San Francisco—One of the first rigorous trials to test the popular herbal extract milk thistle (silymarin) has shown that this treatment does not relieve symptoms or slow disease progression in patients with hepatitis C who are nonresponsive to interferon (IFN).

“We must conclude that oral silymarin, given in higher than customary doses, did not significantly alter biochemical or virologic disease activity in hepatitis C patients previously treated with interferon-based regimens,” said lead author Michael W. Fried, MD, professor of medicine and director of hepatology, University of North Carolina, Chapel Hill. Dr. Fried presented the study at The Liver Meeting 2011.

Milk thistle has been used for 2,000 years as an herbal remedy for many ailments, particularly liver, kidney and gallbladder conditions. However, its value as a liver therapy has never been proven. Several animal studies have shown that milk thistle can help protect the liver, but results from human studies are mixed. Previous studies have been confounded by a lack of well-defined efficacy end points, inclusion of heterogeneous populations of patients and use of nonstandardized silymarin preparations.

In a multicenter trial, 154 patients with hepatitis C who had not responded to IFN therapies were randomized to treatment with placebo or with a standardized silymarin preparation (Legalon® 140, Rottapharm Madaus) at 420 mg daily or 700 mg three times daily. The patients had serum alanine aminotransferase (ALT) enzyme levels greater than 65 IU/L, with a median of 106 IU/L; a normal level is 45 IU/L.

Patients who received silymarin took doses that were 4.5 to 7.5 higher than typically given. The doses were set based on the results of a Phase I pharmacokinetic study (Hoc C et al. Clin Cancer Res 2006;12:2944-2950). Researchers felt that the high doses increased the chance of finding a therapeutic benefit.

After 24 weeks of treatment, serum ALT tests revealed no significant improvements in patients in any of the three arms of the study. Only two participants from each group met the primary end point of serum ALT less than 45 IU/L or a serum ALT decline of at least 50% from baseline.

The secondary end points, too, were similar across the three groups. The change in serum ALT was negligible during the course of treatment and there were no changes in hepatitis C virus (HCV) RNA levels or quality of life.

Silymarin, however, was well tolerated; the most common adverse events were mild and mostly related to gastrointestinal symptoms. Additionally, patients adhered to the medication rules at an unusually high rate. Based on dose cups returned, more than 90% of participants met or exceeded an 80% adherence to the study medications, despite the requirement to take 15 capsules a day.
The study had one notable weakness. The highest dose group included more blacks and more cirrhotics than the other two arms, although analysis did not identify any change in outcomes based on race or cirrhosis.

Is There a Future for Milk Thistle In HCV?
With the latest study results, it is unlikely that oral silymarin will have a future role in the care of patients with hepatitis C infection, although it still will be considered for other liver conditions for which no therapeutic options exist, said Joseph K. Lim, MD, associate professor of medicine and director of the Yale Viral Hepatitis Program at the Yale University School of Medicine, New Haven, Conn.

“Although the study cannot entirely exclude the possibility of a benefit from much higher doses of oral silymarin or intravenous silymarin, in this era of rapid advances in high-potency direct-acting antiviral agents, which may soon eliminate interferon, clinical interest in adjunctive therapies with significant pill burden or intravenous formulations with unproven benefit will be very limited.”

Dr. Lim added, “Once simplified nontoxic, oral–oral regimens with high sustained viral response rates materialize in the next several years, supplements such as silymarin may lose relevance.”
Attendees at the meeting said that they hope patients pay attention to the results of the study.
“Thank you for saving our patients from financial stress and false hope, possibly leading to delays in definitive therapy,” one attendee tweeted during the session.

However, to others, the results were disappointing. In poorer areas of the world where the newer hepatitis drugs are simply too expensive, the silymarin compound could be extremely useful, said one hepatologist.

It may be that there is a future role for silymarin or silibinin in hepatitis treatment when the extract is given in higher doses or different formulations than used in the current randomized study. In one study published in January in the Journal of Hepatology, investigators studied changes in HCV RNA levels in 25 patients receiving 10, 15 or 20 mg/kg per day of Legalon SIL, a chemically hydrophilized version of silibinin (Guedj J et al. 2012;56:1019-1024). Patients showed a significant drop in viral load, particularly between days 2 and 7. The investigators concluded that Legalon SIL may affect hepatitis virus by blocking both viral infection and production/release. In another study, investigators found that IV-administered silibinin had a “substantial antiviral effect” against HCV in 20 IFN nonresponders (Ferenci P et al. Gastroenterology 2008;135:1561-1567). And, still another study showed that oral Silybum marianum significantly affected serum HCV RNA levels, ALT levels, quality of life and psychological well-being (Gordon A et al. J Gastroenterol Hepatol 2006;21:275-280).

Dr. Fried serves on advisory committees on review panels for GlaxoSmithKline; he serves as a consultant for Abbott Laboratories, Merck & Co., Pharmasset, Roche and Tibotec; he receives research support from, Abbott, Anadys Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Roche, Tibotec and Vertex Pharmaceuticals; and he is a shareholder in Pharmasset. Dr. Lim reports research contracts with Abbott Laboratories, Boehringer Ingelheim, Bristol-Meyers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Roche, Tibotec and Vertex Pharmaceuticals; he has received consulting fees/honoraria from Bristol-Meyers Squibb, Gilead Sciences, Merck & Co., and Vertex Pharmaceuticals.