THISTLE - The HIV-HCV Silibinin Trial

Study Overview
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Brief Summary
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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

Official Title
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A Phase II, Multi-center, Open-label, Interventional Study to Evaluate the Safety of Intravenous Silibinin (iSIL) and Its Effect on the Hepatitis C Virus Load in Treatment-experienced HCV-HIV Co-infected Individuals With Advanced Liver Fibrosis in the Swiss HIV Cohort Study (SHCS)

Conditions
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HIV, Hepatitis C

Intervention / Treatment
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* Drug: Intravenous Silibinin (iSIL)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Intravenous Silibinin (iSIL)|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events during iSIL treatment. | The participants will be followed for the duration of study-drug administration and one day follow-up, which counts for 15days | Day 15 (after 14days of treatment) | 
| Kinetics of the decline in HCV-RNA after 2 weeks of iSIL treatment (difference in IU/ml from day 1 to day 15). | The participants will be followed for the duration of study-drug administration and one day follow-up, which counts for 15days | Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug levels of iSIL and its influence on the drug-level of co-administrated ART. | The participants will be followed for the duration of study-drug administration and one day follow-up, which counts for 15days | Day 15 | 
| Proportion of patients with HIV virological failure, i.e. confirmed viremia >50cp/ml. | The participants will be followed for the duration of study-drug administration and one day follow-up, which counts for 15days | Day 15 |