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1. Phylogenetic analysis in the clinical risk management of an outbreak of hepatitis C virus infection among transfused thalassaemia patients in Italy.

Author

Mazzucco W, Chiara di Maio V, Bronte F, Fabeni L, Pipitone RM, Grimaudo S, Ferraro D, Marotta C, Aragri M, Macaluso M, Vitale F, Di Raimondo F, Ceccherini-Silberstein F, and Di Marco V

Subjects
Antiviral Agents therapeutic use, Bayes Theorem, Disease Outbreaks, Genotype, Hepacivirus genetics, Humans, Italy epidemiology, Phylogeny, Risk Management, Hepatitis C epidemiology, Thalassemia complications, Thalassemia epidemiology, Thalassemia therapy
Abstract

Background: Occurrence of hepatitis C virus (HCV) infection is reduced by effective risk management procedures, but patient-to-patient transmission continues to be reported in healthcare settings., Aim: To report the use of phylogenetic analysis in the clinical risk management of an HCV outbreak among 128 thalassaemia outpatients followed at a thalassaemia centre of an Italian hospital., Methods: Epidemiological investigation and root-cause analysis were performed. All patients with acute hepatitis and known chronic infection were tested for HCV RNA, HCV genotyping, and NS3, NS5A, and NS5B HCV genomic region sequencing. To identify transmission clusters, phylogenetic trees were built for each gene employing Bayesian methods., Findings: All patients with acute hepatitis were infected with HCV genotype 1b. Root-cause analysis, including a lookback procedure, excluded blood donors as the source of HCV transmission. The phylogenetic analysis, conducted on seven patients with acute infection and eight patients with chronic infection, highlighted four transmission clusters including at least one patient with chronic and one patient with acute HCV infection. All patients in the same cluster received a blood transfusion during the same day. Two patients with acute hepatitis spontaneously cleared HCV within four weeks and nine patients received ledipasvir plus sofosbuvir for six weeks, all achieving a sustained virological response., Conclusion: Combined use of root-cause analysis and molecular epidemiology was effective in ascertaining the origin of the HCV outbreak. Antiviral therapy avoided the chronic progression of the infection and further spread in care units and in the family environment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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2. Successful ongoing retreatment with glecaprevir/pibrentasvir + sofosbuvir + ribavirin in a patient with HCV genotype 3 who failed glecaprevir/pibrentasvir with both NS3 and NS5A resistance.

Author

Aragri M, Milana M, Di Maio VC, Lenci I, Carioti L, Perno CF, Svicher V, Angelico M, and Ceccherini-Silberstein F

Subjects
Drug Therapy, Combination, Genotype, Hepacivirus drug effects, Hepatitis C diagnosis, Hepatitis C virology, Humans, Leucine therapeutic use, Male, Middle Aged, Proline therapeutic use, Pyrrolidines, Treatment Outcome, Aminoisobutyric Acids therapeutic use, Antiviral Agents therapeutic use, Benzimidazoles therapeutic use, Cyclopropanes therapeutic use, Hepacivirus genetics, Hepatitis C drug therapy, Lactams, Macrocyclic therapeutic use, Leucine analogs & derivatives, Proline analogs & derivatives, Quinoxalines therapeutic use, Sofosbuvir therapeutic use, Sulfonamides therapeutic use
Published
2020
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3. NS5A Gene Analysis by Next Generation Sequencing in HCV Nosocomial Transmission Clusters of HCV Genotype 1b Infected Patients.

Author

Bellocchi MC, Aragri M, Carioti L, Fabeni L, Pipitone RM, Brancaccio G, Sorbo MC, Barbaliscia S, Di Maio VC, Bronte F, Grimaudo S, Mazzucco W, Frigeri F, Cantone M, Pinto A, Perno CF, Craxì A, Gaeta GB, Di Marco V, and Ceccherini-Silberstein F

Subjects
Acute Disease, Adult, Amino Acid Substitution, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Blood Transfusion, Chronic Disease, Cross Infection drug therapy, Cross Infection transmission, Drug Resistance, Viral genetics, Female, Genotype, Hepacivirus pathogenicity, Hepatitis C drug therapy, Hepatitis C transmission, High-Throughput Nucleotide Sequencing, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Interferons genetics, Interferons immunology, Male, Middle Aged, Phylogeny, Polymorphism, Single Nucleotide, beta-Thalassemia genetics, beta-Thalassemia immunology, Cross Infection virology, Hepacivirus genetics, Hepatitis C virology, Viral Nonstructural Proteins genetics, beta-Thalassemia therapy
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. HCV very late relapse following an atypical viral kinetics in a HIV patient treated for hepatitis C with direct-acting antivirals.

