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Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals

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Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. / Dietz, Julia; Susser, Simone; Vermehren, Johannes; Peiffer, Kai-Henrik; Grammatikos, Georgios; Berger, Annemarie; Ferenci, Peter; Buti, Maria; Müllhaupt, Beat; Hunyady, Bela; Hinrichsen, Holger; Mauss, Stefan; Petersen, Jörg; Buggisch, Peter; Felten, Gisela; Hüppe, Dietrich; Knecht, Gaby; Lutz, Thomas; Schott, Eckart; Berg, Christoph; Spengler, Ulrich; von Hahn, Thomas; Berg, Thomas; Zeuzem, Stefan; Sarrazin, Christoph; European HCV Resistance Study Group.

in: GASTROENTEROLOGY, Jahrgang 154, Nr. 4, 03.2018, S. 976-988.e4.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Dietz, J, Susser, S, Vermehren, J, Peiffer, K-H, Grammatikos, G, Berger, A, Ferenci, P, Buti, M, Müllhaupt, B, Hunyady, B, Hinrichsen, H, Mauss, S, Petersen, J, Buggisch, P, Felten, G, Hüppe, D, Knecht, G, Lutz, T, Schott, E, Berg, C, Spengler, U, von Hahn, T, Berg, T, Zeuzem, S, Sarrazin, C & European HCV Resistance Study Group 2018, 'Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals', GASTROENTEROLOGY, Jg. 154, Nr. 4, S. 976-988.e4. https://doi.org/10.1053/j.gastro.2017.11.007

APA

Dietz, J., Susser, S., Vermehren, J., Peiffer, K-H., Grammatikos, G., Berger, A., Ferenci, P., Buti, M., Müllhaupt, B., Hunyady, B., Hinrichsen, H., Mauss, S., Petersen, J., Buggisch, P., Felten, G., Hüppe, D., Knecht, G., Lutz, T., Schott, E., ... European HCV Resistance Study Group (2018). Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. GASTROENTEROLOGY, 154(4), 976-988.e4. https://doi.org/10.1053/j.gastro.2017.11.007

Vancouver

Dietz J, Susser S, Vermehren J, Peiffer K-H, Grammatikos G, Berger A et al. Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. GASTROENTEROLOGY. 2018 Mär;154(4):976-988.e4. https://doi.org/10.1053/j.gastro.2017.11.007

Bibtex

@article{ebc9f09689f245c3b05c58743eb20ec4,
title = "Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals",
abstract = "BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments.METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-na{\"i}ve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis.RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed.CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.",
keywords = "Antiviral Agents, Drug Resistance, Viral, Drug Substitution, Drug Therapy, Combination, Europe, Genotype, Hepacivirus, Hepatitis C, Chronic, Humans, Phenotype, Protease Inhibitors, Retreatment, Retrospective Studies, Time Factors, Treatment Failure, Viral Nonstructural Proteins, Comparative Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't",
author = "Julia Dietz and Simone Susser and Johannes Vermehren and Kai-Henrik Peiffer and Georgios Grammatikos and Annemarie Berger and Peter Ferenci and Maria Buti and Beat M{\"u}llhaupt and Bela Hunyady and Holger Hinrichsen and Stefan Mauss and J{\"o}rg Petersen and Peter Buggisch and Gisela Felten and Dietrich H{\"u}ppe and Gaby Knecht and Thomas Lutz and Eckart Schott and Christoph Berg and Ulrich Spengler and {von Hahn}, Thomas and Thomas Berg and Stefan Zeuzem and Christoph Sarrazin and {European HCV Resistance Study Group} and Lohse, {Ansgar Wilhelm}",
note = "Copyright {\textcopyright} 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = mar,
doi = "10.1053/j.gastro.2017.11.007",
language = "English",
volume = "154",
pages = "976--988.e4",
journal = "GASTROENTEROLOGY",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

RIS

TY - JOUR

T1 - Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals

AU - Dietz, Julia

AU - Susser, Simone

AU - Vermehren, Johannes

AU - Peiffer, Kai-Henrik

AU - Grammatikos, Georgios

AU - Berger, Annemarie

AU - Ferenci, Peter

AU - Buti, Maria

AU - Müllhaupt, Beat

AU - Hunyady, Bela

AU - Hinrichsen, Holger

AU - Mauss, Stefan

AU - Petersen, Jörg

AU - Buggisch, Peter

AU - Felten, Gisela

AU - Hüppe, Dietrich

AU - Knecht, Gaby

AU - Lutz, Thomas

AU - Schott, Eckart

AU - Berg, Christoph

AU - Spengler, Ulrich

AU - von Hahn, Thomas

AU - Berg, Thomas

AU - Zeuzem, Stefan

AU - Sarrazin, Christoph

AU - European HCV Resistance Study Group

AU - Lohse, Ansgar Wilhelm

N1 - Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2018/3

Y1 - 2018/3

N2 - BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments.METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis.RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed.CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

AB - BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments.METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis.RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed.CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

KW - Antiviral Agents

KW - Drug Resistance, Viral

KW - Drug Substitution

KW - Drug Therapy, Combination

KW - Europe

KW - Genotype

KW - Hepacivirus

KW - Hepatitis C, Chronic

KW - Humans

KW - Phenotype

KW - Protease Inhibitors

KW - Retreatment

KW - Retrospective Studies

KW - Time Factors

KW - Treatment Failure

KW - Viral Nonstructural Proteins

KW - Comparative Study

KW - Journal Article

KW - Multicenter Study

KW - Research Support, Non-U.S. Gov't

U2 - 10.1053/j.gastro.2017.11.007

DO - 10.1053/j.gastro.2017.11.007

M3 - SCORING: Journal article

C2 - 29146520

VL - 154

SP - 976-988.e4

JO - GASTROENTEROLOGY

JF - GASTROENTEROLOGY

SN - 0016-5085

IS - 4

ER -