Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients

Thomas Kuntzen, Joerg Timm, Andrew Berical, Niall Lennon, Aaron M. Berlin, Sarah K. Young, Bongshin Lee, David Heckerman, Jonathan Carlson, Laura L. Reyor, Marianna Kleyman, Cory M. McMahon, Christopher Birch, Julian Schulze zur Wiesch, Timothy Ledlie, Michael Koehrsen, Chinnappa Kodira, Andrew D. Roberts, Georg M. Lauer, Hugo R. Rosen & 25 others Florian Bihl, Andreas Cerny, Ulrich Spengler, Zhimin Liu, Arthur Y. Kim, Yanming Xing, Arne Schneidewind, Margaret A. Madey, Jaquelyn F. Fleckenstein, Vicki M. Park, James E. Galagan, Chad Nusbaum, Bruce D. Walker, Gerond V. Lake-Bakaar, Eric S. Daar, Ira M. Jacobson, Edward D. Gomperts, Brian R. Edlin, Sharyne M. Donfield, Raymond T. Chung, Andrew H. Talal, Tony Marion, Bruce W. Birren, Matthew R. Henn, Todd M. Allen

Research output: Contribution to journalArticle

320 Citations (Scopus)

Abstract

Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow > 1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

Original languageEnglish (US)
Pages (from-to)1769-1778
Number of pages10
JournalHepatology
Volume48
Issue number6
DOIs
StatePublished - Dec 1 2008

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Protease Inhibitors
Hepacivirus
Mutation
Viral Load
Genotype
danoprevir
Drug Resistance
Therapeutics
Antiviral Agents
Population
Ribavirin
Multiple Drug Resistance
Drug Combinations
Switzerland
Pharmaceutical Preparations
Germany
Sequence Analysis
Peptide Hydrolases
Genome
Viruses

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Kuntzen, T., Timm, J., Berical, A., Lennon, N., Berlin, A. M., Young, S. K., ... Allen, T. M. (2008). Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology, 48(6), 1769-1778. https://doi.org/10.1002/hep.22549

Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. / Kuntzen, Thomas; Timm, Joerg; Berical, Andrew; Lennon, Niall; Berlin, Aaron M.; Young, Sarah K.; Lee, Bongshin; Heckerman, David; Carlson, Jonathan; Reyor, Laura L.; Kleyman, Marianna; McMahon, Cory M.; Birch, Christopher; zur Wiesch, Julian Schulze; Ledlie, Timothy; Koehrsen, Michael; Kodira, Chinnappa; Roberts, Andrew D.; Lauer, Georg M.; Rosen, Hugo R.; Bihl, Florian; Cerny, Andreas; Spengler, Ulrich; Liu, Zhimin; Kim, Arthur Y.; Xing, Yanming; Schneidewind, Arne; Madey, Margaret A.; Fleckenstein, Jaquelyn F.; Park, Vicki M.; Galagan, James E.; Nusbaum, Chad; Walker, Bruce D.; Lake-Bakaar, Gerond V.; Daar, Eric S.; Jacobson, Ira M.; Gomperts, Edward D.; Edlin, Brian R.; Donfield, Sharyne M.; Chung, Raymond T.; Talal, Andrew H.; Marion, Tony; Birren, Bruce W.; Henn, Matthew R.; Allen, Todd M.

In: Hepatology, Vol. 48, No. 6, 01.12.2008, p. 1769-1778.

