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1. Impact of Analytical Treatment Interruption on Burden and Diversification of HIV Peripheral Reservoir: A Pilot Study

Author

Rossana Scutari, Valentino Costabile, Laura Galli, Maria Concetta Bellocchi, Luca Carioti, Silvia Barbaliscia, Andrea Poli, Andrea Galli, Carlo Federico Perno, Maria Mercedes Santoro, Antonella Castagna, Francesca Ceccherini-Silberstein, Claudia Alteri, and Vincenzo Spagnuolo

Subjects
HIV-1, HIV-1 diversification, analytical treatment interruption, HIV-1 reservoir, Microbiology, QR1-502
Abstract

Background: If analytical antiretroviral-treatment (ART) interruption (ATI) might significantly impact quantitative or qualitative peripheral-total HIV-DNA is still debated. Methods: Six chronically HIV-1 infected patients enrolled in APACHE-study were analysed for peripheral-total HIV-DNA and residual viremia, major-resistance-mutations (MRMs) and C2-V3-C3 evolution at pre-ATI (T1), during ATI (T2) and at achievement of virological success after ART-resumption (post-ATI, T3). These data were obtained at three comparable time-points in five chronically HIV-1 infected patients on suppressive ART for ≥1 year, enrolled in MODAt-study. Results: At T1, APACHE and MODAt individuals had similar peripheral-total HIV-DNA and residual viremia (p = 0.792 and 0.662, respectively), and no significant changes for these parameters were observed between T1 and T3 in both groups. At T1, 4/6 APACHE and 2/5 MODAt carried HIV-DNA MRMs. MRMs disappeared at T3 in 3/4 APACHE. All disappearing MRMs were characterized by T1 intra-patient prevalence p = 0.04), while no significant changes were found in MODAt. Accordingly, maximum likelihood trees (bootstrap > 70%) and genealogical sorting indices (GSI > 0.50 with p-value < 0.05) showed that T1 C2-V3-C3 DNA sequences were distinct from T2 and T3 viruses in 4/6 APACHE. Virus populations at all three time-points were highly interspersed in MODAt. Conclusions: This pilot study indicates that short ATI does not alter peripheral-total HIV-DNA burden and residual viremia, but in some cases could cause a genetic diversification of peripheral viral reservoir in term of both MRMs rearrangement and viral evolution.

Published
2021
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2. Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b

Author

Mohammad Alkhatib, Velia Chiara Di Maio, Valentina De Murtas, Ennio Polilli, Martina Milana, Elisabetta Teti, Gianluca Fiorentino, Vincenza Calvaruso, Silvia Barbaliscia, Ada Bertoli, Rossana Scutari, Luca Carioti, Valeria Cento, Maria Mercedes Santoro, Alessandro Orro, Ivana Maida, Ilaria Lenci, Loredana Sarmati, Antonio Craxì, Caterina Pasquazzi, Giustino Parruti, Sergio Babudieri, Luciano Milanesi, Massimo Andreoni, Mario Angelico, Carlo Federico Perno, Francesca Ceccherini-Silberstein, Valentina Svicher, Romina Salpini, and on behalf of HIRMA (Hepatocarcinoma Innovative Research MArkers) and Fondazione Vironet C (HCV Virology Italian Resistance

Subjects
hepatitis C virus, hepatocellular carcinoma, cirrhosis, NS5A, genotype 1b, genetic variability, Microbiology, QR1-502
Abstract

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

Published
2021
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3. NS5A Gene Analysis by Next Generation Sequencing in HCV Nosocomial Transmission Clusters of HCV Genotype 1b Infected Patients

Author

Maria Concetta Bellocchi, Marianna Aragri, Luca Carioti, Lavinia Fabeni, Rosaria Maria Pipitone, Giuseppina Brancaccio, Maria Chiara Sorbo, Silvia Barbaliscia, Velia Chiara Di Maio, Fabrizio Bronte, Stefania Grimaudo, Walter Mazzucco, Ferdinando Frigeri, Marco Cantone, Antonio Pinto, Carlo Federico Perno, Antonio Craxì, Giovanni Battista Gaeta, Vito Di Marco, and Francesca Ceccherini-Silberstein

Subjects
HCV, acute infection, chronic infection, nosocomial transmission, sequencing, NGS, Cytology, QH573-671
Abstract

