43 results on '"Iapadre, N"'
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2. HDV epidemic in Central Italy is stable over the last two decades and is characterized by the circulation of multiple HDV sub-genotypes 1 inducing different inflammatory stimuli
- Author
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Salpini, R., primary, Piermatteo, L., additional, Torre, G., additional, D'Anna, S., additional, Khan, S., additional, Duca, L., additional, Bertoli, A., additional, Malagnino, V., additional, Paba, P., additional, Ciotti, M., additional, Lenci, I., additional, Francioso, S., additional, Paquazzi, C., additional, Lichtner, M., additional, Mastroianni, C., additional, Santopaolo, F., additional, De Sanctis, G., additional, Marignani, M., additional, Pellicelli, A., additional, Galati, G., additional, Moretti, A., additional, Colucci, G., additional, Casinelli, K., additional, Caterini, L., additional, Iapadre, N., additional, Parruti, G., additional, Vecchiet, I., additional, Paoloni, M., additional, Grelli, S., additional, Ceccherini-Silberstein, F., additional, Sarmati, L., additional, and Svicher, V., additional
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- 2023
- Full Text
- View/download PDF
3. 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
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Di Maio, V. C., Cento, V., Di Paolo, D., Aragri, M., De Leonardis, F., Tontodonati, M., Micheli, V., Bellocchi, M. C., Antonucci, F. P., Bertoli, A., Lenci, I., Milana, M., Gianserra, L., Melis, M., Di Biagio, A., Sarrecchia, C., Sarmati, L., Landonio, S., Francioso, S., Lambiase, L., Nicolini, L. A., Marenco, S., Nosotti, L., Giannelli, V., Siciliano, M., Romagnoli, D., Pellicelli, A., Vecchiet, J., Magni, C. F., Babudieri, S., Mura, M. S., 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, C. F., Ceccherini-Silberstein, F., Mariani, R., Paoloni, M., Iapadre, N., Grimaldi, A., Menzaghi, B., Quirino, T., Vecchiet, J., Bruzzone, B., De Maria, A., Di Biagio, A., Marenco, S., Nicolini, L. A., Picciotto, A., Viscoli, C., Casinelli, K., Monache, M. Delle, Lichtner, M., Mastroianni, C., Aghemo, A., Bruno, S., Cerrone, M., Colombo, M., Monforte, A. DʼArminio, Danieli, E., Donato, F., Gubertini, G., Landonio, S., Magni, C. F., Mancon, A., Micheli, V., Monico, S., Niero, F., Puoti, M., Rizzardini, G., Russo, M. L., Alfieri, R., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Romagnoli, D., Brancaccio, G., Caporaso, N., Gaeta, G. B., Lembo, V., Morisco, F., Calvaruso, V., Craxì, A., Di Marco, V., Mazzola, A., Petta, S., DʼAmico, E., Cacciatore, P., Consorte, A., Palitti, V. Pace, Parruti, G., Pieri, A., Polilli, E., Tontodonati, M., Andreoni, M., Angelico, M., Antenucci, F., Antonucci, F. P., Aragri, M., Armenia, D., Baiocchi, L., Bellocchi, M., Bertoli, A., Biliotti, E., Biolato, M., Carioti, L., Ceccherini-Silberstein, F., Cento, V., Cerasari, G., Cerva, C., Ciotti, M., DʼAmbrosio, C., DʼEttorre, G., De Leonardis, F., De Sanctis, A., Di Maio, V. C., Di Paolo, D., Francioso, S., Furlan, C., Gallo, P., Gasbarrini, A., Giannelli, V., Gianserra, L., Grieco, A., Grieco, S., Lambiase, L., Lattanzi, B., Lenci, I., Malagnino, V., Manuelli, M., Merli, M., Miglioresi, L., Milana, M., Nosotti, L., Palazzo, D., Pasquazzi, C., Pellicelli, A., Perno, C. F., Romano, M., Santopaolo, F., Santoro, M. M., Sarmati, L., Sarrecchia, C., Sforza, D., Siciliano, M., Sorbo, M. C., Spaziante, M., Svicher, V., Taliani, G., Teti, E., Tisone, G., Vespasiani-Gentilucci, U., Vullo, V., Mangia, A., Babudieri, S., Maida, I., Melis, M., Mura, M. S., Falconi, L., Di Giammartino, D., and Tarquini, P.
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- 2016
- Full Text
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4. Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy
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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, Bertoli A., Sorbo M. C., Aragri M., Lenci I., Teti E., Polilli E., Di Maio V. C., Gianserra L., Biliotti E., Masetti C., Magni C. F., Babudieri S., Nicolini L. A., Milana M., Cacciatore P., Sarmati L., Pellicelli A., Paolucci S., Craxi A., Morisco F., Palitti V. P., Siciliano M., Coppola N., Iapadre N., Puoti M., Rizzardini G., Taliani G., Pasquazzi C., Andreoni M., Parruti G., Angelico M., Perno C. F., 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. B., 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., 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, Bertoli A., Sorbo M. C., Aragri M., Lenci I., Teti E., Polilli E., Di Maio V. C., Gianserra L., Biliotti E., Masetti C., Magni C. F., Babudieri S., Nicolini L. A., Milana M., Cacciatore P., Sarmati L., Pellicelli A., Paolucci S., Craxi A., Morisco F., Palitti V. P., Siciliano M., Coppola N., Iapadre N., Puoti M., Rizzardini G., Taliani G., Pasquazzi C., Andreoni M., Parruti G., Angelico M., Perno C. F., 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. B., 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., and Zazzi M.
- 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
5. Analysis of resistance and phylogenetic clusters in HCV-2c infected patients within the Italian network Vironet C
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Barbaliscia, S., primary, Di Maio, V.C., additional, Fabeni, L., additional, Teti, E., additional, Paolucci, S., additional, Minichini, C., additional, Aragri, M., additional, Rosa, K. Yu La, additional, Carioti, L., additional, Pasquazzi, C., additional, Milana, M., additional, Foroghi, L., additional, Pollicino, T., additional, Licata, A., additional, Pieri, A., additional, Palitti, V. Pace, additional, Bruzzone, B., additional, Micheli, V., additional, Bertoli, A., additional, Baiocchi, L., additional, Callegaro, A.P., additional, Pellicelli, A., additional, Morisco, F., additional, Gulminetti, R., additional, Novati, S., additional, Lichtner, M., additional, Mastroianni, C., additional, Di Lorenzo, F., additional, Andreone, P., additional, Rossetti, B., additional, Marenco, S., additional, Taliani, G., additional, Boeri, E., additional, Hasson, H., additional, Monno, L., additional, Nicolini, L.A., additional, Landonio, S., additional, Paternoster, C., additional, Puoti, M., additional, Babudieri, S., additional, Quartini, M., additional, Iapadre, N., additional, Cozzolongo, R., additional, Sangiovanni, V., additional, Parruti, G., additional, Sarmati, L., additional, Coppola, N., additional, Baldanti, F., additional, Marco, V. Di, additional, Zazzi, M., additional, Raimondo, G., additional, Angelico, M., additional, Perno, C.F., additional, Andreoni, M., additional, Craxì, A., additional, and Ceccherini-Silberstein, F., additional
- Published
