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106. Declino delle Sostituzioni associate a resistenza (RAS) ad inibitori di NS3 ed NS5A al fallimento con DAA nel virus dell’epatite C in Italia negli anni 2015-2018

Author

Paglicci, L., Redi, D., Rossetti, B., Di Maio, V. C., Aragri, M., Paolucci, S., Masetti, C., Bruzzone, B., Minichini, C., FRANCESCA MONTAGNANI, Micheli, V., Landonio, S., Degasperi, E., Giacomo Zanelli, Maserati, R., Maida, I., Callegaro, A. P., Barbaliscia, S., Bertoli, A., Paternoster, C., Marenco, S., Morisco, F., Calvaruso, V., Taliani, G., Puoti, M., Cenderello, G., Santis, A., Lichtner, M., Coppola, N., Gulminetti, R., Cento, V., Rendina, M., Teti, E., Parruti, G., Ruggiero, T., Ghisetti, V., Pasquazzi, C., Nicolini, L. A., Vullo, V., Pellicelli, A., Prestileo, T., Cozzolongo, R., Sangiovanni, V., Biolato, M., Lenci, I., Licata, A., Ciaccio, A., Pace Palitti, V., Giorgini, A., Cariti, G., Ciancio, A., Aghemo, A., Borghi, V., Andreone, P., Brunetto, M., Pollicino, T., Santantonio, T., Cuomo, N., Caudai, C., Babudieri, S., Lampertico, P., Gaeta, G. B., Raimondo, G., Andreoni, M., Rizzardini, G., Angelico, M., Perno, C. F., Craxì, A., Maurizio Zazzi, and Ceccherini-Silberstein, F.

107. Treatment of chronic hepatitis C with pegylated interferon-α in a patient with recurrent autoimmune thrombotic thrombocytopenic purpura Treatment of chronic hepatitis C with pegylated interferon-α in a patient with recurrent autoimmune thrombotic thrombocytopenic purpura

Author

Lotta, L. A., Degasperi, E., Aghemo, A., Ferrari, B., Peyvandi, F., and Colombo, M.

Subjects
*LETTERS to the editor, *HEPATITIS C treatment, *INTERFERONS
Abstract

A letter to the editor is presented regarding the use of pegylated interferon-α in the treatment of chronic hepatitisCvirus (HCV) infection in patient with thrombotic thrombocytopenic purpura (TTP).

Published
2013
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108. Trends in chronic hepatitis B virus infection in Italy over a 10-year period: Clues from the nationwide PITER and MASTER cohorts toward elimination

Author

Giuseppina Brancaccio, Barbara Coco, Alessandra Nardi, Maria Giovanna Quaranta, Maria Elena Tosti, Luigina Ferrigno, Irene Cacciola, Vincenzo Messina, Luchino Chessa, Filomena Morisco, Michele Milella, Francesco Barbaro, Alessia Ciancio, Francesco Paolo Russo, Nicola Coppola, Pierluigi Blanc, Ernesto Claar, Gabriella Verucchi, Massimo Puoti, Anna Linda Zignego, Liliana Chemello, Salvatore Madonia, Stefano Fagiuoli, Alfredo Marzano, Carlo Ferrari, Pietro Lampertico, Vito Di Marco, Antonio Craxì, Teresa Antonia Santantonio, Giovanni Raimondo, Maurizia R. Brunetto, Giovanni Battista Gaeta, Loreta A. Kondili, Luisa Pasulo, Carmine Coppola, Federica Pisano, Mariarosaria Romano, Carmen Porcu, Irene Francesca Bottalico, Valentina Cossiga, Xhimi Tata, Caterina Sagnelli, Piera Pierotti, Elisabetta Degasperi, Valerio Rosato, Lorenzo Badia, Dontella Ieluzzi, Monica Monti, Maria Grazia Bavetta, Luisa Cavalletto, Pierluigi Toniutto, Ezio Fornasiere, Antonio Colecchia, Alberto Ferrarese, Gerardo Nardone, Alba Rocco, Mauro Viganò, Francesco Giuseppe Foschi, Fabio Conti, Giulia Morsica, Stefania Salpietro, Carlo Torti, Chiara Costa, Alessandro Federico, Marcello Dallio, Alessia Giorgini, Marco Anselmo, Pasqualina De Leo, Serena Zaltron, Anna Cambianica, Fabio Piscaglia, Ilaria Serio, Simona Schivazappa, Antonio Mastroianni, Luciana Chidichimo, Marco Massari, Cesare Mazzaro, Aldo Marrone, Francesca Maria D'Amore, Gianpiero D'Offizi, Anna Licata, Grazia Anna Niro, Teresa Pollicino, Alessio Aghemo, Brancaccio, G., Coco, B., Nardi, A., Quaranta, M. G., Tosti, M. E., Ferrigno, L., Cacciola, I., Messina, V., Chessa, L., Morisco, F., Milella, M., Barbaro, F., Ciancio, A., Russo, F. P., Coppola, N., Blanc, P., Claar, E., Verucchi, G., Puoti, M., Zignego, A. L., Chemello, L., Madonia, S., Fagiuoli, S., Marzano, A., Ferrari, C., Lampertico, P., Di Marco, V., Craxi, A., Santantonio, T. A., Raimondo, G., Brunetto, M. R., Gaeta, G. B., Kondili, L. A., Pasulo, L., Coppola, C., Pisano, F., Romano, M., Porcu, C., Bottalico, I. F., Cossiga, V., Tata, X., Sagnelli, C., Pierotti, P., Degasperi, E., Rosato, V., Badia, L., Ieluzzi, D., Monti, M., Bavetta, M. G., Cavalletto, L., Toniutto, P., Fornasiere, E., Colecchia, A., Ferrarese, A., Nardone, G., Rocco, A., Vigano, M., Foschi, F. G., Conti, F., Morsica, G., Salpietro, S., Torti, C., Costa, C., Federico, A., Dallio, M., Giorgini, A., Anselmo, M., De Leo, P., Zaltron, S., Cambianica, A., Piscaglia, F., Serio, I., Schivazappa, S., Mastroianni, A., Chidichimo, L., Massari, M., Mazzaro, C., Marrone, A., D'Amore, F. M., D'Offizi, G., Licata, A., Niro, G. A., Pollicino, T., Aghemo, A., Brancaccio, G, Coco, B, Nardi, A, Quaranta, M, Tosti, M, Ferrigno, L, Cacciola, I, Messina, V, Chessa, L, Morisco, F, Milella, M, Barbaro, F, Ciancio, A, Russo, F, Coppola, N, Blanc, P, Claar, E, Verucchi, G, Puoti, M, Zignego, A, Chemello, L, Madonia, S, Fagiuoli, S, Marzano, A, Ferrari, C, Lampertico, P, Di Marco, V, Craxì, A, Santantonio, T, Raimondo, G, Brunetto, M, Gaeta, G, Kondili, L, Pasulo, L, Coppola, C, Pisano, F, Romano, M, Porcu, C, Bottalico, I, Cossiga, V, Tata, X, Sagnelli, C, Pierotti, P, Degasperi, E, Rosato, V, Badia, L, Ieluzzi, D, Monti, M, Bavetta, M, Cavalletto, L, Toniutto, P, Fornasiere, E, Colecchia, A, Ferrarese, A, Nardone, G, Rocco, A, Viganò, M, Foschi, F, Conti, F, Morsica, G, Salpietro, S, Torti, C, Costa, C, Federico, A, Dallio, M, Giorgini, A, Anselmo, M, De Leo, P, Zaltron, S, Cambianica, A, Piscaglia, F, Serio, I, Schivazappa, S, Mastroianni, A, Chidichimo, L, Massari, M, Mazzaro, C, Marrone, A, D'Amore, F, D'Offizi, G, Licata, A, Niro, G, Pollicino, T, and Aghemo, A

Subjects
Microbiology (medical), Infectious Diseases, Epidemiology, Hepatitis Delta, Migrant, General Medicine, Chronic, Hepatitis B, Migrants, Hepatitis control
Abstract

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy. Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used. Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P