Background: The aim of the study was to investigate the intra-host variability through next-generation-sequencing (NGS) of the NS5A-gene in nosocomial transmission-clusters observed in two Italian hospitals among hepatitis C virus (HCV)-genotype-1b infected patients. Methods: HCV-sequencing was performed by Sanger-sequencing (NS3 + NS5A + NS5B) and by NGS (NS5A, MiSeq-Illumina) in 15 HCV-1b infected patients [five acute with onco-hematologic-disease and 10 (4/6 acute/chronic) with β-thalassemia]. Resistance-associated-substitutions (RAS) were analysed by Geno2pheno-algorithm. Nucleotide-sequence-variability (NSV, at 1%, 2%, 5%, 10% and 15% NGS-cutoffs) and Shannon entropy were estimated. Phylogenetic analysis was performed by Mega6-software and Bayesian-analysis. Results: Phylogenetic analysis showed five transmission-clusters: one involving four HCV-acute onco-hematologic-patients; one involving three HCV-chronic β-thalassemia-patients and three involving both HCV-acute and chronic β-thalassemia-patients. The NS5A-RAS Y93H was found in seven patients, distributed differently among chronic/acute patients involved in the same transmission-clusters, independently from the host-genetic IL-28-polymorphism. The intra-host NSV was higher in chronic-patients versus acute-patients, at all cutoffs analyzed (p < 0.05). Even though Shannon-entropy was higher in chronic-patients, significantly higher values were observed only in chronic β-thalassemia-patients versus acute β-thalassemia-patients (p = 0.01). Conclusions: In nosocomial HCV transmission-clusters, the intra-host HCV quasispecies divergence in patients with acute-infection was very low in comparison to that in chronic-infection. The NS5A-RAS Y93H was often transmitted and distributed differently within the same transmission-clusters, independently from the IL-28-polymorphism.

Published
2019
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4. Impact of analytical treatment interruption on burden and diversification of HIV peripheral reservoir: a pilot study

Author

Vincenzo Spagnuolo, Francesca Ceccherini-Silberstein, Rossana Scutari, Valentino Costabile, A Castagna, L. Galli, Silvia Barbaliscia, L. Carioti, Carlo Federico Perno, Maria Concetta Bellocchi, Andrea Poli, Maria Mercedes Santoro, Claudia Alteri, Andrea Galli, Scutari, R., Costabile, V., Galli, L., Bellocchi, M. C., Carioti, L., Barbaliscia, S., Poli, A., Galli, A., Perno, C. F., Santoro, M. M., Castagna, A., Ceccherini-Silberstein, F., Alteri, C., and Spagnuolo, V.

Subjects
0301 basic medicine, Adult, Male, Human immunodeficiency virus (HIV), Antiretroviral Therapy, Viremia, HIV Infections, Pilot Projects, Biology, Diversification (marketing strategy), medicine.disease_cause, Microbiology, Article, Virus, Medication Adherence, Settore MED/07, 03 medical and health sciences, 0302 clinical medicine, HIV-1 reservoir, Virology, Antiretroviral Therapy, Highly Active, HIV-1, HIV-1 diversification, analytical treatment interruption, Anti-Retroviral Agents, DNA, Viral, Disease Reservoirs, Female, Humans, Middle Aged, Mutation, Viral Load, medicine, Highly Active, 030212 general & internal medicine, Viral, Genetic diversification, Analytical treatment interruption, DNA, medicine.disease, QR1-502, Peripheral, 030104 developmental biology, Infectious Diseases, Treatment interruption, Viral evolution, Immunology
Abstract

