Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Anita Y.M. Howe; Chaturaka Rodrigo; SHARED Collaborators; Evan B. Cunningham; Mark W. Douglas; Julia Dietz; Jason Grebely; Stephanie Popping; Javier Alejandro Sfalcin; Milosz Parczewski; Christoph Sarrazin; Adolfo de Salazar; Ana Fuentes; Murat Sayan; Josep Quer; Midori Kjellin; Hege Kileng; Orna Mor; Johan Lennerstrand; Slim Fourati; Velia Chiara Di Maio; Vladimir Chulanov; Jean Michel Pawlotsky; P. Richard Harrigan; Francesca Ceccherini-Silberstein; Federico Garcia

doi:10.1016/j.jhepr.2022.100462

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Anita Y.M. Howe^*, Chaturaka Rodrigo, SHARED Collaborators, Evan B. Cunningham, Mark W. Douglas, Julia Dietz, Jason Grebely, Stephanie Popping, Javier Alejandro Sfalcin, Milosz Parczewski, Christoph Sarrazin, Adolfo de Salazar, Ana Fuentes, Murat Sayan, Josep Quer, Midori Kjellin, Hege Kileng, Orna Mor, Johan Lennerstrand, Slim FouratiVelia Chiara Di Maio, Vladimir Chulanov, Jean Michel Pawlotsky, P. Richard Harrigan, Francesca Ceccherini-Silberstein, Federico Garcia

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

Original language	English
Article number	100462
Journal	JHEP Reports
Volume	4
Issue number	5
Early online date	23 Feb 2022
DOIs	https://doi.org/10.1016/j.jhepr.2022.100462
Publication status	Published - 1 May 2022

Bibliographical note

Funding Information:
No financial support was received for the writing of this article. The initial SHARED development was funded in part by Merck and a User Partnership Program grant from Genome British Columbia to P.R.H and A.Y.M.H (UPP029). The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian (or any other) Government. C.R. and J.G. are supported by an NHMRC Investigator Grant (nos. 1173666, 1176131). An NHMRC Program Grant supported RAS testing and data collection by M.W.D. (1053206) and small grants from the Australian Centre for HIV and Hepatitis Virology Research, The University of Sydney, Western Sydney Local Health District Research Education Network, and the Robert W. Storr bequest to the Sydney Medical Foundation (University of Sydney). S.P. received personal fees from Gilead Sciences. Regarding the Italian data, the work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1?), by the Italian Ministry of Health (RF-2016-02362422), and by Aviralia and Vironet C Foundations.

Funding Information:
J.M.P. has been an advisor and/or speaker for AbbVie, Assembly Biosciences, Arbutus, Merck, Gilead, Regulus, and Memo Therapeutics. J.D. receives research support from Gilead. A.Y.M.H. is a consultant for Boston Pharmaceuticals. Outside the submitted work, J.G. reports grants and personal fees from AbbVie, Gilead Sciences, Merck, and Cepheid and grants from Hologic and Indivior. M.W.D has been an advisor and/or speaker for Gilead, AbbVie, and Merck and has received grants from Gilead and AbbVie. F.G.G. has been an advisor and/or speaker for AbbVie, Merck, and Gilead. S.F. has been an advisor and/or speaker for Abbott diagnostics, AbbVie, Gilead, and AB Science. F.C.S. has been an advisor and/or speaker for AbbVie, Merck, and Gilead and received grants from Merck and Gilead.

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© 2022 The Authors

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Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antiviralsFinal published version, 1.44 MBLicence: CC BY-NC-ND

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Howe, A. Y. M., Rodrigo, C., SHARED Collaborators, Cunningham, E. B., Douglas, M. W., Dietz, J., Grebely, J., Popping, S., Sfalcin, J. A., Parczewski, M., Sarrazin, C., de Salazar, A., Fuentes, A., Sayan, M., Quer, J., Kjellin, M., Kileng, H., Mor, O., Lennerstrand, J., ... Garcia, F. (2022). Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals. JHEP Reports, 4(5), Article 100462. https://doi.org/10.1016/j.jhepr.2022.100462

