Is There a Future for Milk Thistle In HCV?

This summary highlights current information on the use of oral silymarin (the active ingredient in milk thistle found in the seeds of the plant) for hepatitis C.

As once a HCV patient myself who successfully treated the virus with conventional therapy in 2000, I never used the supplement, nor do I endorse it, but I had a few close friends who did. They found it to be well tolerated when used according to the recommended dose, as for the benefits? I can only comment that it seemed to help my friends endure the virus, especially when standard therapy failed them.

Today I point you to the research, a few studies which offer a better understanding of the popular supplement, including the possible benefits. Personally I have no opinions of my own to share, except a grave concern for anyone using milk thistle under the pretense it will eradicate the virus. Still, a part of me can't help to wonder if HCV patients will continue to use milk thistle after interferon free therapies become available? Yes, no, maybe. 

When It All Began

In 1990 when blood screening for hepatitis C began there was little hope for people infected with the virus. Back then milk thistle was commonly used by HCV patients, although the use of milk thistle is not as common as it once was, in regards to liver disease it is still used today by people living with the virus.

Why Was Milk Thistle Considered An Alternative To HCV Treatment?

In 1990 HCV was still in its early infancy, we didn't have many treatment options, from 1991-1997 interferon was the only therapy available. Not until 1998 was ribavirin added to interferon with the approval of  Rebetron - Schering’s combo of Intron A and ribavirin. Later in 2001 the first pegylated interferon went to market, it was Schering’s Peg-Intron followed in 2002 by Genentech’s Pegasys.

A decade later standard therapy for genotype 1 HCV patients still involves peginterferon and ribavirin, used along with (Incivek) Telaprevir or (Vicrelis) Boceprevir both protease inhibitors were approved in 2011. However, not everyone will respond to triple therapy or a regimen of peginterferon and ribavirin alone, plus some people are unable to tolerate interferon. With few options left milk thistle is generally explored by HCV patients.

Use of Herbal Supplements for Hepatitis C

Research on silymarin suggests that it may protect the liver from inflammation. But it does not have a direct effect on viruses that cause hepatitis, such as the hepatitis C. The National Institutes of Health, National Center for Complementary and Alternative Medicine this month updated - Hepatitis C and Dietary Supplements:What the Science Says

Another great resource on the use of herbs and supplements including their interactions is available at HCV Advocate, download the PDF here, updated April 2013.

A few words about the supplements listed in this glossary:

The goal was to choose supplements that may be particularly pertinent to those with liver disease, especially viral hepatitis

The information applies to supplements, NOT food. For instance, under artichoke, it says,

“Avoid with bile duct obstruction or gallstones. Use cautiously in liver patients with clotting problems as artichoke may increase risk of bleeding.” This means to use caution when taking extracts and formulations that have high doses of the active ingredients

Heads Up

This information is not intended as medical advice or endorsement of the use of dietary supplements. Always talk to your medical provider before taking any herbs or supplements. All herbs, drugs, and other substances have potential side effects. Allergic reactions have been reported for nearly every herb, sometimes with life-threatening consequences. If you suspect you are having an allergic reaction or other serious side effect, stop taking the substance and seek immediate medical advice. If you have trouble breathing or feel faint, call 911.

If you are scheduled for a medical or surgical procedure, particularly if anesthesia will be used, or plan to undergo chemotherapy, report supplement use to your medical provider. You may need to stop supplement use for a week or more before the procedure since many supplements interfere with anesthesia and/or blood clotting.
Download PDF 

Commercial Milk Thistle

The U.S. Food and Drug Administration (FDA) does not regulate supplements in the same way it regulates medicines. A dietary supplement can be sold with limited or no research on how well it works. The form you buy in health food or grocery stores may not be the same as the form used in research. For instance in one article "Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements" researchers analyzed 45 products from local stores for their silymarin content, antioxidant activities, and antiviral activity against HCV. Some of these samples were found to vary widely in their silymarin content.

The 2013 research paper Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements - Anthony, K.; Subramanya, G.; Uprichard, S.; Hammouda, F.; Saleh, M. is available online @ MDPI AG - Antioxidants
*About the journal.