Author

Guardigni V, Cento V, Ianniruberto S, Badia L, Aragri M, Conti M, Perno CF, Viale P, Ceccherini-Silberstein F, and Verucchi G

Subjects
Antiviral Agents pharmacology, Genotype, HIV Infections drug therapy, Hepacivirus genetics, Humans, Male, Middle Aged, Phylogeny, RNA, Viral, Recurrence, Treatment Outcome, Antiviral Agents therapeutic use, Coinfection, HIV Infections virology, Hepacivirus drug effects, Hepatitis C drug therapy, Hepatitis C virology, Viral Load
Abstract

Direct-acting antivirals (DAAs) for the treatment of HCV have dramatically increased the rate of sustained virological response: patients not achieving sustained virological response represent a challenge and rates of late recurrent viremia are very low. We describe here the first case of a very late HCV relapse, following an atypical kinetics (characterized by a spontaneous but transient HCV clearance after an early virological relapse), in a HIV co-infected patient treated with DAAs. Optimal adherence to the therapy was well documented and a phylogenetic analysis ruled out a possible reinfection from a different HCV strain. In conclusion, our case underlines the importance of a long follow-up (> 48 weeks) after DAAs therapies in HCV-HIV co-infected patients who might benefit the most from a very rigorous virological surveillance.

Published
2018
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5. Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy.

Author

Bertoli A, Sorbo MC, Aragri M, Lenci I, Teti E, Polilli E, Di Maio VC, Gianserra L, Biliotti E, Masetti C, Magni CF, Babudieri S, Nicolini LA, Milana M, Cacciatore P, Sarmati L, Pellicelli A, Paolucci S, Craxì A, Morisco F, Palitti VP, Siciliano M, Coppola N, Iapadre N, Puoti M, Rizzardini G, Taliani G, Pasquazzi C, Andreoni M, Parruti G, Angelico M, Perno CF, Cento V, and Ceccherini-Silberstein F

Subjects
Adult, Aged, Female, Hepatitis C drug therapy, Hepatitis C epidemiology, Humans, Italy epidemiology, Male, Middle Aged, Prevalence, Drug Resistance, Viral genetics, Genotype, Hepacivirus genetics, Hepatitis C genetics, Viral Nonstructural Proteins genetics
Abstract

Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2-45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4-19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1-4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

Published
2018
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6. Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy.

Author

Cuypers L, Vrancken B, Fabeni L, Marascio N, Cento V, Di Maio VC, Aragri M, Pineda-Peña AC, Schrooten Y, Van Laethem K, Balog D, Focà A, Torti C, Nevens F, Perno CF, Vandamme AM, and Ceccherini-Silberstein F

Subjects
Antiviral Agents pharmacology, Bayes Theorem, Drug Resistance, Viral, Genotype, Hepacivirus drug effects, Hepacivirus genetics, Hepatitis C epidemiology, Humans, Italy epidemiology, Simeprevir pharmacology, Hepacivirus physiology, Hepatitis C virology
Abstract

Background: In-depth phylogeographic analysis can reveal migration patterns relevant for public health planning. Here, as a model, we focused on the provenance, in the current Italian HCV subtype 1a epidemic, of the NS3 resistance-associated variant (RAV) Q80K, known to interfere with the action of NS3/4A protease inhibitor simeprevir. HCV1a migration patterns were analysed using Bayesian phylodynamic tools, capitalising on newly generated and publicly available time and geo-referenced NS3 encoding virus genetic sequence data., Results: Our results showed that both immigration and local circulation fuel the current Italian HCV1a epidemic. The United States and European continental lineages dominate import into Italy, with the latter taking the lead from the 1970s onwards. Since similar migration patterns were found for Q80K and other lineages, no clear differentiation of the risk for failing simeprevir can be made between patients based on their migration and travel history. Importantly, since HCV only occasionally recombines, these results are readily transferable to the genetic sequencing policy concerning NS5A RAVs., Conclusions: The patient migration and travel history cannot be used to target only part of the HCV1a infected population for drug resistance testing before start of antiviral therapy. Consequently, it may be cost-effective to expand genotyping efforts to all HCV1a infected patients eligible for simeprevir-based therapies.