Background: If analytical antiretroviral-treatment (ART) interruption (ATI) might significantly impact quantitative or qualitative peripheral-total HIV-DNA is still debated. Methods: Six chronically HIV-1 infected patients enrolled in APACHE-study were analysed for peripheral-total HIV-DNA and residual viremia, major-resistance-mutations (MRMs) and C2-V3-C3 evolution at pre-ATI (T1), during ATI (T2) and at achievement of virological success after ART-resumption (post-ATI, T3). These data were obtained at three comparable time-points in five chronically HIV-1 infected patients on suppressive ART for ≥1 year, enrolled in MODAt-study. Results: At T1, APACHE and MODAt individuals had similar peripheral-total HIV-DNA and residual viremia (p = 0.792 and 0.662, respectively), and no significant changes for these parameters were observed between T1 and T3 in both groups. At T1, 4/6 APACHE and 2/5 MODAt carried HIV-DNA MRMs. MRMs disappeared at T3 in 3/4 APACHE. All disappearing MRMs were characterized by T1 intra-patient prevalence &lt, 80%, and mainly occurred in APOBEC3-related sites. All MRMs persisted over-time in the 2 MODAt. C2-V3-C3 genetic-distance significantly changed from T1 to T3 in APACHE individuals (+0.36[0.11–0.41], p = 0.04), while no significant changes were found in MODAt. Accordingly, maximum likelihood trees (bootstrap &gt, 70%) and genealogical sorting indices (GSI &gt, 0.50 with p-value &lt, 0.05) showed that T1 C2-V3-C3 DNA sequences were distinct from T2 and T3 viruses in 4/6 APACHE. Virus populations at all three time-points were highly interspersed in MODAt. Conclusions: This pilot study indicates that short ATI does not alter peripheral-total HIV-DNA burden and residual viremia, but in some cases could cause a genetic diversification of peripheral viral reservoir in term of both MRMs rearrangement and viral evolution.

Published
2021

5. THU-117-Evaluation of risk factors associated with failure to a first-line NS5A-containing regimen in HCV-infected patients naive to direct acting antivirals: Particular focus on natural resistance

Author

Pietro Lampertico, Giulia Morsica, Silvia Galli, Giustino Parruti, Pietro Andreone, Adriano M. Pellicelli, Velia Chiara Di Maio, Rossana Scutari, Carlo Federico Perno, Antonio Craxì, Ada Bertoli, Filomena Morisco, Caterina Pasquazzi, Stefano Bonora, Vincenza Calvaruso, Roberta D'Ambrosio, Laura Ambra Nicolini, Riccardo Campoli, Francesca Ceccherini Silberstein, Valeria Ghisetti, Elisabetta Teti, V. Boccaccio, Gloria Taliani, Miriam Lichtner, Silvia Barbaliscia, Valeria Micheli, Luca Foroghi, Carlo Magni, Massimo Siciliano, Massimo Andreoni, Giovanni Battista Gaeta, P Paba, Ennio Polilli, Giuliano Rizzardini, Martina Milana, Bianca Bruzzone, Valeria Pace Palitti, Stefania Paolucci, Massimo Puoti, Angelico Mario, Vanni Borghi, C. Masetti, Renato Maserati, Coppola Nicola, Sergio Babudieri, Valeria Cento, N. Iapadre, Loredana Sarmati, Marianna Aragri, and Gianluca Fiorentino

Subjects
Oncology, medicine.medical_specialty, Focus (computing), Hepatology, business.industry, First line, HCV, NS5A, risk factors, DIRECT ACTING ANTIVIRALS, NS5A, Natural resistance, Regimen, Internal medicine, HCV, medicine, risk factors, business
Published
2019

6. Frequent NS5A and multiclass resistance in almost all HCV genotypes at DAA failures: What are the chances for second-line regimens?