Excerpt from a 2010 article found in the HCV Advocate Newsletter, written by Lucinda K. Porter, RN

All milk thistle is not alike and what is in the bottle may not match what is promised on the label. In a startling report published by ConsumerLab.com (CL), only one of 10 products passed the necessary tests in order to carry the CL seal of approval.

CL is an independent organization that provides information and testing of nutritional products. They have been around for about ten years. Some information is free, but product reports are available only to subscribers. A one year subscription is $30 and worth every penny. www.consumerlab.com

Continue reading....

The Research

In 2013 patients with hepatitis C still use alternative therapies in hopes of some added benefit. The most common as mentioned above is silymarin, an antioxidant that exhibits anti-inflammatory properties.  According to research close to a third of HCV and cirrhosis patients report using the milk thistle extract, even when studies have shown inconsistent results regarding its benefit.

The most rigorous trial to date to test the herbal extract milk thistle (silymarin), was published in the 2012 issue of  the Journal of the American Medical Association (JAMA),  researchers reported oral silymarin was not superior to placebo (A substance containing no medication) in decreasing disease activity or its symptoms.

The Study

Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA 2012 Jul 18; 308:274. 

How many patients were in the study?

154 patients (median age, 54; 71% men) with chronic HCV infection who previously failed interferon-based therapy.

What dose of silymarin did the patients receive?

The researchers randomly assigned the patients to one of three groups, two of which took high doses of a standardized form of silymarin at 420mg or 700mg three times daily for 24 weeks. The third group took a placebo.

The two oral doses of pure silymarin were determined by earlier dose finding studies and were three to five times higher than concentrations used in previous studies.

Unlike previous trials, this study used a pure, quantifiable formulation of silymarin and well-defined outcomes, its cohort was large and representative of the patient population, the treatment period was sufficiently long, and both medication and visit adherence rates were high.

What was the baseline ALT of patients who participated in the study?

The patients in the study had serum alanine aminotransferase (ALT) enzyme levels greater than 65 IU/L, with a median of 106 IU/L at baseline. A normal level is 45 IU/L.

Did patients respond, was ALT lowered?

Of the 138 patients who completed the 24-week study, 90% were able to adhere to at least 80% of the pill regimen. In spite of the compliance, however, the mean drop in serum ALT was not significantly different between the three groups.

After six months, one person in the placebo group had a serum ALT less then 45 IU, as did two patients in each of the silymarin arms. Additionally, two patients in the placebo and high-dose silymarin groups had at least a 50% decline in baseline ALT to less then 65 IU, as did one patient in the 420-mg silymarin arm.

Side effects

The most common types of adverse events were gastrointestinal, musculoskeletal, dermatologic, infection, and physical injury. Six patients in the 420-mg silymarin arm and five in the 700-mg arm had serious adverse events, compared with one in the placebo group.

This trial found that oral silymarin used at higher than customary doses (three to five times the typical dose) did  not significantly alter biochemical or virological markers of disease activity.

Source
MedPage Today
 2012 issue of JAMA

Video summary of trial published in the Journal of the American Medical Association

Milk Thistle Extract Efficacy for Hepatitis C

Is There a Future for Milk Thistle In HCV?

In the June 2012 issue of Gastroenterology & Endoscopy News, Christina Frangou reported on the AASLD 2011 meeting and the above study, the author noted commentary from Joseph K. Lim, MD on the future role of milk thistle for patients with liver disease and hepatitis C. The director of the Yale Viral Hepatitis Program cited three studies of interest where the extract was given in higher doses or different formulations

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).

Mushroom Poisoning and intravenous silibinin

In 2011 Georgetown University researchers reported that intravenous silibinin, another milk thistle extract, helped patients with liver toxicity resulting from mushroom poisoning.

Treating HCV without Interferon

HCV drugs currently in clinical trials without interferon have shown great promise, Gilead Sciences Inc and Abbvie Inc are two pharmaceutical companies that seem to be leading the race, with treatments that are predicted to reach the market some time next year. Pegylated interferons will hopefully one day be obsolete, however most likely, treatment may still include ribavirin, a drug with difficult side effects. The future is looking promising for the millions of people currently afflicted with HCV. But these therapies may come to late for HCV patients in need of a liver transplant or battling liver cancer. Dr. Scott Biggins with the University of Colorado School of Medicine recently reported there were 126,862 new candidates for first liver transplant registered with Organ Procurement and Transplantation Network (OPTN), with 41% of these having HCV, the article is available here.