Published
2017
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7. HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels.

Author

Di Maio VC, Cento V, Di Paolo D, Aragri M, De Leonardis F, Tontodonati M, Micheli V, Bellocchi MC, Antonucci FP, Bertoli A, Lenci I, Milana M, Gianserra L, Melis M, Di Biagio A, Sarrecchia C, Sarmati L, Landonio S, Francioso S, Lambiase L, Nicolini LA, Marenco S, Nosotti L, Giannelli V, Siciliano M, Romagnoli D, Pellicelli A, Vecchiet J, Magni CF, Babudieri S, Mura MS, Taliani G, Mastroianni C, Vespasiani-Gentilucci U, Romano M, Morisco F, Gasbarrini A, Vullo V, Bruno S, Baiguera C, Pasquazzi C, Tisone G, Picciotto A, Andreoni M, Parruti G, Rizzardini G, Angelico M, Perno CF, and Ceccherini-Silberstein F

Subjects
Genotype, Hepacivirus genetics, Hepacivirus isolation & purification, Humans, RNA, Viral genetics, Retrospective Studies, Sequence Analysis, DNA, Drug Resistance, Viral, Genotyping Techniques methods, Hepacivirus classification, Hepacivirus drug effects, Hepatitis C virology, Mutation, Viral Nonstructural Proteins genetics
Abstract

Objectives: This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen., Methods: NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays., Results: Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11)., Conclusions: HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Published
2016
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8. Resistance analysis and treatment outcomes in hepatitis C virus genotype 3-infected patients within the Italian network VIRONET-C

