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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. Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy

Author

Ada Bertoli, Michael P. Manns, M. Katja Deterding, Vanni Borghi, Silvia Barbaliscia, Elisabetta Degasperi, Julian Schulze zur Wiesch, Velia Chiara Di Maio, Ansgar W. Lohse, Wolfgang Schmidt, Markus Cornberg, Christophe Moreno, Tomas Beyer, Federico García, Johannes Vermehren, Pietro Lampertico, Andreas E. Kremer, Laura Sighinolfi, Felix Piecha, Magdalena Lara, Pier Luigi Toniutto, Christoph Sarrazin, Antonio Craxì, Francesca Ceccherini-Silberstein, Jonas Schreiber, Jesús Santos, Ana Belén Pérez, Alessio Aghemo, William Gennari, Lorenzo Magenta, Manuel Alberto Macias Rodriguez, Heiner Wedermeyer, Ana Fuentes, Stephan Grunwald, Jose Miguel Rosales Zabal, Francisco Téllez, Dolores Merino, Burkhard Jäger, Miguel García Deltoro, Juan Manuel Pascasio-Acevedo, Blanca Figueruela, Andreas Stallmach, Renate Heyne, Valeria Ghisetti, Christoph P. Berg, Carlo Federico Perno, Elisa Fernández-Fuertes, Nikolaus Kordecki, Ana María Martinez Sapiña, Natalia Chueca, Andreas Herrmann, Eva Jägel-Guedes, Vincenza Calvaruso, Maurizio Zazzi, Massimo Andreoni, Lucio Boglione, Mario Angelico, Simona Francioso, Giuseppe Cariti, Cristina Quilez, Tiziano Allice, Christiana Graf, Leopoldo Muñoz-Medina, Fausto Baldanti, Rudolf E. Stauber, Jürgen Siebler, Julia Dietz, Maria Josefa Rodriguez Pardo, Kerstin Port, Heinz Zoller, Juan Carlos Alados, Stefan Zeuzem, Juan Ignacio Arenas Ruiz-Tapiador, Joaquín Cabezas, Stefania Paolucci, Axels Baumgarten, Kai-Henrik Peiffer, Adolfo de Salazar, Pietro Pozzoni, Miguel Jimenez, Hjördis Möller, Dietz J., Di Maio V.C., de Salazar A., Merino D., Vermehren J., Paolucci S., Kremer A.E., Lara M., Pardo M.R., Zoller H., Degasperi E., Peiffer K.-H., Sighinolfi L., Tellez F., Graf C., Ghisetti V., Schreiber J., Fernandez-Fuertes E., Boglione L., Munoz-Medina L., Stauber R., Gennari W., Figueruela B., Santos J., Lampertico P., Zeuzem S., Ceccherini-Silberstein F., Garcia F., Sarrazin C., Aghemo A., Allice T., Andreoni M., Angelico M., Baldanti F., Barbaliscia S., Bertoli A., Borghi V., Calvaruso V., Cariti G., Craxi A., Francioso S., Perno C.F., Pozzoni P., Toniutto P.L., Zazzi M., Perez A.B., Quilez C., Alados J.C., Cabezas J., Ruiz-Tapiador J.I.A., Jimenez M., Pascasio-Acevedo J.M., Rodriguez M.A.M., Zabal J.M.R., Deltoro M.G., Sapina A.M.M., Fuentes A., Chueca N., Berg C.P., Herrmann A., Stallmach A., Port K., Katja Deterding M., Wedermeyer H., Cornberg M., Manns M.P., Moreno C., Wiesch J.S.Z., Piecha F., Lohse A., Siebler J., Kordecki N., Magenta L., Jager B., Moller H., Heyne R., Beyer T., Grunwald S., Baumgarten A., Jagel-Guedes E., and Schmidt W.

Subjects
0301 basic medicine, Hepatitis C Virus, medicine.medical_specialty, Sofosbuvir, Voxilaprevir, Population, resistance-associated substitutions, Direct-acting antiviral, Voxilaprevir/velpatasvir/sofosbuvir, Gastroenterology, Settore MED/07, Telaprevir, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Voxilaprevir/Velpatasvir/Sofosbuvir, Internal medicine, Boceprevir, Rescue therapy, medicine, Resistance-associated substitution, education, direct-acting antivirals, DAA, education.field_of_study, Hepatology, business.industry, virus diseases, Glecaprevir, HCV, rescue therapy, digestive system diseases, Pibrentasvir, Regimen, 030104 developmental biology, chemistry, 030211 gastroenterology & hepatology, Hepatitis C viru, business, medicine.drug
Abstract

Background & Aims There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. Conclusions VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. Lay summary The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Published
2021

5. 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

6. Optimal cure rate by personalized HCV regimens in real-life: a proof-of-concept study

Author

Ada Bertoli, Valeria Cento, Luca Foroghi, Valeria Pace Palitti, Silvia Barbaliscia, Massimo Andreoni, Alessandro Pieri, Marianna Aragri, Carlo Federico Perno, Francesca Ceccherini-Silberstein, Giustino Parruti, Ennio Polilli, Velia Chiara Di Maio, Loredana Sarmati, and Elisabetta Teti