- 2020
- Full Text
- View/download PDF
6. 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
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Di Maio, V C, Cento, V, Di Paolo, D, Aragri, M, De Leonardis, F, Tontodonati, M, Micheli, V, Bellocchi, M C, Antonucci, F P, Bertoli, A, Lenci, I, Milana, M, Gianserra, L, Melis, M, Di Biagio, A, Sarrecchia, C, Sarmati, L, Landonio, S, Francioso, S, Lambiase, L, Nicolini, L A, Marenco, S, Nosotti, L, Giannelli, V, Siciliano, M, Romagnoli, D, Pellicelli, A, Vecchiet, J, Magni, C F, Babudieri, S, Mura, M S, 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, C F, Ceccherini-Silberstein, F, Collaborators (129) Mariani R, HCV Italian Resistance Network Study Group., Paoloni, M, Iapadre, N, Grimaldi, A, Menzaghi, B, Quirino, T, Bruzzone, B, De Maria, A, Nicolini, La, Viscoli, C, Casinelli, K, Monache, Md, Lichtner, M, Aghemo, A, Cerrone, M, Colombo, M, Monforte, Ad, Danieli, E, Donato, F, Gubertini, G, Magni, Cf, Mancon, A, Monico, S, Niero, F, Puoti, M, Russo, Ml, Alfieri, R, Gnocchi, M, Orro, A, Milanesi, L, Baldelli, E, Bertolotti, M, Borghi, V, Mussini, C, Brancaccio, G, Caporaso, N, Gaeta, Gb, Lembo, V, Calvaruso, V, Craxì, A, Di Marco, V, Mazzola, A, Petta, S, D'Amico, E, Cacciatore, P, Consorte, A, Palitti, Vp, Pieri, A, Polilli, E, Antenucci, F, Antonucci, Fp, Armenia, D, Baiocchi, L, Bellocchi, M, Biliotti, E, Biolato, M, Carioti, L, Cerasari, G, Cerva, C, Ciotti, M, D'Ambrosio, C, D'Ettorre, G, De Sanctis, A, Di Maio VC, Furlan, C, Gallo, P, Grieco, A, Grieco, S, Lattanzi, B, Malagnino, V, Manuelli, M, Merli, M, Miglioresi, L, Palazzo, D, Perno, Cf, Santopaolo, F, Santoro, Mm, Sforza, D, Sorbo, Mc, Spaziante, M, Svicher, V, Teti, E, Mangia, A, Maida, I, Mura, Ms, Falconi, L, Di Giammartino, D, Tarquini, P., Di Maio, V C, Cento, V, Di Paolo, D, Aragri, M, De Leonardis, F, Tontodonati, M, Micheli, V, Bellocchi, M C, Antonucci, F P, Bertoli, A, Lenci, I, Milana, M, Gianserra, L, Melis, M, Di Biagio, A, Sarrecchia, C, Sarmati, L, Landonio, S, Francioso, S, Lambiase, L, Nicolini, L A, Marenco, S, Nosotti, L, Giannelli, V, Siciliano, M, Romagnoli, D, Pellicelli, A, Vecchiet, J, Magni, C F, Babudieri, S, Mura, M S, 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, C F, Ceccherini-Silberstein, F, HCV Italian Resistance Network Study Group., Collaborators (129) Mariani R, Paoloni, M, Iapadre, N, Grimaldi, A, Menzaghi, B, Quirino, T, Bruzzone, B, De Maria, A, Nicolini, La, Viscoli, C, Casinelli, K, Monache, Md, Lichtner, M, Aghemo, A, Cerrone, M, Colombo, M, Monforte, Ad, Danieli, E, Donato, F, Gubertini, G, Magni, Cf, Mancon, A, Monico, S, Niero, F, Puoti, M, Russo, Ml, Alfieri, R, Gnocchi, M, Orro, A, Milanesi, L, Baldelli, E, Bertolotti, M, Borghi, V, Mussini, C, Brancaccio, G, Caporaso, N, Gaeta, Gb, Lembo, V, Calvaruso, V, Craxì, A, Di Marco, V, Mazzola, A, Petta, S, D'Amico, E, Cacciatore, P, Consorte, A, Palitti, Vp, Pieri, A, Polilli, E, Antenucci, F, Antonucci, Fp, Armenia, D, Baiocchi, L, Bellocchi, M, Biliotti, E, Biolato, M, Carioti, L, Cerasari, G, Cerva, C, Ciotti, M, D'Ambrosio, C, D'Ettorre, G, De Sanctis, A, Di Maio, Vc, Furlan, C, Gallo, P, Grieco, A, Grieco, S, Lattanzi, B, Malagnino, V, Manuelli, M, Merli, M, Miglioresi, L, Palazzo, D, Perno, Cf, Santopaolo, F, Santoro, Mm, Sforza, D, Sorbo, Mc, Spaziante, M, Svicher, V, Teti, E, Mangia, A, Maida, I, Mura, M, Falconi, L, Di Giammartino, D, Tarquini, P., Di Maio, V. C, Bellocchi, M. C, Antonucci, F. P, Nicolini, L. A, Magni, C. F, Mura, M. S, Vespasiani Gentilucci, U, Morisco, Filomena, Perno, C. F, Ceccherini Silberstein, F., Caporaso, Nicola, Di Maio, V., Cento, V., Di Paolo, D., Aragri, M., De Leonardis, F., Tontodonati, M., Micheli, V., Bellocchi, M., Antonucci, F., Bertoli, A., Lenci, I., Milana, M., Gianserra, L., Melis, M., Di Biagio, A., Sarrecchia, C., Sarmati, L., Landonio, S., Francioso, S., Lambiase, L., Nicolini, L., Marenco, S., Nosotti, L., Giannelli, V., Siciliano, M., Romagnoli, D., Pellicelli, A., Vecchiet, J., Magni, C., Babudieri, S., Mura, M., 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, C., Ceccherini-Silberstein, F., Mariani, R., Paoloni, M., Iapadre, N., Grimaldi, A., Menzaghi, B., Quirino, T., Bruzzone, B., De Maria, A., Viscoli, C., Casinelli, K., Delle Monache, M., Lichtner, M., Aghemo, A., Cerrone, M., Colombo, M., D'Arminio Monforte, A., Danieli, E., Donato, F., Gubertini, G., Mancon, A., Monico, S., Niero, F., Puoti, M., Russo, M., Alfieri, R., Gnocchi, M., Orro, A., Milanesi, L., Baldelli, E., Bertolotti, M., Borghi, V., Mussini, C., Brancaccio, G., Caporaso, N., Gaeta, G., Lembo, V., Calvaruso, V., Craxã, A., DI MARCO, V., Mazzola, A., Petta, S., D'Amico, E., Cacciatore, P., Consorte, A., Pace Palitti, V., Pieri, A., Polilli, E., Antenucci, F., Armenia, D., Baiocchi, L., Biliotti, E., Biolato, M., Carioti, L., Cerasari, G., Cerva, C., Ciotti, M., D'Ambrosio, C., D'Ettorre, G., De Sanctis, A., Furlan, C., Gallo, P., Grieco, A., Grieco, S., Lattanzi, B., Malagnino, V., Manuelli, M., Merli, M., Miglioresi, L., Palazzo, D., Santopaolo, F., Santoro, M., Sforza, D., Sorbo, M., Spaziante, M., Svicher, V., Teti, E., Mangia, A., Maida, I., Falconi, L., and Di Giammartino, D.
- Subjects
0301 basic medicine ,ns3 ,Genotyping Techniques ,viruses ,Drug Resistance ,Hepacivirus ,Viral Nonstructural Proteins ,medicine.disease_cause ,Gastroenterology ,Telaprevir ,chemistry.chemical_compound ,genotype ,genotyping techniques ,hepacivirus ,hepatitis C ,humans ,RNA viral ,retrospective studies ,sequence analysis ,DNA ,viral nonstructural proteins ,drug resistance, viral ,mutation ,pharmacology ,infectious diseases ,0302 clinical medicine ,Retrospective Studie ,Genotype ,Pharmacology (medical) ,Viral ,Hepatitis C ,Humans ,RNA, Viral ,Retrospective Studies ,Sequence Analysis, DNA ,Drug Resistance, Viral ,Mutation ,Proteolytic enzymes ,virus diseases ,Settore MED/07 - Microbiologia e Microbiologia Clinica ,hcv-rna levels ,Infectious Diseases ,HCV-RNA ,030211 gastroenterology & hepatology ,Sequence Analysis ,medicine.drug ,Human ,Microbiology (medical) ,medicine.medical_specialty ,Hepatitis C virus ,Concordance ,Settore MED/12 - GASTROENTEROLOGIA ,Pharmacology ,Biology ,03 medical and health sciences ,Boceprevir ,Internal medicine ,medicine ,hcv ,Genotyping ,Hepaciviru ,Viral Nonstructural Protein ,Settore MED/09 - MEDICINA INTERNA ,Virology ,digestive system diseases ,030104 developmental biology ,chemistry ,Sequence Analysi ,RNA ,Genotyping Technique - 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.
- Published
- 2016
7. Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies
- Author
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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.