Author

Velia Chiara Di Maio, Valeria Cento, Marianna Aragri, Stefania Paolucci, Teresa Pollicino, Nicola Coppola, Bianca Bruzzone, Valeria Ghisetti, Maurizio Zazzi, Maurizia Brunetto, Ada Bertoli, Silvia Barbaliscia, Silvia Galli, William Gennari, Fausto Baldanti, Giovanni Raimondo, Carlo Federico Perno, Francesca Ceccherini-Silberstein, Pietro Andreone, Massimo Andreoni, Mario Angelico, Sergio Babudieri, Giorgio Barbarini, Vincenzo Boccaccio, Lucio Boglione, Matteo Bolis, Stefano Bonora, Vanni Borghi, Giuseppina Brancaccio, Savino Bruno, Pierluigi Cacciatore, Vincenza Calvaruso, Nicola Caporaso, Antonio Ciaccio, Alessia Ciancio, Piero Colombatto, Raffaele Cozzolongo, Antonio Craxì, Cecilia D'Ambrosio, Gabriella D'Ettorre, Andrea De Luca, Antonio Di Biagio, Giovanni Di Perri, Simona Francioso, Giovanni Battista Gaeta, Alessia Giorgini, Antonio Grieco, Guido Gubertini, Roberto Gulminetti, Lara Lambiase, Ilaria Lenci, Miriam Lichtner, Ivana Maida, Simona Marenco, Letizia Marinaro, Renato Maserati, Chiara Masetti, Michela Melis, Elisa Meregalli, Valeria Micheli, Filomena Morisco, Fosca Niero, Laura Ambra Nicolini, Valeria Pace Palitti, Maurizio Paoloni, Giustino Parruti, Caterina Pasquazzi, Adriano Pellicelli, Ennio Polilli, Maria Laura Ponti, Massimo Puoti, Maria Rendina, Giuliano Rizzardini, Barbara Rossetti, Tina Ruggiero, Vincenzo Sangiovanni, Mario Starace, Laura Sticchi, Pierluigi Tarquini, Pierluigi Toniutto, Vincenzo Vullo, Di Maio VC, Cento V, Aragri M, Paolucci S, Pollicino T3, Coppola N4, Bruzzone B5, Ghisetti V6, Zazzi M7, Brunetto M8, Bertoli A1, Barbaliscia S1, Galli S9, Gennari W10, Baldanti F2, Raimondo G3, Perno CF1, Ceccherini-Silberstein F11, Andreone P, Andreoni M, Angelico M, Babudieri S, Barbarini G, Boccaccio V, Boglione L, Bolis M, Bonora S, Borghi V, Brancaccio G, Bruno S, Cacciatore P, Calvaruso Vincenza, Caporaso N, Ciaccio A, Ciancio A, Colombatto P, Cozzolongo R, Craxì Antonio, D'Ambrosio C, D'Ettorre G, De Luca A, Di Biagio A, Di Perri G, Francioso S, Gaeta GB, Giorgini A, Grieco A, Gubertini G, Gulminetti R, Lambiase L, Lenci I, Lichtner M, Maida I, Marenco S, Marinaro L, Maserati R, Masetti C, Melis M, Meregalli E, Micheli V, Morisco F, Niero F, Nicolini LA, Palitti VP, Paoloni M, Parruti G, Pasquazzi C, Pellicelli A, Polilli E, Ponti ML, Puoti M, Rendina M, Rizzardini G, Rossetti B, Ruggiero T, Sangiovanni V, Starace M, Sticchi L, Tarquini P, Toniutto P, Vullo V., Di Maio, Vc, Cento, V, Aragri, M, Paolucci, S, Pollicino, T, Coppola, N, Bruzzone, B, Ghisetti, V, Zazzi, M, Brunetto, M, Bertoli, A, Barbaliscia, S, Galli, S, Gennari, W, Baldanti, F, Raimondo, G, Perno, Cf, Ceccherini-Silberstein, F., Andreone P, Andreoni, M, Angelico, M, Babudieri, S, Barbarini, G, Boccaccio, V, Boglione, L, Bolis, M, Bonora, S, Borghi, V, Brancaccio, G, Bruno, S, Cacciatore, P, Calvaruso, V, Caporaso, N, Ciaccio, A, Ciancio, A, Colombatto, P, Cozzolongo, R, Craxì, A, D'Ambrosio, C, D'Ettorre, G, De Luca, A, Di Biagio, A, Di Perri, G, Francioso, S, Gaeta, Gb, Giorgini, A, Grieco, A, Gubertini, G, Gulminetti, R, Lambiase, L, Lenci, I, Lichtner, M, Maida, I, Marenco, S, Marinaro, L, Maserati, R, Masetti, C, Melis, M, Meregalli, E, Micheli, V, Morisco, F, Niero, F, Nicolini, La, Palitti, Vp, Paoloni, M, Parruti, G, Pasquazzi, C, Pellicelli, A, Polilli, E, Ponti, Ml, Puoti, M, Rendina, M, Rizzardini, G, Rossetti, B, Ruggiero, T, Sangiovanni, V, Starace, M, Sticchi, L, Tarquini, P, Toniutto, P, Vullo, V., Di Maio, V, Perno, C, Ceccherini-Silberstein, F, Andreone, P, Craxi, A, Gaeta, G, Nicolini, L, Palitti, V, Ponti, M, and Vullo, V