Published
2023

109. Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort

Author

Maria Giovanna Quaranta, Luigina Ferrigno, Xhimi Tata, Franca D'Angelo, Marco Massari, Carmine Coppola, Elisa Biliotti, Alessia Giorgini, Diletta Laccabue, Alessia Ciancio, Pier Luigi Blanc, Marzia Margotti, Donatella Ieluzzi, Maurizia Rossana Brunetto, Francesco Barbaro, Francesco Paolo Russo, Ilaria Beretta, Giulia Morsica, Gabriella Verucchi, Annalisa Saracino, Massimo Galli, Loeta A. Kondili, Cesare Mazzaro, Manuela Bertola, Ornella Schioppa, Antonio Benedetti, Laura Schiadà, Monica Cucco, Andrea Giacometti, Laura Brescini, Sefora Castelletti, Alessandro Fiorentini, Gioacchino Angarano, Michele Milella, Alfredo Di Leo, Maria Rendina, Fulvio Salvatore D'abramo, Chiara Lillo, Andrea Iannone, Mariano Piazzolla, Lorenzo Badia, Fabio Piscaglia, Francesca Benevento, Ilaria Serio, Francesco Castelli, Serena Zaltron, Angiola Spinetti, Silvia Odolini, Raffaele Bruno, Mario Mondelli, Luchino Chessa, Martina Loi, Carlo Torti, Chiara Costa, Maria Mazzitelli, Vincenzo Pisani, Vincenzo Scaglione, Enrico Maria Trecarichi, Anna Linda Zignego, Monica Monti, Francesco Madia, Letizia Attala, Piera Pierotti, Elena Salomoni, Elisa Mariabelli, Teresa Antonia Santantonio, Serena Rita Bruno, Ester Marina Cela, Matteo Bassetti, Giovanni Mazzarello, Anna Ida Alessandrini, Antonio Di Biagio, Laura Ambra Nicolini, Giovanni Raimondo, Roberto Filomia, Alessio Aghemo, Rossella Meli, Adriano Lazzarin, Stefania Salpietro, Anna Ludovica Fracanzani, Erika Fatta, Rosa Lombardi, Pietro Lampertico, Marta Borghi, Roberta D'ambrosio, Elisabetta Degasperi, Massimo Puoti, Chiara Baiguera, Federico D'amico, Maria Vinci, Maria Grazia Rumi, Massimo Zuin, Paola Zermiani, Pietro Andreone, Paolo Caraceni, Valeria Guarneri, Erica Villa, Veronica Bernabucci, Laura Bristot, Maria Luisa Paradiso, Guglielmo Migliorino, Alessandra Gambaro, Giuseppe Lapadula, Anna Spolti, Alessandro Soria, Pietro Invernizzi, Antonio Ciaccio, Martina LucÀ, Federica Malinverno, Laura Ratti, Daniela Caterina Amoruso, Federica Pisano, Ferdinando Scarano, Laura Staiano, Filomena Morisco, Valentina Cossiga, Ivan Gentile, Antonio Riccardo Buonomo, Maria Foggia, Emanuela Zappulo, Alessandro Federico, Marcello Dallio, Nicola Coppola, Caterina Sagnelli, Salvatore Martini, Caterina Monari, Gerardo Nardone, Costantino Sgamato, Liliana Chemello, Luisa Cavalletto, Daniela Sterrantino, Alberto Zanetto, Paola Zanaga, Giuseppina Brancaccio, Antonio Craxì, Salvatore Petta, Vincenza Calvaruso, Luciano Crapanzano, Salvatore Madonia, Marco Cannizzaro, Erica Maria Bruno, Anna Licata, Simona Amodeo, Adele Rosaria Capitano, Carlo Ferrari, Elisa Negri, Alessandra Orlandini, Marco Pesci, Roberto Gulminetti, Layla Pagnucco, Giustino Parruti, Paola Di Stefano, Barbara Coco, Romina Corsini, Elisa Garlassi, Massimo Andreoni, Elisabetta Teti, Carlotta Cerva, Lorenzo Baiocchi, Giuseppe Grassi, Antonio Gasbarrini, Maurizio Pompili, Martina De Siena, Gloria Taliani, Martina Spaziante, Marcello Persico, Mario Masarone, Andrea Aglitti, Gemma Calvanese, Marco Anselmo, Pasqualina De Leo, Monica Marturano, Giorgio Maria Saracco, Quaranta M.G., Ferrigno L., Tata X., D'Angelo F., Massari M., Coppola C., Biliotti E., Giorgini A., Laccabue D., Ciancio A., Blanc P.L., Margotti M., Ieluzzi D., Brunetto M.R., Barbaro F., Russo F.P., Beretta I., Morsica G., Verucchi G., Saracino A., Galli M., Kondili L.A., Mazzaro C., Bertola M., Benedetti A., Schiada L., Cucco M., Giacometti A., Brescini L., Castelletti S., Fiorentini A., Angarano G., Milella M., Leo A.D., Rendina M., Salvatore D'ABRAMO F., Lillo C., Iannone A., Piazzolla M., Badia L., Piscaglia F., Benevento F., Serio I., Castelli F., Zaltron S., Spinetti A., Odolini S., Bruno R., Mondelli M., Chessa L., Loi M., Torti C., Costa C., Mazzitelli M., Pisani V., Scaglione V., Trecarichi E.M., Zignego A.L., Monti M., Madia F., Attala L., Pierotti P., Salomoni E., Mariabelli E., Santantonio T.A., Bruno S.R., Cela E.M., Bassetti M., Mazzarello G., Alessandrini A.I., Biagio A.D., Nicolini L.A., Raimondo G., Filomia R., Aghemo A., Meli R., Lazzarin A., Salpietro S., Fracanzani A.L., Fatta E., Lombardi R., Lampertico P., Borghi M., D'ambrosio R., Degasperi E., Puoti M., Baiguera C., D'AMICO F., Vinci M., Rumi M.G., Zuin M., Zermiani P., Andreone P., Caraceni P., Guarneri V., Villa E., Bernabucci V., Bristot L., Paradiso M.L., Migliorino G., Gambaro A., Lapadula G., Spolti A., Soria A., Invernizzi P., Ciaccio A., LucA M., Malinverno F., Ratti L., Amoruso D.C., Pisano F., Scarano F., Staiano L., Morisco F., Cossiga V., Gentile I., Buonomo A.R., Foggia M., Zappulo E., Federico A., Dallio M., Coppola N., Sagnelli C., Martini S., Monari C., Nardone G., Sgamato C., Chemello L., Cavalletto L., Sterrantino D., Zanetto A., Zanaga P., Brancaccio G., Craxi A., Petta S., Calvaruso V., Crapanzano L., Madonia S., Cannizzaro M., Bruno E.M., Licata A., Amodeo S., Capitano A.R., Ferrari C., Negri E., Orlandini A., Pesci M., Gulminetti R., Pagnucco L., Parruti G., Stefano P.D., Coco B., Corsini R., Garlassi E., Andreoni M., Teti E., Cerva C., Baiocchi L., Grassi G., Gasbarrini A., Pompili M., Siena M.D., Taliani G., Spaziante M., Persico M., Masarone M., Aglitti A., Calvanese G., Anselmo M., Leo P.D., Marturano M., Saracco G.M., Quaranta, M, Ferrigno, L, Tata, X, D'Angelo, F, Massari, M, Coppola, C, Biliotti, E, Giorgini, A, Laccabue, D, Ciancio, A, Blanc, P, Margotti, M, Ieluzzi, D, Brunetto, M, Barbaro, F, Russo, F, Beretta, I, Morsica, G, Verucchi, G, Saracino, A, Galli, M, Kondili, L, Mazzaro, C, Bertola, M, Benedetti, A, Schiada, L, Cucco, M, Giacometti, A, Brescini, L, Castelletti, S, Fiorentini, A, Angarano, G, Milella, M, Leo, A, Rendina, M, Salvatore D'ABRAMO, F, Lillo, C, Iannone, A, Piazzolla, M, Badia, L, Piscaglia, F, Benevento, F, Serio, I, Castelli, F, Zaltron, S, Spinetti, A, Odolini, S, Bruno, R, Mondelli, M, Chessa, L, Loi, M, Torti, C, Costa, C, Mazzitelli, M, Pisani, V, Scaglione, V, Trecarichi, E, Zignego, A, Monti, M, Madia, F, Attala, L, Pierotti, P, Salomoni, E, Mariabelli, E, Santantonio, T, Bruno, S, Cela, E, Bassetti, M, Mazzarello, G, Alessandrini, A, Biagio, A, Nicolini, L, Raimondo, G, Filomia, R, Aghemo, A, Meli, R, Lazzarin, A, Salpietro, S, Fracanzani, A, Fatta, E, Lombardi, R, Lampertico, P, Borghi, M, D'Ambrosio, R, Degasperi, E, Puoti, M, Baiguera, C, D'Amico, F, Vinci, M, Rumi, M, Zuin, M, Zermiani, P, Andreone, P, Caraceni, P, Guarneri, V, Villa, E, Bernabucci, V, Bristot, L, Paradiso, M, Migliorino, G, Gambaro, A, Lapadula, G, Spolti, A, Soria, A, Invernizzi, P, Ciaccio, A, Luca, M, Malinverno, F, Ratti, L, Amoruso, D, Pisano, F, Scarano, F, Staiano, L, Morisco, F, Cossiga, V, Gentile, I, Buonomo, A, Foggia, M, Zappulo, E, Federico, A, Dallio, M, Coppola, N, Sagnelli, C, Martini, S, Monari, C, Nardone, G, Sgamato, C, Chemello, L, Cavalletto, L, Sterrantino, D, Zanetto, A, Zanaga, P, Brancaccio, G, Craxi, A, Petta, S, Calvaruso, V, Crapanzano, L, Madonia, S, Cannizzaro, M, Bruno, E, Licata, A, Amodeo, S, Capitano, A, Ferrari, C, Negri, E, Orlandini, A, Pesci, M, Gulminetti, R, Pagnucco, L, Parruti, G, Stefano, P, Coco, B, Corsini, R, Garlassi, E, Andreoni, M, Teti, E, Cerva, C, Baiocchi, L, Grassi, G, Gasbarrini, A, Pompili, M, Siena, M, Taliani, G, Spaziante, M, Persico, M, Masarone, M, Aglitti, A, Calvanese, G, Anselmo, M, Leo, P, Marturano, M, Saracco, G, Quaranta, M. G., Ferrigno, L., Tata, X., D'Angelo, F., Massari, M., Coppola, C., Biliotti, E., Giorgini, A., Laccabue, D., Ciancio, A., Blanc, P. L., Margotti, M., Ieluzzi, D., Brunetto, M. R., Barbaro, F., Russo, F. P., Beretta, I., Morsica, G., Verucchi, G., Saracino, A., Galli, M., Kondili, L. A., Mazzaro, C., Bertola, M., Benedetti, A., Schiada, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Fiorentini, A., Angarano, G., Milella, M., Leo, A. D., Rendina, M., Salvatore D'ABRAMO, F., Lillo, C., Iannone, A., Piazzolla, M., Badia, L., Piscaglia, F., Benevento, F., Serio, I., Castelli, F., Zaltron, S., Spinetti, A., Odolini, S., Bruno, R., Mondelli, M., Chessa, L., Loi, M., Torti, C., Costa, C., Mazzitelli, M., Pisani, V., Scaglione, V., Trecarichi, E. M., Zignego, A. L., Monti, M., Madia, F., Attala, L., Pierotti, P., Salomoni, E., Mariabelli, E., Santantonio, T. A., Bruno, S. R., Cela, E. M., Bassetti, M., Mazzarello, G., Alessandrini, A. I., Biagio, A. D., Nicolini, L. A., Raimondo, G., Filomia, R., Aghemo, A., Meli, R., Lazzarin, A., Salpietro, S., Fracanzani, A. L., Fatta, E., Lombardi, R., Lampertico, P., Borghi, M., D'Ambrosio, R., Degasperi, E., Puoti, M., Baiguera, C., D'Amico, F., Vinci, M., Rumi, M. G., Zuin, M., Zermiani, P., Andreone, P., Caraceni, P., Guarneri, V., Villa, E., Bernabucci, V., Bristot, L., Paradiso, M. L., Migliorino, G., Gambaro, A., Lapadula, G., Spolti, A., Soria, A., Invernizzi, P., Ciaccio, A., Luca, M., Malinverno, F., Ratti, L., Amoruso, D. C., Pisano, F., Scarano, F., Staiano, L., Morisco, F., Cossiga, V., Gentile, I., Buonomo, A. R., Foggia, M., Zappulo, E., Federico, A., Dallio, M., Coppola, N., Sagnelli, C., Martini, S., Monari, C., Nardone, G., Sgamato, C., Chemello, L., Cavalletto, L., Sterrantino, D., Zanetto, A., Zanaga, P., Brancaccio, G., Craxi, A., Petta, S., Calvaruso, V., Crapanzano, L., Madonia, S., Cannizzaro, M., Bruno, E. M., Licata, A., Amodeo, S., Capitano, A. R., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Gulminetti, R., Pagnucco, L., Parruti, G., Stefano, P. D., Coco, B., Corsini, R., Garlassi, E., Andreoni, M., Teti, E., Cerva, C., Baiocchi, L., Grassi, G., Gasbarrini, A., Pompili, M., Siena, M. D., Taliani, G., Spaziante, M., Persico, M., Masarone, M., Aglitti, A., Calvanese, G., Anselmo, M., Leo, P. D., Marturano, M., and Saracco, G. M.

