more rapid progression of severe liver fibrosis in children with cystic fibrosis‐related liver disease: A multi‐center study validated by liver biopsy

“…For patients identified early as more rapid progressors, there is emerging evidence from retrospective studies of the potential benefit of CFTR modulators to improve liver biomarkers or even reduce the incidence of cirrhosis in those with CFLD. 41,42 In the future, targeted gene therapy or other proposed medications that promote bile flow or reduce portal pressures could also be considered. 43 We also found a negative association between severe liver-biopsy proven fibrosis with pancreatic insufficiency and F508del homozygosity which merits further study and validation by others.…”

“…In summary, this study provides a unique assessment of the clinical and biochemical variables over time that are associated with the development of liver biopsy‐validated severe paediatric CFLD, including moderate pulmonary dysfunction defined as FEV 1 % <64%. For patients identified early as more rapid progressors, there is emerging evidence from retrospective studies of the potential benefit of CFTR modulators to improve liver biomarkers or even reduce the incidence of cirrhosis in those with CFLD 41,42 . In the future, targeted gene therapy or other proposed medications that promote bile flow or reduce portal pressures could also be considered 43 .…”

Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations

“…[105][106][107] One large retrospective review of a US private insurance claims database examined 955 patients with CF on CFTR modulators between 2012 and 2017 and found decreased cirrhosis in those on modulators. [109] Potential effects of elexacaftor/tezacaftor/ivacaftor are less clear, with one study showing decreased liver stiffness, but another showing no change, or even increased liver stiffness in PwCF on elexacaftor/tezacaftor/ ivacaftor. [103,104] Some evidence suggests improvements in hepatic steatosis.…”