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- 2017
8. 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
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Di Maio, V, Cento, V, Di Paolo, D, Aragri, M, De Leonardis, F, Tontodonati, M, Micheli, V, Bellocchi, M, Antonucci, F, Bertoli, A, Lenci, I, Milana, M, Gianserra, L, Melis, M, Di Biagio, A, Sarrecchia, C, Sarmati, L, Landonio, S, Francioso, S, Lambiase, L, Nicolini, L, Marenco, S, Nosotti, L, Giannelli, V, Siciliano, M, Romagnoli, D, Pellicelli, A, Vecchiet, J, Magni, C, Babudieri, S, Mura, M, 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, C, Ceccherini-Silberstein, F, Mariani, R, Paoloni, M, Iapadre, N, Grimaldi, A, Menzaghi, B, Quirino, T, Bruzzone, B, De Maria, A, Viscoli, C, Casinelli, K, Delle Monache, M, Lichtner, M, Aghemo, A, Cerrone, M, Colombo, M, D'Arminio Monforte, A, Danieli, E, Donato, F, Gubertini, G, Mancon, A, Monico, S, Niero, F, Puoti, M, Russo, M, Alfieri, R, Gnocchi, M, Orro, A, Milanesi, L, Baldelli, E, Bertolotti, M, Borghi, V, Mussini, C, Brancaccio, G, Caporaso, N, Gaeta, G, Lembo, V, Calvaruso, V, Craxi, A, Di Marco, V, Mazzola, A, Petta, S, D'Amico, E, Cacciatore, P, Consorte, A, Pace Palitti, V, Pieri, A, Polilli, E, Antenucci, F, Armenia, D, Baiocchi, L, Biliotti, E, Biolato, M, Carioti, L, Cerasari, G, Cerva, C, Ciotti, M, D'Ambrosio, C, D'Ettorre, G, De Sanctis, A, Furlan, C, Gallo, P, Grieco, A, Grieco, S, Lattanzi, B, Malagnino, V, Manuelli, M, Merli, M, Miglioresi, L, Palazzo, D, Santopaolo, F, Santoro, M, Sforza, D, Sorbo, M, Spaziante, M, Svicher, V, Teti, E, Mangia, A, Maida, I, Falconi, L, Di Giammartino, D, Tarquini, P, Di Maio V. C., Cento V., Di Paolo D., Aragri M., De Leonardis F., Tontodonati M., Micheli V., Bellocchi M. C., Antonucci F. P., Bertoli A., Lenci I., Milana M., Gianserra L., Melis M., Di Biagio A., Sarrecchia C., Sarmati L., Landonio S., Francioso S., Lambiase L., Nicolini L. A., Marenco S., Nosotti L., Giannelli V., Siciliano M., Romagnoli D., Pellicelli A., Vecchiet J., Magni C. F., Babudieri S., Mura M. S., 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 C. F., Ceccherini-Silberstein F., Mariani R., Paoloni M., Iapadre N., Grimaldi A., Menzaghi B., Quirino T., Bruzzone B., De Maria A., Viscoli C., Casinelli K., Delle Monache M., Lichtner M., Aghemo A., Cerrone M., Colombo M., D'Arminio Monforte A., Danieli E., Donato F., Gubertini G., Mancon A., Monico S., Niero F., Puoti M., Russo M. L., Alfieri R., Gnocchi M., Orro A., Milanesi L., Baldelli E., Bertolotti M., Borghi V., Mussini C., Brancaccio G., Caporaso N., Gaeta G. B., Lembo V., Calvaruso V., Craxi A., Di Marco V., Mazzola A., Petta S., D'Amico E., Cacciatore P., Consorte A., Pace Palitti V., Pieri A., Polilli E., Antenucci F., Armenia D., Baiocchi L., Biliotti E., Biolato M., Carioti L., Cerasari G., Cerva C., Ciotti M., D'Ambrosio C., D'Ettorre G., De Sanctis A., Furlan C., Gallo P., Grieco A., Grieco S., Lattanzi B., Malagnino V., Manuelli M., Merli M., Miglioresi L., Palazzo D., Santopaolo F., Santoro M. M., Sforza D., Sorbo M. C., Spaziante M., Svicher V., Teti E., Mangia A., Maida I., Falconi L., Di Giammartino D., Tarquini P., Di Maio, V, Cento, V, Di Paolo, D, Aragri, M, De Leonardis, F, Tontodonati, M, Micheli, V, Bellocchi, M, Antonucci, F, Bertoli, A, Lenci, I, Milana, M, Gianserra, L, Melis, M, Di Biagio, A, Sarrecchia, C, Sarmati, L, Landonio, S, Francioso, S, Lambiase, L, Nicolini, L, Marenco, S, Nosotti, L, Giannelli, V, Siciliano, M, Romagnoli, D, Pellicelli, A, Vecchiet, J, Magni, C, Babudieri, S, Mura, M, 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, C, Ceccherini-Silberstein, F, Mariani, R, Paoloni, M, Iapadre, N, Grimaldi, A, Menzaghi, B, Quirino, T, Bruzzone, B, De Maria, A, Viscoli, C, Casinelli, K, Delle Monache, M, Lichtner, M, Aghemo, A, Cerrone, M, Colombo, M, D'Arminio Monforte, A, Danieli, E, Donato, F, Gubertini, G, Mancon, A, Monico, S, Niero, F, Puoti, M, Russo, M, Alfieri, R, Gnocchi, M, Orro, A, Milanesi, L, Baldelli, E, Bertolotti, M, Borghi, V, Mussini, C, Brancaccio, G, Caporaso, N, Gaeta, G, Lembo, V, Calvaruso, V, Craxi, A, Di Marco, V, Mazzola, A, Petta, S, D'Amico, E, Cacciatore, P, Consorte, A, Pace Palitti, V, Pieri, A, Polilli, E, Antenucci, F, Armenia, D, Baiocchi, L, Biliotti, E, Biolato, M, Carioti, L, Cerasari, G, Cerva, C, Ciotti, M, D'Ambrosio, C, D'Ettorre, G, De Sanctis, A, Furlan, C, Gallo, P, Grieco, A, Grieco, S, Lattanzi, B, Malagnino, V, Manuelli, M, Merli, M, Miglioresi, L, Palazzo, D, Santopaolo, F, Santoro, M, Sforza, D, Sorbo, M, Spaziante, M, Svicher, V, Teti, E, Mangia, A, Maida, I, Falconi, L, Di Giammartino, D, Tarquini, P, Di Maio V. C., Cento V., Di Paolo D., Aragri M., De Leonardis F., Tontodonati M., Micheli V., Bellocchi M. C., Antonucci F. P., Bertoli A., Lenci I., Milana M., Gianserra L., Melis M., Di Biagio A., Sarrecchia C., Sarmati L., Landonio S., Francioso S., Lambiase L., Nicolini L. A., Marenco S., Nosotti L., Giannelli V., Siciliano M., Romagnoli D., Pellicelli A., Vecchiet J., Magni C. F., Babudieri S., Mura M. S., 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 C. F., Ceccherini-Silberstein F., Mariani R., Paoloni M., Iapadre N., Grimaldi A., Menzaghi B., Quirino T., Bruzzone B., De Maria A., Viscoli C., Casinelli K., Delle Monache M., Lichtner M., Aghemo A., Cerrone M., Colombo M., D'Arminio Monforte A., Danieli E., Donato F., Gubertini G., Mancon A., Monico S., Niero F., Puoti M., Russo M. L., Alfieri R., Gnocchi M., Orro A., Milanesi L., Baldelli E., Bertolotti M., Borghi V., Mussini C., Brancaccio G., Caporaso N., Gaeta G. B., Lembo V., Calvaruso V., Craxi A., Di Marco V., Mazzola A., Petta S., D'Amico E., Cacciatore P., Consorte A., Pace Palitti V., Pieri A., Polilli E., Antenucci F., Armenia D., Baiocchi L., Biliotti E., Biolato M., Carioti L., Cerasari G., Cerva C., Ciotti M., D'Ambrosio C., D'Ettorre G., De Sanctis A., Furlan C., Gallo P., Grieco A., Grieco S., Lattanzi B., Malagnino V., Manuelli M., Merli M., Miglioresi L., Palazzo D., Santopaolo F., Santoro M. M., Sforza D., Sorbo M. C., Spaziante M., Svicher V., Teti E., Mangia A., Maida I., Falconi L., Di Giammartino D., and Tarquini P.
- 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
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- 2016
9. Characterization of baseline factors associated with treatment outcome in HCV-infected patients naive to direct acting antivirals: particular focus on natural resistance
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Barbaliscia, S., primary, Di Maio, V.C., additional, Teti, E., additional, Aragri, M., additional, Paolucci, S., additional, Masetti, C., additional, D’Ambrosio, R., additional, Degasperi, E., additional, Polilli, E., additional, Palitti, V. Pace, additional, Fiorentino, G., additional, Foroghi, L., additional, Cento, V., additional, Scutari, R., additional, Bruzzone, B., additional, Calvaruso, V., additional, Coppola, N., additional, Gaeta, G.B., additional, Morsica, G., additional, Ghisetti, V., additional, Bertoli, A., additional, Milana, M., additional, Nicolini, L.A., additional, Gennari, W., additional, Campoli, R., additional, Galli, S., additional, Magni, C.F., additional, Micheli, V., additional, Boccaccio, V., additional, Maserati, R., additional, Bonora, S., additional, Iapadre, N., additional, Morisco, F., additional, Siciliano, M., additional, Guarneri, V., additional, Lichtner, M., additional, Borghi, V., additional, Paba, P., additional, Sarmati, L., additional, Puoti, M., additional, Pellicelli, A., additional, Babudieri, S., additional, Rizzardini, G., additional, Taliani, G., additional, Parruti, G., additional, Lampertico, P., additional, Pasquazzi, C., additional, Angelico, M., additional, Baldanti, F., additional, Craxì, A., additional, Andreoni, M., additional, Perno, C.F., additional, and Ceccherini-Silberstein, F., additional
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- 2019
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10. Key mutations in HBsAg C-terminus correlate with lower HBsAg levels in vivo, hinder HBsAg release in vitro and affect HBsAg structural stability in HBeAg-negative chronic HBV genotype D infection
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Piermatteo, L., primary, Battisti, A., additional, Carioti, L., additional, Anastasiou, O., additional, Gill, U.S., additional, Colagrossi, L., additional, Bertoli, A., additional, Aragri, M., additional, Iuvara, A., additional, Malagnino, V., additional, Cerva, C., additional, Lichtner, M., additional, Mastroianni, C.M., additional, De Sanctis, G.M., additional, Maurizio, P., additional, Marignani, M., additional, Pasquazzi, C., additional, Iapadre, N., additional, Mari, T., additional, Parruti, G., additional, Vecchiet, J., additional, Sarmati, L., additional, Andreoni, M., additional, Mario, A., additional, Grelli, S., additional, Kennedy, P., additional, Verheyen, J., additional, Silberstein, F. Ceccherini, additional, Perno, C.F., additional, Salpini, R., additional, and Svicher, V., additional
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- 2019
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11. A hyper-glycosylation of HBV surface antigen characterizes immunosuppression-driven HBV reactivation and hinders HBsAg recognition in vitro
