High-dose Silibinin Rescue Treatment for HCV-infected Patients Showing Suboptimal Virologic Response to Standard Combination Therapy
Posted: 08/10/2012; J Viral Hepat. 2012;19(8):547-553. © 2012 Blackwell Publishing
Introduction and Discussion Only
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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
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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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