Prolonged release pirfenidone restores miRNA expression and CpG island methylation in patients with HCV sustained virological response and residual liver fibrosis

Introduction and Objectives

Patients with residual liver fibrosis after hepatitis C virus-infection clearance represent an important challenge due to the risk of progression and hepatocarcinoma development. The primary end of this study was to evaluate epigenetic marks in DAA-responders HCV non-European patients presenting remaining fibrosis. The secondary aim was to assess the efficacy of 12 months of treatment with prolonged-release pirfenidone (PR-PFD) in liver fibrosis regression.

Materials and Patients

Forty-four DAA-responders HCV patients presenting remaining fibrosis (73% women) were enrolled in the study and received PR-PFD (1200 mg/day) for 12 months. Six patients dropped out. Liver biopsies and serum samples were analyzed at the beginning and end of treatment. Besides, six non-fibrotic controls were included to compare epigenetics marks.

Results

After 12 months of treatment, 28.94% of patients showed a reduction in at least 1 fibrosis stage based on liver biopsies, while 57.57% experienced fibrosis reversion according to transient elastography. Bilirubin, alkaline phosphatase, AST, INR, and APRI values significantly decreased, and only minor adverse events were reported. Profibrogenic miRNAs displayed a significant increase in expression in advanced fibrosis versus controls without fibrosis. Noteworthy, PR-PFD treatment induced their decrease and restored the expression of miR-34a, miR-16, miR-192, miR-200a and miR-122 correlating with the downgrade of fibrosis stage. Specific PDGFa CpGs exhibited hypermethylation in both cell-free-DNA and liver biopsies in both mild and advanced fibrosis. Interestingly, four CpGs in PPARd promoter were hypomethylated versus controls. PR-PFD treatment resulted in hypermethylation in three TGFb1-CpGs after 12 months, suggesting down-regulation of this profibrogenic cytokine.

Conclusions

These findings suggest, for the first time, that PR-PFD might exert its therapeutic effects in Hispanic patients with residual fibrosis by modulating the expression of miRNAs and methylation of specific CpG sites.