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Salpini, R., primary, Piermatteo, L., additional, Battisti, A., additional, Colagrossi, L., additional, Aragri, M., additional, Fabeni, L., additional, Bertoli, A., additional, Mastroianni, C.M., additional, Marignani, M., additional, Maylin, S., additional, Delaugerre, C., additional, Morisco, F., additional, Nicola, C., additional, Marrone, A., additional, Iapadre, N., additional, Mario, A., additional, Sarmati, L., additional, Andreoni, M., additional, Verheyen, J., additional, Silberstein, F.C., additional, Levrero, M., additional, Perno, C.F., additional, Belloni, L., additional, and Svicher, V., additional
- Published
- 2018
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12. Key mutational patterns in HBsAg C-terminus profoundly affect HBsAg levels in HBeAg-negative chronic HBV genotype D infection
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Salpini, R., primary, Battisti, A., additional, Carioti, L., additional, Carlo, D.D., additional, Anastasiou, O., additional, Gill, U.S., additional, Colagrossi, L., additional, Bertoli, A., additional, Aragri, M., additional, Fabeni, L., additional, Fini, V., additional, Piermatteo, L., additional, Iuvara, A., additional, Malagnino, V., additional, Cerva, C., additional, Lichtner, M., additional, Mastroianni, C.M., additional, Sanctis, G.M.D., additional, Maurizio, P., additional, Marignani, M., additional, Pasquazzi, C., additional, Iapadre, N., additional, Mari, T., additional, Parruti, G., additional, Vecchiet, J., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Grelli, S., additional, Kennedy, P., additional, Verheyen, J., additional, Silberstein, F.C., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2018
- Full Text
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13. Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro
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Salpini, R, Surdo, M, Warner, N, Cortese, MF, Colledge, D, Soppe, S, Bellocchi, MC, Armenia, D, Carioti, L, Continenza, F, Di Carlo, D, Saccomandi, P, Mirabelli, C, Pollicita, M, Longo, R, Romano, S, Cappiello, G, Spano, A, Trimoulet, P, Fleury, H, Vecchiet, J, Iapadre, N, Barlattani, A, Bertoli, A, Mari, T, Pasquazzi, C, Missale, G, Sarrecchia, C, Orecchini, E, Michienzi, A, Andreoni, M, Francioso, S, Angelico, M, Verheyen, J, Ceccherini-Silberstein, F, Locarnini, S, Perno, CF, Svicher, V, Salpini, R, Surdo, M, Warner, N, Cortese, MF, Colledge, D, Soppe, S, Bellocchi, MC, Armenia, D, Carioti, L, Continenza, F, Di Carlo, D, Saccomandi, P, Mirabelli, C, Pollicita, M, Longo, R, Romano, S, Cappiello, G, Spano, A, Trimoulet, P, Fleury, H, Vecchiet, J, Iapadre, N, Barlattani, A, Bertoli, A, Mari, T, Pasquazzi, C, Missale, G, Sarrecchia, C, Orecchini, E, Michienzi, A, Andreoni, M, Francioso, S, Angelico, M, Verheyen, J, Ceccherini-Silberstein, F, Locarnini, S, Perno, CF, and Svicher, V
- Abstract
BACKGROUND: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. METHODS: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry. RESULTS: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P <0.001); P203Q+S210R (17.4% [4/23] in HCC vs 0% [0/110] in non-HCC, P=0.001). Both mutations reside in trans-membrane C-terminal domain critical for HBsAg-secretion. In in-vitro experiments, P203Q, S210R and P203Q+S210R significantly reduced the ratio [secreted/intracellular HBsAg] compared to wt at each time-point analysed (P <0.05), supporting an impaired HBsAg-secretion. Furthermore, P203Q and P203Q+S210R increased the percentage of cells in S-phase compared to wt, indicating cell-cycle progression (P203Q:26±13%; P203Q+S210R:29±14%; wt:18%±9, P <0.01. Additionally, S210R increased the percentage of cells in G2/M-phase (26±8% for wt versus 33±6% for S210R, P <0.001). CONCLUSIONS: Specific mutations in HBsAg C-terminus significantly correlate with HBV-induced HCC. They hamper HBsAg-secretion and are associated with increased cellular proliferation, supporting their involvement in HCC-development. The identification of viral genetic markers associated with HCC is critical to identify patients at higher HCC-risk that may deserve intensive liver monitoring, and/or early anti-HBV therapy.
- Published
- 2017
14. Natural HCV resistance is common in Italy and differently associated to genotypes
- Author
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Sorbo, M.C., primary, Cento, V., additional, Bertoli, A., additional, Lenci, I., additional, Polilli, E., additional, Masetti, C., additional, Gianserra, L., additional, Teti, E., additional, Biliotti, E., additional, Magni, C.F., additional, Aragri, M., additional, Micheli, V., additional, Melis, M., additional, Nicolini, L.A., additional, Marenco, S., additional, Calvaruso, V., additional, Paolucci, S., additional, Baldanti, F., additional, Morisco, F., additional, Siciliano, M., additional, Pace Palitti, V., additional, Andreone, P., additional, Bruzzone, B., additional, Coppola, N., additional, Ruggiero, T., additional, Lichtner, M., additional, Menzaghi, B., additional, Romagnoli, D., additional, Iapadre, N., additional, Di Maio, V.C., additional, De Leonardis, F., additional, Milana, M., additional, Cacciatore, P., additional, Pieri, A., additional, Sarmati, L., additional, Landonio, S., additional, Gasbarrini, A., additional, Puoti, M., additional, Craxì, A., additional, Vullo, V., additional, Pellicelli, A., additional, Babudieri, S., additional, Rizzardini, G., additional, Taliani, G., additional, Andreoni, M., additional, Pasquazzi, C., additional, Parruti, G., additional, Angelico, M., additional, Perno, C.F., additional, and Ceccherini-Silberstein, F., additional
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- 2017
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15. In HBeAg-negative chronic HBV infection, HBsAg levels profoundly differ among HBV-genotypes and can be affected by the extent of HBsAg variability: Can quantitative HBsAg truly reflect intra-hepatic HBV reservoir?
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Salpini, R., primary, Battisti, A., additional, Anastasiou, O., additional, Gill, U., additional, Colagrossi, L., additional, Bertoli, A., additional, Fabeni, L., additional, Fini, V., additional, Piermatteo, L., additional, Iuvara, A., additional, Malagnino, V., additional, Cerva, C., additional, Lichtner, M., additional, Mastroianni, C., additional, De Sanctis, G., additional, Paoloni, M., additional, Marignani, M., additional, Pasquazzi, C., additional, Iapadre, N., additional, Mari, T., additional, Parruti, G., additional, Vecchiet, I., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Grelli, S., additional, Kennedy, P., additional, Verheyen, J., additional, Perno, C.-F., additional, and Svicher, V., additional
- Published
- 2017
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16. An elevated degree of genetic variability characterizes Hepatitis Delta Antigen (HDAg) and correlates with high levels of serum HDV-RNA: Implication for disease progression and design of new pharmacological targets
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Colagrossi, L., primary, Salpini, R., additional, Scutari, R., additional, Battisti, A., additional, Piermatteo, L., additional, Bertoli, A., additional, Minichini, C., additional, Trimoulet, P., additional, Fleury, H., additional, Nebuloso, E., additional, De Cristofaro, M., additional, Cappiello, G., additional, Spanò, A., additional, Malagnino, V., additional, Mari, T., additional, Barlattani, A., additional, Iapadre, N., additional, Lichtner, M., additional, Mastroianni, C.M., additional, Lenci, I., additional, Pasquazzi, C., additional, De Sanctis, G.M., additional, Galeota Lanza, A., additional, Stanzione, M., additional, Stornaiuolo, G., additional, Marignani, M., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Perno, C.F., additional, Coppola, N., additional, and Svicher, V., additional
- Published
- 2017
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17. The circulation of specific vaccine-escape HBsAg mutations in HBV genotype D infected patients correlates with high viremia and affects HBsAg detection and quantification
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Salpini, R., primary, Piermatteo, L., additional, Di Carlo, D., additional, Battisti, A., additional, Colagrossi, L., additional, Bertoli, A., additional, Fabeni, L., additional, Fini, V., additional, Iuvara, A., additional, Ricciardi, A., additional, Cerva, C., additional, Sarrecchia, C., additional, Lichtner, M., additional, Mastroianni, C., additional, De Sanctis, G., additional, Paoloni, M., additional, Marignani, M., additional, Pasquazzi, C., additional, Iapadre, N., additional, Mari, T., additional, Parruti, G., additional, Romano, S., additional, Visca, M., additional, Moretti, A., additional, Vecchiet, J., additional, Sarmati, L., additional, Andreoni, M., additional, Cappiello, G., additional, Spanò, A., additional, Grelli, S., additional, Angelico, M., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2017
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18. In HBeAg-negative chronic HBV infection, HBsAg levels profoundly vary among different HBV-genotypes and can be influenced by the degree of HBsAg variability: can quantitative HBsAg truly reflect intra-hepatic HBV reservoir?