Author

Di Maio, V. C., Barbaliscia, S., Teti, E., Fiorentino, G., Milana, M., Paolucci, S., Pollicino, T., Morsica, G., Starace, M., Bruzzone, B., Gennari, W., Micheli, V., Yu La Rosa, K., Foroghi, L., Calvaruso, V., Lenci, I., Polilli, E., Babudieri, S., Aghemo, A., Raimondo, G., Sarmati, L., Coppola, N., Pasquazzi, C., Baldanti, F., Parruti, G., Perno, C. F., Angelico, M., Craxi, A., Andreoni, M., Ceccherini-Silberstein, F., Andreone, P., Aragri, M., Bertoli, A., Boeri, E., Brancaccio, G., Brunetto, M., Callegaro, A. P., Cenderello, G., Cento, V., Ciaccio, A., Ciancio, A., Cuomo, N., De Santis, A., Di Biagio, A., Di Marco, V., Di Perri, G., Di Stefano, M. A., Gaeta, G. B., Ghisetti, V., Gulminetti, R., Lampertico, P., Landonio, S., Lichtner, M., Lleo, A., Maida, I., Marenco, S., Masetti, C., Mastroianni, C., Minichini, C., Milano, E., Monno, L., Novati, S., Pace Palitti, V., Paternoster, C., Pellicelli, A., Pieri, A., Puoti, M., Rizzardini, G., Ruggiero, T., Rossetti, B., Sangiovanni, V., Santantonio, T., Taliani, G., Toniutto, P., Vullo, V., Zazzi, M., Di Maio, V, Barbaliscia, S, Teti, E, Fiorentino, G, Milana, M, Paolucci, S, Pollicino, T, Morsica, G, Starace, M, Bruzzone, B, Gennari, W, Micheli, V, Yu La Rosa, K, Foroghi, L, Calvaruso, V, Lenci, I, Polilli, E, Babudieri, S, Aghemo, A, Raimondo, G, Sarmati, L, Coppola, N, Pasquazzi, C, Baldanti, F, Parruti, G, Perno, C, Angelico, M, Craxi, A, Andreoni, M, Ceccherini-Silberstein, F, Andreone, P, Aragri, M, Bertoli, A, Boeri, E, Brancaccio, G, Brunetto, M, Callegaro, A, Cenderello, G, Cento, V, Ciaccio, A, Ciancio, A, Cuomo, N, De Santis, A, Di Biagio, A, Di Marco, V, Di Perri, G, Di Stefano, M, Gaeta, G, Ghisetti, V, Gulminetti, R, Lampertico, P, Landonio, S, Lichtner, M, Lleo, A, Maida, I, Marenco, S, Masetti, C, Mastroianni, C, Minichini, C, Milano, E, Monno, L, Novati, S, Pace Palitti, V, Paternoster, C, Pellicelli, A, Pieri, A, Puoti, M, Rizzardini, G, Ruggiero, T, Rossetti, B, Sangiovanni, V, Santantonio, T, Taliani, G, Toniutto, P, Vullo, V, Zazzi, M, Di Maio, Vc, Perno, Cf, Craxì, A, Di Maio V.C., Barbaliscia S., Teti E., Fiorentino G., Milana M., Paolucci S., Pollicino T., Morsica G., Starace M., Bruzzone B., Gennari W., Micheli V., Yu La Rosa K., Foroghi L., Calvaruso V., Lenci I., Polilli E., Babudieri S., Aghemo A., Raimondo G., Sarmati L., Coppola N., Pasquazzi C., Baldanti F., Parruti G., Perno C.F., Angelico M., Craxi A., Andreoni M., Ceccherini-Silberstein F., Andreone P., Aragri M., Bertoli A., Boeri E., Brancaccio G., Brunetto M., Callegaro A.P., Cenderello G., Cento V., Ciaccio A., Ciancio A., Cuomo N., De Santis A., Di Biagio A., Di Marco V., Di Perri G., Di Stefano M.A., Gaeta G.B., Ghisetti V., Gulminetti R., Lampertico P., Landonio S., Lichtner M., Lleo A., Maida I., Marenco S., Masetti C., Mastroianni C., Minichini C., Milano E., Monno L., Novati S., Pace Palitti V., Paternoster C., Pellicelli A., Pieri A., Puoti M., Rizzardini G., Ruggiero T., Rossetti B., Sangiovanni V., Santantonio T., Taliani G., Toniutto P., Vullo V., and Zazzi M.

Subjects
Male, Sofosbuvir, Sustained Virologic Response, Drug Resistance, Hepacivirus, Viral Nonstructural Proteins, Gastroenterology, Settore MED/06, direct-acting antivirals, failure, genotype 3, HCV, resistance, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Viral, Chronic, Phylogeny, Dasabuvir, hcv, virus diseases, Hepatitis C, Pibrentasvir, Italy, 030220 oncology & carcinogenesis, Combination, Drug Therapy, Combination, 030211 gastroenterology & hepatology, Female, medicine.drug, Ledipasvir, medicine.medical_specialty, Daclatasvir, Genotype, Antiviral Agents, Drug Resistance, Viral, Humans, Hepatitis C, Chronic, 03 medical and health sciences, Drug Therapy, Internal medicine, Antiviral Agent, direct-acting antiviral, Hepaciviru, Hepatology, business.industry, Viral Nonstructural Protein, Glecaprevir, direct acting antivirals, Regimen, chemistry, Paritaprevir, business
Abstract

Aim: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3). Methods: Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols. Results: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N=91/15) and glecaprevir (G)/pibrentasvir (P) (N=9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D±RBV (Paritaprevir/r+Ombitasvir+Dasabuvir, N=15), SOF+Simeprevir (SIM) (N=1) or SOF/Ledipasvir (LDV)±RBV (N=4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P&nbsp

Published
2021

9. 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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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. Phylogenetic analysis in the clinical risk management of an outbreak of hepatitis C virus infection among transfused thalassaemia patients in Italy

Author

Stefania Grimaudo, Francesca Ceccherini-Silberstein, Lavinia Fabeni, V. Di Marco, Marianna Aragri, F. Di Raimondo, Claudia Marotta, Mazzucco W, Fabrizio Bronte, Maurizio Macaluso, Francesco Vitale, V. Chiara di Maio, Donatella Ferraro, Rosaria Maria Pipitone, Mazzucco W., Chiara di Maio V., Bronte F., Fabeni L., Pipitone R.M., Grimaudo S., Ferraro D., Marotta C., Aragri M., Macaluso M., Vitale F., Di Raimondo F., Ceccherini-Silberstein F., and Di Marco V.