Subjects
Male, HCV genotypes, Ethnic group, Linked-to-care patient, Comorbidity, Hepacivirus, Logistic regression, medicine.disease_cause, Comorbidities, Direct acting antivirals, HCV Cohort, Linked-to-care patients, Aged, Antiviral Agents, Coinfection, Female, Hepatitis C, Chronic, Humans, Italy, Middle Aged, Transients and Migrants, 0302 clinical medicine, Medicine, Chronic, Gastroenterology, virus diseases, Hepatitis C, Life evaluation, 030220 oncology & carcinogenesis, Cohort, 030211 gastroenterology & hepatology, Comorbiditie, Human, Hepatitis C virus, Settore MED/12 - GASTROENTEROLOGIA, 03 medical and health sciences, Disease severity, Antiviral Agent, Hepaciviru, Hepatology, business.industry, Settore MED/09 - MEDICINA INTERNA, medicine.disease, digestive system diseases, Direct acting antiviral, business, Demography
Abstract

Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.

Published
2021

110. Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort

Author

Sergio Lazzaroni, Paolo Grossi, Chiara Molteni, Maria Grazia Valsecchi, Pietro Lampertico, Luca Valenti, Alessio Aghemo, Alessia Giorgini, Antonella d'Arminio Monforte, Roberta D'Ambrosio, Federico Gatti, Omar Giglio, Daniele Bella, Davide Paolo Bernasconi, Giuseppe Lapadula, Sherrie Bhoori, Hamid Hasson, Monica Schiavini, Elisa Colella, Roberto Boldizzoni, A. Ciaccio, Simona Landonio, Andrea Capretti, Maria Cristina Vinci, Giuliano Rizzardini, Barbara Menzaghi, Elisabetta Degasperi, Caterina Uberti-Foppa, Chiara Baiguera, Andrea Lombardi, Gianpiero Aimo, Layla Pagnucco, Paolo Perini, Giuliana Cologni, Natalia Terreni, Paolo Bonfanti, Mauro Viganò, Paolo Viganò, Alessandro Soria, Roberto Rossotti, Massimo Puoti, Ombretta Spinelli, Canio Carriero, Silvia Polo, Guglielmo Marco Migliorino, Silvia Colombo, Riccardo Centenaro, Luisa Pasulo, Anna De Bona, E. Dionigi, Paolo Poggio, Franco Noventa, Isabella Carderi, Angelo Pan, Angiola Spinetti, Mariella Di Marco, Cecilia Liani, Stefano Fagiuoli, Marie Graciella Pigozzi, Marco Fava, Massimo Graffeo, Maria Grazia Rumi, Alberto Colombo, Soria, A., Fava, M., Bernasconi, D. P., Lapadula, G., Colella, E., Valsecchi, M. G., Migliorino, G. M., D'Ambrosio, R., Landonio, S., Schiavini, M., Spinetti, A., Carriero, C., Degasperi, E., Cologni, G., Gatti, F., Vigano, P., Hasson, H., Uberti-Foppa, C., Pasulo, L., Baiguera, C., Rossotti, R., Vinci, M., Puoti, M., Giorgini, A., Menzaghi, B., Lombardi, A., Pan, A., Aghemo, A., Grossi, P. A., Boldizzoni, R., Colombo, S., Vigano, M., Rumi, M. G., Del Poggio, P., Valenti, L., Giglio, O., De Bona, A., d'Arminio Monforte, A., Colombo, A., Spinelli, O., Pigozzi, M. G., Molteni, C., Bonfanti, P., Terreni, N., Perini, P., Capretti, A., Bella, D., Liani, C., Polo, S., Aimo, G., Pagnucco, L., Bhoori, S., Centenaro, R., Graffeo, M., Ciaccio, A., Dionigi, E., Lazzaroni, S., Carderi, I., Di Marco, M., Rizzardini, G., Noventa, F., Lampertico, P., Fagiuoli, S., Soria, A, Fava, M, Bernasconi, D, Lapadula, G, Colella, E, Valsecchi, M, Migliorino, G, D'Ambrosio, R, Landonio, S, Schiavini, M, Spinetti, A, Carriero, C, Degasperi, E, Cologni, G, Gatti, F, Vigano, P, Hasson, H, Uberti-Foppa, C, Pasulo, L, Baiguera, C, Rossotti, R, Vinci, M, Puoti, M, Giorgini, A, Menzaghi, B, Lombardi, A, Pan, A, Aghemo, A, Grossi, P, Boldizzoni, R, Colombo, S, Vigano, M, Rumi, M, Del Poggio, P, Valenti, L, Giglio, O, De Bona, A, d'Arminio Monforte, A, Colombo, A, Spinelli, O, Pigozzi, M, Molteni, C, Bonfanti, P, Terreni, N, Perini, P, Capretti, A, Bella, D, Liani, C, Polo, S, Aimo, G, Pagnucco, L, Bhoori, S, Centenaro, R, Graffeo, M, Ciaccio, A, Dionigi, E, Lazzaroni, S, Carderi, I, Di Marco, M, Rizzardini, G, Noventa, F, Lampertico, P, and Fagiuoli, S

Subjects
Male, medicine.medical_specialty, Daclatasvir, Genotype, Sofosbuvir, ribavirin, pibrentasvir, daclatasvir, genotype 3, glecaprevir, Hepatitis C, sofosbuvir, sustained virological response, velpatasvir, Hepacivirus, Antiviral Agents, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Ribavirin, medicine, Humans, Univariate analysis, Hepatology, business.industry, Glecaprevir, Hepatitis C, Chronic, medicine.disease, Pibrentasvir, Regimen, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

Background & Aims: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap. Methods: Sustained virological response 12weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression. Results: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF+DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF+DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P=.065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P=.007) and lower median pretreatment Log10HCV-RNA (5.87 vs 6.20, P=.001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF+DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12. Conclusions: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF+DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this <> genotype.

Published
2020

111. From current status to optimization of HCV treatment: Recommendations from an expert panel

Author

Salvatore Petta, Adriano M. Pellicelli, Gloria Taliani, Mauro Viganò, Pietro Andreone, Carlo Ferrari, Anna Linda Zignego, Giovanni Raimondo, Stefano Fagiuoli, Massimo Andreoni, Alessio Aghemo, Stefano Bonora, Elisabetta Degasperi, Savino Bruno, Giovanni Di Perri, Antonio Chirianni, Erica Villa, Massimo Puoti, Carlo Federico Perno, Antonio Craxì, Giovanni Battista Gaeta, Alessia Ciancio, Alfredo Alberti, Nicola Caporaso, Maurizia Rossana Brunetto, Francesca Ceccherini-Silberstein, Craxi, A, Perno, C, Vigano, M, Ceccherini-Silberstein, F, Petta, S, Aghemo, A, Alberti, A, Andreone, P, Andreoni, M, Bonora, S, Brunetto, M, Bruno, S, Caporaso, N, Chirianni, A, Ciancio, A, Degasperi, E, Di Perri, G, Fagiuoli, S, Ferrari, C, Gaeta, G, Pellicelli, A, Puoti, M, Raimondo, G, Taliani, G, Villa, E, Zignego, A, Craxì, Antonio, Perno, Carlo Federico, Viganò, Mauro, Ceccherini Silberstein, Francesca, Petta, Salvatore, Aghemo A4, Alberti A5, Caporaso, Nicola, Aghemo, Alessio, Alberti, Alfredo, Andreone, Pietro, Andreoni, Massimo, Bonora, Stefano, Brunetto, Maurizia Rossana, Bruno, Savino, Chirianni, Antonio, Ciancio, Alessia, Degasperi, Elisabetta, Di Perri, Giovanni, Fagiuoli, Stefano, Ferrari, Carlo, Gaeta, Giovanni Battista, Pellicelli, Adriano, Puoti, Massimo, Raimondo, Giovanni, Taliani, Gloria, Villa, Erica, Zignego, Anna Linda, Craxi, A., Perno, C., Viganã², M., Ceccherini-Silberstein, F., Petta, S., Aghemo, A., Alberti, A., Andreone, P., Andreoni, M., Bonora, S., Brunetto, M., Bruno, S., Caporaso, N., Chirianni, A., Ciancio, A., Degasperi, E., Di Perri, G., Fagiuoli, S., Ferrari, C., Gaeta, G., Pellicelli, A., Puoti, M., Raimondo, G., Taliani, G., Villa, E., and Zignego, A.

