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

Disclosures

J Viral Hepat. 2012;19(8):547-553. 

In This Article

Methods and Patients

Patients

Only patients who repeatedly showed persistence of hepatitis C viremia at low levels during antiviral treatment with pegylated interferon alpha-2a plus weight-based ribavirin were included in the study. According to their (non-) response pattern to antiviral treatment, patients were allocated to three different groups (see also Fig. 1) as follows: Group 1 (n = 4): viral rebound after cessation of an HCV-specific protease inhibitor and during continued pegylated interferon alpha-2a plus ribavirin therapy, Group 2 (n = 9): plateau of hepatitis C viremia with low HCV RNA levels after an initial but incomplete response to pegylated interferon alpha-2a plus ribavirin and Group 3 (n = 7): continuous but protracted decline of HCV RNA levels with persistence of hepatitis C viremia >12 weeks after the start of antiviral therapy.

Figure 1.

Viral kinetics of twenty patients during antiviral treatment prior to rescue treatment with two infusions of silibinin (Legalon SIL®; Rottapharm-Madaus, Köln, Germany). Patients are separated into three different response groups according to their (non-)response pattern to antiviral treatment. Panel a (n = 4): viral rebound after cessation of an HCV-specific protease-inhibitor and during continued pegylated interferon alpha-2a plus ribavirin. Panel b (n = 9): plateau of hepatitis C viremia with low HCV RNA levels after an initial but incomplete response to pegylated interferon alpha-2a plus ribavirin. Panel c (n = 7): continuous but protracted decline of HCV RNA levels with persistence of hepatitis C viremia ≥12 weeks after the start of antiviral therapy. BLQ, below limit of quantification; BLD, below limit of detection.

Initially, no cut-off level for the definition of minimal persistence of hepatitis C viremia was defined. However, after the first experience in patients 2 and 3 who had HCV RNA levels above 2000 IU/mL and failed to achieve a complete virologic response after short-term silibinin infusions, the upper limit of HCV RNA for eligibility was set to 1000 IU/mL.

Main baseline characteristics of the patients are shown in Table 1. Twenty patients were included in this trial and received silibinin infusions on two consecutive days between December 2008 and June 2010: 19 patients were from the Berlin study site and one patient was from the Frankfurt study site. Twelve patients were men, and the mean age of patients at the time of silibinin infusion was 47 years (range, 28–69 years). Of the 20 patients, 19 were infected with HCV genotype 1. The remaining patient was infected with HCV genotype 4. Noninvasive measurement of fibrosis with Fibroscan® revealed minimal to moderate fibrosis in seven patients, advanced fibrosis in seven patients and cirrhosis in six patients. Ten patients had previously received antiviral treatment with peginterferon alpha and ribavirin, nine of them had shown a nonresponse, and one suffered a viral relapse after the end of treatment. The remaining ten patients were treatment naïve.

Administration of Study Drug

A fixed dose of 1400 mg of silibinin (Legalon SIL®; Rottapharm Madaus) was dissolved in 500 mL NaCl 0.9% and administered intravenously over 120 to 360 min. The daily silibinin dose per kilogram body weight ranged from 14.3 to 29.2. A second Infusion was administered 24 h after beginning of the first – usually over a shorter time period (45–120 min).

Detection of HCV RNA

HCV RNA testing was performed with Cobas TaqMan (Roche Diagnostics GmbH, Mannheim, Germany) and revealed three different response categories: first, quantifiable (i.e. ≥25 IU/mL); second, detectable but not quantifiable (<25 IU/mL, but positive signal); and third, nondetectable. All samples below the detection limit of the quantitative assays were tested in duplicate with the more sensitive qualitative transcription-mediated amplification (Versant® TMA assay; Siemens Healthcare Diagnostics GmbH, Eschborn, Germany), to exclude presence of minimal residual viremia.

Fibroscan® Analysis

Fibroscan was performed on all patients at the beginning of antiviral treatment. The mean of ten measurements was calculated, and an interquartile range of 0.21[10] was not exceeded in any of the patients included. Statistically reliable cut-off values have been established for chronic hepatitis C infection: values above 7.65 kPa correspond to relevant fibrosis, and values above 13.01 kPa correspond to cirrhosis.[11]

IL28B Genotyping

In our cohort, the most strongly associated SNP, rs12979860, located about 3 kb upstream of the IL28B gene, was selected for genotyping (Ge et al.) and tested with a PCR-based endpoint genotyping assay using custom designed rs12979860 primers and hydrolysis probes (Applied Biosystems GmbH, Darmstadt, Germany; forward primer 5′-GCCTGTCGTGTACTGAACCA-3′, reverse primer 5′-GCGCGGAGTGCAATTCAAC-3′ and allele-specific MGB-probes 5′-VIC-TGGTTCGCGCCTTC-BHQ-3′ and 5′-FAM-CTGGTTCACGCCTTC-BHQ-3′). Based on the assay results, each sample was defined as CC, CT or TT (IL28B genotype), respectively.

Statistical Methods

This report uses descriptive methods only. The data collection and analysis are retrospective, and the treatment algorithm, however, was designed prospectively and was not subject to further changes after the initial results of the first three treated patients had been evaluated.

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