@article{00a6d3c792d84f379fc468753b9c5704,

title = "Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals",

abstract = "Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.",

author = "Howe, {Anita Y.M.} and Chaturaka Rodrigo and {SHARED Collaborators} and Cunningham, {Evan B.} and Douglas, {Mark W.} and Julia Dietz and Jason Grebely and Stephanie Popping and Sfalcin, {Javier Alejandro} and Milosz Parczewski and Christoph Sarrazin and {de Salazar}, Adolfo and Ana Fuentes and Murat Sayan and Josep Quer and Midori Kjellin and Hege Kileng and Orna Mor and Johan Lennerstrand and Slim Fourati and {Di Maio}, {Velia Chiara} and Vladimir Chulanov and Pawlotsky, {Jean Michel} and Harrigan, {P. Richard} and Francesca Ceccherini-Silberstein and Federico Garcia and Marianne Martinello and Gail Matthews and Fernando, {Fay Fabi{\'a}n} and Esteban, {Juan I.} and Beat M{\"u}llhaupt and Wiesch, {Julian Schulze zur} and Peter Buggisch and Christoph Neumann-Haefelin and Thomas Berg and Berg, {Christoph P.} and Schattenberg, {J{\"o}rn M.} and Christophe Moreno and Rudolf Stauber and Andrew Lloyd and Gregory Dore and Tanya Applegate and Juan Ignacio and Damir Garcia-Cehic and Josep Gregori and Francisco Rodriguez-Frias and Ariadna Rando and Yael Gozlan and Mario Angelico and Massimo Andreoni and Bart Rijnders",

note = "Funding Information: No financial support was received for the writing of this article. The initial SHARED development was funded in part by Merck and a User Partnership Program grant from Genome British Columbia to P.R.H and A.Y.M.H (UPP029). The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian (or any other) Government. C.R. and J.G. are supported by an NHMRC Investigator Grant (nos. 1173666, 1176131). An NHMRC Program Grant supported RAS testing and data collection by M.W.D. (1053206) and small grants from the Australian Centre for HIV and Hepatitis Virology Research, The University of Sydney, Western Sydney Local Health District Research Education Network, and the Robert W. Storr bequest to the Sydney Medical Foundation (University of Sydney). S.P. received personal fees from Gilead Sciences. Regarding the Italian data, the work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1?), by the Italian Ministry of Health (RF-2016-02362422), and by Aviralia and Vironet C Foundations. Funding Information: J.M.P. has been an advisor and/or speaker for AbbVie, Assembly Biosciences, Arbutus, Merck, Gilead, Regulus, and Memo Therapeutics. J.D. receives research support from Gilead. A.Y.M.H. is a consultant for Boston Pharmaceuticals. Outside the submitted work, J.G. reports grants and personal fees from AbbVie, Gilead Sciences, Merck, and Cepheid and grants from Hologic and Indivior. M.W.D has been an advisor and/or speaker for Gilead, AbbVie, and Merck and has received grants from Gilead and AbbVie. F.G.G. has been an advisor and/or speaker for AbbVie, Merck, and Gilead. S.F. has been an advisor and/or speaker for Abbott diagnostics, AbbVie, Gilead, and AB Science. F.C.S. has been an advisor and/or speaker for AbbVie, Merck, and Gilead and received grants from Merck and Gilead. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

day = "1",

doi = "10.1016/j.jhepr.2022.100462",

language = "English",

volume = "4",

journal = "JHEP Reports",

issn = "2589-5559",

publisher = "Elsevier",

number = "5",

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Howe, AYM, Rodrigo, C, SHARED Collaborators, Cunningham, EB, Douglas, MW, Dietz, J, Grebely, J, Popping, S, Sfalcin, JA, Parczewski, M, Sarrazin, C, de Salazar, A, Fuentes, A, Sayan, M, Quer, J, Kjellin, M, Kileng, H, Mor, O, Lennerstrand, J, Fourati, S, Di Maio, VC, Chulanov, V, Pawlotsky, JM, Harrigan, PR, Ceccherini-Silberstein, F & Garcia, F 2022, 'Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals', JHEP Reports, vol. 4, no. 5, 100462. https://doi.org/10.1016/j.jhepr.2022.100462

TY - JOUR

T1 - Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

AU - Howe, Anita Y.M.

