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Title: HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir

Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. 58 chronic HCV patients were treated with 12-week sofosbuvir + simeprevir (n = 19), sofosbuvir + daclatasvir (n = 19), or sofosbuvir + ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12 weeks post EOT. Furthermore, mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid. All but one patient who relapsed achieved SVR. Mean age was 60 ± 11 years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV <15 IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predictedmore » to reach cure within 6, 8, 10, 12 and 13 weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir + ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43–45% and 17–30% in subjects who had HCV <15 IU/ml at weeks 2 and 4, respectively. Finally, the use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16–20% per 100-treated persons.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [7] ;  [8] ;  [9] ;  [8] ;  [4] ;  [10]
  1. Loyola Univ. Medical Center, Maywood, IL (United States). The Program for Experimental and Theoretical Modeling; Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group
  2. Loyola Univ. Medical Center, Maywood, IL (United States). The Program for Experimental and Theoretical Modeling; Univ. of Edinburgh, Scotland (United Kingdom). Center for Immunity
  3. Heidelberg Univ. (Germany). Cetner for Modeling and Simulation in the Biosciences
  4. Loyola Univ. Medical Center, Maywood, IL (United States). The Program for Experimental and Theoretical Modeling
  5. Univ. of Sao Paulo Hospital das Cinicas (Brazil)
  6. Alphabio Lab., Marseille (France)
  7. European Hospital, Marseille (France). Internal Medicine and Infectious Disease
  8. Saint Joseph Hospital, Marseille (France). Division of Hepatology
  9. CH Hyeres (France). Division of Hepatology
  10. Alphabio Lab., Marseille (France); European Hospital, Marseille (France). Internal Medicine and Infectious Disease
Publication Date:
Report Number(s):
LA-UR-15-27222
Journal ID: ISSN 0168-8278
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Journal of Hepatology
Additional Journal Information:
Journal Volume: 64; Journal Issue: 6; Journal ID: ISSN 0168-8278
Publisher:
Elsevier
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science
OSTI Identifier:
1334130
Alternate Identifier(s):
OSTI ID: 1467524

Dahari, Harel, Canini, Laetitia, Graw, Frederik, Uprichard, Susan L., Araújo, Evaldo S. A., Penaranda, Guillaume, Coquet, Emilie, Chiche, Laurent, Riso, Aurelie, Renou, Christophe, Bourliere, Marc, Cotler, Scott J., and Halfon, Philippe. HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir. United States: N. p., Web. doi:10.1016/j.jhep.2016.02.022.
Dahari, Harel, Canini, Laetitia, Graw, Frederik, Uprichard, Susan L., Araújo, Evaldo S. A., Penaranda, Guillaume, Coquet, Emilie, Chiche, Laurent, Riso, Aurelie, Renou, Christophe, Bourliere, Marc, Cotler, Scott J., & Halfon, Philippe. HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir. United States. doi:10.1016/j.jhep.2016.02.022.
Dahari, Harel, Canini, Laetitia, Graw, Frederik, Uprichard, Susan L., Araújo, Evaldo S. A., Penaranda, Guillaume, Coquet, Emilie, Chiche, Laurent, Riso, Aurelie, Renou, Christophe, Bourliere, Marc, Cotler, Scott J., and Halfon, Philippe. 2016. "HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir". United States. doi:10.1016/j.jhep.2016.02.022. https://www.osti.gov/servlets/purl/1334130.
@article{osti_1334130,
title = {HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir},
author = {Dahari, Harel and Canini, Laetitia and Graw, Frederik and Uprichard, Susan L. and Araújo, Evaldo S. A. and Penaranda, Guillaume and Coquet, Emilie and Chiche, Laurent and Riso, Aurelie and Renou, Christophe and Bourliere, Marc and Cotler, Scott J. and Halfon, Philippe},
abstractNote = {Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. 58 chronic HCV patients were treated with 12-week sofosbuvir + simeprevir (n = 19), sofosbuvir + daclatasvir (n = 19), or sofosbuvir + ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12 weeks post EOT. Furthermore, mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid. All but one patient who relapsed achieved SVR. Mean age was 60 ± 11 years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV <15 IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13 weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir + ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43–45% and 17–30% in subjects who had HCV <15 IU/ml at weeks 2 and 4, respectively. Finally, the use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16–20% per 100-treated persons.},
doi = {10.1016/j.jhep.2016.02.022},
journal = {Journal of Hepatology},
number = 6,
volume = 64,
place = {United States},
year = {2016},
month = {6}
}