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Salpini, R., primary, Battisti, A., additional, Anastasiou, O., additional, Gill, U., additional, Colagrossi, L., additional, Bertoli, A., additional, Fabeni, L., additional, Fini, V., additional, Piermatteo, L., additional, Iuvara, A., additional, Malagnino, V., additional, Cerva, C., additional, Lichtner, M., additional, Mastroianni, C., additional, De Sanctis, G., additional, Paoloni, M., additional, Marignani, M., additional, Pasquazzi, C., additional, Iapadre, N., additional, Mari, T., additional, Parruti, G., additional, Vecchiet, J., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Grelli, S., additional, Kennedy, P., additional, Verheyen, J., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2017
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19. Hepatitis Delta Antigen (HDAg) is characterized by an extensive degree of genetic variability that correlates with elevated levels of serum HDV-RNA
- Author
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Colagrossi, L., primary, Salpini, R., additional, Scutari, R., additional, Battisti, A., additional, Piermatteo, L., additional, Bertoli, A., additional, Menichini, C., additional, Trimoulet, P., additional, Fleury, H., additional, Nebuloso, E., additional, De Cristofaro, M., additional, Cappiello, G., additional, Spanò, A., additional, Malagnino, V., additional, Mari, T., additional, Barlattani, A., additional, Iapadre, N., additional, Lichtner, M., additional, Mastroianni, C.M., additional, Lenci, I., additional, Pasquazzi, C., additional, De Sanctis, G.M., additional, Lanza, A.G., additional, Stanzione, M., additional, Stornaiuolo, G., additional, Marignani, M., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Perno, C.F., additional, Coppola, N., additional, and Svicher, V., additional
- Published
- 2017
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20. Gain of positively charged amino acids at specific positions of HBsAg C-terminus tightly correlates with HBV-induced hepatocellular carcinoma by altering the structural folding of this domain
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Salpini, R., primary, Carioti, L., additional, Aragri, M., additional, Di Carlo, D., additional, Colagrossi, L., additional, Battisti, A., additional, Piermatteo, L., additional, Bertoli, A., additional, Fabeni, L., additional, Ricciardi, A., additional, Longo, R., additional, Romano, S., additional, Cappiello, G., additional, Spanò, A., additional, Trimoulet, P., additional, Fleury, H., additional, Vecchiet, J., additional, Iapadre, N., additional, Barlattani, A., additional, Mari, T., additional, Pasquazzi, C., additional, Lenci, I., additional, Francioso, S., additional, Parruti, G., additional, Sarmati, L., additional, Andreoni, M., additional, Angelico, M., additional, Ceccherini-Silberstein, F., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2017
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21. Vaccine-escape HBsAg mutants circulating among genotype D HBV-infected patients correlate with atypical serological profiles, high viremia and transaminases: Potential impact on vaccination strategies
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Salpini, R., primary, Battisti, A., additional, Colagrossi, L., additional, Alteri, C., additional, Bertoli, A., additional, Fabeni, L., additional, Sarrecchia, C., additional, Di Carlo, D., additional, Pollicita, M., additional, Lichtner, M., additional, Mastroianni, C., additional, De Sanctis, G., additional, Paoloni, M., additional, Marignani, M., additional, Pasquazzi, C., additional, Di Paolo, D., additional, Iapadre, N., additional, Mari, T., additional, Puoti, C., additional, Parruti, G., additional, Romano, S., additional, Visca, M., additional, Vecchiet, I., additional, Andreoni, M., additional, Cappiello, G., additional, Spanò, A., additional, Angelico, M., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2016
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22. HBV-HDV co-infection constrains HBV genetic evolution in HBsAg
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Colagrossi, L., primary, Scutari, R., additional, Salpini, R., additional, Battisti, A., additional, Pollicita, M., additional, Bertoli, A., additional, Minichini, C., additional, Trimoulet, P., additional, Fleury, H., additional, Nebuloso, E., additional, De Cristofaro, M., additional, Cappiello, G., additional, Spanò, A., additional, Malagnino, V., additional, Sarmati, L., additional, Mari, T., additional, Barlattani, A., additional, Iapadre, N., additional, Lichtner, M., additional, Mastroianni, C., additional, Lenci, I., additional, Baiocchi, L., additional, Pasquazzi, C., additional, Sanctis, G. Maria De, additional, Lanza, A.G., additional, Stanzione, M., additional, Stornaiuolo, G., additional, Marignani, M., additional, Andreoni, M., additional, Angelico, M., additional, Perno, C.F., additional, Coppola, N., additional, and Svicher, V., additional
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- 2016
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23. Immunosuppression-driven HBV reactivation in patients with resolved HBV infection correlates with a relevant risk of death and with evolution towards active chronical infection
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Battisti, A., primary, Salpini, R., additional, Colagrossi, L., additional, Alteri, C., additional, Pollicita, M., additional, Ricciardi, A., additional, Cerva, C., additional, Maffongelli, G., additional, Lichtner, M., additional, Mastroianni, C., additional, Casinelli, K., additional, Paoloni, M., additional, Marignani, M., additional, Maylin, S., additional, Delaugerre, C., additional, Morisco, F., additional, Coppola, N., additional, Marrone, A., additional, Brega, A., additional, Francioso, S., additional, Venditti, A., additional, Mari, T., additional, Mazzoni, E., additional, Iapadre, N., additional, Di Paolo, D., additional, Sarrecchia, C., additional, Sarmati, L., additional, Andreoni, M., additional, Taliani, G., additional, Angelico, M., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2016
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24. HBsAg mutations correlated with HCC in vivo affect HBsAg release and favor cell proliferation in vitro
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Salpini, R., primary, Surdo, M., additional, Warner, N., additional, Cortese, M.F., additional, Mirabelli, C., additional, Colledge, D., additional, Soppe, S., additional, Saccomandi, P., additional, Pollicita, M., additional, Longo, R., additional, Romano, S., additional, Cappiello, G., additional, Spanò, A., additional, Trimoulet, P., additional, Fleury, H., additional, Vecchiet, J., additional, Iapadre, N., additional, Barlattani, A., additional, Bertoli, A., additional, Mari, T., additional, Pasquazzi, C., additional, Missale, G., additional, Sarrecchia, C., additional, Orecchini, E., additional, Michienzi, A., additional, Andreoni, M., additional, Francioso, S., additional, Angelico, M., additional, Ceccherini-Silberstein, F., additional, Locarnini, S., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2016
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25. Vaccine-Escape HBsAg Mutations Circulating in a Relevant Proportion of HBV Genotype D Infected Patients Correlate with Atypical Serological Profiles, High Viremia and Transaminases: Potential Implication for Vaccine Success
- Author
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Salpini, R., primary, Battisti, A., additional, Colagrossi, L., additional, Alteri, C., additional, Bertoli, A., additional, Fabeni, L., additional, Sarrecchia, C., additional, Di Carlo, D., additional, Pollicita, M., additional, Lichtner, M., additional, Mastroianni, C., additional, De Sanctis, G., additional, Paoloni, M., additional, Marignani, M., additional, Pasquazzi, C., additional, Di Paolo, D., additional, Iapadre, N., additional, Mari, T., additional, Parruti, G., additional, Romano, S., additional, Visca, M., additional, Vecchiet, I., additional, Andreoni, M., additional, Cappiello, G., additional, Spanò, A., additional, Angelico, M., additional, Perno, C.F., additional, and Svicher, V., additional
- Published
- 2016
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26. SAT-350 - A hyper-glycosylation of HBV surface antigen characterizes immunosuppression-driven HBV reactivation and hinders HBsAg recognition in vitro
- Author
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Salpini, R., Piermatteo, L., Battisti, A., Colagrossi, L., Aragri, M., Fabeni, L., Bertoli, A., Mastroianni, C.M., Marignani, M., Maylin, S., Delaugerre, C., Morisco, F., Nicola, C., Marrone, A., Iapadre, N., Mario, A., Sarmati, L., Andreoni, M., Verheyen, J., Silberstein, F.C., Levrero, M., Perno, C.F., Belloni, L., and Svicher, V.
- Published
- 2018
- Full Text
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27. FRI-293 - Key mutational patterns in HBsAg C-terminus profoundly affect HBsAg levels in HBeAg-negative chronic HBV genotype D infection
- Author
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Salpini, R., Battisti, A., Carioti, L., Carlo, D.D., Anastasiou, O., Gill, U.S., Colagrossi, L., Bertoli, A., Aragri, M., Fabeni, L., Fini, V., Piermatteo, L., Iuvara, A., Malagnino, V., Cerva, C., Lichtner, M., Mastroianni, C.M., Sanctis, G.M.D., Maurizio, P., Marignani, M., Pasquazzi, C., Iapadre, N., Mari, T., Parruti, G., Vecchiet, J., Sarmati, L., Andreoni, M., Angelico, M., Grelli, S., Kennedy, P., Verheyen, J., Silberstein, F.C., Perno, C.F., and Svicher, V.
- Published
- 2018
- Full Text
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28. P0614 : Key HBsAg mutations significantly correlate with HCC, hamper HBsAg secretion and promote cell proliferation in vitro
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Surdo, M., primary, Salpini, R., additional, Warner, N., additional, Cortese, M.F., additional, Mirabelli, C., additional, Colledge, D., additional, Soppe, S., additional, Pollicita, M., additional, Longo, R., additional, Romano, S., additional, Cappiello, G., additional, Spanò, A., additional, Trimoulet, P., additional, Fleury, H., additional, Vecchiet, J., additional, Iapadre, N., additional, Barlattani, A., additional, Bertoli, A., additional, Mari, T., additional, Pasquazzi, C., additional, Missale, G., additional, Sarrecchia, C., additional, Orecchini, E., additional, Michienzi, A., additional, Andreoni, M., additional, Francioso, S., additional, Angelico, M., additional, Ceccherini-Silberstein, F., additional, Locarnini, S., additional, Perno, C.-F., additional, and Svicher, V., additional
- Published
- 2015
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29. THU-160 - Vaccine-Escape HBsAg Mutations Circulating in a Relevant Proportion of HBV Genotype D Infected Patients Correlate with Atypical Serological Profiles, High Viremia and Transaminases: Potential Implication for Vaccine Success
- Author
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Salpini, R., Battisti, A., Colagrossi, L., Alteri, C., Bertoli, A., Fabeni, L., Sarrecchia, C., Di Carlo, D., Pollicita, M., Lichtner, M., Mastroianni, C., De Sanctis, G., Paoloni, M., Marignani, M., Pasquazzi, C., Di Paolo, D., Iapadre, N., Mari, T., Parruti, G., Romano, S., Visca, M., Vecchiet, I., Andreoni, M., Cappiello, G., Spanò, A., Angelico, M., Perno, C.F., and Svicher, V.