Subjects
Liver Cirrhosis, Direct-acting antiviral agent, medicine.medical_treatment, Resistance, Antiviral therapy, Cirrhosis, Direct-acting antiviral agents, HCV, Hepatitis C, Liver transplantation, Antiviral Agents, Carcinoma, Hepatocellular, Coinfection, Drug Therapy, Combination, HIV Infections, Hepacivirus, Hepatitis C, Chronic, Humans, Interferon-alpha, Italy, Liver Neoplasms, Practice Guidelines as Topic, Ribavirin, Societies, Medical, Viral Load, Hepatology, Gastroenterology, Liver disease, 0302 clinical medicine, HIV Infection, 030212 general & internal medicine, Chronic, Settore MED/07 - Microbiologia e Microbiologia Clinica, Liver Neoplasm, Combination, 030211 gastroenterology & hepatology, Viral load, Human, medicine.medical_specialty, Liver Cirrhosi, Alpha interferon, 03 medical and health sciences, Drug Therapy, Medical, Internal medicine, medicine, Intensive care medicine, Antiviral Agent, Cirrhosi, Hepaciviru, business.industry, Public health, Carcinoma, Hepatocellular, medicine.disease, Surgery, Position paper, Societies, business
Abstract

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper.

Published
2016

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

Author

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

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

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

Published
2021

113. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study

Author

Gianpaolo Lorini, Roberta D'Ambrosio, Monia Mendeni, Angelo Pan, Valentina Zuccaro, Canio Carriero, Massimo Colombo, Gianpiero Aimo, Natalia Terreni, Barbara Menzaghi, Massimo Memoli, Alessandro Soria, Aldo Autolitano, Elisabetta Degasperi, Serena Pelusi, M. Puoti, Luca Valenti, Cristiana Bianco, Ombretta Spinelli, Elisabetta Buscarini, Antonella d'Arminio Monforte, Sara Gritti, Paolo Del Poggio, Alessia Giorgini, Tiziana Quirino, T. Re, Marie Graciella Pigozzi, Maria Grazia Rumi, Maria Chiara Colombo, Giuliana Cologni, Daniele Prati, Angiola Spinetti, Stefano Fagiuoli, Mauro Viganò, Isabella Carderi, Luisa Pasulo, Pietro Lampertico, Alessio Aghemo, Paolo Bonfanti, C. Iegri, Valenti, L, Pelusi, S, Aghemo, A, Gritti, S, Pasulo, L, Bianco, C, Iegri, C, Cologni, G, Degasperi, E, D'Ambrosio, R, del Poggio, P, Soria, A, Puoti, M, Carderi, I, Pigozzi, M, Carriero, C, Spinetti, A, Zuccaro, V, Memoli, M, Giorgini, A, Vigano, M, Rumi, M, Re, T, Spinelli, O, Colombo, M, Quirino, T, Menzaghi, B, Lorini, G, Pan, A, D'Arminio Monforte, A, Buscarini, E, Autolitano, A, Bonfanti, P, Terreni, N, Aimo, G, Mendeni, M, Prati, D, Lampertico, P, and Fagiuoli, S

Subjects
Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Sustained Virologic Response, Chronic liver disease, Gastroenterology, Antiviral Agents, Cohort Studies, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Medicine, Humans, 2. Zero hunger, Hepatology, business.industry, Hazard ratio, Liver Neoplasms, Odds ratio, Hepatitis C, Chronic, medicine.disease, 3. Good health, Metformin, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, HCV, 030211 gastroenterology & hepatology, business, Body mass index, medicine.drug
Abstract

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n=748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P&nbsp

Published
2021

114. Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach

Author

Cristina Rigamonti, Rosanna Venere, Carla De Benedittis, Guido Carpino, Pietro Invernizzi, Italian Pbc Registry, Elisabetta Degasperi, Giacomo Mulinacci, Marco Carbone, Sarah Elisabeth O’Donnell, Diletta Overi, Sara Labanca, Vito Di Marco, A. Ciaccio, Vincenzo Cardinale, Mauro Viganò, Andrea Palermo, Annarosa Floreani, Daphne D’Amato, Nora Cazzagon, Vincenzo Ronca, Donatella Barisani, Laura Cristoferi, Federica Malinverno, Marco Marzioni, Domenico Alvaro, Clara Mancuso, Vincenza Calvaruso, Anna Fichera, Martina Lucà, Federica Cerini, Alessandra Nardi, Eugenio Gaudio, Antonino Picciotto, Nicola Zucchini, Monica Leutner, Alessio Gerussi, Laura Cristoferi, Vincenza Calvaruso, Diletta Overi 5 , Mauro Viganò 6 , Cristina Rigamonti 7 , Elisabetta Degasperi 8 , Vincenzo Cardinale 9 , Sara Labanca 10 , Nicola Zucchini 11 , Anna Fichera, Vito Di Marco, Monica Leutner 12 , Rosanna Venere 13 , Antonino Picciotto 10 , Martina Lucà 1 2 , Giacomo Mulinacci 1 2 , Andrea Palermo 1 2 , Alessio Gerussi 1 2 , Daphne D'Amato 1 2 , Sarah Elisabeth O'Donnell 1 2 , Federica Cerini 6 , Carla De Benedittis 7 , Federica Malinverno 1 2 , Vincenzo Ronca 1 2 , Clara Mancuso 1 2 , Nora Cazzagon 14 , Antonio Ciaccio 1 2 , Donatella Barisani 1 , Marco Marzioni 15 , Annarosa Floreani 16 17 , Domenico Alvaro 9 , Eugenio Gaudio 5 , Pietro Invernizzi 1 2 , Guido Carpino # 18 , Alessandra Nardi # 19 , Marco Carbone, Cristoferi, L, Calvaruso, V, Overi, D, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Fichera, A, Di Marco, V, Leutner, M, Venere, R, Picciotto, A, Lucà, M, Mulinacci, G, Palermo, A, Gerussi, A, D'Amato, D, O'Donnell, S, Cerini, F, De Benedittis, C, Malinverno, F, Ronca, V, Mancuso, C, Cazzagon, N, Ciaccio, A, Barisani, D, Marzioni, M, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, Nardi, A, and Carbone, M

Subjects
area under curve, 0301 basic medicine, medicine.medical_specialty, liver cirrhosis, Diagnostic accuracy, risk stratification, PBC, Gastroenterology, primary biliary cholangiti, elasticity imaging techniques, female, humans, biliary, male, middle aged, ROC curve, sensitivity and specificity, Therapy naive, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, medicine, Hepatology, Receiver operating characteristic, medicine.diagnostic_test, Liver Cirrhosis, Biliary, business.industry, Original Articles, medicine.disease, transient elastography, Autoimmune, Cholestatic and Biliary Disease, 030104 developmental biology, Liver biopsy, Cohort, Original Article, 030211 gastroenterology & hepatology, diagnostic accuracy, Cut-off, Transient elastography, business, fibrosi
Abstract

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Published
2021

115. Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: An individual patient data meta-analysis