Subjects
0301 basic medicine, medicine.medical_specialty, hepacivirus, HCV RAS, Treatment outcome, Drug Resistance, HCV genotypes, Drug resistance, Biology, NS5A, 03 medical and health sciences, 0302 clinical medicine, Second line, drug resistance viral, humans, retreatment, treatment outcome, antiviral agents, hepatitis c chronic, Internal medicine, Drug Resistance, Viral, Humans, Retreatment, Treatment Outcome, Antiviral Agents, Hepacivirus, Hepatitis C, Chronic, medicine, Viral, Chronic, Hepatology, Hepatitis C, Settore MED/07 - Microbiologia e Microbiologia Clinica, medicine.disease, Virology, Hepatology, HCV, NS5A, 030104 developmental biology, HCV, 030211 gastroenterology & hepatology
Published
2018

7. Optimal efficacy of interferon-free HCV retreatment after protease inhibitor failure in real life

Author

L. Lambiase, Anna Claudia Pellicelli, Gloria Taliani, Barbara Menzaghi, Stefania Paolucci, Giuliano Rizzardini, Valeria Cento, Cesare Sarrecchia, Marianna Aragri, Francesca Ceccherini-Silberstein, M. Melis, M. Andreoni, Stefano Novati, Carlo Magni, Silvia Barbaliscia, Ilaria Lenci, V.C. Di Maio, Martina Milana, Elisabetta Teti, Mario Angelico, Caterina Pasquazzi, Aldo Bertoli, M. Puoti, A. Pecchioli, Valeria Micheli, Margherita Macera, Sergio Babudieri, Dante Romagnoli, Valeria Ghisetti, Laura Ambra Nicolini, Elisa Biliotti, Y. Troshina, Carlo Federico Perno, Fausto Baldanti, Simona Marenco, Nicola Coppola, T. Ruggiero, Manuele Koci Siciliano, Stefano Bonora, Alessia Ciancio, Cento, V, Barbaliscia, S, Lenci, I, Ruggiero, T, Magni, C, Paolucci, S, Babudieri, S, Siciliano, M, Pasquazzi, C, Ciancio, A, Perno, C, Ceccherini-Silberstein, F, Micheli, V, Troshina, Y, Biliotti, E, Milana, M, Melis, M, Teti, E, Lambiase, L, Menzaghi, B, Nicolini, L, Marenco, S, Di Maio, V, Aragri, M, Pecchioli, A, Bertoli, A, Sarrecchia, C, Macera, M, Coppola, N, Puoti, M, Romagnoli, D, Pellicelli, A, Bonora, S, Novati, S, Baldanti, F, Ghisetti, V, Andreoni, M, Taliani, G, Rizzardini, G, Angelico, M, Barbaliscia, I, and Ceccherini Silberstein, F

Subjects
0301 basic medicine, Male, Cirrhosis, Genotyping Techniques, Sustained Virologic Response, Hepacivirus, Treatment failure, chemistry.chemical_compound, Liver disease, 0302 clinical medicine, NS5A-inhibitors, Genotypic resistance testing, Treatment Failure, Chronic, HCV resistance, biology, Direct acting antivirals, HCV failure, Protease-inhibitors, Retreatment, Adult, Aged, Antiviral Agents, Female, Hepatitis C, Chronic, Humans, Microbial Sensitivity Tests, Middle Aged, Protease Inhibitors, Sequence Analysis, DNA, General Medicine, Settore MED/07 - Microbiologia e Microbiologia Clinica, Protease-inhibitor, Hepatitis C, humanities, Infectious Diseases, DIrect acting antivirals, HCVFailure, hcv-resistance, 030211 gastroenterology & hepatology, Sequence Analysis, Microbiology (medical), medicine.medical_specialty, 03 medical and health sciences, Internal medicine, medicine, In real life, Protease inhibitor (pharmacology), Cirrhosi, business.industry, Ribavirin, DNA, biology.organism_classification, medicine.disease, Surgery, Regimen, 030104 developmental biology, chemistry, NS5A-inhibitor, Direct acting antiviral, business
Abstract

