Chronic hepatitis C virus (HCV) is a major cause of morbidity and mortality worldwide with an
estimated number of 180 million infected patients. Until 2012 the current standard of care
(SOC) treatment of patients with chronic hepatitis C was a 24 to 72 weeks therapy with
pegylated interferon- and ribavirin (PR). In 2012, the protease-inhibitors (PI's) telaprevir
and boceprevir as first directly acting HCV drugs have been approved by the local Swiss
authority for hepatitis C mono-infected and HCV-HIV-co-infected individuals. However, therapy
success is strongly limited in null-responders (NR) to previous PR. Treatment of HCV-HIV
co-infected individuals with the new PI's is accompanied by additional challenges (e.g.
drug-drug interactions, toxicity, high pill burden). Patients with advanced fibrosis are at
highest risk for decompensated liver disease and hepatocellular carcinoma (HCC) and prompt
initiation of treatment is strongly recommended. Recently, data in mono-infected patients
showed, that in prior non responders a 12 week course of a triple therapy (TT) with
telaprevir and PR followed by another 24 weeks of PR resulted in an sustained virologic
response (SVR) of only 29%. In HCV-HIV co-infected non-responders with unfavourable
preconditions (e.g. HCV-genotype 1, interleukin 28 B non-CC genotype, advanced liver
fibrosis, high baseline HCV viral load) SVR after TT is even expected to be lower. These
patients urgently need additional therapeutic options with the goal to eradicate HCV in order
to prevent further fibrosis progression and to reduce morbidity and mortality. A promising
substance in the field of drugs targeting the HCV replication is silibinin. Silibinin is the
main component of silymarin, an extract of the milk thistle Silybum marianum. Intravenous
silibinin (iSIL) targets multiple steps in the virus life cycle and exhibits anti-oxidant,
anti-inflammatory, anti-viral and immunomodulatory properties. iSIL inhibits the HCV NS5B
polymerase activity directly or by interfering with the binding of RNA to this enzyme. In
addition, iSIL appears to block virus entry, virus transmission and virus secretion.In 2008
Ferenci et al. for the first time reported the substantial clinical antiviral-effect of
intravenous silibinin (iSIL) against HCV in PR non-responders. The administration of 20mg/kg
iSIL in 20 patients led to a highly significant decrease in viral load. We intend to
investigate the effect and tolerability of iSIL in HIV-HCV co-infected individuals with
advanced liver fibrosis and previous non- or partial response to SOC. All included
study-subjects will receive a lead-in therapy with iSIL in a dosage of 20mg/kg/day (expressed
as silibinin concentration) once a day for 14 days. At the end of the THISTLE study, i.e.
after the day of completion of the 14-day iSIL administration (day 15), the patients will be
considered for eligibility to receive standard of care. We assume that the decline in HCV
viral load would substantially improve the chances of SVR as the reduction of viral load
should both increase the efficacy of PR and reduce the odds of drug resistance to
HCV-specific protease inhibitor.
- Trial with medicinal product