Author

Javier Crespo, Amit G. Singal, Pei-Chien Tsai, Giuseppe Cabibbo, Zoe Mariño, Alberto Zanetto, Elisabetta Degasperi, Xavier Forns, Pierre Nahon, Hiroko Nagata, Calogero Cammà, Francesco Paolo Russo, Mohamed El Kassas, Stefano Brillanti, Mina Nakagawa, Luisa Cavalletto, Tatsuya Minami, Giacomo Emanuele Maria Rizzo, Rob Bielen, Maria Reig, Liliana Chemello, Caitlin C. Murphy, Ming-Lung Yu, Mohamed Kohla, Sarah Shalaby, Gaetano Serviddio, Jose Luis Calleja, Angelo Sangiovanni, Ashraf Omar, Rosanna Villani, Franco Trevisani, Yasuhiro Asahina, Victor Sapena, Jean-François Dufour, Claudio Zavaglia, Fabio Conti, Jordi Bruix, Kévin Jean, Ciro Celsa, José Ríos, Hend Ibrahim Shousha, Nicolás Merchante, Stanislas Pol, C. Masetti, Marco Enea, Ferran Torres, Ryosuke Tateishi, Hidenori Toyoda, Universitat de Barcelona (UB), Università degli studi di Palermo - University of Palermo, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), The University of Tokyo (UTokyo), Università degli Studi di Milano [Milano] (UNIMI), University of Bologna, University of Milan, National Kaohsiung University of Science and Technology [Taiwan], Laboratoire Modélisation, épidémiologie et surveillance des risques sanitaires (MESuRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Helwan University [Caire], Cairo University - Faculty of Medicine, Tokyo Medical and Dental University [Japan] (TMDU), University of Texas Southwestern Medical Center, National Liver Institute [Menoufia, Egypt], Menoufia University [Egypte], PoliclinicoTor Vergata - Fondatione PTV, Bern University Hospital [Berne] (Inselspital), Universita degli Studi di Padova, ANRS France Recherche Nord & sud Sida-hiv hépatites, Universidad de Cantabria [Santander], Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Università degli Studi di Foggia - University of Foggia, Hasselt University (UHasselt), Alma Mater Studiorum University of Bologna (UNIBO), The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors., Jean, Kevin/0000-0001-6462-7185, Tateishi, Ryosuke/0000-0003-3021-2517, Rios, Jose/0000-0002-0716-8784, Reig, Maria/0000-0002-5711-9534, Bruix, Jordi/0000-0002-9826-0753, Celsa, Ciro/0000-0002-5662-2162, Youssef, Naglaa/0000-0002-0368-1759, Torres, Ferran/0000-0002-7355-7913, Sapena, Victor/0000-0003-4379-6486, RUSSO, FRANCESCO PAOLO/0000-0003-4127-8941, Minami, Tatsuya/0000-0002-2918-892X, Rizzo, Giacomo Emanuele, Maria/0000-0001-9335-6740, Merchante, Nicolas/0000-0003-1120-8942, Crespo, Javier/0000-0001-8248-0172, SHALABY, SARAH/0000-0002-8700-6282, El Kassas, Mohamed/0000-0002-3396-6894, Sapena, Victor, Enea, Marco, Torres , Ferran, Celsa, Ciro, Rios, Jose, Rizzo, Giacomo Emanuele Maria, Nahon, Pierre, Marino, Zoe, Tateishi, Ryosuke, Minami, Tatsuya, Sangiovanni, Angelo, Forns, Xavier, Toyoda, Hidenori, Brillanti, Stefano, Conti, Fabio, Degasperi, Elisabetta, Yu, Ming-Lung, Tsai, Pei-Chien, Jean, Kevin, El Kassas, Mohamed, Shousha, Hend Ibrahim, Omar, Ashraf, Zavaglia, Claudio, Nagata, Hiroko, Nakagawa, Mina, Asahina, Yasuhiro, Singal, Amit G., Murphy, Caitlin, Kohla, Mohamed, Masetti, Chiara, Dufour, Jean-Francois, Merchante, Nicolas, Cavalletto, Luisa, Chemello, Liliana L. C., Pol, Stanislas, Crespo, Javier, Calleja, Jose Luis, Villani, Rosanna, Serviddio, Gaetano, Zanetto, Alberto, Shalaby, Sarah, Russo, Francesco Paolo, BIELEN, Rob, Trevisani, Franco, Camma, Calogero, Bruix, Jordi, Cabibbo, Giuseppe, Reig, Maria, Sapena V., Enea M., Torres F., Celsa C., Rios J., Rizzo G.E.M., Nahon P., Marino Z., Tateishi R., Minami T., Sangiovanni A., Forns X., Toyoda H., Brillanti S., Conti F., Degasperi E., Yu M.-L., Tsai P.-C., Jean K., El Kassas M., Shousha H.I., Omar A., Zavaglia C., Nagata H., Nakagawa M., Asahina Y., Singal A.G., Murphy C., Kohla M., Masetti C., Dufour J.-F., Merchante N., Cavalletto L., Chemello L.L.C., Pol S., Crespo J., Calleja J.L., Villani R., Serviddio G., Zanetto A., Shalaby S., Russo F.P., Bielen R., Trevisani F., Camma C., Bruix J., Cabibbo G., Reig M., Università degli Studi di Milano = University of Milan (UNIMI), University of Bologna/Università di Bologna, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Università degli Studi di Padova = University of Padua (Unipd), Università degli Studi di Foggia = University of Foggia (Unifg), and Cammà Calogero

Subjects
medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Antiviral Agents, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, antiviral therapy, medicine, Humans, Propensity Score, hepatocellular carcinoma, meta-analysis, business.industry, Liver Neoplasms, Antiviral therapy, Patient data, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Meta-analysis, Hepatocellular carcinoma, Relative risk, Cohort, 030211 gastroenterology & hepatology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neoplasm Recurrence, Local, business, Direct acting
Abstract

ObjectiveThe benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.DesignWe pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.ResultsRecurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; pConclusionEffects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.

Published
2021

116. Accuracy of liver stiffness measurement in assessing liver fibrosis in naive patients with primary biliary cholangitis

Author

LAURA CRISTOFERI, Nardi, Alessandra, Vigano, Mauro, Rigamonti, Cristina, Degasperi, Elisabetta, Cardinale, Vincenzo, Labanca, Sara, Zucchini, Nicola, Leutner, Monica, Venere, Rosanna, Picciotto, Antonino, Cazzagon, Nora, Luca, Martina, Overi, Diletta, Gerussi, Alessio, D Amato, Daphne, O Donnell, Sarah Elisabeth, Cerini, Federica, Benedittis, Carla, Cadamuro, Massimiliano, Malinverno, Federica, Floreani, Annarosa, Alvaro, Domenico, Gaudio, Eugenio, Invernizzi, Pietro, Carpino, Guido, Carbone, Marco, Cristoferi, L, Nardi, A, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Leutner, M, Venere, R, Picciotto, A, Cazzagon, N, Lucà, M, Overi, D, Gerussi, A, D’Amato, D, O’Donnell, S, Cerini, F, De Benedittis, C, Cadamuro, M, Malinverno, F, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, and Carbone, M

Subjects
Hepatology, Primary biliary cholangiti, Fibrosi, Autoimmune liver disease, Vibration-Controlled Transient Elastography, Risk stratification
Abstract

Background and Aims: Non-invasive evaluation of liver fibrosis in primary biliary cholangitis (PBC) with Liver Stiffness Measurements (LSM) by Transient Elastography (TE) is routinely undertaken at diagnosis for disease staging and risk stratification. However, evidence on correlation between LSM and liver fibrosis is based on cross-sectional studies in PBC-treated patients. Moreover, the impact of potential confounders, e.g. cholestasis and steatosis, is unclear. Aim of our study was to investigate the accuracy of LSM to predict moderate to severe fibrosis in newly diagnosed PBC patients naïve to therapy. Method: We collected data from 182 adult patients who underwent liver biopsy (LB) for PBC at diagnosis in five Italian liver centers from Jan 2006 through Aug 2019. TE examinations within 3 months from LB were included. LB were scored centrally by two expert pathologists, blinded to clinical data and disease stage, according to Ludwig staging system. In all patients Fibrosis-4 (FIB-4) and aspartate aminotransferase [AST]/platelet ratio (APRI) score have been calculated. Diagnostic accuracy of LSM, FIB-4 and APRI score was estimated using the area under the receiver operating characteristic curves (AUROCs) for fibrosis. The effects of liver biochemistry and histological parameters were appraised using multivariable logistic model. Results: 123 PBC patients had adequate LB (≥9 portal tracts) and valid LSM values. According to histological assessment, Ludwig stage distribution was as follows: stage I = 38 (30.9%), stage II = 46(37.4%), stage III = 27 (21.9%), stage IV = 12 (9.8%). TE identified patients with Ludwig stage III/IV with an AUROC of 0.83 (95% confidence interval [CI] (0.74, 0.90)) (Fig.1). The optimal threshold was identified at 6.75kPa (CI (6.55, 7.50)), with 85% of sensitivity, 75% of specificity, 78% of accuracy and 6 false negative. TE was superior to APRI and FIB-4 having AUROC of 0.638 (CI = (0.535, 0.740)) and 0.641 (CI = (0.516, 0.766)), respectively. At multivariable analysis only LSM was associated with liver fibrosis and no significant effect of biochemical measures and steatosis was found. Conclusion: LSM is accurate to predict moderate to severe liver fibrosis at diagnosis in PBC naïve patients using a threshold of 6.75kPa with an AUROC of 0.83. TE outperformed FIB-4 and APRI score and is not confounded by liver biochemistry and steatosis. These data can inform strategies for patient surveillance and trial design in PBC.