Subjects
0301 basic medicine, Microbiology (medical), medicine.medical_specialty, Cure rate, Settore MED/17 - Malattie Infettive, Genotype, Sustained Virologic Response, Personalized treatment, Administration, Oral, Context (language use), Hepacivirus, Microbial Sensitivity Tests, Antiviral Agents, Proof of Concept Study, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, In real life, Pharmacology (medical), Precision Medicine, Pharmacology, business.industry, Ribavirin, Sequence Analysis, DNA, Guideline, Hepatitis C, Chronic, Surgery, Discontinuation, Regimen, Treatment Outcome, 030104 developmental biology, Infectious Diseases, chemistry, RNA, Viral, 030211 gastroenterology & hepatology, business
Abstract

Background Pretreatment evaluation of HCV-infected patients is a complex interplay between multiple clinical and viral parameters, leading to a tailored approach that may bring real-life sustained virological response (SVR) rates close to 98%-99%. Objectives As proof-of-concept, we evaluated the efficacy of all-oral direct-acting antiviral (DAA) regimens in patients whose personalization included pre-therapy evaluation of natural resistance-associated substitutions (RASs), in addition to international guideline recommendations. Methods One hundred and thirty-one patients who started a first-line all-oral DAA regimen between April 2015 and December 2016 were tested for baseline NS3 and NS5A RASs by Sanger sequencing. SVR12 was defined as HCV-RNA undetectability 12 weeks after treatment discontinuation. Results Compatibly with a real-life context, 74.0% (97 of 131) of patients presented ≥2 pretreatment risk factors for failure to achieve SVR12 (infection by GT-1a/GT-3a; cirrhosis; previous treatment experience; HCV-RNA ≥800 000 IU/mL) and 33.6% had ≥3 risk factors. Natural RASs were frequently detected (32.1% prevalence), with substantial prevalence of NS5A RASs (15.3%), mostly represented by Y93H in GT-1b (3 of 36, 8.3%) and GT-3a (3 of 25, 12.0%) and F28C in GT-2c (2 of 11, 18.2%). Overall, personalized treatment led to 100% SVR12, even in those patients for whom treatment strategy was either strengthened (by ribavirin inclusion and/or duration increase) or simplified (by ribavirin exclusion and/or duration reduction), thanks to baseline RAS evaluation. Conclusions Even with newer DAA regimens, an integrated interpretation of clinical and virological pretreatment parameters, including natural RASs, may play a relevant role in bringing SVR rates close to the highest achievable. Treatment tailoring can be foreseen in 'hard-to-treat' patients, but also in 'easy' patients with favourable indicators, whereby a simplification/shortening of recommended regimens can be indicated.

Published
2017

7. Analysis of resistance and phylogenetic clusters in HCV-2c infected patients within the Italian network Vironet C

Author

Anna Claudia Pellicelli, Alessandro Pieri, Enzo Boeri, V. Pace Palitti, Roberto Gulminetti, V. Di Marco, Stefania Paolucci, Simona Landonio, F. Di Lorenzo, Laura Monno, L. Sarmati, Stefano Novati, Annapaola Callegaro, Simona Marenco, G. Raimondo, Lavinia Fabeni, Maurizio Zazzi, Silvia Barbaliscia, Nicola Coppola, P. Andreone, L. Carioti, Claudio Maria Mastroianni, Anna Licata, Fausto Baldanti, M. Andreoni, M. Quartini, M. Lichtner, Gloria Taliani, Laura Ambra Nicolini, Francesca Ceccherini-Silberstein, C.F. Perno, Luca Foroghi, Giustino Parruti, Bianca Bruzzone, Caterina Pasquazzi, C. Paternoster, Martina Milana, Sergio Babudieri, K. Yu La Rosa, M. Puoti, Hamid Hasson, Teresa Pollicino, N. Iapadre, C. Minichini, Raffaele Cozzolongo, Valeria Micheli, Barbara Rossetti, Aldo Bertoli, Elisabetta Teti, Marianna Aragri, Antonio Craxì, Filomena Morisco, V.C. Di Maio, Vincenzo Sangiovanni, Leonardo Baiocchi, and Mario Angelico

Subjects
Genetics, Hepatology, Resistance (ecology), Phylogenetic tree, business.industry, Gastroenterology, Medicine, business
Published
2020

8. VIRONET-C real life experience of resistance-guided retreatment in HCV infected patients who previously failed a NS5A inhibitor-containing regimen