This brings us full circle to a paper published in the March 2013 issue of Journal of Hepatology - Silibinin: An old drug in the high tech era of liver transplantation. 

The study concluded:
Intravenous silibinin (Iv-SIL) is safe but by the currently used applications cannot prevent graft reinfection or eradicate HCV from the transplanted liver in most patients. At present there is no alternative of an interferon-free approach in the peritransplant setting and silibinin may be the ideal drug until safe and effective HCV RNA polymerase inhibitors with a high genetic barrier become available. Nevertheless, there is a need for improvements in treatment schedules before such a treatment can be recommended. Flushing the liver graft with a solution containing silibinin as it has been done to prevent oxidative damage to the liver [15] should be tested in order to determine if it helps prevent recurrence.

In the future hepatitis C patients will be spared the debilitating side effects of interferon. The dream begins. Fast forward to today with online analysts predicating interferon-free regimens reaching patients by 2014. However, some people infected with HCV will still be left behind, for these people silymarin will most likely be used and yes - even relevant.

Additional Links

More on silibinin

Expert's Picks: Silymarin for NAFLD

From National Institutes of Health • National Center for Complementary and Alternative Medicine
Updated May 2013
Hepatitis C and Dietary Supplements

 

Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period

"Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period"





Dr. Zoe Mariño discusses her article "Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period"

Abstract - http://www.journal-of-hepatology.eu/article/S0168-8278(12)00768-4/abstract

Editorial - Silibinin: An old drug in the high tech era of liver transplantation

Silibinin: An old drug in the high tech era of liver transplantation

Silibinin: An old drug in the high tech era of liver transplantation

Journal of Hepatology
Volume 58, Issue 3 , Pages 409-411, March 2013

Article Outline

Keywords: silibinin, liver transplantation, hepatitis C

HCV re-infection after liver transplantation is constant and accelerated in patients who are PCR-positive at the time of transplantation. Reinfection significantly impairs patient and graft survival [1]. At present, there are limited options available to prevent graft reinfection after transplantation or to successfully treat reinfected patients. Pretransplant antiviral combination therapy with (peg)interferon/ribavirin (PegIFN/RBV) is poorly tolerated and not very effective in patients infected with HCV genotype 1. In a prospective randomized controlled study, pretransplant treatment with PegIFN/RBV prevented post-transplant recurrence of HCV in 22% of a highly selected group of patients with HCV genotypes 1,4,6 [2]. Treatment after transplantation has also a limited efficacy and is associated with serious adverse effects. Currently, studies using triple therapy with PegIFN/RBV and a protease inhibitor (boceprevir or telaprevir) are ongoing, but again poor tolerance is a major issue.
Thus there is urgent medical need to develop safe and effective treatments for this group of patients. Two case reports indicated that therapy with intravenous silibinin (iv-SIL; Legalon SIL®, Rottapharm–Madaus) successfully eradicated the virus after transplantation [3], [4]. Based on these encouraging observations, iv silibinin got EMA orphan drug designation for prevention of recurrent hepatitis C. Iv-SIL is a 1:1 mixture of silibinin A and silibinin B and is available as intravenous therapeutic agent for treatment of mushroom poisoning. However, acute liver failure related to mushroom (amanita or lepiota) poisoning is an uncommon condition and there is no definitive evidence that silibinin improves the outcome of these patients.

In 2008, the potent antiviral activity of iv-SIL against HCV was described [5] and confirmed by in vitro studies [6]. Silibinin inhibits the HCV NS5B polymerase activity directly [7] or by interfering with the binding of the RNA to this enzyme [8]. Furthermore, the mechanisms of the antiviral action of silibinin appear also to include blocking of virus entry, transmission, and secretion (for review see [9]).

In this issue of the Journal, 2 groups from Spain report their experience with iv-SIL in the transplant setting [10], [11]. Both studies involved only a very small number of patients, but both included a control group: in the study performed in Madrid this was a historical control [10], while in the one performed in Barcelona, patients in the control group were treated with a placebo according to a prospective randomized, double-blind, placebo-controlled design [11].The Madrid group [10] started iv-SIL during the anhepatic phase and continued treatment for 21days. In contrast, the Barcelona group [11] treated patients for up to 21days prior transplantation, and continued or restarted the infusion for further 7days after transplantation. Both studies confirmed the robust antiviral efficacy and the safety of iv silibinin in this difficult-to-treat patients, with the apparent lack of interaction with immunosuppressants, but not surprisingly, both approaches failed to eradicate the virus in a single patient, although quite a few had undetectable HCV RNA at the end of iv silibinin administration.

