P-26 EPIGENETIC MARKS IN PATIENTS WITH SUSTAINED VIRAL RESPONSE TO HCV AND RESIDUAL LIVER FIBROSIS ARE RESTORED BY PROLONGED-RELEASE PIRFENIDONE

Conflict of interest

No

Introduction and Objectives

Patients with residual liver fibrosis following the eradication of hepatitis C virus (HCV) represent a significant clinical challenge due to the continuous risk of disease progression and the development of hepatocellular carcinoma. This study aimed to evaluate the efficacy of a 12-month treatment with prolonged-release pirfenidone (PR-PFD) plus standard of care for the regression of liver fibrosis and its effect on key epigenetic marks.

Patients / Materials and Methods

HCV patients who responded to direct-acting antivirals (DAAs) and had residual fibrosis received PR-PFD (1200 mg/day) for 12 months. Liver biopsies and serum samples were analyzed at the beginning and end of the treatment. Additionally, six non-fibrotic controls were included to compare the epigenetic marks.

Results and Discussion

38 patients completed the 12-month treatment, and 28.94% showed a reduction of at least one fibrosis stage according to liver biopsies, while 57.57% experienced an improvement in fibrosis according to transient elastography. Levels of bilirubin, alkaline phosphatase, AST, INR, and APRI significantly decreased. Profibrogenic miRNAs (miR-34a, miR-21, miR-16, miR-181b, miR-200a, and miR-200b) showed a significant increase in advanced fibrosis compared to non-fibrotic controls. Notably, PR-PFD treatment restored the expression of miR-34a, miR-16, miR-192, miR-200a, and miR-122. In cell-free DNA (liquid biopsy), PDGFα showed hypermethylation in patients with mild fibrosis, while in liver tissue hypomethylation was present in non-fibrotic controls. In the circulating DNA of non-fibrotic controls, PPAR-δ was hypermethylated compared to mild and advanced fibrosis cohorts. Treatment with PR-PFD induced hypermethylation in three islets of TGFβ1, suggesting a decrease in the transcription of this profibrogenic cytokine.

Conclusions

These findings indicate, for the first time, that PR-PFD treatment could exert therapeutic effects in Hispanic patients with residual fibrosis by modulating miRNA expression and methylation of specific CpG sites.