Published
2020

117. Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure

Author

Elisabetta, Degasperi, Angiola, Spinetti, Andrea, Lombardi, Simona, Landonio, Maria Cristina, Rossi, Luisa, Pasulo, Pietro, Pozzoni, Alessia, Giorgini, Paolo, Fabris, Antonietta, Romano, Lorenzo, Lomonaco, Massimo, Puoti, Maria, Vinci, Federico, Gatti, Giada, Carolo, Alessia, Zoncada, Paolo, Bonfanti, Russo, FRANCESCO PAOLO, Alessio, Aghemo, Alessandro, Soria, Riccardo, Centenaro, Franco, Maggiolo, Pierangelo, Rovere, Francesca, Pasin, Veronica, Paon, Giovanni, Faggiano, Alessandro, Vario, Glenda, Grossi, Roberta, Soffredini, Canio, Carriero, Stefania, Paolucci, Franco, Noventa, Alfredo, Alberti, Pietro, Lampertico, Stefano, Fagiuoli, NAVIGATORE-Lombardia and Veneto Study Groups, Degasperi, E, Spinetti, A, Lombardi, A, Landonio, S, Rossi, M, Pasulo, L, Pozzoni, P, Giorgini, A, Fabris, P, Romano, A, Lomonaco, L, Puoti, M, Vinci, M, Gatti, F, Carolo, G, Zoncada, A, Bonfanti, P, Russo, F, Aghemo, A, Soria, A, Centenaro, R, Maggiolo, F, Rovere, P, Pasin, F, Paon, V, Faggiano, G, Vario, A, Grossi, G, Soffredini, R, Carriero, C, Paolucci, S, Noventa, F, Alberti, A, Lampertico, P, and Fagiuoli, S

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Sofosbuvir, Sustained Virologic Response, Resistance, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, Direct-acting antiviral, Direct-acting antivirals, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Sulfonamides, Liver Neoplasms, Hepatitis C, Middle Aged, Drug Combinations, Treatment Outcome, Italy, Hepatocellular carcinoma, HCV, RAS, Retreatment, RNA, Viral, 030211 gastroenterology & hepatology, Female, medicine.drug, medicine.medical_specialty, Carcinoma, Hepatocellular, Macrocyclic Compounds, Anemia, Voxilaprevir, Hepatitis C virus, Antiviral Agents, Heterocyclic Compounds, 4 or More Rings, 03 medical and health sciences, Internal medicine, Drug Resistance, Viral, medicine, Humans, Intention-to-treat analysis, Hepatology, business.industry, Ribavirin, Hepatitis C, Chronic, medicine.disease, 030104 developmental biology, chemistry, Carbamates, business
Abstract

Background & Aims Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. Methods All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. Results A total of 179 patients were included: median age 57 (18–88) years, 74% males, median HCV-RNA 1,081,817 (482–25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). Conclusions SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. Lay summary This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Published
2019

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

Author

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

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

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

Published
2019

119. Treatment of Hepatitis C virus infection in Italy: A consensus report from an expert panel

Author

Carlo Federico Perno, Elisabetta Degasperi, Stefano Fagiuoli, Vincenza Calvaruso, Salvatore Petta, Raffaele Bruno, Alessia Ciancio, Giovanni Battista Gaeta, Giovanni Raimondo, Carlo Ferrari, Anna Linda Zignego, Massimo Andreoni, Massimo Puoti, Stefano Bonora, Giovanni Di Perri, Gloria Taliani, Pietro Andreone, Alfredo Alberti, Maurizia Rossana Brunetto, Vito Di Marco, Erica Villa, Sara Piovesan, Alessio Aghemo, Mauro Viganò, Francesca Ceccherini-Silberstein, Francesco Paolo Russo, Savino Bruno, Ugo Trama, Adriano M. Pellicelli, Antonio Craxì, Gianpiero D'Offizi, Piero Colombatto, Nicola Caporaso, Valeria Cento, Viganò, Mauro, Perno, Carlo Federico, Craxì, Antonio, Aghemo, Alessio, Alberti, Alfredo, Andreone, Pietro, Andreoni, Massimo, Bonora, Stefano, Brunetto, Maurizia Rossana, Bruno, Raffaele, Bruno, Savino, Calvaruso, Vincenza, Caporaso, Nicola, Ceccherini-Silberstein, Francesca, Cento, Valeria, Ciancio, Alessia, Colombatto, Piero, Degasperi, Elisabetta, Di Marco, Vito, Di Perri, Giovanni, D'offizi, Gianpiero, Fagiuoli, Stefano, Ferrari, Carlo, Gaeta, Giovanni Battista, Pellicelli, Adriano, Petta, Salvatore, Piovesan, Sara, Puoti, Massimo, Raimondo, Giovanni, Russo, Francesco Paolo, Taliani, Gloria, Trama, Ugo, Villa, Erica, Zignego, Anna Linda, Savino, Bruno, Vito, Marco, D'Offizi, Gianpiero, Russo, FRANCESCO PAOLO, Gaeta, G. B., Viganã², M., Perno, C., Craxi, A., Calvaruso, V, Di Marco, V, Petta, S, Vigano, M, Perno, C, Craxi, A, Aghemo, A, Alberti, A, Andreone, P, Andreoni, M, Bonora, S, Brunetto, M, Bruno, R, Bruno, S, Caporaso, N, Ceccherini-Silberstein, F, Cento, V, Ciancio, A, Colombatto, P, Degasperi, E, Di Perri, G, D'Offizi, G, Fagiuoli, S, Ferrari, C, Gaeta, G, Pellicelli, A, Piovesan, S, Puoti, M, Raimondo, G, Russo, F, Taliani, G, Trama, U, Villa, E, and Zignego, A

Subjects
Liver Cirrhosis, Direct-acting antiviral agent, Fibrosi, Hepacivirus, Chronic liver disease, medicine.disease_cause, Clinical knowledge, Virological response, 0302 clinical medicine, 80 and over, 030212 general & internal medicine, Chronic, Antiviral treatment, Cirrhosis, Direct-acting antiviral agents, Hepatitis C, RAV, Treatment failure, Aged, 80 and over, Gastroenterology, Hepatology, Middle Aged, Viral Load, Settore MED/07 - Microbiologia e Microbiologia Clinica, Italy, Liver, Combination, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Human, Adult, medicine.medical_specialty, Consensus, Hepatitis C virus, Liver Cirrhosi, Consensu, Antiviral Agents, Unmet needs, 03 medical and health sciences, Young Adult, Drug Therapy, Internal medicine, medicine, Humans, Intensive care medicine, Aged, Antiviral Agent, Hepaciviru, Cirrhosi, business.industry, Hepatitis C, Chronic, medicine.disease, Virology, Fibrosis, Position paper, business
Abstract

Hepatitis C virus (HCV) infection remains one of the main causes of chronic liver disease worldwide. The advent of direct-acting antivirals (DAAs) has significantly improved the course of patients with chronic HCV infection (CHC), due to the ability of these drugs to achieve high rates of sustained virological response (SVR). These exceedingly high rates of SVR and the excellent safety data have been confirmed in real life practice. Evolving guidelines have been issued by national and international scientific societies in accordance with the progression of clinical knowledge and the availability of new DAAs. These recommendations, however, may not be applied universally because of delays in drugs reimbursability in different countries and because some National Health Systems identify only patients with advanced disease as a treatment priority. Italy in this regard is a prototype about DAAs treatment of CHC patients. With the aim to assess the Italian treatment experience with DAAs and to respond to unmet needs in treatment optimization of antiviral therapy in specific settings of CHC patients, a group of Italian experts met in Stresa in February 2017. The summary of the considerations arising from this two-day meeting and some statements regarding a few open issues are reported in this position paper.

Published
2017

120. Real life data on elbasvir/grazoprevir efficacy, safety and drug-drug interaction profile in patients with chronic hepatitis C viral infection: a prospective analysis in the PITER cohort

Author

Gianluca Brancaccio, Pierluigi Blanc, Giulia Morsica, Monica Monti, Elisabetta Degasperi, Anna Licata, M. Cannizzaro, Luisa Cavalletto, D.C. Amoruso, Roberto Filomia, F. Tamburini, Luigina Ferrigno, Guglielmo Migliorino, Alberto Zanetto, P. Di Stefano, Stefano Rosato, M.G. Quaranta, Loreta A. Kondili, E. Castelli, Quaranta, M.G., Rosato, S., Ferrigno, L., Amoruso, D.C., Monti, M., Di Stefano, P., Filomia, R., Tamburini, F., Migliorino, G., Zanetto, A., Degasperi, E., Cavalletto, L., Brancaccio, G., Blanc, P., Cannizzaro, M., Castelli, E., Morsica, G., Licata, A., and Kondili, L.A.

Subjects
medicine.medical_specialty, Hepatology, business.industry, Drug-drug interaction, Gastroenterology, elbasvir grazoprevir efficacy, drug-drug interaction, Hepatitic HCV, Piter cohort, Real life data, Viral infection, Prospective analysis, Chronic hepatitis, Internal medicine, Cohort, medicine, Elbasvir, Grazoprevir, In patient, business
Abstract

Introduction: In a previous study, based on PITER cohort data, it was reported that of patients, undergoing direct acting antiviral (DAA) therapy, 30%-44%, are at risk of potential drug-drug interactions (DDI). Aim: We aimed to evaluate the prospective profile of elbasvir/grazoprevir (EBR/GZR) efficacy and safety combined with real life comedication profile. Method: Data from 312 patients (mean age 63 ± 10 years; 44% male, 90% of genotype 1.85% fibrosis stage ≤ F3, 15% with child A cirrhosis), enrolled in PITER by 15 clinical centers and treated with EBR/GZR, with at least three months of follow up after the end of treatment, were evaluated. Comedication profiles (no changes, drugs interrupted, or modified as posology, or those added) were evaluated and the potential DDI were assigned according to HepC Drug Interactions. Results: The SVR12 was reached in 299 (96%) patients. Gender, age, fibrosis stage, previous interferon therapy, diabetes and fatty liver were not related to failure by logistic regression analysis. Of 312 treated patients, 187 (60%) had at least one comorbidity (median: 2 range: 1–6 comorbidities). Follow up data on comedications used were available in 182 patients (21% have taken 1 drug, 24% two drugs, and the remaining 55% from 3–10 drugs). Of 328 comedications used during the DAA therapy, 3% were modified in posology, 2% were interrupted and 3% were new drugs added. None of changes was due to potential DDI. None but statins (in 2% of patients) were reported to require monitoring by HepC Drug Interactions. EBR/GZR was well tolerated. An increase in ALT levels (lower than 3 times of normal levels), were observed in 12 (4%) patients during the DAA therapy. Conclusion: EBR/GZR demonstrated high cure rates and a good safety profile. No drug-drug interactions were recorded in this cohort of treated patients with different comorbidities and comedications used.

Published
2019

121. Sodium taurocholate cotransporting polypeptide (NTCP) polymorphisms may influence HDV RNA load and early response to bulevirtide.