Objectives First-generation protease-inhibitors (PIs) have suboptimal efficacy in GT-1 patients with advanced liver disease, and patients experiencing treatment failure may require urgent retreatment. Our objective was to analyse the real-life efficacy of interferon (IFN)-free retreatment after PI-failure, and the role of genotypic-resistance-testing (GRT) in guiding retreatment choice. Methods In this multi-centre observational study, patients retreated with IFN-free regimens after first-generation PI-failure (telaprevir-boceprevir-simeprevir) were included. Sustained-virological-response (SVR) was evaluated at week 12 of follow-up. GRT was performed by population-sequencing. Results After PI-failure, 121 patients (cirrhotic = 86.8%) were retreated following three different strategies: A) with ‘GRT-guided’ regimens (N = 18); B) with ‘AASLD/EASL recommended, not GRT-guided’ regimens (N = 72); C) with ‘not recommended, not GRT-guided’ regimens (N = 31). Overall SVR rate was 91%, but all 18 patients treated with ‘GRT-guided’ regimens reached SVR (100%), despite heterogeneity in treatment duration, use of PI and ribavirin, versus 68/72 patients (94.4%) receiving ‘AASLD/EASL recommended, not GRT-guided’ regimens. SVR was strongly reduced (77.4%) among the 31 patients who received a ‘not recommended, not GRT-guided regimen’ (p

