Antiviral effects of silymarin against hepatitis C: The jury is still out
Authors: Stephen J. Polyak, Chihiro Morishima, Roy Hawke
Journal: Hepatology (2008)

We read with great interest the results of the recent study by Seeff et al. on the usage of herbal medicines in patients with chronic hepatitis C enrolled in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial.1 Given this particular cohort of patients with advanced disease who were nonresponders to standard antiviral therapy, and the potentially debilitating side effects associated with long-term pegylated interferon therapy, it is perhaps not surprising that one-fifth of all HALT-C trial patients opted for complementary and alternative medicine (CAM)–based adjuncts to the management of their disease. Silymarin (SM) was by far the most frequently used herbal preparation, with anywhere from 8% to 33% of patients consuming botanicals, depending on geographic region. Silymarin, the active ingredient of milk thistle (from the plant Silybum marianum) is thought to promote a healthy liver and is further thought to have antioxidant, anti-inflammatory, immunomodulatory, and antitumor effects.2, 3 The extract contains multiple flavonolignans including silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin.4 Very little is known regarding the mechanisms of action of SM and the individual flavonolignans in patients with chronic hepatitis C. However, recent work from our laboratories has demonstrated that SM at concentrations between 1–20 μg/mL inhibits in vitro hepatitis C virus (HCV) infection,5 although this is at odds with most clinical studies that have not found antiviral effects against HCV in vivo. In healthy subjects, customary doses of SM result in very low plasma concentrations of the six major flavonolignans in the range of 50–300 ng/mL due to their rapid metabolism to glucuronide and sulfate conjugates which are not thought to have biological activity.6-10 The first pharmacokinetic evaluation of SM in patients with liver disease recently indicated there may be substantial differences in silymarin metabolism between patients with mild and advanced chronic HCV, resulting in three-fold to five-fold higher plasma concentrations of flavonolignan conjugates as compared to healthy subjects.11 Still, concentrations of SM required to inhibit HCV replication in vitro appear to be one to two orders of magnitude higher than those observed in patients with chronic HCV using customary doses. In light of these new in vitro antiviral and pharmacokinetic data in patients with liver disease, conclusions regarding potential antiviral effects of SM based on previous findings must be reevaluated. Prior studies which failed to demonstrate antiviral effects with SM may have missed subtle antiviral effects of SM due to relatively late timing of blood draws for assessment of antiviral effects (12 weeks,12 12 months,13 and 24 months14). Moreover, trials that only dosed SM one to two times per day may not have achieved high enough plasma concentrations due to the rapid half-life observed in patients with liver disease.11 Therefore, if SM exerts any antiviral activity in vivo, it may be transient, and would require adequate plasma and, perhaps more importantly, liver concentrations following repeated daily dosing. As acknowledged by Seeff et al., the brands of SM used by HALT-C patients were not determined, and questions regarding nonstandardized flavonolignan compositions, the adequacy of the doses administered, and duration of treatment preclude definitive conclusions regarding the effectiveness of SM therapy. Those nay-sayers who challenge that in vitro doses shown to inhibit HCV infection are an order of magnitude higher than those obtainable in vivo are referred to a recent study in patients with prostate cancer where high doses of silipide were associated with plasma levels of silybin A and B up to 40 μg/mL.15 These data suggest it may be possible to achieve plasma concentrations in patients with chronic HCV infection that are associated with in vitro antiviral activity. Clearly, the gap between in vitro versus in vivo concentrations of SM appears to be narrowing. Clinical trials such as the SyNCH trial16 (www.clinicaltrials.gov identifier NCT000389376) offer hope that adequate plasma levels of hepatoprotective flavonolignans can be realized. However, we believe that a final verdict has not yet been delivered for SM as an antiviral therapy for HCV infection. We call for prospective studies in which HCV-infected patients are appropriately dosed with SM to test its antiviral potential. Should SM fail to demonstrate in vivo antiviral activity at target concentrations associated with antiviral activity in vitro, we will have gained knowledge about the limitations of replicon models with respect to certain mechanisms of antiviral activity. Furthermore, we may discover the mechanisms responsible for the altered disposition of SM in patients with liver disease that may preclude the antiviral activity of other investigational compounds that are similarly metabolized and excreted. Stephen J. Polyak Ph.D.* §, Chihiro Morishima MD*, Roy Hawke Pharm.D. Ph.D. , * Department of Laboratory Medicine, University of Washington, Seattle, WA, Department of Global Health, University of Washington, Seattle, WA, Department of Microbiology, University of Washington, Seattle, WA, § School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC.