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Title: The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics?

Abstract

High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a proteaseinhibitor (GS-9451) and after 12 weeks with sofosbuvir+ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.

Authors:
 [1]; ORCiD logo [2];  [3];  [4];  [5];  [6]
  1. IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ. Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France
  2. IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ. Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France; Université Paris-Est, Hopital Henri Mondor, Creteil, France
  3. Loyola Univ. Medical Center, Department of Medicine, Maywood, Illinois, USA
  4. St. Joseph’s Hospital, Dignity Health, Phoenix, Arizona, USA
  5. National Inst. of Health (NIH), Laboratory of Immunoregulation, NIAID, Bethesda, MD, USA; Bethesda, MD (United States)
  6. Los Alamos, NM, USA; Los Alamos National Lab. (LANL), Theoretical Biology and Biophysics Group, Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
Contributing Org.:
National Institutes of Health
OSTI Identifier:
1643698
Grant/Contract Number:  
AC52-06NA25396; R01-AI078881; R01-AI116868; R01-AI028433; R01-OD011095
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Science & Technology - Other Topics

Citation Formats

Nguyen, Thi Huyen Tram, Guedj, Jérémie, Uprichard, Susan L., Kohli, Anita, Kottilil, Shyam, and Perelson, Alan S. The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics?. United States: N. p., 2017. Web. doi:10.1038/s41598-017-09776-z.
Nguyen, Thi Huyen Tram, Guedj, Jérémie, Uprichard, Susan L., Kohli, Anita, Kottilil, Shyam, & Perelson, Alan S. The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics?. United States. https://doi.org/10.1038/s41598-017-09776-z
Nguyen, Thi Huyen Tram, Guedj, Jérémie, Uprichard, Susan L., Kohli, Anita, Kottilil, Shyam, and Perelson, Alan S. Thu . "The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics?". United States. https://doi.org/10.1038/s41598-017-09776-z. https://www.osti.gov/servlets/purl/1643698.
@article{osti_1643698,
title = {The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics?},
author = {Nguyen, Thi Huyen Tram and Guedj, Jérémie and Uprichard, Susan L. and Kohli, Anita and Kottilil, Shyam and Perelson, Alan S.},
abstractNote = {High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a proteaseinhibitor (GS-9451) and after 12 weeks with sofosbuvir+ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.},
doi = {10.1038/s41598-017-09776-z},
url = {https://www.osti.gov/biblio/1643698}, journal = {Scientific Reports},
issn = {2045-2322},
number = 1,
volume = 7,
place = {United States},
year = {2017},
month = {8}
}

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    Innovative Approximate Analytical Solution for Standard Model of Viral Dynamics: Hepatitis C with Direct-Acting Agents as an Implemented Case
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    Early HCV viral kinetics under DAAs may optimize duration of therapy in patients with compensated cirrhosis
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    Modelling how responsiveness to interferon improves interferon-free treatment of hepatitis C virus infection
    journal, July 2018


    Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era
    journal, August 2018