It is quite clear that giving an antiviral drug as monotherapy for just 21days is not able to eradicate HCV. The so far shortest successful treatment in HCV genotype 1 patients having the IL28B CC genotype using peginterferon/ribavirin and telaprevir was 12weeks [12]. Comparison with other published reports of iv silibinin (Table 1) shows that the best results in terms of SVR were obtained in patients in whom a low viral load was achieved by administering the drug before transplant and then continuing it for 3–4weeks after transplant [4]. Taken together, the data published so far seem to indicate that HCV RNA levels below the level of quantification (LOQ) at the end of iv silibinin administration and SVR can be reached in 12/14 (85.7%) and 3/14 (21.4%) patients with a continuous pre-/post-transplant administration, respectively, while in patients receiving iv silibinin only after transplant, the same results could be achieved only in 6/35 (17.1%) and 2/35 (5.7%) patients, respectively (Table 1).

Table 1. Cases treated with intravenous silibinin in the transplant setting.

Click To Enlarge

Studies in the transplant setting are difficult to design. The problems even increase if patients immediately prior to transplantation are involved. They are usually very sick and safety becomes the prime issue. Pretreating patients with iv-SIL is feasible and safe, but is limited by the need of daily infusions. The optimal timing for transplantation would be if the patient becomes HCV RNA undetectable, but the timing of transplantation depends on the availability of a donor organ, which is increasingly challenging in an era of donor organ shortage. Therefore, in some patients, infusion therapy had to be stopped before transplantation was performed.

In the Barcelona study, this was the case in 4 patients. Iv silibinin was restarted 7 to 38days after the 21days of silibinin administration. HCV below the level of quantification (LOQ) was achieved only in 1 of 4 of them in contrast to all of the 4 patients treated continuously. Similarly, in 3 patients treated pretransplant in our center, no liver was available when the targeted low or undetectable viral load was reached (updated from [13]). One patient even subsequently achieved SVR but died on the waiting list. Obviously the best approach would be to do the study at centers offering living donor transplantation. In such centers, treatment and transplantation can be scheduled exactly. A very important aspect in such a study would be to investigate the needed duration of silibinin monotherapy and/or the need for consecutive treatment with peginterferon/ribavirin, possibly in combination with a direct acting antiviral agent. It is conceivable that the optimization of the duration of treatment with iv-SIL, even after cadaveric donor transplantation (e.g., for at least 4weeks) and/or combination therapy could improve the virological response by reducing viral load in the first weeks after transplantation. This may prevent, delay, or decrease the severity of recurrent hepatitis C, with favourable histological findings at 6–12months [14]. This would represent per se a clinically relevant outcome.

So what do we learn from these studies? Iv-SIL is safe but by the currently used applications cannot prevent graft reinfection or eradicate HCV from the transplanted liver in most patients. At present there is no alternative of an interferon-free approach in the peritransplant setting and silibinin may be the ideal drug until safe and effective HCV RNA polymerase inhibitors with a high genetic barrier become available. Nevertheless, there is a need for improvements in treatment schedules before such a treatment can be recommended. Flushing the liver graft with a solution containing silibinin as it has been done to prevent oxidative damage to the liver [15] should be tested in order to determine if it helps prevent recurrence.

Conflict of interest
PF is a member of the global advisory boards of Roche, MSD, Vertex/Tibotec, Madaus–Rottapharm, Böhringer Ingelheim, Idenix, Gilead and Achillion.
He receives an unrestricted research grant from Roche Austria and MSD Austria.