- Published
- 2016
- Full Text
- View/download PDF
30. THU-106 - HBV-HDV Co-Infection Constrains HBV Genetic Evolution in HBsAg
- Author
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Colagrossi, L., Scutari, R., Battisti, A., Salpini, R., Pollicita, M., Bertoli, A., Minichini, C., Trimoulet, P., Fleury, H., Nebuloso, E., Longo, R., Cappiello, G., Spanó, A., Malagnino, V., Sarmati, L., Mari, T., Barlattani, A., Iapadre, N., Lichtner, M., Mastroianni, C., Lenci, I., Baiocchi, L., Pasquazzi, C., De Sanctis, G.M., Lanza, A.G., Stanzione, M., Stornaiuolo, G., Marignani, M., Andreoni, M., Angelico, M., Perno, C.-F., Coppola, N., and Svicher, V.
- Published
- 2016
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31. A hyper-glycosylation of HBV surface antigen correlates with HBsAg-Negativity at immunosuppression-driven HBV reactivation in vivo and hinders HBsAg recognition in vitro
- Author
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Francesca Ceccherini-Silberstein, Carlotta Cerva, Ada Bertoli, Carlo Federico Perno, Massimo Marignani, Miriam Lichtner, Aldo Marrone, L. Colagrossi, Jens Verheyen, Valentina Svicher, Katia Yu La Rosa, N. Iapadre, Constance Delaugerre, L. Piermatteo, Massimo Levrero, Sarah Maylin, Marianna Aragri, Nicola Coppola, Loredana Sarmati, Stefano Aquaro, A. Battisti, Romina Salpini, Laura Belloni, Massimo Andreoni, Mario Angelico, Patrizia Saccomandi, Filomena Morisco, Salpini, R., Piermatteo, L., Battisti, A., Colagrossi, L., Aragri, M., Rosa, K. Y. L., Bertoli, A., Saccomandi, P., Lichtner, M., Marignani, M., Maylin, S., Delaugerre, C., Morisco, F., Coppola, N., Marrone, A., Iapadre, N., Cerva, C., Aquaro, S., Angelico, M., Sarmati, L., Andreoni, M., Verheyen, J., Ceccherini-Silberstein, F., Levrero, M., Perno, C. F., Belloni, L., Svicher, V., Salpini, Romina, Piermatteo, Lorenzo, Battisti, Arianna, Colagrossi, Luna, Aragri, Marianna, Yu La Rosa, Katia, Bertoli, Ada, Saccomandi, Patrizia, Lichtner, Miriam, Marignani, Massimo, Maylin, Sarah, Delaugerre, Constance, Morisco, Filomena, Coppola, Nicola, Marrone, Aldo, Iapadre, Nerio, Cerva, Carlotta, Aquaro, Stefano, Angelico, Mario, Sarmati, Loredana, Andreoni, Massimo, Verheyen, Jen, Ceccherini-Silberstein, Francesca, Levrero, Massimo, Federico Perno, Carlo, Belloni, Laura, and Svicher, Valentina
- Subjects
0301 basic medicine ,Male ,HBsAg ,Glycosylation ,lcsh:QR1-502 ,Medizin ,medicine.disease_cause ,lcsh:Microbiology ,HBV ,HBV reactivation ,N-linked glycosylation ,0302 clinical medicine ,biology ,virus diseases ,Middle Aged ,Infectious Diseases ,030211 gastroenterology & hepatology ,Female ,Antibody ,Hepatitis B virus ,Article ,Cell Line ,03 medical and health sciences ,Antigen ,In vivo ,Virology ,medicine ,Humans ,Hepatitis B Antibodies ,Aged ,Immune Evasion ,Hepatitis ,Immunosuppression Therapy ,Hepatitis B Surface Antigens ,business.industry ,medicine.disease ,In vitro ,Settore MED/17 ,digestive system diseases ,030104 developmental biology ,Reinfection ,Mutation ,biology.protein ,Virus Activation ,business - Abstract
Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3&ndash, 8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >, 1 additional NLGSs (p <, 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.
- Published
- 2020
32. HDV can constrain HBV genetic evolution in hbsag: Implications for the identification of innovative pharmacological targets
- Author
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A. Battisti, Alberto Spanò, G. Stornaiuolo, L. Colagrossi, Francesca Ceccherini-Silberstein, Ada Bertoli, Ilaria Lenci, Carmine Minichini, Rossana Scutari, A. Barlattani, Valentina Svicher, T. Mari, Vincenzo Malagnino, Maria De Cristofaro, Lavinia Fabeni, Nicola Coppola, Giuseppina Cappiello, Carlo Federico Perno, Massimo Marignani, Pascale Trimoulet, Alfonso Galeota Lanza, Romina Salpini, L. Carioti, Hervé Fleury, L. Piermatteo, Massimo Andreoni, Mario Angelico, N. Iapadre, Loredana Sarmati, E. Nebuloso, Maria Stanzione, Giuseppe Maria De Sanctis, Miriam Lichtner, Caterina Pasquazzi, Claudio Maria Mastroianni, Colagrossi, L, Salpini, R, Scutari, R, Carioti, L, Battisti, A, Piermatteo, L, Bertoli, A, Fabeni, L, Minichini, C, Trimoulet, P, Fleury, H, Nebuloso, E, De Cristofaro, M, Cappiello, G, Spano', Antonio, Malagnino, V, Mari, T, Barlattani, A, Iapadre, N, Lichtner, M, Mastroianni, C, Lenci, I, Pasquazzi, C, De Sanctis, Gm, Galeota Lanza, A, Stanzione, M, Stornaiuolo, G, Marignani, M, Sarmati, L, Andreoni, M, Angelico, M, Ceccherini-Silberstein, F, Perno, Cf, Coppola, N, and Svicher, V.
- Subjects
0301 basic medicine ,Models, Molecular ,Male ,HBsAg ,Cirrhosis ,HDV-RNA ,Protein Conformation ,viruses ,lcsh:QR1-502 ,lcsh:Microbiology ,Models ,Genotype ,Viral ,Phylogeny ,Coinfection ,virus diseases ,Middle Aged ,Hepatitis B ,Clinical Practice ,Infectious Diseases ,Hepatocellular carcinoma ,RNA, Viral ,HDAg ,Adult ,Antiviral Agents ,Female ,Genetic Variation ,Hepatitis B Surface Antigens ,Hepatitis B virus ,Hepatitis Delta Virus ,Humans ,Mutation ,Viral Proteins ,Evolution, Molecular ,Microbial Interactions ,Settore MED/17 - Malattie Infettive ,Evolution ,Biology ,Article ,03 medical and health sciences ,Genetic Evolution ,Virology ,medicine ,infectious diseases ,virology ,Molecular ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Structural plasticity ,RNA ,Hepatic decompensation - Abstract
Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients&rsquo, age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p <, 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection.
- Published
- 2018
33. Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy
- Author
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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
34. Prevalence of hepatitis D virus infection in Central Italy has remained stable across the last 2 decades with dominance of subgenotypes 1 and characterized by elevated viral replication.
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Salpini R, Piermatteo L, Torre G, D'Anna S, Khan S, Duca L, Bertoli A, La Frazia S, Malagnino V, Teti E, Iannetta M, Paba P, Ciotti M, Lenci I, Francioso S, Paquazzi C, Lichtner M, Mastroianni C, Santopaolo F, De Sanctis G, Pellicelli A, Galati G, Moretti A, Casinelli K, Caterini L, Iapadre N, Parruti G, Vecchiet I, Paoloni M, Marignani M, Ceccherini-Silberstein F, Baiocchi L, Grelli S, Sarmati L, and Svicher V
- Subjects
- Humans, Hepatitis B Surface Antigens genetics, Hepatitis B virus, Italy epidemiology, Phylogeny, Prevalence, RNA, Seroepidemiologic Studies, Virus Replication, Adult, Middle Aged, Hepatitis D diagnosis, Hepatitis D epidemiology, Hepatitis Delta Virus genetics
- Abstract
Objectives: Here we investigate Hepatitis D virus (HDV)-prevalence in Italy and its fluctuations over time and we provide an extensive characterization of HDV-infected patients., Methods: The rate of HDV seroprevalence and HDV chronicity was assessed in 1579 hepatitis B surface antigen (HBsAg)+ patients collected from 2005 to 2022 in Central Italy., Results: In total, 45.3% of HBsAg+ patients received HDV screening with an increasing temporal trend: 15.6% (2005-2010), 45.0% (2011-2014), 49.4% (2015-2018), 71.8% (2019-2022). By multivariable model, factors correlated with the lack of HDV screening were alanine-aminotransferase (ALT) less than two times of upper limit of normality (<2ULN) and previous time windows (P <0.002). Furthermore, 13.4% of HDV-screened patients resulted anti-HDV+ with a stable temporal trend. Among them, 80.8% had detectable HDV-ribonucleic acid (RNA) (median [IQR]:4.6 [3.6-5.6] log copies/ml) with altered ALT in 89.3% (median [IQR]:92 [62-177] U/L). Anti-HDV+ patients from Eastern/South-eastern Europe were younger than Italians (44 [37-54] vs 53 [47-62] years, P <0.0001), less frequently nucleos(t)ide analogs (NUC)-treated (58.5% vs 80%, P = 0.026) with higher HDV-RNA (4.8 [3.6-5.8] vs 3.9 [1.4-4.9] log copies/ml, P = 0.016) and HBsAg (9461 [4159-24,532] vs 4447 [737-13,336] IU/ml, P = 0.032). Phylogenetic analysis revealed the circulation of HDV subgenotype 1e (47.4%) and -1c (52.6%). Notably, subgenotype 1e correlated with higher ALT than 1c (168 [89-190] vs 58 [54-88] U/l, P = 0.015) despite comparable HDV-RNA., Conclusions: HDV-screening awareness is increasing over time even if some gaps persist to achieve HDV screening in all HBsAg+ patients. HDV prevalence in tertiary care centers tend to scarcely decline in native/non-native patients. Detection of subgenotypes, triggering variable inflammatory stimuli, supports the need to expand HDV molecular characterization., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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35. Unexpected rise in the circulation of complex HBV variants enriched of HBsAg vaccine-escape mutations in HBV genotype-D: potential impact on HBsAg detection/quantification and vaccination strategies.