Subjects
Sofosbuvir, Clinical risk management, Hepatitis C virus (HCV), Molecular epidemiology, Nosocomial outbreak, Phylogenetic analysis, Antiviral Agents, Bayes Theorem, Disease Outbreaks, Genotype, Hepacivirus, Humans, Italy, Phylogeny, Risk Management, Hepatitis C, Thalassemia, Hepacivirus, 030501 epidemiology, Settore MED/42 - Igiene Generale E Applicata, medicine.disease_cause, Disease Outbreaks, Settore MED/07, chemistry.chemical_compound, Settore BIO/13 - Biologia Applicata, Epidemiology, Medicine, Phylogeny, Settore MED/12 - Gastroenterologia, 0303 health sciences, Clinical risk management, Phylogenetic analysis, biology, Transmission (medicine), virus diseases, General Medicine, Hepatitis C, Hepatitis C virus (HCV), Infectious Diseases, Italy, Molecular epidemiology, Thalassemia, 0305 other medical science, medicine.drug, Microbiology (medical), Ledipasvir, medicine.medical_specialty, Genotype, Hepatitis C virus, Antiviral Agents, 03 medical and health sciences, Phylogenetic analysi, Internal medicine, Humans, Risk Management, 030306 microbiology, business.industry, Nosocomial outbreak, Bayes Theorem, biology.organism_classification, medicine.disease, digestive system diseases, Chronic infection, chemistry, business
Abstract

Background: Occurrence of hepatitis C virus (HCV) infection is reduced by effective risk management procedures, but patient-to-patient transmission continues to be reported in healthcare settings. Aim: To report the use of phylogenetic analysis in the clinical risk management of an HCV outbreak among 128 thalassaemia outpatients followed at a thalassaemia centre of an Italian hospital. Methods: Epidemiological investigation and root-cause analysis were performed. All patients with acute hepatitis and known chronic infection were tested for HCV RNA, HCV genotyping, and NS3, NS5A, and NS5B HCV genomic region sequencing. To identify transmission clusters, phylogenetic trees were built for each gene employing Bayesian methods. Findings: All patients with acute hepatitis were infected with HCV genotype 1b. Root-cause analysis, including a lookback procedure, excluded blood donors as the source of HCV transmission. The phylogenetic analysis, conducted on seven patients with acute infection and eight patients with chronic infection, highlighted four transmission clusters including at least one patient with chronic and one patient with acute HCV infection. All patients in the same cluster received a blood transfusion during the same day. Two patients with acute hepatitis spontaneously cleared HCV within four weeks and nine patients received ledipasvir plus sofosbuvir for six weeks, all achieving a sustained virological response. Conclusion: Combined use of root-cause analysis and molecular epidemiology was effective in ascertaining the origin of the HCV outbreak. Antiviral therapy avoided the chronic progression of the infection and further spread in care units and in the family environment.