Author

Toniutto P, Falleti E, Cmet S, Cussigh A, Degasperi E, Anolli MP, Sambarino D, Facchetti F, Borghi M, Perbellini R, Monico S, and Lampertico P

Subjects
Humans, Female, Male, Retrospective Studies, Middle Aged, Cross-Sectional Studies, Adult, Antiviral Agents therapeutic use, Hepatitis D, Chronic drug therapy, Hepatitis D, Chronic genetics, Longitudinal Studies, Polymorphism, Genetic, Genotype, Treatment Outcome, Polymorphism, Single Nucleotide, Symporters genetics, Organic Anion Transporters, Sodium-Dependent genetics, Hepatitis Delta Virus genetics, Hepatitis Delta Virus drug effects, Viral Load drug effects, RNA, Viral genetics, RNA, Viral blood
Abstract

Background & Aims: Genetic polymorphisms in the sodium taurocholate cotransporting peptide (NTCP encoded by SLC10A1) have been described, but their role in untreated and treated patients with chronic hepatitis delta (CHD) remains unknown. Virological response (VR) to the NTCP inhibitor bulevirtide (BLV) was achieved at week 48 by >70% of patients with CHD, but nearly 15% experienced virological non-response (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in patients with CHD., Methods: BLV-untreated and -treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing., Results: Of the six NTCP polymorphisms studied in 209 untreated patients with CHD, carriers of the rs17556915 TT/CC (n = 142) compared to CT (n = 67) genotype presented with higher median HDV RNA levels (5.39 vs. 4.75 log 10  IU/ml, p = 0.004). Of 209 patients receiving BLV monotherapy at 2 mg/day, 76 were evaluated at week 24 and 40 up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (n = 43) compared to CT (n = 33) carriers (5.38 vs. 4.72 log 10  IU/ml, p = 0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 vs. 17/33, p = 0.565), the former group presented VNR more often than PR (9/11 vs. 9/23, p = 0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment., Conclusions: The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in BLV-untreated and -treated patients with CHD and may contribute to identifying patients with different early virological responses to BLV., Impact and Implications: Although several sodium taurocholate cotransporting polypeptide (NTCP) genetic polymorphisms have been described, no data are available on their potential role in modifying HDV RNA load or treatment response to bulevirtide (BLV) in patients with chronic hepatitis delta (CHD). In this study, we demonstrated that patients with CHD, either treated or untreated, carrying NTCP rs17556915 TT/CC, presented higher baseline HDV RNA levels compared to those with the CT genotype. Higher HDV RNA levels in TT/CC carriers compared to CT carriers were also confirmed in patients with CHD treated with BLV monotherapy up to 96 weeks. Furthermore, carriers of TT/CC, compared to CT genotype, more frequently showed viral non-response (VNR) than partial response (PR) at week 24 of BLV treatment, and 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. This is the first study demonstrating a potential role of NTCP genetic polymorphisms in influencing HDV viral load and early virological response to BLV monotherapy. Since no direct HDV resistance to BLV has been described so far, if confirmed in larger studies, the genetic polymorphisms in NTCP may help identify patients with different patterns of early virological response to BLV., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2024
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122. Development and Validation of a Scoring System to Predict Response to Obeticholic Acid in Primary Biliary Cholangitis.

Author

De Vincentis A, Ampuero J, Terracciani F, D'Amato D, Gerussi A, Cristoferi L, Cazzagon N, Bonaiuto E, Floreani A, Calvaruso V, Cadamuro L, Degasperi E, Morgando A, Vanni E, Lleo A, Colapietro F, Alvaro D, Castellaneta A, Labanca S, Viganò M, Distefano M, Pace Palitti V, Ricci C, De Matthaeis N, Marzioni M, Gómez-Dominguez E, Montero JL, Molina E, Garcia-Buey L, Casado M, Berenguer M, Conde I, Simon MA, Fuentes J, Costa-Moreira P, Macedo G, Jorquera F, Morillas RM, Presa J, Sousa JM, Gomes D, Santos L, Olveira A, Hernandez-Guerra M, Aburruza L, Santos A, Carvalho A, Uriz J, Gutierrez ML, Perez E, Chessa L, Pellicelli A, Marignani M, Muratori L, Niro GA, Brunetto M, Ponziani FR, Pompili M, Marra F, Galli A, Mussetto A, Alagna G, Simone L, Bertino G, Rosina F, Cozzolongo R, Russello M, Baiocchi L, Saitta C, Terreni N, Zolfino T, Rigamonti C, Vigano R, Cuccorese G, Pozzoni P, Pedone C, Grasso S, Picardi A, Invernizzi P, Sacco R, Izzi A, Fernandez-Rodriguez C, Vespasiani-Gentilucci U, and Carbone M

Subjects
Humans, Female, Male, Middle Aged, Prospective Studies, Aged, Liver Cirrhosis, Biliary drug therapy, Treatment Outcome, Adult, Cholagogues and Choleretics therapeutic use, Italy, Chenodeoxycholic Acid analogs & derivatives, Chenodeoxycholic Acid therapeutic use
Abstract

Background & Aims: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA., Methods: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months., Results: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease., Conclusions: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2024
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123. HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B.

Author

Vecchi A, Rossi M, Tiezzi C, Fisicaro P, Doselli S, Gabor EA, Penna A, Montali I, Ceccatelli Berti C, Reverberi V, Montali A, Fletcher SP, Degasperi E, Sambarino D, Laccabue D, Facchetti F, Schivazappa S, Loggi E, Coco B, Cavallone D, Rosselli Del Turco E, Massari M, Pedrazzi G, Missale G, Verucchi G, Andreone P, Brunetto MR, Lampertico P, Ferrari C, and Boni C

Subjects
Humans, Female, Adult, Male, Middle Aged, Hepatitis B Core Antigens immunology, Hepatitis B Core Antigens blood, Drug Therapy, Combination, Hepatitis B Surface Antigens blood, Hepatitis B virus immunology, T-Lymphocytes immunology, T-Lymphocytes drug effects, Treatment Outcome, Nucleosides therapeutic use, Hepatitis B, Chronic drug therapy, Hepatitis B, Chronic immunology, Hepatitis B, Chronic blood, Interferon-alpha therapeutic use, Antiviral Agents therapeutic use, Recombinant Proteins therapeutic use, Polyethylene Glycols therapeutic use, Killer Cells, Natural immunology, Killer Cells, Natural drug effects, Hepatitis B e Antigens blood
Abstract

Objective: Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on., Design: 53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy., Results: Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values., Conclusions: PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients., Competing Interests: Competing interests: CF: Grant: Gilead, Abbvie. Consultant: Gilead, Abbvie, Vir Biotechnology Inc, Arrowhead, Transgene, BMS; MRB: speaker Bureau for AbbVie, Gilead, EISAI-MSD and advisor for AbbVie, Gilead, Janssen, AstraZeneca; PL: advisor and speaker bureau for Advisory Board/Speaker Bureau for Roche Pharma/diagnostics, Gilead Sciences, GSK, Abbvie, Janssen, Myr, Eiger, Antios, Aligos, Vir, Grifols, Altona, Roboscreen; SPF is employee of and stock-holder in Gilead Sciences, Inc. The remaining authors disclose no conflicts., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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124. A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort.

Author

Kondili LA, Brancaccio G, Tosti ME, Coco B, Quaranta MG, Messina V, Ciancio A, Morisco F, Cossiga V, Claar E, Rosato V, Ciarallo M, Cacciola I, Ponziani FR, Cerrito L, Coppola R, Longobardi F, Biliotti E, Rianda A, Barbaro F, Coppola N, Stanzione M, Barchiesi F, Fagiuoli S, Viganò M, Massari M, Russo FP, Ferrarese A, Laccabue D, Di Marco V, Blanc P, Marrone A, Morsica G, Federico A, Ieluzzi D, Rocco A, Foschi FG, Soria A, Maida I, Chessa L, Milella M, Rosselli Del Turco E, Madonia S, Chemello L, Gentile I, Toniutto P, Bassetti M, Surace L, Baiocchi L, Pellicelli A, De Santis A, Puoti M, Degasperi E, Niro GA, Zignego AL, Craxi A, Raimondo G, Santantonio TA, Brunetto MR, and Gaeta GB

Subjects
Humans, Female, Male, Italy epidemiology, Adult, Middle Aged, Cross-Sectional Studies, Cohort Studies, Liver Cirrhosis epidemiology, Liver Cirrhosis virology, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular virology, Comorbidity, Aged, Hepatitis B Surface Antigens blood, Liver Neoplasms epidemiology, Liver Neoplasms virology, Interferons therapeutic use, Antiviral Agents therapeutic use, Hepatitis D, Chronic epidemiology, Hepatitis Delta Virus immunology, Hepatitis Delta Virus genetics
Abstract

Background and Aims: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility., Methods: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model., Results: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care., Conclusions: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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125. Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series.

Author

Dietz-Fricke C, Degasperi E, Jachs M, Maasoumy B, Reiter FP, Geier A, Grottenthaler JM, Berg CP, Sprinzl K, Zeuzem S, Gödiker J, Schlevogt B, Herta T, Wiegand J, Soffredini R, Wedemeyer H, Deterding K, Reiberger T, and Lampertico P

Subjects
Humans, Male, Female, Retrospective Studies, Middle Aged, Adult, Aged, Treatment Outcome, Liver Cirrhosis drug therapy, Antiviral Agents therapeutic use, Antiviral Agents adverse effects, Hepatitis D, Chronic drug therapy, Hepatitis D, Chronic complications, Hepatitis Delta Virus, Off-Label Use
Abstract

Background and Aims: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis., Approach and Results: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12)., Conclusions: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2024
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126. Advances in hepatitis delta research: emerging insights and future directions.