Author

Mario Starace, Valerio Giannelli, Nunzia Cuomo, Vanni Borghi, Aldo Bertoli, Anna Licata, Anna Claudia Pellicelli, C. Minichini, M. Andreoni, M. Di Stefano, Giuseppe Cariti, Enzo Boeri, Raffaele Cozzolongo, Roberto Gulminetti, E. Milano, Valeria Cento, Elisabetta Degasperi, Laura Sighinolfi, A. Raddi, Ivana Maida, Barbara Rossetti, Teresa Santantonio, Valeria Micheli, C. Masetti, P. Andreone, Giustino Parruti, F. Di Lorenzo, Ilaria Lenci, Tiziano Allice, Annapaola Callegaro, Elisa Biliotti, M. Lichtner, Teresa Pollicino, Pietro Lampertico, Gloria Taliani, Caterina Pasquazzi, Piero Colombatto, Alessia Giorgini, G. Raimondo, Antonio Craxì, Francesca Ceccherini-Silberstein, Filomena Morisco, Valeria Ghisetti, V.C. Di Maio, Giuliano Rizzardini, Silvia Galli, Stefania Paolucci, A. De Santis, A. Lleo, Vincenzo Sangiovanni, A. Ciancio, Maurizio Zazzi, Elisabetta Teti, Simona Marenco, William Gennari, Stefano Novati, Giovanni Cenderello, Simona Landonio, Manuela Merli, A. Scuteri, Nicola Coppola, C.F. Perno, Giulia Morsica, I. Beretta, Claudio Maria Mastroianni, Simona Francioso, Mario Angelico, Laura Ambra Nicolini, Chiara Dentone, Silvia Barbaliscia, G.B. Gaeta, Marianna Aragri, Ennio Polilli, L. Donnarumma, Vincenza Calvaruso, Bianca Bruzzone, Fausto Baldanti, V. Pace Palitti, Roberto Ganga, Maurizia Rossana Brunetto, C. Paternoster, Sergio Babudieri, M. Puoti, Hamid Hasson, and M. Rendina

Subjects
medicine.medical_specialty, Regimen, Hepatology, business.industry, Internal medicine, Gastroenterology, medicine, business, NS5A
Published
2020

9. 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

10. 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

11. THU-133-Resistance-guided retreatment of HCV infected patients with a previous failure to an NS5A inhibitor-containing regimen: Italian real life experience

Author

Ada Bertoli, Gloria Taliani, Ilaria Lenci, Stefano Novati, Teresa Santantonio, Raffaele Cozzolongo, C. Masetti, Nunzia Cuomo, Laura Donnarumma, Giovanni Cenderrello, Silvia Barbaliscia, Adriano De Santis, Bianca Bruzzone, Giovanni Raimondo, Massimo Puoti, Carlo Federico Perno, Simona Landonio, Roberto Gulminetti, Elisabetta Degasperi, Giustino Parruti, Vincenza Calvaruso, Marianna Aragri, Teresa Pollicino, Pietro Lampertico, Laura Ambra Nicolini, Velia Chiara Di Maio, Valeria Ghisetti, Adriano M. Pellicelli, Ivana Maida, Caterina Pasquazzi, Valeria Cento, Roberto Ganga, Coppola Nicola, C. Paternoster, Maurizia Rossana Brunetto, Alessia Ciancio, Sergio Babudieri, Massimo Andreoni, Silberstein Francesca Ceccherini, Maurizio Zazzi, Maria Rendina, Miriam Lichtner, Angelico Mario, Ennio Polilli, Giuliano Rizzardini, Vanni Borghi, Maria Paola Callegaro, Valeria Pace Palitti, Stefania Paolucci, Carmine Minichini, Simona Marenco, Antonio Craxì, Filomena Morisco, Vincenzo Sangiovanni, Giulia Morsica, Valeria Micheli, Elisabetta Teti, and Pietro Andreone

Subjects
medicine.medical_specialty, Regimen, Hepatology, business.industry, Internal medicine, medicine, NS5A, business
Published
2019

12. SAT-159-Genetic determinants in critical domains of NS5A are associated with genotype 1b HCV-induced hepatocellular carcinoma

Author

Rossana Scutari, Valeria Cento, C. Masetti, Elisabetta Teti, Francesca Ceccherini Silberstein, Cristina Mussini, Massimo Andreoni, Ada Bertoli, Simona Francioso, Caterina Pasquazzi, Marianna Aragri, Silvia Barbaliscia, Carlo Federico Perno, Vincenza Calvaruso, Ivana Maida, Giustino Parruti, Valentina De Murtas, Angelica Sacco, Velia Chiara Di Maio, Mohammad Alkhatib, Ilaria Lenci, Federica Sozio, Angelico Mario, Alessandro Pieri, Maria Mercedes Santoro, Vanni Borghi, Antonio Craxì, Filomena Morisco, Valeria Pace Palitti, Romina Salpini, Valentina Svicher, Sergio Babudieri, Ennio Polilli, and P. Cacciatore

Subjects
Hepatology, Genotype 1b, Hepatocellular carcinoma, medicine, Cancer research, Biology, NS5A, medicine.disease
Published
2019

13. Characterization of baseline factors associated with treatment outcome in HCV-infected patients naive to direct acting antivirals: particular focus on natural resistance

