Silymarin is a potent antiviral drug against HCV in nonresponders to Peginterferon/Ribavirin – Dose finding and viral kinetics studies

Background: Silibinin (SIL) is the main flavonoid extracted from milk thistle (Silibum marianum G.). By chance we detected that iv. SIL is a potent antiviral compound in patients with chronic hepatitis C not responding to standard antiviral therapy. In this study the optimal dose of SIL was investigated. Furthermore the viral kinetics were studied. For dose finding different dosages of intravenous Silibinin (Legalon Sil®; Madaus, Köln) were given.

Patients and Methods: Fifteen nonresponders to full dose peginterferon/ribavirin combination therapy (f: n=1, m: n=14; age: 56±13.6 [mean±SD]; baseline viral load: 3.7±3.84×106 MIU/ml [mean±SD], genotype: 1a: n=7, 1b: n=6, each one 2 and 4; liver histology: F0:n=1, F1:n=1, F2:n=6, F4:n=4, not available:n=3) were studied.

Patients received iv. SIL (Legalon Sil®, Madaus, Köln) at different doses (5mg/kg: n=3, 10mg/kg: n=3, 15mg/kg: n=4, 20mg/kg: n=5) daily over 4 hours for 14 days.

From day 8 on 180! g of Peginterferon alpha 2a (PEGASYS®; Roche, Basel) and 1–1.2g/day of ribavirin (COPEGUS®; Roche, Basel) were added. After the end of the SIL infusion period 840mg/d of Silymarin (Legalon®, Madaus, Köln) were given. Viral load was determined daily during the SIL infusion period, thereafter in 2 weekly intervals. HCV-RNA was quantified by the TaqMan® assay (Roche Diagnostics).

Results:

On SIL monotherapy viral load decreased dose dependently in all patients (log drop: 5mg: 0.7±0.6; 10mg: 2.1±0.8; 15mg: 2.3±1.5; 20mg: 3.6±1.1, [mean±SD], p=0.0006). On combined SIL/PGIFN/RBV viral load decreased further (viral load day 15: 5mg: 88400±101452 MIU/ml; 10mg: 455±5749; 15mg:4852±32007; 20mg: 15±206). At the time of writing this abstract, all patients were still on PEGIFN/RBV therapy. HCV-RNA became negative or unquantifiable in 6/8 patients in the 15 and 20mg groups at week 2. 4 of them became rapid virologic responders.

SIL was well tollerated, the only complaint in the high dose groups was sensation of heat at the start of SIL infusions which subsided without treatment within 30 minutes.

Conclusion: Intravenous SIL therapy monotherapy is well tolerated and shows its greatest antiviral effect when administered with a daily dose of 20mg/kg. Half of the patients with a HCV RNA <15MIU/ml at day 15 became rapid virologic responders.

Thus, iv. SIL in combination with standard antiviral therapy has a great potential to cure nonresponders.