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

  • Author Footnotes
    † These authors equally contributed as joint first authors.
    Harel Dahari
    Correspondence
    Corresponding authors. Addresses: Internal Medicine and Infectious Diseases Department, Hôpital Europeen, Laboratoire Alphabio, 1 Rue Melchior Guinot, 13003 Marseille, France. Tel.: +33 4 13 42 81 20; fax: +33 4 91 79 20 44 (P. Halfon). The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153, USA. Tel.: +1 708 216 4682; fax: +1 708 216 6299 (H. Dahari).
    Footnotes
    † These authors equally contributed as joint first authors.
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA

    Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA
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  • Author Footnotes
    † These authors equally contributed as joint first authors.
    Laetitia Canini
    Footnotes
    † These authors equally contributed as joint first authors.
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA

    Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
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  • Frederik Graw
    Affiliations
    Center for Modeling and Simulation in the Biosciences, BioQuant Center, Heidelberg University, Heidelberg, Germany
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  • Susan L. Uprichard
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA
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  • Evaldo S.A. Araújo
    Affiliations
    University of Sao Paulo Hospital das Clınicas, Sao Paulo, Brazil
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  • Guillaume Penaranda
    Affiliations
    Laboratoire Alphabio, Marseille, France
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  • Emilie Coquet
    Affiliations
    Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France
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  • Laurent Chiche
    Affiliations
    Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France
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  • Aurelie Riso
    Affiliations
    Division of Hepatology, Hôpital Saint Joseph, Marseille, France
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  • Christophe Renou
    Affiliations
    Division of Hepatology, CH Hyères, Hyères, France
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  • Marc Bourliere
    Affiliations
    Division of Hepatology, Hôpital Saint Joseph, Marseille, France
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  • Scott J. Cotler
    Affiliations
    The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA
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  • Philippe Halfon
    Correspondence
    Corresponding authors. Addresses: Internal Medicine and Infectious Diseases Department, Hôpital Europeen, Laboratoire Alphabio, 1 Rue Melchior Guinot, 13003 Marseille, France. Tel.: +33 4 13 42 81 20; fax: +33 4 91 79 20 44 (P. Halfon). The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153, USA. Tel.: +1 708 216 4682; fax: +1 708 216 6299 (H. Dahari).
    Affiliations
    Laboratoire Alphabio, Marseille, France

    Internal Medicine and Infectious Disease, Hôpital Européen, Marseille, France
    Search for articles by this author
  • Author Footnotes
    † These authors equally contributed as joint first authors.
Published:February 21, 2016DOI:https://doi.org/10.1016/j.jhep.2016.02.022

      Background & Aims

      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.

      Methods

      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. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid.

      Results

      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.

      Conclusions

      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.

      Graphical abstract

      Abbreviations:

      HCV (hepatitis C virus), DAAs (direct-acting antiviral agents), SVR (sustained virological response)

      Keywords

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