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Piermatteo L, D'Anna S, Bertoli A, Bellocchi M, Carioti L, Fabeni L, Alkhatib M, Frazia S, Lichtner M, Mastroianni C, Sanctis G, Marignani M, Pasquazzi C, Iapadre N, Parruti G, Cappiello G, Vecchiet J, Malagnino V, Grelli S, Ceccherini-Silbertein F, Andreoni M, Sarmati L, Svicher V, and Salpini R
- Subjects
- Humans, Hepatitis B Vaccines, Mutation, Vaccination, Genotype, DNA, Viral genetics, Hepatitis B Surface Antigens genetics, Hepatitis B virus
- Abstract
Specific HBsAg mutations are known to hamper HBsAg recognition by neutralizing antibodies thus challenging HBV-vaccination efficacy. Nevertheless, information on their impact and spreading over time is limited. Here, we characterize the circulation of vaccine-escape mutations from 2005 to 2019 and their correlation with virological parameters in a large cohort of patients infected with HBV genotype-D ( N = 947), dominant in Europe. Overall, 17.7% of patients harbours ≥1 vaccine-escape mutation with the highest prevalence in subgenotype-D3. Notably, complex profiles (characterized by ≥2 vaccine-escape mutations) are revealed in 3.1% of patients with a prevalence rising from 0.4% in 2005-2009 to 3.0% in 2010-2014 and 5.1% in 2015-2019 ( P = 0.007) (OR[95%CI]:11.04[1.42-85.58], P = 0.02, by multivariable-analysis). The presence of complex profiles correlates with lower HBsAg-levels (median[IQR]:40[0-2905]IU/mL for complex profiles vs 2078[115-6037]IU/ml and 1881[410-7622]IU/mL for single or no vaccine-escape mutation [ P < 0.02]). Even more, the presence of complex profiles correlates with HBsAg-negativity despite HBV-DNA positivity (HBsAg-negativity in 34.8% with ≥2 vaccine-escape mutations vs 6.7% and 2.3% with a single or no vaccine-escape mutation, P < 0.007). These in-vivo findings are in keeping with our in-vitro results showing the ability of these mutations in hampering HBsAg secretion or HBsAg recognition by diagnostic antibodies. In conclusion, vaccine-escape mutations, single or in complex profiles, circulate in a not negligible fraction of HBV genotype-D infected patients with an increasing temporal trend, suggesting a progressive enrichment in the circulation of variants able to evade humoral responses. This should be considered for a proper clinical interpretation of HBsAg-results and for the development of novel vaccine formulations for prophylactic and therapeutic purposes.
- Published
- 2023
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36. Droplet digital PCR assay as an innovative and promising highly sensitive assay to unveil residual and cryptic HBV replication in peripheral compartment.
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Piermatteo L, Scutari R, Chirichiello R, Alkhatib M, Malagnino V, Bertoli A, Iapadre N, Ciotti M, Sarmati L, Andreoni M, Ceccherini-Silberstein F, Salpini R, and Svicher V
- Subjects
- DNA, Viral genetics, Humans, Polymerase Chain Reaction, Reproducibility of Results, Sensitivity and Specificity, Hepatitis B virus genetics, Hepatitis B, Chronic diagnosis, Hepatitis B, Chronic drug therapy, Hepatitis B, Chronic genetics
- Abstract
Droplet digital PCR is an innovative and promising approach for highly sensitive quantification of nucleic acids that is being increasingly used in the field of clinical virology, including the setting of hepatitis B virus (HBV). Here, we comprehensively report a robust and reproducible ddPCR assay for the highly sensitive quantification of serum HBV-DNA. The assay showed a limit of detection of 4 copies/ml (<1IU/ml) by Probit analysis, showed a good linearity (R
2 = 0.94) and a high intra- and inter-run reproducibility with differences between the values obtained in the same run or in two independent runs never exceeding 0.14logcopies/mL and 0.21logcopies/mL, respectively. By analysing serum samples from chronically HBV infected patients (mostly under antiviral treatment), ddPCR successfully quantified serum HBV-DNA in 89.8% of patients with detectable serum HBV-DNA < 20 IU/mL [equivalent to <112copies/ml] by classical Real-Time PCR assay, with a median (IQR) of 8(5-14)IU/mL [45(28-78)copies/ml], and in 66.7% of patients with undetectable serum HBV-DNA, with a median (IQR) of 5(4-9)IU/mL [28(20-50)copies/ml]. Similarly, by analysing serum samples from patients with a serological profile compatible with occult HBV infection (anti-HBc+/HBsAg-), ddPCR successfully quantified serum HBV-DNA in 40% of patients with a median (IQR) value of 1(1-2)IU/mL [5(5-11)copies/ml], in line with the extremely limited viral replication typically observed in occult HBV infection. Overall, the availability of assays for the highly sensitive quantification of serum HBV-DNA can provide an added value in optimizing the diagnosis of occult hepatitis B infection, improving the therapeutic management of chronically HBV infected patients, also in the light of innovative drugs (upcoming in clinical practise) aimed at achieving HBV functional cure., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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37. PaO 2 /FiO 2 ratio forecasts COVID-19 patients' outcome regardless of age: a cross-sectional, monocentric study.
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Sinatti G, Santini SJ, Tarantino G, Picchi G, Cosimini B, Ranfone F, Casano N, Zingaropoli MA, Iapadre N, Bianconi S, Armiento A, Carducci P, Ciardi MR, Mastroianni CM, Grimaldi A, and Balsano C
- Subjects
- Cross-Sectional Studies, Humans, Oxygen, SARS-CoV-2, COVID-19, Respiratory Insufficiency therapy
- Abstract
We studied the predictive value of the PaO
2 /FiO2 ratio for classifying COVID-19-positive patients who will develop severe clinical outcomes. One hundred fifty patients were recruited and categorized into two distinct populations ("A" and "B"), according to the indications given by the World Health Organization. Patients belonging the population "A" presented with mild disease not requiring oxygen support, whereas population "B" presented with a severe disease needing oxygen support. The AUC curve of PaO2 /FiO2 in the discovery cohort was 0.838 (95% CI 0.771-0.908). The optimal cut-off value for distinguishing population "A" from the "B" one, calculated by Youden's index, with sensitivity of 71.79% and specificity 85.25%, LR+4.866, LR-0.339, was < 274 mmHg. The AUC in the validation cohort of 170 patients overlapped the previous one, i.e., 0.826 (95% CI 0.760-0.891). PaO2 /FiO2 ratio < 274 mmHg was a good predictive index test to forecast the development of a severe respiratory failure in SARS-CoV-2-infected patients. Moreover, our work highlights that PaO2 /FiO2 ratio, compared to inflammatory scores (hs-CRP, NLR, PLR and LDH) indicated to be useful in clinical managements, results to be the most reliable parameter to identify patients who require closer respiratory monitoring and more aggressive supportive therapies. Clinical trial registration: Prognostic Score in COVID-19, prot. NCT04780373 https://clinicaltrials.gov/ct2/show/NCT04780373 (retrospectively registered)., (© 2021. The Author(s).)- Published
- 2022
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38. Key mutations in the C-terminus of the HBV surface glycoprotein correlate with lower HBsAg levels in vivo , hinder HBsAg secretion in vitro and reduce HBsAg structural stability in the setting of HBeAg-negative chronic HBV genotype-D infection.