Published
2021

12. Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy

Author

Bertoli, Ada, Sorbo, Maria Chiara, Aragri, Marianna, Lenci, Ilaria, Teti, Elisabetta, Polilli, Ennio, Di Maio, Velia Chiara, Gianserra, Laura, Biliotti, Elisa, Masetti, Chiara, Magni, Carlo F., Babudieri, Sergio, Nicolini, Laura A., Milana, Martina, Cacciatore, Pierluigi, Sarmati, Loredana, Pellicelli, Adriano, Paolucci, Stefania, Craxì, Antonio, Morisco, Filomena, Palitti, Valeria Pace, Siciliano, Massimo, Coppola, Nicola, Iapadre, Nerio, Puoti, Massimo, Rizzardini, Giuliano, Taliani, Gloria, Pasquazzi, Caterina, Andreoni, Massimo, Parruti, Giustino, Angelico, Mario, Perno, Carlo Federico, Cento, Valeria, Ceccherini-Silberstein, Francesca, Andreone, Pietro, Baldanti, Fausto, Barbarini, Giorgio, Boccaccio, Vincenzo, Boglione, Lucio, Bolis, Matteo, Bonora, Stefano, Borghi, Vanni, Brancaccio, Giuseppina, Bruno, Savino, Bruzzone, Bianca, Calvaruso, Vincenza, Caporaso, Nicola, Ciaccio, Antonio, Ciancio, Alessia, Colombatto, Piero, Cozzolongo, Raffaele, D'Ambrosio, Cecilia, D'Ettorre, Gabriella, De Leonardis, Francesco, De Luca, Andrea, Di Biagio, Antonio, Di Perri, Giovanni, Francioso, Simona, Gaeta, Giovanni Battista, Gasbarrini, Antonio, Ghisetti, Valeria, Giorgini, Alessia, Grieco, Antonio, Gubertini, Guido, Gulminetti, Roberto, Lambiase, Lara, Landonio, Simona, Lichtner, Miriam, Maida, Ivana, Marenco, Simona, Marinaro, Letizia, Maserati, Renato, Melis, Michela, Menzaghi, Barbara, Meregalli, Elisa, Micheli, Valeria, Niero, Fosca, Paoloni, Maurizio, Pieri, Alessandro, Rendina, Maria, Romagnoli, Dante, Rossetti, Barbara, Ruggiero, Tina, Sangiovanni, Vincenzo, Starace, Mario, Sticchi, Laura, Tarquini, Pierluigi, Toniutto, Pierluigi, Vullo, Vincenzo, Zazzi, Maurizio, HCV Virology Italian Resistance Network, Bertoli A1, Sorbo MC1, Aragri M1, Lenci I2, Teti E3, Polilli E4, Di Maio VC1, Gianserra L5, Biliotti E6, Masetti C2, Magni CF7, Babudieri S8, Nicolini LA9, Milana M2, Cacciatore P4, Sarmati L3, Pellicelli A10, Paolucci S11, Craxì A, Morisco F13, Palitti VP14, Siciliano M15, Coppola N16, Iapadre N17, Puoti M18, Rizzardini G7, Taliani G6, Pasquazzi C5, Andreoni M3, Parruti G4, Angelico M2, Perno CF19, Cento V20, Ceccherini-Silberstein F1, HCV Virology Italian Resistance Network (VIRONET-C)., Bertoli, Ada, Sorbo, Maria Chiara, Aragri, Marianna, Lenci, Ilaria, Teti, Elisabetta, Polilli, Ennio, Di Maio, Velia Chiara, Gianserra, Laura, Biliotti, Elisa, Masetti, Chiara, Magni, Carlo F., Babudieri, Sergio, Nicolini, Laura A., Milana, Martina, Cacciatore, Pierluigi, Sarmati, Loredana, Pellicelli, Adriano, Paolucci, Stefania, Craxì, Antonio, Morisco, Filomena, Palitti, Valeria Pace, Siciliano, Massimo, Coppola, Nicola, Iapadre, Nerio, Puoti, Massimo, Rizzardini, Giuliano, Taliani, Gloria, Pasquazzi, Caterina, Andreoni, Massimo, Parruti, Giustino, Angelico, Mario, Perno, Carlo Federico, Cento, Valeria, Ceccherini-Silberstein, Francesca, Andreone, Pietro, Baldanti, Fausto, Barbarini, Giorgio, Boccaccio, Vincenzo, Boglione, Lucio, Bolis, Matteo, Bonora, Stefano, Borghi, Vanni, Brancaccio, Giuseppina, Bruno, Savino, Bruzzone, Bianca, Calvaruso, Vincenza, Caporaso, Nicola, Ciaccio, Antonio, Ciancio, Alessia, Colombatto, Piero, Cozzolongo, Raffaele, D'Ambrosio, Cecilia, D'Ettorre, Gabriella, De