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Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome

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Harvard

Fahnøe, U, Pedersen, MS, Sølund, C, Ernst, A, Krarup, HB, Røge, BT, Christensen, PB, Laursen, AL, Gerstoft, J, Thielsen, P, Madsen, LG, Pedersen, AG, Schønning, K, Weis, N & Bukh, J 2021, 'Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome', Journal of Viral Hepatitis, bind 28, nr. 2, s. 302-316. https://doi.org/10.1111/jvh.13430

APA

Fahnøe, U., Pedersen, M. S., Sølund, C., Ernst, A., Krarup, H. B., Røge, B. T., Christensen, P. B., Laursen, A. L., Gerstoft, J., Thielsen, P., Madsen, L. G., Pedersen, A. G., Schønning, K., Weis, N., & Bukh, J. (2021). Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome. Journal of Viral Hepatitis, 28(2), 302-316. https://doi.org/10.1111/jvh.13430

CBE

Fahnøe U, Pedersen MS, Sølund C, Ernst A, Krarup HB, Røge BT, Christensen PB, Laursen AL, Gerstoft J, Thielsen P, Madsen LG, Pedersen AG, Schønning K, Weis N, Bukh J. 2021. Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome. Journal of Viral Hepatitis. 28(2):302-316. https://doi.org/10.1111/jvh.13430

MLA

Vancouver

Author

Fahnøe, Ulrik ; Pedersen, Martin S ; Sølund, Christina ; Ernst, Anja ; Krarup, Henrik B ; Røge, Birgit T ; Christensen, Peer B ; Laursen, Alex L ; Gerstoft, Jan ; Thielsen, Peter ; Madsen, Lone G ; Pedersen, Anders G ; Schønning, Kristian ; Weis, Nina ; Bukh, Jens. / Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome. I: Journal of Viral Hepatitis. 2021 ; Bind 28, Nr. 2. s. 302-316.

Bibtex

@article{235822e6f6ce469f9d3feb6b79bad92a,
title = "Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome",
abstract = "Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.",
keywords = "direct-acting antivirals, genome-wide association studies, hepatitis C virus, next-generation sequencing, resistance-associated substitution, treatment failure",
author = "Ulrik Fahn{\o}e and Pedersen, {Martin S} and Christina S{\o}lund and Anja Ernst and Krarup, {Henrik B} and R{\o}ge, {Birgit T} and Christensen, {Peer B} and Laursen, {Alex L} and Jan Gerstoft and Peter Thielsen and Madsen, {Lone G} and Pedersen, {Anders G} and Kristian Sch{\o}nning and Nina Weis and Jens Bukh",
note = "{\textcopyright} 2020 John Wiley & Sons Ltd.",
year = "2021",
month = feb,
doi = "10.1111/jvh.13430",
language = "English",
volume = "28",
pages = "302--316",
journal = "Journal of Viral Hepatitis",
issn = "1352-0504",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "2",

}

RIS

TY - JOUR

T1 - Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome

AU - Fahnøe, Ulrik

AU - Pedersen, Martin S

AU - Sølund, Christina

AU - Ernst, Anja

AU - Krarup, Henrik B

AU - Røge, Birgit T

AU - Christensen, Peer B

AU - Laursen, Alex L

AU - Gerstoft, Jan

AU - Thielsen, Peter

AU - Madsen, Lone G

AU - Pedersen, Anders G

AU - Schønning, Kristian

AU - Weis, Nina

AU - Bukh, Jens

N1 - © 2020 John Wiley & Sons Ltd.

PY - 2021/2

Y1 - 2021/2

N2 - Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

AB - Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p = .0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

KW - direct-acting antivirals

KW - genome-wide association studies

KW - hepatitis C virus

KW - next-generation sequencing

KW - resistance-associated substitution

KW - treatment failure

UR - http://www.scopus.com/inward/record.url?scp=85096683109&partnerID=8YFLogxK

U2 - 10.1111/jvh.13430

DO - 10.1111/jvh.13430

M3 - Journal article

C2 - 33131178

VL - 28

SP - 302

EP - 316

JO - Journal of Viral Hepatitis

JF - Journal of Viral Hepatitis

SN - 1352-0504

IS - 2

ER -

ID: 61309448