Combination therapy with silibinin, pegylated interferon and ribavirin in a patient with hepatitis C virus genotype 3 reinfection after liver transplantation: a case report

Hepatitis C virus (HCV) reinfection occurs universally after liver transplantation (LT) [1]. Under immunosuppression, the time course of recurrent HCV is accelerated, with cirrhosis rates of up to 30% within 5 years of LT [2]. So far, antiviral therapy has been limited to a combination of pegylated interferon (peg-IFN) and ribavirin (RBV) with sustained virological response (SVR) rates of approximately 30% post-LT [3‐5]. With the approval of the viral NS3/4A protease inhibitor (PI) simeprevir and NS5B ribonucleic acid (RNA)-dependent RNA polymerase inhibitor (RdRpI) sofosbuvir, combination therapy offers new therapeutic options resulting in considerably higher SVR rates of 66% and 75% in treatment-naïve patients infected with HCV genotype 1 in the non-transplant setting [6, 7]. However, the management of HCV reinfection after LT is complicated by drug interactions, tolerability and pre-treatment [8, 9]. Therefore an individual treatment regimen is often required. However, PI-based triple therapy is limited to patients infected with HCV genotype 1. To date, very few data exist on the treatment of recurrent non-genotype 1 HCV-infection after LT.

As silibinin has been shown to be a potent antiviral agent in prior non-responders to dual therapy [10, 11], we present here the first case of antiviral therapy with peg-IFN and RBV in combination with silibinin post-LT in a genotype 3 reinfected patient with prior non-response.

A 50-year-old Caucasian man underwent a liver transplant in 2008 due to hepatocellular carcinoma based on chronic HCV genotype 3a-associated liver cirrhosis. HCV was diagnosed in 1996. He was pre-treated with dual antiviral therapy pre-LT in 1997, resulting in primary non-response. In 2008, recurrent HCV was detected in liver biopsy. Therefore, he underwent a second attempt of dual antiviral therapy over 48 weeks, resulting in a relapse. He was referred to our LT out-patient clinic in a good state of general health (body mass index 26.2, 180cm, 85kg) with a request for antiviral therapy. HCV-RNA measured 14×10⁶ IU/mL (COBAS® TaqMan® HCV test, version 2.0, Roche Diagnostics AG, Rotkreuz, Switzerland; lower limit of quantification: 25IU/mL; lower limit of detection: 10IU/mL). His serum transaminases were slightly elevated: alanine aminotransferase 103U/L, upper limit of normal (ULN <50IU/L; aspartate aminotransferase 114U/L, ULN 35IU/L). All other liver values were within the normal range (alkaline phosphatase, gamma-glutamyltransferase, bilirubin, international normalized ratio and albumin). Haemoglobin, leukocyte and thrombocyte counts were 16.6mg/dL, 8.6/nL and 118/nL, respectively (Figure 1). Side diagnoses included hypertension and diabetes mellitus type 2.

As silibinin has shown potent antiviral activity in prior non-responders to dual therapy, informed consent was given for a triple combination therapy of silibinin, peg-IFN and RBV. He was given tacrolimus 1mg twice a day (BID) and mycophenolate-mofetil 500mg BID for immunosuppression as well as co-medication with amlodipine (5mg/day) and pantoprazole (40mg/day); insulin injections were also continued. Silibinin was administered 20mg/kg/day intravenously for 2 weeks and continued orally 560mg/day for 47 weeks in combination with a 48-week peg-IFN and RBV therapy with 180μg/week and 800mg/day started on day 8. Peg-IFN and RBV doses were adapted to 135μg/week and 600mg/day. After 4 weeks of therapy, the viral load declined 6 log₁₀ and became undetectable in week 6, resulting in SVR 24. Therapy was well tolerated; side effects included dyspnoea, pruritus and anaemia, leading to the application of 250mg BID ursodeoxycholic acid and 30μg erythropoietin/week. Red blood cell, leukocyte and platelet counts, as well as tacrolimus through levels, were checked once a week.

Antiviral therapy of recurrent HCV after LT is an issue of high interest and the time course of fibrosis progression is accelerated under immunosuppression [2]. Improvements in antiviral therapy are urgently required as SVR rates for dual therapy in patients who are HCV positive after LT are low [3, 4]. PI and RdRpI-based combination for antiviral therapy in non-LT cohorts leads to significantly higher SVR rates compared to a dual therapy [6‐10]. However, the management of HCV post-LT is complicated by drug interactions, side effects and pre-treatment [11, 12].

However, PI-based triple therapy is limited to patients infected with HCV genotype 1. To date, very few data exist on the therapy of recurrent non-genotype 1 HCV-infection after LT.

In vitro experiments have shown that HCV replication is significantly inhibited by silibinin [13]. Silibinin has a strong anti-oxidative effect [14]. This may improve the response to IFN in non-responders to dual therapy since oxidative stress leads to impaired IFN signalling [15]. However, evidence for beneficial effects in humans has been equivocal. Therefore, the efficacy and safety of high-dose intravenous silibinin, followed by a lower dose oral application in combination with dual antiviral therapy, were evaluated by Ferenci et al. [16] in 2008 in chronic HCV genotype 1, 2 and 4 infected former non-responders. This study showed that silibinin is well tolerated and reveals a substantial antiviral effect against HCV in non-responders [16]. A recent study reported similar results in the transplant setting for patients reinfected with HCV genotype 1 [17]. We present here the first case of successful antiviral treatment with silibinin in combination with peg-IFN and RBV in a patient reinfected with HCV genotype 3 after LT with prior non-response to dual therapy. Treatment with silibinin might result in an IFN-sensitising effect in IFN non-responders following LT.

Combination therapy of peg-IFN, RBV and silibinin resulted in SVR 24 in a patient who had a liver transplanted, who was reinfected with HCV genotype 3 and who was therapy naïve. Combination therapy with silibinin might be a useful approach for the therapy of recurrent non-genotype 1 HCV infection after LT.

Written informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.