PR0-C3 determined active fibrogenesis is a predictor of liver-related outcomes in patients with chronic hepatitis C

Abstract

Background and Aims: Patients with untreated chronic hepatitis C (CHC) infection are at increased risk of developing a liver related outcome. Despite the availability of simplified direct acting antiviral therapy, the prevalence of CHC remains unchanged in many industrialized countries. Biomarkers that can predict which chronic liver disease patients with inflammatory injury are at greatest risk of developing a clinical outcome are required. In a study population from The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (HALT-C) (ClinicalTrials.gov #NCT00006164), we investigated the ability of PRO-C3 as a marker of active fibrogenesis to predict liver-related outcomes compared to METAVIR fibrosis stage on biopsy in patients with hepatitis C virus (HCV) who were non-responders to prior interferon-based standard-of-care. Method: Serum levels of the fibrogenesis marker, nordicPRO-C3™, was measured in stored serum samples using a competitive ELISA. Fibrosis stage was assessed by liver biopsy at baseline and end-of-study. Cox proportional hazard regression analysis was employed for investigation of the association between baseline PRO-C3 levels or METAVIR stage and risk of clinical outcome. Kaplan-Meier analysis was employed to examine the event-free survival probability when stratifying PRO-C3 into below and above the lower quartile (Q1=27.6 ng/mL) and METAVIR stage (F1-F2 vs F3-F4). Results: This study population included a subgroup of 340 patients from the HALT-C cohort with a median age of 50 years, BMI of 29.4 kg/m2, and 65% of the patients were male. Sixty-seven patients (20%) had a liver-related outcome over median follow-up 839 days (Q1-Q3: 474-1132). When dividing patients into baseline PRO-C3 above and below the Q1 cut-off, the Hazard Ratio (HR) for having an outcome was 3.71 times higher (95% CI= [1.60-8.57], p<0.01) in patients with high baseline PRO-C3. For biopsy-determined fibrosis stage, the HR for having an outcome was 3.20 times higher (95% CI= [1.71-5.98], p<0.001) in patients with F3-F4 compared to F1-F2. For METAVIR stage, F2-4, patients have an estimated HR of appr. 2% per ng/mL change in PRO-C3 for a liver-related outcome. No events occurred in patients with F1 at baseline. Conclusion: Fibrosis activity, represented by the level of type III collagen formation (PRO-C3), is associated with an increased risk of developing a liver-related outcome in patients with untreated HCV infection. PRO-C3 provided a higher risk predictor for outcomes than advanced fibrosis on biopsy. Further validation following HCV cure is still required. Pro-fibrogenic markers such as PRO-C3 could provide prognostic utility in other chronic liver disease patients with ongoing inflammatory injury.