Author

M. Siciliano, Giulia Morsica, Anna Claudia Pellicelli, Silvia Galli, F. Ceccherini-Silberstein, Fausto Baldanti, Bianca Bruzzone, R. Campoli, Giuliano Rizzardini, Vincenza Calvaruso, Gloria Taliani, V. Pace Palitti, C. Masetti, P Paba, Antonio Craxì, Filomena Morisco, Ennio Polilli, V.C. Di Maio, Martina Milana, William Gennari, C.F. Perno, Rossana Scutari, Aldo Bertoli, Valeria Cento, M. Andreoni, V. Boccaccio, Marianna Aragri, G.B. Gaeta, M. Lichtner, Caterina Pasquazzi, Vanni Borghi, Laura Ambra Nicolini, Renato Maserati, G. Fiorentino, Sergio Babudieri, Elisabetta Degasperi, Giustino Parruti, Mario Angelico, L. Foroghi, Valeria Ghisetti, Silvia Barbaliscia, Carlo Magni, Valeria Micheli, Elisabetta Teti, Nicola Coppola, Stefania Paolucci, L. Sarmati, R. D’Ambrosio, Pietro Lampertico, M. Puoti, N. Iapadre, Stefano Bonora, and V. Guarneri

Subjects
Natural resistance, Oncology, Focus (computing), medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Treatment outcome, Gastroenterology, medicine, Baseline (configuration management), DIRECT ACTING ANTIVIRALS, business
Published
2019

14. Resistance test guided retreatment of HCV infected patients with a previous failure to a NS5A inhibitor-containing regimen: the Italian Vironet C real life experience

Author

Pietro Lampertico, Valeria Cento, Claudio Maria Mastroianni, M. Puoti, Giuliano Rizzardini, Maurizio Zazzi, M. Lichtner, Bianca Bruzzone, Ivana Maida, Elisabetta Degasperi, C.F. Perno, M. Rendina, Giustino Parruti, Vincenza Calvaruso, Gloria Taliani, F. Di Lorenzo, Ilaria Lenci, Anna Claudia Pellicelli, Caterina Pasquazzi, Stefania Paolucci, A. Raddi, Marianna Aragri, Ennio Polilli, Giulia Morsica, Mario Starace, M. Andreoni, M. Di Stefano, C. Minichini, L. Donnarumma, V. Guarneri, Simona Marenco, Simona Landonio, Raffaele Cozzolongo, V. Pace Palitti, N. Cuomo, P. Andreone, Nicola Coppola, Silvia Galli, Mario Angelico, C. Paternoster, Roberto Ganga, Vanni Borghi, Elisabetta Teti, Sergio Babudieri, Silvia Barbaliscia, Anna Licata, Giovanni Cenderello, Antonio Craxì, Filomena Morisco, Maurizia Rossana Brunetto, V.C. Di Maio, Vincenzo Sangiovanni, A. Ciancio, Piero Colombatto, Valeria Micheli, Teresa Pollicino, Laura Ambra Nicolini, Alessia Giorgini, Valeria Ghisetti, S. Novati, Annapaola Callegaro, Aldo Bertoli, E. Milano, Roberto Gulminetti, A. De Santis, F. Ceccherini-Silberstein, Teresa Santantonio, C. Masetti, G. Raimondo, Di Maio, V.C., Aragri, M., Masetti, C., Paolucci, S., Bruzzone, B., Degasperi, E., Barbaliscia, S., Pollicino, T., Minichini, C., Calvaruso, V., Rendina, M., Cento, V., Teti, E., Micheli, V., Ghisetti, V., Polilli, E., Palitti, V. Pace, Landonio, S., Lenci, I., Donnarumma, L., Nicolini, L.A., Bertoli, A., Starace, M., Pasquazzi, C., Callegaro, A.P., Morisco, F., Cenderello, G., Marenco, S., Gulminetti, R., Novati, S., Guarneri, V., Andreone, P., Galli, S., Ciancio, A., Sangiovanni, V., Cuomo, N., Raddi, A., Morsica, G., Borghi, V., Maida, I., Brunetto, M., Colombatto, P., Cozzolongo, R., De Santis, A., Lichtner, M., Babudieri, S., Taliani, G., Santantonio, T., Di Stefano, M., Paternoster, C., Ganga, R., Puoti, M., Rizzardini, G., Pellicelli, A., Milano, E., Mastroianni, C., Licata, A., Di Lorenzo, F., Giorgini, A., Lampertico, P., Parruti, G., Coppola, N., Zazzi, M., Raimondo, G., Andreoni, M., Craxì, A., Angelico, M., Perno, C.F., and Ceccherini-Silberstein, F.