Research output: Contribution to journalArticle

Kuntzen, T, Timm, J, Berical, A, Lennon, N, Berlin, AM, Young, SK, Lee, B, Heckerman, D, Carlson, J, Reyor, LL, Kleyman, M, McMahon, CM, Birch, C, zur Wiesch, JS, Ledlie, T, Koehrsen, M, Kodira, C, Roberts, AD, Lauer, GM, Rosen, HR, Bihl, F, Cerny, A, Spengler, U, Liu, Z, Kim, AY, Xing, Y, Schneidewind, A, Madey, MA, Fleckenstein, JF, Park, VM, Galagan, JE, Nusbaum, C, Walker, BD, Lake-Bakaar, GV, Daar, ES, Jacobson, IM, Gomperts, ED, Edlin, BR, Donfield, SM, Chung, RT, Talal, AH, Marion, T, Birren, BW, Henn, MR & Allen, TM 2008, 'Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients', Hepatology, vol. 48, no. 6, pp. 1769-1778. https://doi.org/10.1002/hep.22549
Kuntzen, Thomas ; Timm, Joerg ; Berical, Andrew ; Lennon, Niall ; Berlin, Aaron M. ; Young, Sarah K. ; Lee, Bongshin ; Heckerman, David ; Carlson, Jonathan ; Reyor, Laura L. ; Kleyman, Marianna ; McMahon, Cory M. ; Birch, Christopher ; zur Wiesch, Julian Schulze ; Ledlie, Timothy ; Koehrsen, Michael ; Kodira, Chinnappa ; Roberts, Andrew D. ; Lauer, Georg M. ; Rosen, Hugo R. ; Bihl, Florian ; Cerny, Andreas ; Spengler, Ulrich ; Liu, Zhimin ; Kim, Arthur Y. ; Xing, Yanming ; Schneidewind, Arne ; Madey, Margaret A. ; Fleckenstein, Jaquelyn F. ; Park, Vicki M. ; Galagan, James E. ; Nusbaum, Chad ; Walker, Bruce D. ; Lake-Bakaar, Gerond V. ; Daar, Eric S. ; Jacobson, Ira M. ; Gomperts, Edward D. ; Edlin, Brian R. ; Donfield, Sharyne M. ; Chung, Raymond T. ; Talal, Andrew H. ; Marion, Tony ; Birren, Bruce W. ; Henn, Matthew R. ; Allen, Todd M. / Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. In: Hepatology. 2008 ; Vol. 48, No. 6. pp. 1769-1778.
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abstract = "Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1{\%} of the viral quasispecies may still allow > 1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-na{\"i}ve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-na{\"i}ve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3{\%} and 2.8{\%} in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6{\%} of the patients infected with genotype 1a and 1.4{\%} of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-na{\"i}ve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.",
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T1 - Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients

AU - Kuntzen, Thomas

AU - Timm, Joerg

AU - Berical, Andrew

AU - Lennon, Niall

AU - Berlin, Aaron M.

AU - Young, Sarah K.

AU - Lee, Bongshin

AU - Heckerman, David

AU - Carlson, Jonathan

AU - Reyor, Laura L.

AU - Kleyman, Marianna

AU - McMahon, Cory M.

AU - Birch, Christopher

AU - zur Wiesch, Julian Schulze

AU - Ledlie, Timothy

AU - Koehrsen, Michael

AU - Kodira, Chinnappa

AU - Roberts, Andrew D.

AU - Lauer, Georg M.

AU - Rosen, Hugo R.

AU - Bihl, Florian

AU - Cerny, Andreas

AU - Spengler, Ulrich

AU - Liu, Zhimin

AU - Kim, Arthur Y.

AU - Xing, Yanming

AU - Schneidewind, Arne

AU - Madey, Margaret A.

AU - Fleckenstein, Jaquelyn F.

AU - Park, Vicki M.

AU - Galagan, James E.

AU - Nusbaum, Chad

AU - Walker, Bruce D.

AU - Lake-Bakaar, Gerond V.

AU - Daar, Eric S.

AU - Jacobson, Ira M.

AU - Gomperts, Edward D.

AU - Edlin, Brian R.

AU - Donfield, Sharyne M.

AU - Chung, Raymond T.

AU - Talal, Andrew H.

AU - Marion, Tony

AU - Birren, Bruce W.

AU - Henn, Matthew R.

AU - Allen, Todd M.

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow > 1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

AB - Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow > 1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

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