title: Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics.
abstract: OBJECTIVE
  Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR.
  
  
  METHODS
  A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR.
  
  
  RESULTS
  Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33).
  
  
  CONCLUSIONS
  We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.
authors.affiliation: The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.forename: Shimon
authors.initials: S
authors.lastname: Shteingart
authors.forename: Inna
authors.initials: I
authors.lastname: Gafanovich
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Amato
authors.forename: Ralf T
authors.initials: RT
authors.lastname: Pohl
authors.forename: Gali
authors.initials: G
authors.lastname: Weiss
authors.forename: Yaakov J
authors.initials: YJ
authors.lastname: Ashkenazi
authors.forename: Thomas
authors.initials: T
authors.lastname: Tichler
authors.forename: Eran
authors.initials: E
authors.lastname: Goldin
authors.forename: Yoav
authors.initials: Y
authors.lastname: Lurie
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008954:Models, Biological; D057285:Precision Medicine / Q000379:methods*; D012367:RNA, Viral / Q000097:blood*; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D012838:Silymarin; D012254:Ribavirin; D000077385:Silybin
keywords: hepatitis C; individualized therapy; interferon-free treatment; mathematical modelling; silibinin; sustained virological response; viral kinetics