Subjects
Resistance test, medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, DAA failur, Vironet C, NS5A, Regimen, Internal medicine, medicine, retreatment, business
Abstract

Previous article in issueNext article in issue Introduction: There is a limited documentation about the retreatment of patients failing a recommended NS5A-containing regimen in Italy. Materials & methods: Within the VIRONET-C network, 386 NS5A-failing patients infected with different HCV-genotypes (GT) (GT1a/1b/2a-c/3a-b-g-h/4a-d-n-o-v=93/124/19/112/38) were analyzed. Retreatment of 105 failures was investigated. HCV-resistance-test was performed by Sanger-sequencing. Results: Failures following seven different NS5A-containing regimens were studied: 3D/2D (paritaprevir/ombitasvir ± dasabuvir) ± ribavirin (N = 72/4), daclatasvir/ledipasvir/velpatasvir + sofosbuvir ± ribavirin (N = 105/131/20), grazoprevir/elbasvir ± ribavirin (N = 34), glecaprevir/pibrentasvir (N = 20). Notably, 18.1% of NS5A-failing patients did not show any resistance-associated-substitutions (RAS), while 81.9% showed at least one NS5A-RAS, with multiclass-resistance in 35.5%. NS5A-RAS were observed more frequently in glecaprevir/pibrentasvir failures (GT1a 83.3%: Y93H + Q30H/D or +H58D; GT3a: 83.3% Y93H + A30K/G or +L31I) compared to sofosbuvir/velpatasvir (GT1a 16.6%: Y93H + Q30H, p = 0.08; GT3a 20.0%: Y93H/N + A30K/T, p = 0.03). To date, 105 failures have started a retreatment: sofosbuvir/velpatasvir ± ribavirin (N = 30), sofosbuvir/velpatasvir/voxilaprevir ± ribavirin (N = 67), glecaprevir/pibrentasvir (N = 4), grazoprevir/elbasvir ± sofosbuvir + ribavirin (N = 3), 3D + sofosbuvir + ribavirin (N = 1). The majority of patients were cirrhotic (51.9%) and relapsers (87.5%). The prevalence of NS5A-RASs before retreatment was 80.9%, with multiclass-resistance 29.5%. Among patients completing post-retreatment follow-up, a sustained-viral-response at week 12 (SVR12) was observed in 26/33 (78.8%). SVR4 was documented in 49/56 (87.5%). SVR12 was 76.0% with sofosbuvir/velpatasvir ± ribavirin (N = 25). Differently, SVR12 was 100% with glecaprevir/pibrentasvir for 8/12/16 weeks (N = 3), grazoprevir/elbasvir ± sofosbuvir + ribavirin for 12/24 weeks (N = 3) or 3D + sofosbuvir + ribavirin for 24 weeks (N = 1), despite the presence of NS5A-RASs. Until now, 67 patients started sofosbuvir/velpatasvir/voxilaprevir ± ribavirin recommended-retreatment for 12 weeks. 54/67 (80.6%) showed at least one baseline NS5A-RAS, 23/67 (34.3%) multiple-NS5A-RASs, and 22/67 (32.8%) multiclass-resistance. Of 25 patients with available outcome, 96.0% had SVR4. Only 1 GT1b infected patient was non-responder, without RASs before retreatment. Conclusions: In this real-life setting, NS5A-RASs were frequently detected at failure, and multiclass-resistance was around 30%. Overall, SVR after resistance-test-guided retreatment was >95%, with the exception of the sofosbuvir/velpatasvir retreatment. Our results show how HCV resistance-test at failure may be useful to optimize retreatment strategies.

Published
2019

15. Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

Author

Valentina Svicher, Carlo Federico Perno, Valentina Fedele, Fabio Continenza, Maria Concetta Bellocchi, Daniele Armenia, Fabiola Di Santo, Patrizia Saccomandi, Anne-Geneviève Marcelin, Slim Fourati, Lucia Parrotta, Giosuè Costa, Emanuela Balestra, Claudia Alteri, Francesca Ceccherini-Silberstein, Vincent Calvez, Silvia Barbaliscia, Rossana Scutari, Anna Artese, Stefano Alcaro, Stefania Carta, L. Carioti, and Matteo Surdo

Subjects
Nonsynonymous substitution, Receptors, CXCR4, Receptors, CCR5, viruses, Mutant, HIV Infections, V3 loop, Biology, medicine.disease_cause, Antiviral Agents, Neutralization, Virus, Cell Line, Cytosine Deaminase, Evolution, Molecular, Cytidine Deaminase, medicine, Humans, Pharmacology (medical), APOBEC Deaminases, Amino Acid Sequence, APOBEC3G, Pharmacology, chemistry.chemical_classification, Mutation, Base Sequence, virus diseases, Settore MED/07 - Microbiologia e Microbiologia Clinica, Virology, Amino acid, HEK293 Cells, Infectious Diseases, Amino Acid Substitution, chemistry, HIV-1, Leukocytes, Mononuclear
Abstract

