THISTLE - The HIV-HCV Silibinin Trial
THISTLE - The HIV-HCV Silibinin Trial
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
Inclusion criteria:

 -  Age greater or equal 18 years

 -  HIV-HCV co-infection

 -  HCV Genotype 1 infection

 -  At least one liver biopsy since diagnosis of HCV-infection

 -  Fibrosis score METAVIR = 2 documented by biopsy OR a stiffness greater or equal 7.0
 kPa documented by fibroscan during the previous 12 months.

 -  Documented previous null-response or partial-response to SOC

 Exclusion criteria:

 -  Contraindications to the study drug under study, e.g. known hypersensitivity or
 allergy to any ingredient of the study drug

 -  Patients in need of ART with HIV virological failure (= 400 copies/ml) in the last 3
 months