Leonardis, Francesco, De Luca, Andrea, Di Biagio, Antonio, Di Perri, Giovanni, Francioso, Simona, Gaeta, Giovanni Battista, Gasbarrini, Antonio, Ghisetti, Valeria, Giorgini, Alessia, Grieco, Antonio, Gubertini, Guido, Gulminetti, Roberto, Lambiase, Lara, Landonio, Simona, Lichtner, Miriam, Maida, Ivana, Marenco, Simona, Marinaro, Letizia, Maserati, Renato, Melis, Michela, Menzaghi, Barbara, Meregalli, Elisa, Micheli, Valeria, Niero, Fosca, Paoloni, Maurizio, Pieri, Alessandro, Rendina, Maria, Romagnoli, Dante, Rossetti, Barbara, Ruggiero, Tina, Sangiovanni, Vincenzo, Starace, Mario, Sticchi, Laura, Tarquini, Pierluigi, Toniutto, Pierluigi, Vullo, Vincenzo, Zazzi, Maurizio, Bertoli, A, Sorbo, M, Aragri, M, Lenci, I, Teti, E, Polilli, E, Di Maio, V, Gianserra, L, Biliotti, E, Masetti, C, Magni, C, Babudieri, S, Nicolini, L, Milana, M, Cacciatore, P, Sarmati, L, Pellicelli, A, Paolucci, S, Craxi, A, Morisco, F, Palitti, V, Siciliano, M, Coppola, N, Iapadre, N, Puoti, M, Rizzardini, G, Taliani, G, Pasquazzi, C, Andreoni, M, Parruti, G, Angelico, M, Perno, C, Cento, V, Ceccherini-Silberstein, F, Andreone, P, Baldanti, F, Barbarini, G, Boccaccio, V, Boglione, L, Bolis, M, Bonora, S, Borghi, V, Brancaccio, G, Bruno, S, Bruzzone, B, Calvaruso, V, Caporaso, N, Ciaccio, A, Ciancio, A, Colombatto, P, Cozzolongo, R, D'Ambrosio, C, D'Ettorre, G, De Leonardis, F, De Luca, A, Di Biagio, A, Di Perri, G, Francioso, S, Gaeta, G, Gasbarrini, A, Ghisetti, V, Giorgini, A, Grieco, A, Gubertini, G, Gulminetti, R, Lambiase, L, Landonio, S, Lichtner, M, Maida, I, Marenco, S, Marinaro, L, Maserati, R, Melis, M, Menzaghi, B, Meregalli, E, Micheli, V, Niero, F, Paoloni, M, Pieri, A, Rendina, M, Romagnoli, D, Rossetti, B, Ruggiero, T, Sangiovanni, V, Starace, M, Sticchi, L, Tarquini, P, Toniutto, P, Vullo, V, Zazzi, M, Sorbo, Mc, Di Maio, Vc, Magni, Cf, Nicolini, La, Craxì, A, Palitti, Vp, Perno, Cf, Gaeta, Gb, and Zazzi, M.

Subjects
Male, 0301 basic medicine, Sofosbuvir, Hepacivirus, Drug Resistance, lcsh:Medicine, Viral Nonstructural Proteins, medicine.disease_cause, Gastroenterology, Hepatitis C Virus, HCV resistance-test, chemistry.chemical_compound, 0302 clinical medicine, Genotype, Prevalence, Viral, lcsh:Science, Multidisciplinary, biology, Hepatitis C, Middle Aged, Settore MED/07 - Microbiologia e Microbiologia Clinica, Italy, Cohort, HCV, Female, 030211 gastroenterology & hepatology, medicine.drug, Adult, medicine.medical_specialty, HCV RAS, Hepatitis C virus, 03 medical and health sciences, Internal medicine, Drug Resistance, Viral, medicine, Humans, Aged, NS5A, NS5B, business.industry, lcsh:R, Hepatitis C Virus, HCV resistance-test, biology.organism_classification, medicine.disease, 030104 developmental biology, chemistry, lcsh:Q, business
Abstract

Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2–45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4–19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1–4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

Published
2018

13. 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

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