AU - Rodrigo, Chaturaka

AU - SHARED Collaborators

AU - Cunningham, Evan B.

AU - Douglas, Mark W.

AU - Dietz, Julia

AU - Grebely, Jason

AU - Popping, Stephanie

AU - Sfalcin, Javier Alejandro

AU - Parczewski, Milosz

AU - Sarrazin, Christoph

AU - de Salazar, Adolfo

AU - Fuentes, Ana

AU - Sayan, Murat

AU - Quer, Josep

AU - Kjellin, Midori

AU - Kileng, Hege

AU - Mor, Orna

AU - Lennerstrand, Johan

AU - Fourati, Slim

AU - Di Maio, Velia Chiara

AU - Chulanov, Vladimir

AU - Pawlotsky, Jean Michel

AU - Harrigan, P. Richard

AU - Ceccherini-Silberstein, Francesca

AU - Garcia, Federico

AU - Martinello, Marianne

AU - Matthews, Gail

AU - Fernando, Fay Fabián

AU - Esteban, Juan I.

AU - Müllhaupt, Beat

AU - Wiesch, Julian Schulze zur

AU - Buggisch, Peter

AU - Neumann-Haefelin, Christoph

AU - Berg, Thomas

AU - Berg, Christoph P.

AU - Schattenberg, Jörn M.

AU - Moreno, Christophe

AU - Stauber, Rudolf

AU - Lloyd, Andrew

AU - Dore, Gregory

AU - Applegate, Tanya

AU - Ignacio, Juan

AU - Garcia-Cehic, Damir

AU - Gregori, Josep

AU - Rodriguez-Frias, Francisco

AU - Rando, Ariadna

AU - Gozlan, Yael

AU - Angelico, Mario

AU - Andreoni, Massimo

AU - Rijnders, Bart

N1 - Funding Information: No financial support was received for the writing of this article. The initial SHARED development was funded in part by Merck and a User Partnership Program grant from Genome British Columbia to P.R.H and A.Y.M.H (UPP029). The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian (or any other) Government. C.R. and J.G. are supported by an NHMRC Investigator Grant (nos. 1173666, 1176131). An NHMRC Program Grant supported RAS testing and data collection by M.W.D. (1053206) and small grants from the Australian Centre for HIV and Hepatitis Virology Research, The University of Sydney, Western Sydney Local Health District Research Education Network, and the Robert W. Storr bequest to the Sydney Medical Foundation (University of Sydney). S.P. received personal fees from Gilead Sciences. Regarding the Italian data, the work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1?), by the Italian Ministry of Health (RF-2016-02362422), and by Aviralia and Vironet C Foundations. Funding Information: J.M.P. has been an advisor and/or speaker for AbbVie, Assembly Biosciences, Arbutus, Merck, Gilead, Regulus, and Memo Therapeutics. J.D. receives research support from Gilead. A.Y.M.H. is a consultant for Boston Pharmaceuticals. Outside the submitted work, J.G. reports grants and personal fees from AbbVie, Gilead Sciences, Merck, and Cepheid and grants from Hologic and Indivior. M.W.D has been an advisor and/or speaker for Gilead, AbbVie, and Merck and has received grants from Gilead and AbbVie. F.G.G. has been an advisor and/or speaker for AbbVie, Merck, and Gilead. S.F. has been an advisor and/or speaker for Abbott diagnostics, AbbVie, Gilead, and AB Science. F.C.S. has been an advisor and/or speaker for AbbVie, Merck, and Gilead and received grants from Merck and Gilead. Publisher Copyright: © 2022 The Authors

PY - 2022/5/1

Y1 - 2022/5/1

N2 - Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

AB - Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

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DO - 10.1016/j.jhepr.2022.100462

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JF - JHEP Reports

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Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

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