Incomplete APOBEC3G/F neutralization by a defective HIV-1Vif protein can promote genetic diversification by inducing G-to-A mutations in the HIV-1 genome. The HIV-1 Env V3 loop, critical for coreceptor usage, contains several putative APOBEC3G/F target sites. Here, we determined if APOBEC3G/F, in the presence of Vif-defective HIV-1 virus, can induce G-to-A mutations at V3 positions critical to modulation of CXCR4 usage. Peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from 2 HIV-1-negative donors were infected with CCR5-using 81.A-Vif WT virus (i.e., with wild-type [WT] Vif protein), 81.A-Vif E45G , or 81.A-Vif K22E (known to incompletely/partially neutralize APOBEC3G/F). The rate of G-toA mutations was zero or extremely low in 81.A-Vif WT - and 81.A-Vif E45G -infected PBMC from both donors. Conversely, G-to-A enrichment was detected in 81.A-Vif K22E -infected PBMC (prevalence ranging from 2.18% at 7 days postinfection [dpi] to 3.07% at 21 dpi in donor 1 and from 10.49% at 7 dpi to 8.69% at 21 dpi in donor 2). A similar scenario was found in MDM. G-to-A mutations occurred at 8 V3 positions, resulting in nonsynonymous amino acid substitutions. Of them, G24E and E25K strongly correlated with phenotypically/genotypically defined CXCR4-using viruses ( P = 0.04 and 5.5e−7, respectively) and increased the CXCR4 N-terminal binding affinity for V3 (WT, −40.1 kcal/mol; G24E, −510 kcal/mol; E25K, −522 kcal/mol). The analysis of paired V3 and Vif DNA sequences from 84 HIV-1-infected patients showed that the presence of a Vif-defective virus correlated with CXCR4 usage in proviral DNA ( P = 0.04). In conclusion, incomplete APOBEC3G/F neutralization by a single Vif amino acid substitution seeds a CXCR4-using proviral reservoir. This can have implications for the success of CCR5 antagonist-based therapy, as well as for the risk of disease progression.

Published
2015

16. Biotech innovations in the prevention of respiratory infectious diseases

Author

Julia Valeria, Cento, Silvia, Barbaliscia, and Carlo Federico, Perno

Subjects
Community-Acquired Infections, Occupational Diseases, Cross Infection, Silver, Cost of Illness, Humans, Metal Nanoparticles, Gels, Personal Protective Equipment, Respiratory Tract Infections, Filtration, Biotechnology
Abstract

Acute respiratory infections place a huge burden on society in terms of disability, premature mortality, and also direct health service costs (drugs prescriptions) and the indirect costs related to lost production. Therefore, prevention of respiratory infections is an important goal for public health interventions. In this context, silver nanoparticles (AgNPs) represent an interesting perspective for research and development by virtue of their favorable antimicrobial activity against many respiratory pathogens. One of the latest innovations in the biotech field discussed in this review is the creation of a biocompatible, biogel-based nasal filter enriched with AgNPs. Compared to traditional personal protective equipment (PPE), this type of nasal filter has the advantage of combining the antibacterial and antiviral activity of AgNPs with the common filtration capacity shared by other PPEs. This dual mechanism means that AgNP-enriched nasal filters serve to reduce the infecting microbial-load and protect the lower airways, without interfering with the normal respiratory capacity (airflow-resistance5%). Given their antimicrobial characteristics and performance, AgNP-enriched nasal filters can meet many community and occupational currently unmet needs in the prevention of airborne infectious diseases, by ensuring an excellent respiratory-comfort and a continuous day-use.

Published
2017

17. 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

18. Comparison of resistance profiles among DAA-naive and DAA-experienced patients infected with HCV non-1 genotype in Italy

Author

Simona Francioso, A. Ciaccio, Teresa Pollicino, Bianca Bruzzone, G. Fiorentino, V. Boccaccio, Coppola Nicola, M. Puoti, Ivana Maida, Valeria Cento, Lucio Boglione, Francesca Ceccherini Silberstein, Valeria Micheli, Silvia Barbaliscia, Sergio Babudieri, Guido Gubertini, Giustino Parruti, Antonio Craxì, Vincenzo Vullo, Ennio Polilli, M. Andreoni, Filomena Morisco, Vincenzo Sangiovanni, Vincenza Calvaruso, Renato Maserati, Velia Chiara Di Maio, Maurizio Zazzi, Marianna Aragri, A. Ciancio, Barbara Rossetti, Anna Claudia Pellicelli, Elisabetta Teti, C.F. Perno, Caterina Pasquazzi, L. Sarmati, R. D’Ambrosio, Mario Angelico, Fosca Niero, Stefano Bonora, M. Rendina, Gloria Taliani, Luca Foroghi, Laura Ambra Nicolini, Aldo Bertoli, A. Lleo, G. Raimondo, T. Ruggiero, Simona Marenco, Valeria Pace Palitti, G.B. Gaeta, Stefania Paolucci, and Ilaria Lenci

Subjects
Hepatology, Resistance (ecology), business.industry, Genotype, Medicine, business, Virology
Published
2018

19. Characterization of resistance profiles in HCV 2-3-4 DAA-naïve and DAA-experienced infected patients in Italy

Author

V. Boccaccio, Irene Maida, Ennio Polilli, Alessandro Ciaccio, Ilaria Lenci, Anna Claudia Pellicelli, Marilena Rendina, Fabio Niero, Guido Gubertini, Mario Angelico, T. Ruggiero, Stefano Bonora, Barbara Rossetti, Caterina Pasquazzi, Niccolò Gabriele Coppola, Simona Francioso, Silvia Barbaliscia, M. Puoti, M. Andreoni, L. Foroghi, L. Sarmati, Silvia Paolucci, Giuliana Fiorentino, Teresa Pollicino, G.B. Gaeta, C.F. Perno, Giustino Parruti, Valeria Cento, Laura Ambra Nicolini, Gloria Taliani, Elisabetta Teti, Lucio Boglione, Asia Bertoli, Sergio Babudieri, Valeria Micheli, Renato Maserati, Marianna Aragri, F. Ceccherini-Silberstein, Vincenzo Vullo, A. R. D’Ambrosio, Simona Marenco, A. Lleo, Antonio Craxì, Filomena Morisco, V.C. Di Maio, Vincenzo Sangiovanni, Maurizio Zazzi, Vincenza Calvaruso, Alessia Ciancio, V. Pace Palitti, Bianca Bruzzone, and Giacomo Raimondo