Published
2017

8. Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies

Author

Di Maio, Velia C., Cento, Valeria, Lenci, Ilaria, Aragri, Marianna, Rossi, Piera, Barbaliscia, Silvia, Melis, Michela, Verucchi, Gabriella, Magni, Carlo F., Teti, Elisabetta, Bertoli, Ada, Antonucci, Francescopaolo, Bellocchi, Maria C., Micheli, Valeria, Masetti, Chiara, Landonio, Simona, Francioso, Simona, Santopaolo, Francesco, Pellicelli, Adriano M., Calvaruso, Vincenza, Gianserra, Laura, Siciliano, Massimo, Romagnoli, Dante, Cozzolongo, Raffaele, Grieco, Antonio, Vecchiet, Jacopo, Morisco, Filomena, Merli, Manuela, Brancaccio, Giuseppina, Di Biagio, Antonio, Loggi, Elisabetta, Mastroianni, Claudio Maria, Pace Palitti, Valeria, Tarquini, Pierluigi, Puoti, Massimo, Taliani, Gloria, Sarmati, Loredana, Picciotto, Antonino, Vullo, Vincenzo, Caporaso, Nicola, Paoloni, Maurizio, Pasquazzi, Caterina, Rizzardini, Giuliano, Parruti, Giustino, Craxì, Antonio, Babudieri, Sergio, Andreoni, Massimo, Angelico, Mario, Perno, Carlo F., Ceccherini Silberstein, Francesca, Mariani, R., Iapadre, N., Grimaldi, A., Cozzolongo, R., Andreone, P., Verucchi, G., Menzaghi, B., Quirino, T., Pisani, V., Torti, MARIA CHIARA, Vecchiet, J., Bruzzone, B., De Maria, A., Marenco, S., Nicolini, L. A., Viscoli, C., Casinelli, K., Delle Monache, M., Lichtner, Miriam, Aghemo, A., Boccaccio, V., Bruno, S., Cerrone, M., Colombo, M., D'Arminio Monforte, A., Danieli, E., Donato, F., Gubertini, G., Lleo, A., Magni, C. F., Mancon, A., Monico, S., Niero, F., Russo, M. L., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Brancaccio, G., Gaeta, G. B., Lembo, V., Sangiovanni, V., Di Marco, V., Mazzola, A., Petta, S., D'Amico, E., Cacciatore, P., Consorte, A., Pieri, A., Polilli, E., Sozio, F., Antenucci, F., Aragri, M., Baiocchi, L., Barbaliscia, S., Biliotti, Elisa, Biolato, M., Carioti, L., Ceccherini Silberstein, F., Cerasari, G., Cerva, C., Ciotti, M., D'Ambrosio, C., D'Ettorre, G., De Leonardis, F., De Sanctis, A., Di Maio, V. C., Di Paolo, D., Furlan, Caterina, Gallo, P., Gasbarrini, A., Giannelli, V., Grieco, S., Lambiase, L., Lattanzi, B., Lenci, I., Lula, R., Malagnino, V., Manuelli, M., Miglioresi, L., Milana, M., Moretti, A., Nosotti, L., Palazzo, Donatella, Pellicelli, A., Romano, M., Sarrecchia, C., Sforza, D., Sorbo, M. C., Spaziante, M., Svicher, V., Tisone, G., Vespasiani Gentilucci, U., D'Adamo, G., Mangia, A., Maida, I., Mura, M. S., Falconi, L., Di Giammartino, D., Di Maio, V., Cento, V., Lenci, I., Aragri, M., Rossi, P., Barbaliscia, S., Melis, M., Verucchi, G., Magni, C., Teti, E., Bertoli, A., Antonucci, F., Bellocchi, M., Micheli, V., Masetti, C., Landonio, S., Francioso, S., Santopaolo, F., Pellicelli, A., Calvaruso, V., Gianserra, L., Siciliano, M., Romagnoli, D., Cozzolongo, R., Grieco, A., Vecchiet, J., Morisco, F., Merli, M., Brancaccio, G., Di Biagio, A., Loggi, E., Mastroianni, C., Pace Palitti, V., Tarquini, P., Puoti, M., Taliani, G., Sarmati, L., Picciotto, A., Vullo, V., Caporaso, N., Paoloni, M., Pasquazzi, C., Rizzardini, G., Parruti, G., Craxã¬, A., Babudieri, S., Andreoni, M., Angelico, M., Perno, C., Ceccherini-Silberstein, F., Mariani, R., Iapadre, N., Grimaldi, A., Andreone, P., Menzaghi, B., Quirino, T., Pisani, V., Torti, C., Bruzzone, B., De Maria, A., Marenco, S., Nicolini, L., Viscoli, C., Casinelli, K., Delle Monache, M., Lichtner, M., Aghemo, A., Boccaccio, V., Bruno, S., Cerrone, M., Colombo, M., D'Arminio Monforte, A., Danieli, E., Donato, F., Gubertini, G., Lleo, A., Mancon, A., Monico, S., Niero, F., Russo, M., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Gaeta, G., Lembo, V., Sangiovanni, V., DI MARCO, V., Mazzola, A., Petta, S., D'Amico, E., Cacciatore, P., Consorte, A., Pieri, A., Polilli, E., Sozio, F., Antenucci, F., Baiocchi, L., Biliotti, E., Biolato, M., Carioti, L., Cerasari, G., Cerva, C., Ciotti, M., D'Ambrosio, C., D'Ettorre, G., De Leonardis, F., De Sanctis, A., Di Paolo, D., Furlan, C., Gallo, P., Gasbarrini, A., Giannelli, V., Grieco, S., Lambiase, L., Lattanzi, B., Lula, R., Malagnino, V., Manuelli, M., Miglioresi, L., Milana, M., Moretti, A., Nosotti, L., Palazzo, D., Romano, M., Sarrecchia, C., Sforza, D., Sorbo, M., Spaziante, M., Svicher, V., Tisone, G., Vespasiani-Gentilucci, U., D'Adamo, G., Mangia, A., Maida, I., Mura, M., Falconi, L., Di Giammartino, D., Di Maio, V, Cento, V, Lenci, I, Aragri, M, Rossi, P, Barbaliscia, S, Melis, M, Verucchi, G, Magni, C, Teti, E, Bertoli, A, Antonucci, F, Bellocchi, M, Micheli, V, Masetti, C, Landonio, S, Francioso, S, Santopaolo, F, Pellicelli, A, Calvaruso, V, Gianserra, L, Siciliano, M, Romagnoli, D, Cozzolongo, R, Grieco, A, Morisco, F, Merli, M, Brancaccio, G, Di Biagio, A, Loggi, E, Mastroianni, C, Pace Palitti, V, Tarquini, P, Puoti, M, Taliani, G, Sarmati, L, Picciotto, A, Vullo, V, Caporaso, N, Paoloni, M, Pasquazzi, C, Rizzardini, G, Parruti, G, Craxì, A, Babudieri, S, Andreoni, M, Angelico, M, Perno, C, Ceccherini-Silberstein, F, Velia C. Di Maio, Valeria Cento, Ilaria Lenci, Marianna Aragri, Piera Rossi, Silvia Barbaliscia, Michela Meli, Gabriella Verucchi, Carlo F. Magni, Elisabetta Teti, Ada Bertoli, Francesco Paolo Antonucci, Maria C. Bellocchi, Valeria Micheli, Chiara Masetti, Simona Landonio, Simona Francioso, Francesco Santopaolo, Adriano M. Pellicelli, Vincenza Calvaruso, Laura Gianserra, Massimo Siciliano, Dante Romagnoli, Raffaele Cozzolongo, Antonio Grieco, Jacopo Vecchiet, Filomena Morisco, Manuela Merli, Giuseppina Brancaccio, Antonio Di Biagio, Elisabetta Loggi, Claudio M. Mastroianni, Valeria Pace Palitti, Pierluigi Tarquini, Massimo Puoti, Gloria Taliani, Loredana Sarmati, Antonino Picciotto, Vincenzo Vullo, Nicola Caporaso, Maurizio Paoloni, Caterina Pasquazzi, Giuliano Rizzardini, Giustino Parruti, Antonio Craxì, Sergio Babudieri, Massimo Andreoni, Mario Angelico, Carlo F. Perno, Francesca Ceccherini-Silberstein, for the HCV Italian Resistance Network Study Group: [.., P. Andreone, E. Loggi, G. Verucchi, ], Di Maio, Velia C., Cento, Valeria, Lenci, Ilaria, Aragri, Marianna, Rossi, Piera, Barbaliscia, Silvia, Melis, Michela, Verucchi, Gabriella, Magni, Carlo F., Teti, Elisabetta, Bertoli, Ada, Antonucci, Francescopaolo, Bellocchi, Maria C., Micheli, Valeria, Masetti, Chiara, Landonio, Simona, Francioso, Simona, Santopaolo, Francesco, Pellicelli, Adriano M., Calvaruso, Vincenza, Gianserra, Laura, Siciliano, Massimo, Romagnoli, Dante, Cozzolongo, Raffaele, Grieco, Antonio, Vecchiet, Jacopo, Morisco, Filomena, Merli, Manuela, Brancaccio, Giuseppina, Di Biagio, Antonio, Loggi, Elisabetta, Mastroianni, Claudio M., Pace Palitti, Valeria, Tarquini, Pierluigi, Puoti, Massimo, Taliani, Gloria, Sarmati, Loredana, Picciotto, Antonino, Vullo, Vincenzo, Caporaso, Nicola, Paoloni, Maurizio, Pasquazzi, Caterina, Rizzardini, Giuliano, Parruti, Giustino, Craxã¬, Antonio, Babudieri, Sergio, Andreoni, Massimo, Angelico, Mario, Perno, Carlo F., Ceccherini-Silberstein, Francesca, Nicolini, L. A., Magni, C. F., Russo, M. L., Gaeta, G. B., Di Marco, V., Di Maio, V. C., Sorbo, M. C., Mura, M. S., Di Maio, Velia C, Magni, Carlo F, Bellocchi, Maria C, Pellicelli, Adriano M, Mastroianni, Claudio M, Craxì, Antonio, Perno, Carlo F, and Ceccherini Silberstein, Francesca

