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Title: Rapid emergence of hepatitis C virus protease inhibitor resistance is expected

Abstract

Approximately 170 million people worldwide are infected with hepatitis C virus (HCV). Current therapy, consisting of pegylated interferon (PEG-IFN) and ribavirin (RBV), leads to sustained viral elimination in only about 45% of patients treated. Telaprevir (VX-950), a novel HCV NS3-4A serine protease inhibitor, has demonstrated substantial antiviral activity in patients with chronic hepatitis C genotype 1 infection. However, some patients experience viral breakthrough during dosing, with drug resistant variants being 5%-20% of the virus population as early as day 2 after treatment initiation. Why viral variants appear such a short time after the start of dosing is unclear, especially since this has not been seen with monotherapy for either human immunodeficiency virus or hepatitis B virus. Here, using a viral dynamic model, we explain why such rapid emergence of drug resistant variants is expected when potent HCV protease inhibitors are used as monotherapy. Surprisingly, our model also shows that such rapid emergence need not be the case with some potent HCV NS5B polymerase inhibitors. Examining the case of telaprevir therapy in detail, we show the model fits observed dynamics of both wild-type and drug-resistant variants during treatment, and supports combination therapy of direct antiviral drugs with PEG-IFN and/or RBV formore » hepatitis C.« less

Authors:
 [1];  [1];  [1]
  1. Los Alamos National Laboratory
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
956500
Report Number(s):
LA-UR-09-00209; LA-UR-09-209
TRN: US201013%%198
DOE Contract Number:  
AC52-06NA25396
Resource Type:
Journal Article
Journal Name:
Nature
Additional Journal Information:
Journal Name: Nature
Country of Publication:
United States
Language:
English
Subject:
59; GENOTYPE; HEPATITIS; INTERFERON; PATIENTS; POLYMERASES; SERINE; THERAPY

Citation Formats

Rong, Libin, Perelson, Alan S, and Ribeiro, Ruy M. Rapid emergence of hepatitis C virus protease inhibitor resistance is expected. United States: N. p., 2009. Web.
Rong, Libin, Perelson, Alan S, & Ribeiro, Ruy M. Rapid emergence of hepatitis C virus protease inhibitor resistance is expected. United States.
Rong, Libin, Perelson, Alan S, and Ribeiro, Ruy M. Thu . "Rapid emergence of hepatitis C virus protease inhibitor resistance is expected". United States. https://www.osti.gov/servlets/purl/956500.
@article{osti_956500,
title = {Rapid emergence of hepatitis C virus protease inhibitor resistance is expected},
author = {Rong, Libin and Perelson, Alan S and Ribeiro, Ruy M},
abstractNote = {Approximately 170 million people worldwide are infected with hepatitis C virus (HCV). Current therapy, consisting of pegylated interferon (PEG-IFN) and ribavirin (RBV), leads to sustained viral elimination in only about 45% of patients treated. Telaprevir (VX-950), a novel HCV NS3-4A serine protease inhibitor, has demonstrated substantial antiviral activity in patients with chronic hepatitis C genotype 1 infection. However, some patients experience viral breakthrough during dosing, with drug resistant variants being 5%-20% of the virus population as early as day 2 after treatment initiation. Why viral variants appear such a short time after the start of dosing is unclear, especially since this has not been seen with monotherapy for either human immunodeficiency virus or hepatitis B virus. Here, using a viral dynamic model, we explain why such rapid emergence of drug resistant variants is expected when potent HCV protease inhibitors are used as monotherapy. Surprisingly, our model also shows that such rapid emergence need not be the case with some potent HCV NS5B polymerase inhibitors. Examining the case of telaprevir therapy in detail, we show the model fits observed dynamics of both wild-type and drug-resistant variants during treatment, and supports combination therapy of direct antiviral drugs with PEG-IFN and/or RBV for hepatitis C.},
doi = {},
journal = {Nature},
number = ,
volume = ,
place = {United States},
year = {2009},
month = {1}
}