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Title: Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics

Abstract

Providing here our aims and project background, we note that 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. With our method, 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. Our results show that, 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 wasmore » feasible, safe and achieved SVR (week-33). In conclusion, 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.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [5];  [6];  [7];  [7];  [2];  [3]
  1. Loyola Univ. Medical Center, Maywood IL (United States). Division of Hepatology; Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
  2. Share'e Zedek Medical Center, Jerusalem (Israel). Digestive Disease Inst.
  3. Share'e Zedek Medical Center, Jerusalem (Israel). Digestive Disease Inst., Liver Unit
  4. Loyola Univ. Medical Center, Maywood IL (United States). Division of Hepatology
  5. Rottapharm Madaus, Monza (Italy)
  6. Share'e Zedek Medical Center, Jerusalem (Israel). Nursing Division
  7. Share'e Zedek Medical Center, Jerusalem (Israel). Internal medicine
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1282055
Alternate Identifier(s):
OSTI ID: 1321740
Report Number(s):
LA-UR-14-23527
Journal ID: ISSN 1478-3223
Grant/Contract Number:  
AC52-06NA25396; R01-AI078881; P20-GM103452
Resource Type:
Accepted Manuscript
Journal Name:
Liver International
Additional Journal Information:
Journal Volume: 35; Journal Issue: 2; Journal ID: ISSN 1478-3223
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; hepatitis C; individualized therapy; interferon-free treatment; mathematical modelling; silibinin; sustained virological response; viral kinetics; mathematical modeling

Citation Formats

Dahari, Harel, Shteingart, Shimon, Gafanovich, Inna, Cotler, Scott J., D'Amato, Massimo, Pohl, Ralf T., Weiss, Gali, Ashkenazi, Yaakov J., Tichler, Thomas, Goldin, Eran, and Lurie, Yoav. Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics. United States: N. p., 2014. Web. doi:10.1111/liv.12692.
Dahari, Harel, Shteingart, Shimon, Gafanovich, Inna, Cotler, Scott J., D'Amato, Massimo, Pohl, Ralf T., Weiss, Gali, Ashkenazi, Yaakov J., Tichler, Thomas, Goldin, Eran, & Lurie, Yoav. Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics. United States. doi:10.1111/liv.12692.
Dahari, Harel, Shteingart, Shimon, Gafanovich, Inna, Cotler, Scott J., D'Amato, Massimo, Pohl, Ralf T., Weiss, Gali, Ashkenazi, Yaakov J., Tichler, Thomas, Goldin, Eran, and Lurie, Yoav. Fri . "Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics". United States. doi:10.1111/liv.12692. https://www.osti.gov/servlets/purl/1282055.
@article{osti_1282055,
title = {Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics},
author = {Dahari, Harel and Shteingart, Shimon and Gafanovich, Inna and Cotler, Scott J. and D'Amato, Massimo and Pohl, Ralf T. and Weiss, Gali and Ashkenazi, Yaakov J. and Tichler, Thomas and Goldin, Eran and Lurie, Yoav},
abstractNote = {Providing here our aims and project background, we note that 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. With our method, 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. Our results show that, 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). In conclusion, 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.},
doi = {10.1111/liv.12692},
journal = {Liver International},
number = 2,
volume = 35,
place = {United States},
year = {2014},
month = {10}
}

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    Works referencing / citing this record:

    Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection
    journal, June 2015