Intravenous silibinin as 'rescue treatment' for on-treatment non-responders to pegylated interferon/ribavirin combination therapy

Background: Intravenous silibinin (ivSIL) is a potent antiviral agent against HCV. In vitro silibinin (SIL) inhibits viral replication, possibly by inhibiting HCV RNA polymerase. In this proof-of-concept study, ivSIL was tested in on-treatment non-responders to full-dose of pegylated interferon-alpha 2a/ribavirin (standard of care [SOC]). Methods: A total of 27 treatment-naive patients with <2 log drop in viral load after 12 weeks or still detectable HCV RNA after 24 weeks of SOC treatment (mean age 54.4 +/- 6.8 years, male/female 19/8, HCV genotype 1 n=19, 3a n=4 and 4 n=4, liver fibrosis F4 n=14, F3 n=5 and F2 n=3, and interleukin 288 polymorphism C/C n=1, T/C n=22 and T/T n=4) received additionally 20 mg/kg/day SIL (Legalon-SIL (R); Rottapharm-Madaus, Monza, Italy) intravenously for 14 or 21 days. Thereafter, pegylated interferon/ribavirin was continued. HCV RNA was quantified by TaqMan (R) (Roche Diagnostics, Pleasanton, CA, USA). Results: At the end of ivSIL treatment, 23/27 (85.1%) patients had undetectable HCV RNA. In one of the four remaining patients HCV RNA became undetectable 8 weeks after ivSIL on SOC. Five patients relapsed after ivSIL, three of them responded to repeated administration of ivSIL, but relapsed again. The best predictor of response was a low pre-ivSIL HCV RNA level. A total of 19 patients reached one treatment end point (end of SOC treatment HCV RNA undetectable n=11 and non-response n=8); 8 patients were still on SOC (all HCV-RNA-negative). All 11 patients with end-of-treatment response completed 24 weeks of follow-up; 7 patients remained HCV-RNA-negative and 4 relapsed. Except for a slight increase in bilirubin (mean +/- SD 0.98 +/- 0.35 to 2.12 +/- 0.99 mg/dl), treatment was well-tolerated. Conclusions: ivSIL is an effective 'rescue treatment' for on-treatment non-responders to full-dose of SOC.