High-dose Silibinin Rescue Treatment for HCV-infected Patients Showing Suboptimal Virologic Response to Standard Combination Therapy

M. Biermer; B. Schlosser; B. Fülöp; F. van Bömmel; A. Brodzinski; R. Heyne; K. Keller; C. Sarrazin; T. Berg

Disclosures

J Viral Hepat. 2012;19(8):547-553. 

In This Article

Abstract and Introduction

Abstract

Summary. Incomplete suppression of hepatitis C virus (HCV) replication with persistence of minimal viremia (partial virologic response) leading to treatment failure can be observed in a significant proportion of HCV type 1-infected patients during antiviral therapy. Recently, high-dose intravenous silibinin has demonstrated strong antiviral activity against HCV. We were therefore interested in whether patients with partial virologic response can be rescued by the on-treatment addition of a short-term course of high-dose intravenous silibinin infusions. Twenty patients who failed to achieve a complete virologic response to different interferon-based regimens qualified for the rescue strategy and received 1400 mg/day silibinin infusions on two consecutive days. Complete viral suppression (below the limit of detection <6 IU/mL, TMA assay) could be induced in 13 of 20 patients within the first week after the short-term silibinin infusion, and all but one of them also remained HCV RNA negative during the subsequent follow-up period on continued peginterferon plus ribavirin treatment. In the remaining seven patients, no complete suppression could be achieved although four showed a significant HCV RNA reduction in response to silibinin. Silibinin infusions were generally well tolerated, and activation of abdominal peristalsis with nausea, diarrhoea and vomiting were the most prominent side effects. Of the twelve patients who exhibited a durable response to peginterferon and ribavirin treatment, three achieved an SVR, two achieved a week 12 SVR and four suffered a viral relapse. Three patients could not complete the assigned antiviral treatment with peginterferon alpha and ribavirin for nonvirological reasons. Short-term administration of high-dose intravenous silibinin might be an interesting approach to rescue patients with ongoing minimal residual viremia while on interferon-based therapy. These preliminary findings may stimulate further studies to evaluate more refined therapeutic strategies.

Introduction

Oral formulations of extracts from milk thistle (Silybum marianum) have been commonly used to treat liver patients suffering from viral, metabolic or nutritive stress. However, little is known about how this substance works[1] and its therapeutic efficacy in relation to hepatitis C virus (HCV) RNA replication or to the progression of liver disease could not be demonstrated in controlled trials.[2,3] Silibinin, as the main active compound in silymarin extracts (Legalon SIL®; Madaus Rottapharm, Köln, Germany), has been approved for the treatment of acute liver failure caused by Amanita phalloides intoxication mainly observed in European countries.[4]

Recently, Peter Ferenci and his colleagues were able to show that intravenous application of silibinin in high doses could exert a profound antiviral effect on HCV replication.[5] In vitro studies suggest that silibinin inhibits HCV replication by directly blocking NS5B RNA-dependent RNA polymerase activity in vitro[6] and also interferes with crucial steps of the viral lifecycle of HCV such as virus entry and transmission.[7]

Standard antiviral treatment of chronic hepatitis C infection consists of peginterferon alpha and ribavirin. An early and complete virological response to antiviral treatment is the most important predictor of a successful treatment outcome. During antiviral treatment, a significant proportion of patients fail to achieve negative HCV RNA levels despite a marked decline in viral load. Those partial responders eventually have to terminate their antiviral treatment. Treatment enhancement is needed to turn these patients from treatment failures to responders.

Having received FDA approval in June 2011, the first direct acting antiviral compounds boceprevir and telaprevir represent important additions to the arsenal of antiviral drugs. However, these drugs are not available in all countries. More importantly, despite impressive improvements in treatment outcomes through the addition of boceprevir or telaprevir to peginterferon alpha and ribavirin, a significant proportion of patients will still fail to reach undetectable HCV RNA levels during triple therapy. A rescue strategy that offers treatment augmentation at this crucial phase of antiviral treatment has not yet been proposed.[8,9]

Here, we present our preliminary experience indicating that a short-term high-dose silibinin infusion is effective in rescuing the majority of patients with persisting minimal residual viremia during standard antiviral therapy with peginterferon alpha and ribavirin by inducing a complete virologic on-treatment response.

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