Subjects
Hepatology, business.industry, Gastroenterology, Medicine, business, Virology
Published
2018

20. NS5A gene analysis by next generation sequencing in HCV nosocomial transmission clusters of HCV genotype 1b infected patients

Author

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

Subjects
Male, 0301 basic medicine, viruses, Drug Resistance, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, Settore MED/42 - Igiene Generale E Applicata, Gastroenterology, Settore MED/07, chemistry.chemical_compound, 0302 clinical medicine, Genotype 1b, Medicine, Viral, lcsh:QH301-705.5, Phylogeny, Cross Infection, nosocomial transmission, High-Throughput Nucleotide Sequencing, virus diseases, HCV, NGS, acute infection, chronic infection, sequencing, Acute Disease, Adult, Amino Acid Substitution, Antiviral Agents, Blood Transfusion, Chronic Disease, Drug Resistance, Viral, Female, Genotype, Hepatitis C, Host-Pathogen Interactions, Humans, Interferons, Middle Aged, Polymorphism, Single Nucleotide, beta-Thalassemia, Single Nucleotide, General Medicine, 030211 gastroenterology & hepatology, medicine.medical_specialty, Hepatitis C virus, Viral quasispecies, Article, DNA sequencing, 03 medical and health sciences, Internal medicine, Polymorphism, NS5A, NS5B, Gene, Hepatology, business.industry, Nosocomial transmission, biochemical phenomena, metabolism, and nutrition, Virology, digestive system diseases, Chronic infection, 030104 developmental biology, chemistry, lcsh:Biology (General), business
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 &beta, 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 &beta, thalassemia-patients and three involving both HCV-acute and chronic &beta, 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 &lt, 0.05). Even though Shannon-entropy was higher in chronic-patients, significantly higher values were observed only in chronic &beta, thalassemia-patients versus acute &beta, 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

21. Multiclass HCV resistance to interferon-free direct acting antivirals regimens in real life failures advocates for tailored second-line therapies

Author

Ilaria Lenci, A. Di Biagio, Giuliano Rizzardini, L. Marinaro, C. D'Ambrosio, Fausto Baldanti, Ivana Maida, G.B. Gaeta, M. Puoti, T. Ruggiero, Mario Angelico, Vincenza Calvaruso, Laura Sticchi, Mario Starace, Giustino Parruti, P. Cacciatore, Nicola Caporaso, Caterina Pasquazzi, Stefania Paolucci, Anna Claudia Pellicelli, M. Andreoni, C. Masetti, Sergio Babudieri, Gabriella d'Ettorre, Francesco Santopaolo, Raffaele Cozzolongo, P. Andreone, Carlo Magni, Valeria Cento, Guido Gubertini, J. Vecchiet, Stefano Novati, Nicola Coppola, C.F. Perno, Bianca Bruzzone, F. De Leonardis, V. Pace Palitti, Marianna Aragri, A. Grieco, Pierluigi Tarquini, G. De Stefano, G. Raimondo, Teresa Pollicino, Alessia Giorgini, Giorgio Barbarini, Valeria Ghisetti, G. Verucchi, M.C. Sorbo, Savino Bruno, M. Paoloni, F. Ceccherini-Silberstein, Roberto Gulminetti, Antonio Craxì, Filomena Morisco, Manuela Merli, V.C. Di Maio, Vincenzo Sangiovanni, A. Ciancio, Simona Francioso, Simona Landonio, Aldo Bertoli, A. Mancon, Valeria Micheli, Antonio Picciotto, V. Boccaccio, M. Melis, Ennio Polilli, F.P. Antonucci, Dante Romagnoli, and Silvia Barbaliscia

Subjects
Oncology, medicine.medical_specialty, Hepatology, business.industry, Interferon free, Gastroenterology, DIRECT ACTING ANTIVIRALS, 03 medical and health sciences, 0302 clinical medicine, Second line, 030220 oncology & carcinogenesis, Internal medicine, Medicine, In real life, 030211 gastroenterology & hepatology, business
Published
2017