References

1. Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver International. 2012;32:120–128
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2. Everson GT, Terrault NA, Lok AS, Rodrigo DR, Brown Jr. RS, Saab S, et al. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology; in press. http://dx.doi.org/10.1002/hep.25976.
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3. Neumann UP, Biermer M, Eurich D, Neuhaus P, Berg T. Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol. 2010;52:951–952
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4. Beinhardt S, Rasoul-Rockenschaub S, Scherzer TM, Ferenci P. Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. J Hepatol. 2011;54:590–591
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5. Ferenci P, Scherzer TM, Kerschner H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology. 2008;135:1561–1567
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6. Polyak SJ, Morishima C, Shuhart MC, et al. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology. 2007;132:1925–1936
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7. Ahmed-Belkacem A, Ahnou N, Barbotte L, et al. Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Gastroenterology. 2010;138:1112–1122
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10. Barcena R, Moreno A, Rodriguez-Gandía MA, Albillos A, Arocena C, Blesa C et al. Safety and anti-HCV Effect of Prolonged Intravenous Silibinin in HCVGenotype 1 Subjects in the Immediate Liver Transplant Period. J Hepatol; in press.
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11. Mariño Z, Crespo G, D’Amato M, Brambilla N, Giacovelli G, Rovati L. Intravenous silibinin monotherapy shows significant antiviral activity in HCVinfected patients in the peri-transplantation period. J Hepatol; in press.
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12. Bronowicki JP, Hezode C, Bengtsson L, Pol S, Bourliére M, Serfaty L, et al. 100% SVR IN IL28B CC patients treated with 12weeks of telaprevir, peginterferon and ribavirin in the PROVE2 trial. J Hepatol. 2012;56:S430
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High-dose Silibinin Rescue Treatment for HCV-infected Patients Showing Suboptimal Virologic Response to Standard Combination Therapy

From Journal of Viral Hepatitis

High-dose Silibinin Rescue Treatment for HCV-infected Patients Showing Suboptimal Virologic Response to Standard Combination Therapy

M. Biermer; B. Schlosser; B. Fülöp; F. van Bömmel; A. Brodzinski; R. Heyne; K. Keller; C. Sarrazin; T. Berg

Posted: 08/10/2012; J Viral Hepat. 2012;19(8):547-553. © 2012 Blackwell Publishing

Introduction and Discussion Only

Full Text Available @ Medscape

Introduction
Oral formulations of extracts from milk thistle (Silybum marianum) have been commonly used to treat liver patients suffering from viral, metabolic or nutritive stress. However, little is known about how this substance works^[1] and its therapeutic efficacy in relation to hepatitis C virus (HCV) RNA replication or to the progression of liver disease could not be demonstrated in controlled trials.^[2,3] Silibinin, as the main active compound in silymarin extracts (Legalon SIL®; Madaus Rottapharm, Köln, Germany), has been approved for the treatment of acute liver failure caused by Amanita phalloides intoxication mainly observed in European countries.^[4]

Recently, Peter Ferenci and his colleagues were able to show that intravenous application of silibinin in high doses could exert a profound antiviral effect on HCV replication.^[5]In vitro studies suggest that silibinin inhibits HCV replication by directly blocking NS5B RNA-dependent RNA polymerase activity in vitro^[6] and also interferes with crucial steps of the viral lifecycle of HCV such as virus entry and transmission.^[7]

Standard antiviral treatment of chronic hepatitis C infection consists of peginterferon alpha and ribavirin. An early and complete virological response to antiviral treatment is the most important predictor of a successful treatment outcome. During antiviral treatment, a significant proportion of patients fail to achieve negative HCV RNA levels despite a marked decline in viral load. Those partial responders eventually have to terminate their antiviral treatment. Treatment enhancement is needed to turn these patients from treatment failures to responders.

Having received FDA approval in June 2011, the first direct acting antiviral compounds boceprevir and telaprevir represent important additions to the arsenal of antiviral drugs. However, these drugs are not available in all countries. More importantly, despite impressive improvements in treatment outcomes through the addition of boceprevir or telaprevir to peginterferon alpha and ribavirin, a significant proportion of patients will still fail to reach undetectable HCV RNA levels during triple therapy. A rescue strategy that offers treatment augmentation at this crucial phase of antiviral treatment has not yet been proposed.^[8,9
.
Here, we present our preliminary experience indicating that a short-term high-dose silibinin infusion is effective in rescuing the majority of patients with persisting minimal residual viremia during standard antiviral therapy with peginterferon alpha and ribavirin by inducing a complete virologic on-treatment response.

