Silibinin in the treatment of chronic hepatitis C – A review of the latest preclinical and clinical findings

Abstract

Aims: Silymarin, the extract from milk thistle fruits (Silybum marianum) has been used as a hepatoprotectant since ancient times. The potential benefit of silymarin in the treatment of viral induced liver diseases continues to be discussed controversially. Silibinin, a major component of silymarin, is a well known potent scavenger of several oxidizing species. It has been shown in the past that oxidative stress might mediate HCV-induced activation of STAT-3 and at the same time to impair IFN-alpha signalling, causing resistance to the antiviral action of IFN-alpha in chronically HCV infected patients. Consequently, the hypothesis has been developed that antioxidative properties of silymarin or its constituent silibinin may theoretically improve the response in nonresponder hepatitis C patients to the standard of care (SOC) antiviral therapy with pegylated interferon and ribavirin (PegIFN/RBV). Clinical findings: An investigator intiated a multicenter, open-label clinical trial (Prof. Ferenci, University Hospital of Vienna) titled „Nonresponder Study: Multicenter Study to Evaluate the Efficacy of Silymarin in Addition to Combination Therapy with Pegylated Interferon Alfa 2A and Ribavirin in Patients with Chronic Hepatitis C“. The objective of the trial was initially to use silibinin as an antioxidant in hepatitis C patients not responding to SOC. Unexpectedly, silibinin administered parenterally, showed a powerful antiviral activity. A recently done interims analysis showed at week 25 that 57% of the patients (still under PegIFN and RBV combination therapy) were HCV RNA negative. Another therapeutic approach of intravenous administration of silibinin in patients non responding to SOC is the so called „rescue treatment“. After completing at least 24 weeks of SOC therapy non-responding patients received additionally 20mg/kg/d silibinin intravenously for 15 days. Thereafter PegIFN/RBV was continued. It could be shown that silibinin is effective on treatment of nonresponders to full dose of PegIFN/RBV combination therapy. A slightly different approach has been followed by Biermer & Berg in Germany who used silibinin for the successful treatment of a severe CHC-patient in the context of ribavirin. Pre-clinical findings: Meanwhile, the ability of silibinin to inhibit HCV enzymatic functions and replication has been tested in HCV RNA-dependent RNA polymerase (RdRp) and NS3/4A protease enzyme assays. Its ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied. It could be shown that silibinin inhibited RdRp function and also inhibited both HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. Summary: Intravenous silibinin has been shown to be a potent antiviral agent in patients with chronic HCV not responding to standard therapy with pegylated interferon plus ribavirin. Moreover, silibinin has been found to be a direct inhibitor of hepatitis C virus RNA-dependent RNA polymerase in vitro.