Silibinin Milk Thistle Derivatives Demonstrates Antiviral Activity in Non-respon

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Silibinin Milk Thistle Derivatives Demonstrates Antiviral Activity in Non-responders to Interferon-based Therapy for Chronic Hepatitis C Patients By Liz HighleymanGiven that about half of patients with genotype 1 chronic hepatitis C virus (HCV) infection do not achieve a sustained response to standard pegylated interferon/ribavirin therapy, researchers have explored other types of treatment including various alternative or complementary therapies.

Milk thistle (Silybum marianum) has been used in several traditional medicine systems to treat liver disease, and its derivatives (silibinin, silymarin) have been tested in clinical trials. Substantially higher doses can be administered intravenously; the efficacy of oral preparations is unclear.

Ferenci from the University of Vienna in Austria and colleagues reported results of a study of silibinin in chronic hepatitis C patients at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) and in the November 2008 issue of Gastroenterology.

Silibinin, the main flavonoid extracted from milk thistle, has previously been shown to inhibit HCV replication in laboratory studies. In the present study, the researchers initially investigated whether lowering oxidative stress can improve sensitivity to interferon by pre-treating 16 chronic hepatitis C patients with 10 mg/kg intravenous (IV) silibinin for 7 days.

Unexpectedly, they found that HCV RNA declined during silibinin monotherapy (from 6.59 log IU/mL at baseline to 5.26 log IU/mL at day 8; P < 0.001), but increased again in most patients after the infusion period, despite being on pegylated interferon/ribavirin.

The investigators then conducted a dose-finding study and safety assessment of IV silibinin in 20 patients who were non-responders to a previous course of full-dose pegylated interferon/ribavirin (defined as > 2 log decline in HCV RNA at week 12 or lack of end-of-treatment response). Most participants (85%) were men and the mean age was about 53 years. 17 patients had HCV genotype 1 and 7 had advanced liver fibrosis or cirrhosis (stage F3-F4).

Participants first received 5, 10, 15, or 20 mg/kg daily silibinin monotherapy infused over 4 hours for 14 consecutive days. On day 8, they started treatment with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day ribavirin. After day 14, they added 280 mg oral silymarin (another milk thistle product) 3 times daily.

Results

• After 7 days of IV silibinin monotherapy, the 5 mg/kg dose was only marginally effective (HCV RNA log drop 0.5).• The 10, 15, and 20 mg/day doses led to a significant decrease in viral load (log drops of 1.4, 2.1, and 3.0, respectively; P < 0.001). • After 1 week of silibinin combined with pegylated interferon/ribavirin, HCV viral load decreased further (log drops of 1.6, 4.2, 3.7, and 4.8, respectively, with the 5, 10, 15, and 20 mg/day doses; all P < 0.0001 vs baseline). • 2 of the 5 (40%) and 4 of the 9 (44%) patients in the 15 and 20 mg/kg arms, respectively, had undetectable HCV RNA (< 15 IU/mL) at day 15.

• 7 patients experienced rapid virological response (RVR, HCV < 15 IU/mL) at week 4 of combination therapy.• 8 patients (57%) demonstrated early virological response (HCV RNA < 15 IU/mL) at week 12 of combination therapy, but 1 relapsed at week 9. • HCV viral load increased in all patients with HCV RNA > 50 IU/mL at the end of the infusion period. • HCV RNA became undetectable in 3 patients after a second cycle of IV silibinin infusions given after week 12 (pegylated interferon/ribavirin is continuing). • Beside mild gastrointestinal symptoms, IV silibinin monotherapy was well tolerated.

"Intravenous silibinin is a potent antiviral agent and may be a treatment option for treatment of [pegylated interferon/ribavirin] non-responders," the researchers concluded.