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Title: Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs

Abstract

Aim- We present that chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among haemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants. Methods- Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation. Results- No dominant RAVs were identified at baseline, but low-level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (ε) for lead-in ranged from 0 to 0.9745 (mean = 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. A total of 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only one patient. Adverse event profiles were similar to that observed in non-haemophilia cohorts. There was no evidence of factor inhibitor formation. There wasmore » no evidence that lead-in provided benefit in terms of response efficacy. Conclusion- Finally, these data support DAA-based therapy in those with inherited bleeding disorders.« less

Authors:
 [1]; ORCiD logo [2];  [1];  [1];  [1];  [1]; ORCiD logo [2]
  1. University of Cincinnati College of Medicine, Cincinnati, OH (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1471325
Report Number(s):
LA-UR-14-29029
Journal ID: ISSN 1351-8216
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Haemophilia
Additional Journal Information:
Journal Volume: 22; Journal Issue: 4; Journal ID: ISSN 1351-8216
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; direct-acting antivirals; HCV; haemophilia; resistance-associated variants; treatment response; viral dynamic models

Citation Formats

Sherman, Kenneth E., Ke, Ruian, Rouster, Susan D., Abdel-Hameed, E. A., Park, C., Palascak, Joseph, and Perelson, Alan S.. Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs. United States: N. p., 2016. Web. doi:10.1111/hae.12918.
Sherman, Kenneth E., Ke, Ruian, Rouster, Susan D., Abdel-Hameed, E. A., Park, C., Palascak, Joseph, & Perelson, Alan S.. Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs. United States. doi:10.1111/hae.12918.
Sherman, Kenneth E., Ke, Ruian, Rouster, Susan D., Abdel-Hameed, E. A., Park, C., Palascak, Joseph, and Perelson, Alan S.. Thu . "Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs". United States. doi:10.1111/hae.12918. https://www.osti.gov/servlets/purl/1471325.
@article{osti_1471325,
title = {Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs},
author = {Sherman, Kenneth E. and Ke, Ruian and Rouster, Susan D. and Abdel-Hameed, E. A. and Park, C. and Palascak, Joseph and Perelson, Alan S.},
abstractNote = {Aim- We present that chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among haemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants. Methods- Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation. Results- No dominant RAVs were identified at baseline, but low-level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (ε) for lead-in ranged from 0 to 0.9745 (mean = 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. A total of 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only one patient. Adverse event profiles were similar to that observed in non-haemophilia cohorts. There was no evidence of factor inhibitor formation. There was no evidence that lead-in provided benefit in terms of response efficacy. Conclusion- Finally, these data support DAA-based therapy in those with inherited bleeding disorders.},
doi = {10.1111/hae.12918},
journal = {Haemophilia},
number = 4,
volume = 22,
place = {United States},
year = {2016},
month = {3}
}

Journal Article:
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