Discussion
This is the first report of a short-term rescue regimen for HCV-infected patients with partial response to ongoing antiviral treatment with high-dose silibinin infusions. After two infusions of silibinin, a complete virologic response could be observed in 13 of 20 patients (65%). In all except one patient, it was possible to maintain the induced response during the follow-up period of continued antiviral treatment with peginterferon alpha and ribavirin only.

Ferenci and colleagues described the profound antiviral effect of high-dose silibinin infusions in chronic hepatitis C infection.^[5] In their study, 20 patients with nonresponse to prior interferon-based treatment regimens received silibinin infusions for 14 days. Pegylated interferon alpha plus ribavirin was started 7 days after silibinin initiation. Even during the phase of silibinin monotherapy, HCV RNA levels were markedly decreased in a dose-dependent manner.

In contrast to the approach taken by Ferenci et al., we were interested in an on-treatment rescue strategy for patients with a significant but incomplete virologic response to peginterferon alpha and ribavirin treatment. Since in our treatment algorithm, patients received silibinin infusions only at very low HCV RNA levels we decided to reduce silibinin infusions to only two on two consecutive days. Our goal was to focus on the rescue of treatment failures around treatment week 24 when, according to published treatment guidelines for chronic hepatitis C,^[8,9] the likelihood of achieving an SVR with continued peginterferon alpha and ribavirin treatment is very low.

With the recent approval of the first HCV-specific protease inhibitors, it will be very interesting to study a silibinin rescue approach in patients on direct antiviral triple regimens who failed to achieve a rapid virologic response (Advance Study^[12] and Sprint-2 Study^[13]) and who are meeting the stopping rules that apply to antiviral triple treatment. Treatment augmentation at this vulnerable stage of antiviral treatment with an antiviral compound that has no cross-resistance to current protease inhibitors^[14] might be of great therapeutic value.

The initial virologic response rate to a silibinin rescue treatment of 65% seems very promising, and five patients were able to achieve an SVR (three patients reached a week 24 SVR and two patients a week 12 SVR). This corresponds to a 25% SVR rate in an ITT analysis and a 50% SVR rate among those patients who responded to silibinin and completed the maintenance therapy with peginterferon and ribavirin. In other words, one of four patients who faced treatment termination owing to virologic nonresponse could be cured of chronic hepatitis C with two silibinin infusions and continued peginterferon alpha and ribavirin treatment.

The optimal duration and timing of silibinin infusions still have to be worked out. For instance, patients with higher levels of HCV replication may need a more intense rescue approach which consists of either extended treatment periods (i.e. 5–14 days) or higher dosages. In our study, we used a fixed dose of 1400 mg silibinin per day. Accordingly, the individual dose of silibinin per kilogram body weight was in a rather wide range. The mean dose of silibinin was slightly higher in the group of patients responding to silibinin, but both extremes were seen: responders with low silibinin doses and nonresponders with high doses. Rutter et al.^[15] have proposed an on-treatment rescue with 14 consecutive silibinin infusions in a small cohort of nine patients, seven patients initially responded to silibinin but follow-up results of this cohort are still pending.

Most of the patients carrying IL28B genotype CT had a successful initial response to silibinin infusions while most of the patients with a TT genotype failed. Additionally, all five SVR patients carried the CT genotype. Although patient numbers are too low for statistical analysis, it is well possible that patients with TT genotypes should receive a more intense or longer rescue treatment.
Another open question is the optimal duration of peginterferon and ribavirin treatment once a complete virologic response has been induced. When negative HCV RNA levels are not reached before week 24, an extension of treatment to a total of 72 weeks is recommended. Whether successful silibinin rescue at an earlier stage of antiviral treatment (e.g. week 12) would obviate the need for this extended treatment cannot be deducted from our data. While a viral breakthrough was seen in only one patient during continued peginterferon and ribavirin treatments, the relapse rate after end of antiviral treatment was surprisingly high. In conclusion, the very short-term rescue approach with high-dose silibinin infusion has been shown to be effective in partial responder patients with persistent viral replication on peginterferon alpha plus ribavirin therapy. Further studies are needed to clarify whether longer courses of silibinin treatment can provide an advantage and whether silibinin rescue might be of benefit when protease inhibitor-containing triple therapies fail.

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