Glycyrrhizin in Patients Who Failed Previous Interferon Alpha-Based Therapies

Biochemical and Histological Effects After 52 Weeks

M. P. Manns; H. Wedemeyer; A. Singer; N. Khomutjanskaja; H. P. Dienes; T. Roskams; R. Goldin; U. Hehnke; H. Inoue; European SNMC Study Group


J Viral Hepat. 2012;19(8):537-546. 

In This Article

Abstract and Introduction


Summary. Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated.


Treatment of hepatitis C virus (HCV) infection has significantly improved over the past 2 decades. However, the current standard of care (SOC), pegylated interferon alpha (peg-IFNα) plus ribavirin (RBV), has its limitations. Sustained virological response (SVR) rates are less than 50% for genotype 1 patients and there is no SOC for non-responders to date.[1,2] In addition, contraindications as well as intolerance to IFN based therapies leave a large number of patients ineligible for this medication. These patients are at risk to develop cirrhosis and its complications, including hepatocellular carcinoma (HCC).[3]

Studies with long-term application of low dose peg-IFNα failed to achieve reduced progression of liver disease. These studies showed that inflammation and fibrosis progression could not be suppressed.[4,5] However, the COPILOT study demonstrated positive effects on portal hypertension.[5] To what extent new direct acting antivirals (DAAs) will meet the expectations for IFN failure or IFN intolerant patients remains uncertain. Response rates to triple therapy with HCV protease inhibitors, peg-IFNα and ribavirin in previous nonresponder patients with liver cirrhosis are still below 20%.[6] Therefore it is legitimate to search for alternative treatment strategies to suppress inflammatory activity and fibrosis progression in non-responders to IFN-based therapies.

Intravenous glycyrrhizin (GL) has been used for more than 30 years in the treatment of liver diseases in Asian countries, mainly in Japan. Studies performed in Asia and Europe showed that administration of GL in patients with chronic hepatitis C (CHC) leads to an improvement of necro-inflammation and liver function tests in a significant proportion of patients. Such effects were also observed in IFN non-responders. It has been demonstrated that there was a dose-dependent effect of GL on elevated ALT levels. The observed decrease of ALT level was rapid, linear and could be maintained in CHC patients receiving at least three injections weekly for varying duration of treatment.[7–10] ALT is a marker of biochemical necro-inflammatory activity of the liver. Persistently high ALT levels are correlated with disease progression leading to complications such as cirrhosis and HCC.[11] The effect of GL is mediated primarily through a suppression of inflammation and through a decreased liver cell injury. The anti-inflammatory activity of GL may be mediated by the direct binding of the molecule to cell membrane components, especially to lipocortin I or to enzymes like phospholipase-A2, which is the initial enzyme in the arachidonic acid metabolic system. GL also directly binds to lipoxygenase, an enzyme to produce the inflammatory chemical mediators. GL selectively inhibits the activation by phosphorylation of these enzymes.[12,13] Furthermore GL and its derivatives are able to inhibit the production of inflammatory chemokines IL-8 and eotaxin 1, which are both potent chemo-attractants to leukocytes during inflammation, and may counteract the expression of those pro-inflammatory chemokines.[14] Long term treatment with GL reduced the incidence of HCC in some studies.[7,15–17]

Most studies with GL therapy were performed in Asia so far. In this study the efficacy and safety of GL was evaluated in a 52-weeks treatment of European chronic hepatitis C patients not responding or having contraindications to standard therapy (IFN + RBV or peg-IFNα + RBV).


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