Subjects
Male, 0301 basic medicine, hepatitis C virus, Sustained Virologic Response, Sofosbuvir, Hepacivirus, Drug Resistance, resistance-associated substitutions, Viral Nonstructural Proteins, VARIANTS, NS5A, medicine.disease_cause, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, INFECTION, antiviral therapy, Medicine, hepatitis C viru, Viral, Treatment Failure, Chronic, direct-acting antivirals, resistance test, hepatology, biology, GENOTYPE 1, virus diseases, Middle Aged, Settore MED/07 - Microbiologia e Microbiologia Clinica, Hepatitis C, Italy, Combination, Interferon, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Author Keywords:antiviral therapy, RIBAVIRIN, Sequence Analysis, Human, medicine.drug, medicine.medical_specialty, Daclatasvir, Genotype, Hepatitis C virus, Antiviral Agents, LONG-TERM PERSISTENCE, DACLATASVIR, 03 medical and health sciences, Drug Therapy, Aged, Drug Resistance, Viral, Hepatitis C, Chronic, Humans, Interferons, Mutation, Ribavirin, Sequence Analysis, DNA, Hepatology, TREATMENT-NAIVE, Internal medicine, Antiviral Agent, resistance-associated substitution, direct-acting antiviral, Hepaciviru, resistance test KeyWords Plus:HEPATITIS-C VIRUS, business.industry, Viral Nonstructural Protein, DNA, biology.organism_classification, Clinical trial, 030104 developmental biology, SOFOSBUVIR, chemistry, Sequence Analysi, Immunology, business
Abstract

Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N= 200) and whenever possible at baseline (N= 70). Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P= 2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

Published
2017

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