Velia Chiara Di Maio1, Silvia Barbaliscia1, Elisabetta Teti2, Gianluca Fiorentino3, Martina Milana4, Stefania Paolucci5, Teresa Pollicino6, Giulia Morsica7, Mario Starace8, Bianca Bruzzone9, William Gennari10, Valeria Micheli11, Katia Yu La Rosa1, Luca Foroghi2, Vincenza Calvaruso12, Ilaria Lenci4, Ennio Polilli13, Sergio Babudieri14, Alessio Aghemo15, Giovanni Raimondo6, Loredana Sarmati2, Nicola Coppola8,16, Caterina Pasquazzi3, Fausto Baldanti5, Giustino Parruti13, Carlo Federico Perno17, Mario Angelico4, Antonio Craxì12, Massimo Andreoni2, Francesca Ceccherini-Silberstein1. 1. Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. 2. Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy. 3. Infectious Diseases, Sant'Andrea Hospital - "La Sapienza", Rome, Italy. 4. Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy. 5. Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy. 6. Department of Internal Medicine, University Hospital of Messina, Messina, Italy. 7. Division of Infectious Diseases, IRCCS, Ospedale San Raffaele, Milan, Italy. 8. Laboratory for the identification of prognostic factors of response to the treatment against infectious diseases, University of Campania "L. Vanvitelli", Napoli, Italy. 9. Hygiene Unit, IRCCS AOU San Martino-IST, Genoa, Italy. 10. Microbiology Unit, University Hospital of Modena, Modena, Italy. 11. Clinical Microbiology, Virology and Bioemergencies, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy. 12. Gastroenterology, "P. Giaccone" University Hospital, Palermo, Italy. 13. Infectious Disease Unit, Pescara General Hospital, Pescara, Italy. 14. Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy. 15. Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano, Italy. 16. Department of Mental Health and Public Medicine, Infectious Diseases Unit, University of Campania "L. Vanvitelli", Naples, Italy. 17. IRCCS Children Hospital Bambino Gesù, Rome, Italy.
Abstract
AIM: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3). METHODS: Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols. RESULTS: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA-naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A-RASs was observed before treatment in DAA-failures (5/13, 38.5%) vs DAA-naïves (61/393, 15.5%, P = .04). Regarding 228 DAA-naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A-RASs (P = .002). CONCLUSIONS: In this real-life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A-RASs, the most frequent being Y93H. The presence of natural NS5A-RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.
AIM: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3). METHODS: Within the Italian VIRONET-C network, a total of 539 GT3-infectedpatients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols. RESULTS: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA-naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A-RASs was observed before treatment in DAA-failures (5/13, 38.5%) vs DAA-naïves (61/393, 15.5%, P = .04). Regarding 228 DAA-naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A-RASs (P = .002). CONCLUSIONS: In this real-life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A-RASs, the most frequent being Y93H. The presence of natural NS5A-RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.
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