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:
-
[2];
- IAME, UMR 1137, INSERM, F-75018 Paris, France; Univ. Paris Diderot, Sorbonne Paris Cité, F-75018, Paris, France
- 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
- Loyola Univ. Medical Center, Department of Medicine, Maywood, Illinois, USA
- St. Joseph’s Hospital, Dignity Health, Phoenix, Arizona, USA
- National Inst. of Health (NIH), Laboratory of Immunoregulation, NIAID, Bethesda, MD, USA; Bethesda, MD (United States)
- 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 Laboratory (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:
- 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},
journal = {Scientific Reports},
number = 1,
volume = 7,
place = {United States},
year = {Thu Aug 31 00:00:00 EDT 2017},
month = {Thu Aug 31 00:00:00 EDT 2017}
}
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Figures / Tables:
Figure 1: Observed viral kinetics and virologic responses in the SYNERGY and SPARE trials. Upper row: observed median viral load versus time during the first week of treatment (left panel) and during 6 weeks of treatment (right panel). Lower row: proportion of data below the limit of quantification (LOQ) and/ormore »
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