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.

Howe, A., Rodrigo, C., Cunningham, E.b., Douglas, M.w., Dietz, J., Grebely, J., et al. (2022). Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals. JHEP REPORTS, 4(5), 100462 [10.1016/j.jhepr.2022.100462].

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

Di Maio, Velia Chiara;Ceccherini-Silberstein, Francesca;
2022-05

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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07
English
DAA
DAA, direct-acting antiviral
DCV, daclatasvir
DSV, dasabuvir
GT, genotype
HCV
LDV, ledipasvir
NI, nucleoside
NNI, non-nucleoside
NS5A
NS5AI, NS5A replication complex inhibitor
OR, odds ratio
PI, NS3 protease inhibitor
PIB, pibrentasvir
RAS
RASs, resistance-associated substitutions
SHARED, The Surveillance of Hepatitis C Antiviral Resistance, Epidemiology and methoDologies
SOF, sofosbuvir
SVR, sustained virologic response
VEL, velpatasvir
aOR, adjusted odds ratio
sFC, substitution frequency change
virologic failure
Howe, A., Rodrigo, C., Cunningham, E.b., Douglas, M.w., Dietz, J., Grebely, J., et al. (2022). Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals. JHEP REPORTS, 4(5), 100462 [10.1016/j.jhepr.2022.100462].
Howe, Aym; Rodrigo, C; 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, J; Harrigan, Pr; Ceccherini-Silberstein, F; Garcia, F
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/303937
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