: Despite the high efficacy of direct-acting antivirals (DAAs), the selection of resistance-associated substitutions (RASs) after virological failure of hepatitis C virus (HCV) DAAs can impair the cure of chronic HCV. The aim of the study was to characterize RASs after virological failure of DAAs in Italy over the years. Within the Italian network VIRONET-C, the change in prevalence of NS3/4A-NS5A-NS5B RASs was retrospectively evaluated in patients who failed a DAA regimen over the years 2015-2019. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols and the geno2pheno system was used to define HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend. Predictors of RASs at failure were analysed by logistic regression. Among 468 HCV-infected patients, HCV genotype 1 was the most prevalent (1b in 154, 33% and 1a in 109, 23%). DAA regimens were: ledipasvir (LDV)/sofosbuvir (SOF) in 131 patients (28%), daclatasvir (DCV)/SOF in 109 (23%), ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) in 89 (19%), elbasvir (EBR)/grazoprevir (GRZ) in 52 (10.5%), velpatasvir (VEL)/SOF in 53 (11%), glecaprevir (GLE)/pibrentasvir (PIB) in 27 (6%) and ombitasvir/paritaprevir/ritonavir (2D) in 7 (1.5%); ribavirin was administered in 133 (28%). The NS5A fasta sequence was available for all patients, NS5B and NS3/4A both for 93%. The prevalence of NS5A and NS3/4A RASs significantly declined from 2015 to 2019; NS5B RAS remained stable. Independent predictors of any RASs included older age and genotype 1a (vs G2 and vs G4). Notably, at least partial susceptibility to all the agents included in the GLE/PIB and VEL/SOF/Voxilaprevir (VOX) combinations was predicted in >95% of cases. As RASs remain common at the failure of DAAs, their identification could play a crucial role in optimizing re-treatment strategies. In Italy RAS prevalence has been decreasing over the years and susceptibility to the latest developed drug combinations is maintained in most cases.

Rossetti, B., Paglicci, L., Di Maio, V.C., Cassol, C., Barbaliscia, S., Paolucci, S., et al. (2021). Prevalence of resistance-associated substitutions to NS3, NS5A and NS5B inhibitors at DAA-failure in hepatitis C virus in Italy from 2015 to 2019. LE INFEZIONI IN MEDICINA, 29(2), 242-251.

Prevalence of resistance-associated substitutions to NS3, NS5A and NS5B inhibitors at DAA-failure in hepatitis C virus in Italy from 2015 to 2019

Di Maio, Velia C;Barbaliscia, Silvia;Ceccherini-Silberstein, Francesca;
2021-06-01

Abstract

: Despite the high efficacy of direct-acting antivirals (DAAs), the selection of resistance-associated substitutions (RASs) after virological failure of hepatitis C virus (HCV) DAAs can impair the cure of chronic HCV. The aim of the study was to characterize RASs after virological failure of DAAs in Italy over the years. Within the Italian network VIRONET-C, the change in prevalence of NS3/4A-NS5A-NS5B RASs was retrospectively evaluated in patients who failed a DAA regimen over the years 2015-2019. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols and the geno2pheno system was used to define HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend. Predictors of RASs at failure were analysed by logistic regression. Among 468 HCV-infected patients, HCV genotype 1 was the most prevalent (1b in 154, 33% and 1a in 109, 23%). DAA regimens were: ledipasvir (LDV)/sofosbuvir (SOF) in 131 patients (28%), daclatasvir (DCV)/SOF in 109 (23%), ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) in 89 (19%), elbasvir (EBR)/grazoprevir (GRZ) in 52 (10.5%), velpatasvir (VEL)/SOF in 53 (11%), glecaprevir (GLE)/pibrentasvir (PIB) in 27 (6%) and ombitasvir/paritaprevir/ritonavir (2D) in 7 (1.5%); ribavirin was administered in 133 (28%). The NS5A fasta sequence was available for all patients, NS5B and NS3/4A both for 93%. The prevalence of NS5A and NS3/4A RASs significantly declined from 2015 to 2019; NS5B RAS remained stable. Independent predictors of any RASs included older age and genotype 1a (vs G2 and vs G4). Notably, at least partial susceptibility to all the agents included in the GLE/PIB and VEL/SOF/Voxilaprevir (VOX) combinations was predicted in >95% of cases. As RASs remain common at the failure of DAAs, their identification could play a crucial role in optimizing re-treatment strategies. In Italy RAS prevalence has been decreasing over the years and susceptibility to the latest developed drug combinations is maintained in most cases.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/07
eng
Benzimidazoles
Carbamates
Drug Combinations
Fluorenes
Genotype
Hepacivirus
Heterocyclic Compounds, 4 or More Rings
Humans
Italy
Macrocyclic Compounds
Prevalence
Retrospective Studies
Ribavirin
Sofosbuvir
Sulfonamides
Antiviral Agents
Hepatitis C, Chronic
Rossetti, B., Paglicci, L., Di Maio, V.C., Cassol, C., Barbaliscia, S., Paolucci, S., et al. (2021). Prevalence of resistance-associated substitutions to NS3, NS5A and NS5B inhibitors at DAA-failure in hepatitis C virus in Italy from 2015 to 2019. LE INFEZIONI IN MEDICINA, 29(2), 242-251.
Rossetti, B; Paglicci, L; Di Maio, Vc; Cassol, C; Barbaliscia, S; Paolucci, S; Bruzzone, B; Coppola, N; Montagnani, F; Micheli, V; Monno, L; Zanelli, G; Santantonio, T; Cuomo, N; Caudai, C; Zazzi, M; Ceccherini-Silberstein, F; On Behalf Of The Hcv Virology Italian Resistance Network Vironet, C
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/289696
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