- Author
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Salpini R, Battisti A, Piermatteo L, Carioti L, Anastasiou OE, Gill US, Di Carlo D, Colagrossi L, Duca L, Bertoli A, La Rosa KY, Fabeni L, Iuvara A, Malagnino V, Cerva C, Lichtner M, Mastroianni CM, De Sanctis GM, Paoloni M, Marignani M, Pasquazzi C, Iapadre N, Parruti G, Vecchiet J, Sarmati L, Andreoni M, Angelico M, Grelli S, T Kennedy P, Verheyen J, Aquaro S, Silberstein FC, Perno CF, and Svicher V
- Subjects
- Adult, Female, Genotype, Hepatitis B Surface Antigens genetics, Humans, Male, Middle Aged, Mutation, Hepatitis B Surface Antigens analysis, Hepatitis B virus genetics, Hepatitis B virus pathogenicity, Hepatitis B, Chronic diagnosis
- Abstract
Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico .HBsAg-levels were investigated in 323 drug-naïve HBeAg-negative patients chronically infected with HBV genotype-D( N = 228), -A( N = 65) and -E( N = 30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7-3.8]IU/ml; 3.8[3.5-4.2]IU/ml and 3.9[3.7-4.2]IU/ml, P < 0.001). Results confirmed by multivariable analysis correcting for patients'demographics, HBV-DNA, ALT and infection-status.In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAg<1000IU/ml( P -value from <0.001 to 0.04). These mutations lie in divergent pathways involving other HBsAg C-terminus mutations: V190A + F220L (Phi = 0.41, P = 0.003), S204N + L205P (Phi = 0.36, P = 0.005), Y206F + S210R (Phi = 0.47, P < 0.001) and S210N + F220L (Phi = 0.40, P = 0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them( P -value from 0.003 to 0.02). In-vitro , the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt( P -value from <0.001 to 0.02). Structurally, these mutational pairs reduced HBsAg C-terminus stability and determined a rearrangement of this domain.In conclusion, HBsAg-levels in genotype-D are significantly lower than in genotype-A and -E in HBeAg-negative patients. In genotype-D, specific mutational clusters in HBsAg C-terminus correlate with lower HBsAg-levels in-vivo , hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression.
- Published
- 2020
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39. Three Cases of COVID-19 Pneumonia in Female Patients in Italy Who Had Pulmonary Fibrosis on Follow-Up Lung Computed Tomography Imaging.
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Picchi G, Mari A, Ricciardi A, Carucci AC, Sinatti G, Cosimini B, Di Norcia M, Iapadre N, Balsano C, and Grimaldi A
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- Aged, Aged, 80 and over, COVID-19 complications, COVID-19 epidemiology, Female, Humans, Middle Aged, Pandemics, Pulmonary Fibrosis complications, Radiography, Thoracic, COVID-19 diagnosis, Lung diagnostic imaging, Pulmonary Fibrosis diagnosis, SARS-CoV-2, Tomography, X-Ray Computed methods
- Abstract
BACKGROUND Since December 2019, an outbreak caused by a novel coronavirus infection (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) occurred in Wuhan, China, and it rapidly spread all over the world. The clinical spectrum of coronavirus disease 2019 (COVID-19) is wide, with acute respiratory distress syndrome (ARDS) occurring in 15% of patients affected, requiring high oxygen support. Currently, there is no clearly effective antiviral therapy. Steroids and immunomodulators are under investigation for potential activity. Little is known about middle and long-term sequelae on respiratory function. According to some authors, COVID-19 could cause pulmonary fibrosis. We report 3 cases of pulmonary fibrosis detected on follow-up computed tomography (CT) imaging in 3 female patients who recovered from COVID-19 pneumonia in Italy (L'Aquila, Abruzzo). CASE REPORT All patients were female and had no significant previous respiratory disease or history of smoke exposure, and none had received high-flow oxygen support during treatment of the disease. In all cases, late onset of mild dyspnea, slow and incomplete respiratory recovery, and early evidence of fibrous signs on chest CT scan were characteristic of the clinical course. CONCLUSIONS This report focuses on a possible scenario of long-term lung damage in COVID-19 pneumonia survivors. Limitations are lack of long-term follow-up and functional data in the very early phase. It is advantageous that all COVID-19 pneumonia patients undergo serial chest CT and spirometry long-term follow-up for at least 1 year to assess residual damage. This is particularly relevant in those with slow respiratory recovery and long hospitalization.
- Published
- 2020
- Full Text
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40. A Hyper-Glycosylation of HBV Surface Antigen Correlates with HBsAg-Negativity at Immunosuppression-Driven HBV Reactivation in Vivo and Hinders HBsAg Recognition in Vitro.
- Author
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Salpini R, Piermatteo L, Battisti A, Colagrossi L, Aragri M, Yu La Rosa K, Bertoli A, Saccomandi P, Lichtner M, Marignani M, Maylin S, Delaugerre C, Morisco F, Coppola N, Marrone A, Iapadre N, Cerva C, Aquaro S, Angelico M, Sarmati L, Andreoni M, Verheyen J, Ceccherini-Silberstein F, Levrero M, Perno CF, Belloni L, and Svicher V
- Subjects
- Aged, Cell Line, Female, Glycosylation, Hepatitis B Surface Antigens genetics, Hepatitis B virus genetics, Hepatitis B virus immunology, Humans, Male, Middle Aged, Mutation, Virus Activation, Hepatitis B Antibodies immunology, Hepatitis B Surface Antigens chemistry, Hepatitis B Surface Antigens immunology, Immune Evasion genetics, Immunosuppression Therapy, Reinfection virology
- Abstract
Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3-8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >1 additional NLGSs ( p < 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.
- Published
- 2020
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41. HDV Can Constrain HBV Genetic Evolution in HBsAg: Implications for the Identification of Innovative Pharmacological Targets.
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Colagrossi L, Salpini R, Scutari R, Carioti L, Battisti A, Piermatteo L, Bertoli A, Fabeni L, Minichini C, Trimoulet P, Fleury H, Nebuloso E, De Cristofaro M, Cappiello G, Spanò A, Malagnino V, Mari T, Barlattani A, Iapadre N, Lichtner M, Mastroianni C, Lenci I, Pasquazzi C, De Sanctis GM, Galeota Lanza A, Stanzione M, Stornaiuolo G, Marignani M, Sarmati L, Andreoni M, Angelico M, Ceccherini-Silberstein F, Perno CF, Coppola N, and Svicher V
- Subjects
- Adult, Antiviral Agents pharmacology, Coinfection, Female, Genetic Variation, Genotype, Hepatitis B diagnosis, Hepatitis B Surface Antigens chemistry, Hepatitis B virus drug effects, Humans, Male, Middle Aged, Models, Molecular, Mutation, Phylogeny, Protein Conformation, RNA, Viral, Viral Proteins chemistry, Viral Proteins genetics, Viral Proteins metabolism, Evolution, Molecular, Hepatitis B virology, Hepatitis B Surface Antigens genetics, Hepatitis B virus genetics, Hepatitis Delta Virus physiology, Microbial Interactions
- Abstract
Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection ( p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg ( p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection.
- Published
- 2018
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42. Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy.
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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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43. Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro.
- Author
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Salpini R, Surdo M, Warner N, Cortese MF, Colledge D, Soppe S, Bellocchi MC, Armenia D, Carioti L, Continenza F, Di Carlo D, Saccomandi P, Mirabelli C, Pollicita M, Longo R, Romano S, Cappiello G, Spanò A, Trimoulet P, Fleury H, Vecchiet J, Iapadre N, Barlattani A, Bertoli A, Mari T, Pasquazzi C, Missale G, Sarrecchia C, Orecchini E, Michienzi A, Andreoni M, Francioso S, Angelico M, Verheyen J, Ceccherini-Silberstein F, Locarnini S, Perno CF, and Svicher V
- Subjects
- Adult, Aged, Carcinoma, Hepatocellular virology, Cell Cycle, Cell Proliferation, Female, Gene Frequency, Genotype, Hepatitis B Surface Antigens metabolism, Hepatitis B virus metabolism, Hepatitis B virus physiology, Hepatitis B, Chronic virology, Host-Pathogen Interactions, Humans, Liver Neoplasms virology, Male, Middle Aged, Multivariate Analysis, Risk Factors, Carcinoma, Hepatocellular pathology, Hepatitis B Surface Antigens genetics, Hepatitis B virus genetics, Hepatitis B, Chronic pathology, Liver Neoplasms pathology, Mutation
- Abstract
Background: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation., Methods: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry., Results: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P <0.001); P203Q+S210R (17.4% [4/23] in HCC vs 0% [0/110] in non-HCC, P=0.001). Both mutations reside in trans-membrane C-terminal domain critical for HBsAg-secretion. In in-vitro experiments, P203Q, S210R and P203Q+S210R significantly reduced the ratio [secreted/intracellular HBsAg] compared to wt at each time-point analysed (P <0.05), supporting an impaired HBsAg-secretion. Furthermore, P203Q and P203Q+S210R increased the percentage of cells in S-phase compared to wt, indicating cell-cycle progression (P203Q:26±13%; P203Q+S210R:29±14%; wt:18%±9, P <0.01. Additionally, S210R increased the percentage of cells in G2/M-phase (26±8% for wt versus 33±6% for S210R, P <0.001)., Conclusions: Specific mutations in HBsAg C-terminus significantly correlate with HBV-induced HCC. They hamper HBsAg-secretion and are associated with increased cellular proliferation, supporting their involvement in HCC-development. The identification of viral genetic markers associated with HCC is critical to identify patients at higher HCC-risk that may deserve intensive liver monitoring, and/or early anti-HBV therapy.
- Published
- 2017
- Full Text
- View/download PDF
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