22. The challenge of HCV-retreatment after DAA-failure: real-life experience advocates for caution

Author

Vincenza Calvaruso, C. Masetti, Silvia Barbaliscia, Bianca Bruzzone, Giustino Parruti, Sergio Babudieri, Marco Biolato, Marianna Aragri, C.F. Perno, Vincenzo Messina, Valeria Cento, Simona Landonio, M. Melis, Carmine Minichini, Valeria Micheli, F. Ceccherini-Silberstein, Lucio Boglione, Giorgio Barbarini, Mario Angelico, Aldo Bertoli, Monica Schiavini, Laura Ambra Nicolini, Ennio Polilli, Raffaele Cozzolongo, Carlo Magni, Chiara Baiguera, C. Dentone, Giuliano Rizzardini, Anna Claudia Pellicelli, M. Siciliano, Y. Troshina, Antonio Craxì, Filomena Morisco, M. Puoti, V.C. Di Maio, A. Ciancio, Ilaria Lenci, Laura Sticchi, Stefania Paolucci, T. Ruggiero, Simona Marenco, and Nicola Coppola

Subjects
0301 basic medicine, 03 medical and health sciences, medicine.medical_specialty, 030104 developmental biology, 0302 clinical medicine, Hepatology, business.industry, Immunology, medicine, 030211 gastroenterology & hepatology, Intensive care medicine, business
Published
2017

23. Multiclass hepatitis C virus resistance to direct acting antivirals in real life interferon-free regimens failures advocates for tailored second-line therapies

Author

A. Grieco, Valeria Cento, Savino Bruno, M. Paoloni, Anna Claudia Pellicelli, Gabriella d'Ettorre, Raffaele Cozzolongo, G.D. Stefano, Carlo Magni, V. Boccaccio, M. Andreoni, Fausto Baldanti, Silvia Barbaliscia, J. Vecchiet, Valeria Micheli, Antonio Picciotto, Giustino Parruti, Guido Gubertini, M. Melis, Pierluigi Tarquini, Francesca Ceccherini-Silberstein, Bianca Bruzzone, Sergio Babudieri, Antonio Di Biagio, M. Puoti, Manuela Merli, L. Marinaro, Mario Starace, Caterina Pasquazzi, Marianna Aragri, Antonio Craxì, Teresa Pollicino, Filomena Morisco, V.C. Di Maio, Alessia Giorgini, Vincenzo Sangiovanni, Giorgio Barbarini, Valeria Ghisetti, G. Verucchi, T. Ruggiero, Ivana Maida, P. Andreone, Vincenza Calvaruso, Giovanni Raimondo, C. D'Ambrosio, Simona Francioso, F.P. Antonucci, Dante Romagnoli, C.F. Perno, Mario Angelico, Ilaria Lenci, Alessia Ciancio, Roberto Gulminetti, G.B. Gaeta, Simona Landonio, Nicola Caporaso, Francesco Santopaolo, Nicola Coppola, Laura Sticchi, Valeria Pace Palitti, Stefania Paolucci, Aldo Bertoli, and A. Mancon

Subjects
0301 basic medicine, Hepatology, business.industry, Hepatitis C virus, Interferon free, medicine.disease_cause, DIRECT ACTING ANTIVIRALS, Virology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Second line, medicine, In real life, 030211 gastroenterology & hepatology, business
Published
2017

24. DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Author

Aasld, American Association For The Study Of Liver Diseases, Barbara, Rossetti, Redi, David, Velia Chiara Di Maio, Marianna, Aragri, Stefania, Paolucci, Paglicci, Lorenzo, Chiara, Masetti, Bianca, Bruzzone, Carmine, Minichini, FRANCESCA MONTAGNANI, Valeria, Micheli, Simona, Landonio, Giacomo Zanelli, Elisabetta, Degasperi, Renato, Maserati, Ivana, Maida, Annapaola, Callegaro, Silvia, Barbaliscia, Ada, Bertoli, Claudio, Paternoster, Simona, Marenco, Filomena, Morisco, Vincenza, Calvaruso, Gloria, Taliani, Massimo, Puoti, Giovanni, Cenderello, Adriano De Santis, Miriam, Lichtner, Nicola, Coppola, Roberto, Gulminetti, Valeria, Cento, Maria, Rendina, Elisabetta, Teti, Giustino, Parruti, Tina, Ruggiero, Valeria, Ghisetti, Caterina, Pasquazzi, Laura Ambra Nicolini, Vincenzo, Vullo, Adriano, Pellicelli, Tullio, Prestileo, Raffaele, Cozzolongo, Vincenzo, Sangiovanni, Marco, Biolato, Ilaria, Lenci, Anna, Licata, Antonio, Ciaccio, Valeria Pace Palitti, Alessia, Giorgini, Giuseppe, Cariti, Alessia, Ciancio, Alessio, Aghemo, Vanni, Borghi, Pietro, Andreone, Brunetto, Maurizia R., Teresa, Pollicino, Teresa Antonia Santantonio, Nunzia, Cuomo, Cinzia, Caudai, Sergio, Babudieri, Pietro, Lampertico, Giovanni Battista Gaeta, Giovanni, Raimondo, Massimo, Andreoni, Giuliano, Rizzardini, Mario, Angelico, Carlo Federico Perno, Antonio, Craxì, Maurizio Zazzi, Francesca Ceccherini Silberstein, and and HCV Virology Italian Resistance Network (Vironet C)

25. 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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