Gastroenterology

Gastroenterology

Volume 135, Issue 5, November 2008, Pages 1561-1567
Gastroenterology

Clinical Advances in Liver Pancreas and Biliary Tract
Silibinin Is a Potent Antiviral Agent in Patients With Chronic Hepatitis C Not Responding to Pegylated Interferon/Ribavirin Therapy

https://doi.org/10.1053/j.gastro.2008.07.072Get rights and content

Background & Aims

Oral Silibinin (SIL) is widely used for treatment of hepatitis C, but its efficacy is unclear. Substantially higher doses can be administered intravenously (IV).

Methods

Pedigreed nonresponders to full-dose pegylated (Peg)-interferon/ribavirin (PegIFN/RBV) were studied. First, 16 patients received 10 mg/kg/day SIL IV (Legalon Sil; Madaus, Köln, Germany) for 7 days. In a subsequent dose-finding study, 20 patients received 5, 10, 15, or 20 mg/kg/day SIL for 14 days. In both protocols, PegIFNα-2a/RBV were started on day 8. Viral load was determined daily.

Results

Unexpectedly, in the first study, HCV-RNA declined on IV SIL by 1.32 ± 0.55 log (mean ± SD), P < .001 but increased again in spite of PegIFN/RBV after the infusion period. The viral load decrease was dose dependent (log drop after 7 days SIL: 0.55 ± 0.5 [5 mg/kg, n = 3], 1.41 ± 0.59 [10 mg/kg, n = 19], 2.11 ± 1.34 [15 mg/kg, n = 5], and 3.02 ± 1.01 [20 mg/kg, n = 9]; P < .001), decreased further after 7 days combined SIL/PegIFN/RBV (1.63 ± 0.78 [5 mg/kg, n = 3], 4.16 ± 1.28 [10 mg/kg, n = 3], 3.69 ± 1.29 [15 mg/kg, n = 5], and 4.85 ± 0.89 [20 mg/kg, n = 9]; P < .001), and became undetectable in 7 patients on 15 or 20 mg/kg SIL, at week 12. Beside mild gastrointestinal symptoms, IV SIL monotherapy was well tolerated.

Conclusions

IV SIL is well tolerated and shows a substantial antiviral effect against HCV in nonresponders.

Section snippets

Patients

Patients with previous nonresponse to full dose of PegIFN/RBV combination therapy were selected for these studies (Table 1). Nonresponse was defined by the lack of a >2-log drop of viral load after 12 weeks of therapy and/or by not achieving an end-of-treatment response. Patients were required to have had a liver biopsy within 2 years prior to inclusion into this study. Standard inclusion/exclusion criteria for PegIFN/RBV therapy were applied.

Study Protocol

During a screening phase within 35 days prior to the

Protocol 1

Sixteen pedigreed nonresponders (Table 1) were included. All patients had received full-dose treatment with PegIFN (12 PegIFN-α-2a, 2 PegIFN-α-2b) and RBV (1000–1200 mg/day) for at least 12 weeks. Parameters of oxidative stress measured did not change during silibinin infusions (Figure 1).

Serum HCV RNA declined in all patients on IV silibinin-monotherapy (Figure 2) (baseline: 6.59 ± 0.53, day 8: 5.26 ± 0.81 log IU/mL [mean ± SD], P < .001) with a mean log decline of 1.32 ± 0.55 within 1 week.

Discussion

The unexpected finding of this study was the demonstration that IV silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to standard antiviral combination therapy. Intravenous silibinin was well tolerated, and no serious adverse effects were observed. The most commonly reported adverse effect was a transient sensation of heat. The antiviral effect was dose dependent but was not maintained after the end of the infusion period by the oral administration of

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    Trial registered at: www.clinicaltrials.gov: NCT00684268.

    The authors disclose the following: Conflicts of interest: P. Ferenci: Roche, Basel, CH; member of the Global Advisory Board and of the speakers bureau and receives financial support for clinical studies. All other authors have no conflicts of interest.

    Supported by an unrestricted research grant by Roche Austria, and silibinin (Legalon Sil) and silimaryin (Legalon) were provided by Rottapharm-Madaus, Köln, Germany. None of the companies was involved in the design, conduct, and evaluation of this protocol.

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