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

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 tra...

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Autores principales: Howe, Anita Y.M., Rodrigo, Chaturaka, Cunningham, Evan B., Douglas, Mark W., Dietz, Julia, Grebely, Jason, Popping, Stephanie, Sfalcin, Javier Alejandro, Parczewski, Milosz, Sarrazin, Christoph, de Salazar, Adolfo, Fuentes, Ana, Sayan, Murat, Quer, Josep, Kjellin, Midori, Kileng, Hege, Mor, Orna, Lennerstrand, Johan, Fourati, Slim, Di Maio, Velia Chiara, Chulanov, Vladimir, Pawlotsky, Jean-Michel, Harrigan, P. Richard, Ceccherini-Silberstein, Francesca, Garcia, Federico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010635/
https://www.ncbi.nlm.nih.gov/pubmed/35434589
http://dx.doi.org/10.1016/j.jhepr.2022.100462
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author Howe, Anita Y.M.
Rodrigo, Chaturaka
Cunningham, Evan B.
Douglas, Mark W.
Dietz, Julia
Grebely, Jason
Popping, Stephanie
Sfalcin, Javier Alejandro
Parczewski, Milosz
Sarrazin, Christoph
de Salazar, Adolfo
Fuentes, Ana
Sayan, Murat
Quer, Josep
Kjellin, Midori
Kileng, Hege
Mor, Orna
Lennerstrand, Johan
Fourati, Slim
Di Maio, Velia Chiara
Chulanov, Vladimir
Pawlotsky, Jean-Michel
Harrigan, P. Richard
Ceccherini-Silberstein, Francesca
Garcia, Federico
author_facet Howe, Anita Y.M.
Rodrigo, Chaturaka
Cunningham, Evan B.
Douglas, Mark W.
Dietz, Julia
Grebely, Jason
Popping, Stephanie
Sfalcin, Javier Alejandro
Parczewski, Milosz
Sarrazin, Christoph
de Salazar, Adolfo
Fuentes, Ana
Sayan, Murat
Quer, Josep
Kjellin, Midori
Kileng, Hege
Mor, Orna
Lennerstrand, Johan
Fourati, Slim
Di Maio, Velia Chiara
Chulanov, Vladimir
Pawlotsky, Jean-Michel
Harrigan, P. Richard
Ceccherini-Silberstein, Francesca
Garcia, Federico
author_sort Howe, Anita Y.M.
collection PubMed
description 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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spelling pubmed-90106352022-04-16 Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals Howe, Anita Y.M. Rodrigo, Chaturaka Cunningham, Evan B. Douglas, Mark W. Dietz, Julia Grebely, Jason Popping, Stephanie Sfalcin, Javier Alejandro Parczewski, Milosz Sarrazin, Christoph de Salazar, Adolfo Fuentes, Ana Sayan, Murat Quer, Josep Kjellin, Midori Kileng, Hege Mor, Orna Lennerstrand, Johan Fourati, Slim Di Maio, Velia Chiara Chulanov, Vladimir Pawlotsky, Jean-Michel Harrigan, P. Richard Ceccherini-Silberstein, Francesca Garcia, Federico JHEP Rep Research Article 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. Elsevier 2022-02-24 /pmc/articles/PMC9010635/ /pubmed/35434589 http://dx.doi.org/10.1016/j.jhepr.2022.100462 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Howe, Anita Y.M.
Rodrigo, Chaturaka
Cunningham, Evan B.
Douglas, Mark W.
Dietz, Julia
Grebely, Jason
Popping, Stephanie
Sfalcin, Javier Alejandro
Parczewski, Milosz
Sarrazin, Christoph
de Salazar, Adolfo
Fuentes, Ana
Sayan, Murat
Quer, Josep
Kjellin, Midori
Kileng, Hege
Mor, Orna
Lennerstrand, Johan
Fourati, Slim
Di Maio, Velia Chiara
Chulanov, Vladimir
Pawlotsky, Jean-Michel
Harrigan, P. Richard
Ceccherini-Silberstein, Francesca
Garcia, Federico
Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
title Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
title_full Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
title_fullStr Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
title_full_unstemmed Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
title_short Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
title_sort characteristics of hepatitis c virus resistance in an international cohort after a decade of direct-acting antivirals
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010635/
https://www.ncbi.nlm.nih.gov/pubmed/35434589
http://dx.doi.org/10.1016/j.jhepr.2022.100462
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