Author

Degasperi E, Anolli MP, and Lampertico P

Abstract

Objectives: Hepatitis delta virus (HDV) is a defective virus needing the envelope provided by hepatitis B virus (HBV) in order to enter liver cells and propagate. Chronic HDV infection is considered the most severe viral hepatitis, resulting in accelerated fibrosis progression until cirrhosis and its complications (hepatocellular carcinoma, liver decompensation) compared with HBV mono-infected patients. Off-label treatment with interferon has represented the only treatment option in the last 40 years, resulting in suboptimal virological response rates and being limited by safety issues especially in patients with advanced cirrhosis. Recently, the first HBV-HDV entry inhibitor Bulevirtide (BLV) has been approved by the European Medicines Agency (EMA) for treatment of chronic compensated HDV., Methods: This review summarises most recent updates on HDV epidemiology, diagnosis and treatment, with a special focus both on clinical trials and real-life studies about BLV. An overview on new HDV compounds under development is also provided., Results: BLV, the HBV-HDV entry inhibitor, has shown promising safety and efficacy data in clinical trials and in real-life studies, also in patients with advanced cirrhosis and portal hypertension. However, according to EMA label treatment is currently intended long-term until clinical benefit and predictors of responses are still undefined. The potential combination with PegIFNα seems to increase virological and clinical responses. New compounds are under development or in pipeline for treatment of HDV., Conclusion: After more than 40 years since HDV discovery, new treatment options are currently available to provide efficient strategies for chronic hepatitis Delta., Competing Interests: Competing interests: MPA: nothing to disclose. ED: Advisory Board: AbbVie; Speaking and teaching: Gilead, MSD, AbbVie, Roche; Travel Grant: Abbvie, Gilead, Advanz Pharma. PL: advisor and speaker bureau for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie, Janssen, Arrowhead, Alnylam, Eiger, MYR Pharma, Antios, Aligos, Vir., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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128. Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC treated patients with chronic hepatitis B.

Author

Testoni B, Scholtès C, Plissonnier ML, Paturel A, Berby F, Facchetti F, Villeret F, Degasperi E, Scott B, Hamilton A, Heil M, Lampertico P, Levrero M, and Zoulim F

Subjects
Humans, Hepatitis B virus genetics, Hepatitis B Surface Antigens, Hepatitis B e Antigens, DNA, Circular, DNA, Viral, Antiviral Agents therapeutic use, Liver pathology, Hepatitis B Core Antigens, RNA, Biomarkers, Hepatitis B, Chronic diagnosis, Hepatitis B, Chronic drug therapy
Abstract

Objective: A convenient, reproducible biomarker of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) transcriptional activity is lacking. We measured circulating HBV RNA (cirB-RNA) in untreated and nucleos(t)ide analogues (NUC) treated chronic hepatitis B (CHB) patients to define its correlation with intrahepatic viral markers and HBV core-related antigen (HBcrAg)., Design: Paired liver biopsy and serum samples were collected from 122 untreated and 30 NUC-treated CHB patients. We measured cirB-RNA, HBV DNA, hepatitis B surface antigen (HBsAg), HBcrAg and alanine aminotransferase levels. cirB-RNA was quantified using an investigational HBV RNA assay for use on the cobas 6800 system. The test detects a region spanning the HBV canonical polyadenylation site. cccDNA and 3.5 kb RNA in liver tissue were assessed by quantitative PCR and droplet digital PCR., Results: cirB-RNA was detectable in 100% of HBeAg(+) chronic hepatitis (CH), 57% and 14% of HBeAg(-) CH and chronic infection untreated patients and 47% of NUC-treated patients. cirB-RNA undetectability was associated with lower intrahepatic cccDNA transcriptional activity, as well as serum HBcrAg, but no significant differences in HBsAg, in both untreated and treated patients. In untreated HBeAg(-) patients, cirB-RNA correlated with intrahepatic 3.5 kb RNA and cccDNA transcriptional activity, serum HBV DNA and HBcrAg, but not with HBsAg or total cccDNA levels. Combined undetectability of both cirB-RNA and HBcrAg detection in untreated HBeAg(-) patients identified a subgroup with the lowest levels of intrahepatic transcriptionally active cccDNA., Conclusion: Our results support the usefulness of quantification of circulating HBV RNA expressed from cccDNA as an indicator of intrahepatic active viral reservoir in both untreated and NUC-treated CHB patients., Trial Registration Number: NCT02602847., Competing Interests: Competing interests: BS, AH and MH are employees and stockholders of Roche Molecular Systems (Pleasanton, CA, USA). ED served as speaker for Gilead and Abbvie, participated in advisory board of Gilead, Abbvie and Roche, received grant from Gilead and travel grant from Gilead and Advanz Pharma. PL served as speaker and/or participated in advisory board for Roche Pharma/Diagnostics, Gilead Sciences, GSK, Abbvie, Janssen, Myr, Eiger, Antios, Aligos, Vir, Grifols, Altona, Roboscreen. FZ received consulting fees from: Aligos, Antios, Assembly, Gilead, GSK; FZ and BT received research funding to INSERM from: Assembly, Beam Therapeutics, Blue Jay and Janssen. FZ is an Associate Editor of the journal., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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129. Quantification of serum HDV RNA by Robogene 2.0 in HDV patients is significantly influenced by the extraction methods.

Author

Anolli MP, Renteria SU, Degasperi E, Borghi M, Facchetti F, Sambarino D, Perbellini R, Monico S, Ceriotti F, and Lampertico P

Subjects
Male, Humans, Middle Aged, Female, RNA, Viral, DNA, Viral, Germany, Hepatitis B virus genetics, Hepatitis B Surface Antigens, Antiviral Agents therapeutic use, Hepatitis Delta Virus genetics, Hepatitis D drug therapy
Abstract

Background and Aim: Management of chronic hepatitis delta (CHD) requires reliable tests for HDV RNA quantification. The aim of the study was to compare two extraction methods for the quantification of HDV RNA in untreated and bulevirtide (BLV)-treated CHD patients., Methods: Frozen sera from untreated and BLV-treated CHD patients were tested in a single-centre study for HDV RNA levels (Robogene 2.0, Roboscreen GmbH, Leipzig, Germany; LOD 6 IU/mL) with two extraction methods: manual (INSTANT Virus RNA/DNA kit; Roboscreen GmbH, Leipzig, Germany) versus automated (EZ1 DSP Virus Kit; Qiagen, Hilden, Germany). BLV-treated patients were sampled at baseline and during therapy., Results: Two hundred sixty-four sera collected from 157 CHD (139 untreated, 18 BLV-treated) patients were analysed: age 51 (28-78), 59% males, 90% of European origin, 60% cirrhotics, ALT 85 (17-889) U/L, HBsAg 3.8 (1.7-4.6) Log IU/mL, 81% HBV DNA undetectable, 98% HDV genotype 1. Median HDV RNA was 4.53 (.70-8.10) versus 3.77 (.70-6.93) Log IU/mL by manual versus automated extraction (p < .0001). Manual extraction reported similar HDV RNA levels in 31 (20%) patients, higher in 119 (76%) [+.5 and +1 log10 in 60; > +1 log10 in 59] and lower in 7 (4%). Among 18 BLV-treated patients, rates of HDV RNA < LOD significantly differed between the two assays at Weeks 16 and 24 (0% vs. 22%, p = .02; 11% vs. 44%, p = .03), but not at later timepoints. By contrast, virological response rates were similar., Conclusions: Quantification of HDV RNA by Robogene 2.0 is influenced by the extraction method, the manual extraction being 1 Log more sensitive., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2024
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130. Liver stiffness measurement as a noninvasive method for the diagnosis of liver cirrhosis in patients with chronic hepatitis D virus infection.

Author

Sandmann L, Degasperi E, Port K, Aleman S, Wallin JJ, Manuilov D, Da BL, Cornberg M, Lampertico P, Maasoumy B, Wedemeyer H, and Deterding K

Subjects
Humans, Retrospective Studies, Liver Cirrhosis diagnostic imaging, Liver Cirrhosis etiology, Fibrosis, Biopsy, Liver diagnostic imaging, Liver pathology, ROC Curve, Hepatitis D, Chronic pathology, Elasticity Imaging Techniques methods
Abstract

Background: Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited., Aims: To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients., Methods: We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies., Results: Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB-4], and 0.69 [AAR]). The optimal cut-off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut-off for diagnosing non-advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients., Conclusions: LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut-offs of <10.2 and < 15.2 kPa reliably diagnose non-advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients., (© 2024 John Wiley & Sons Ltd.)

Published
2024
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131. Real-world effectiveness of voxilaprevir/velpatasvir/sofosbuvir in patients following DAA failure.

Author

Graf C, D'Ambrosio R, Degasperi E, Paolucci S, Llaneras J, Vermehren J, Dultz G, Peiffer KH, Finkelmeier F, Herrmann E, Zeuzem S, Buti M, Lampertico P, Dietz J, and Sarrazin C

Abstract

Background & Aims: Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection. In the present study, predictors of virologic treatment response were analyzed in an integrative analysis of three large real-world cohorts., Methods: Consecutive patients re-treated with VOX/VEL/SOF after DAA failure were enrolled between 2016 and 2021 in Austria, Belgium, Germany, Italy, Spain and Switzerland., Results: A total of 746 patients were included: median age was 56 (16-88) years and 77% were male. Most patients were infected with HCV genotype 1 (56%) and 3 (32%). 86% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Overall, 95.4% (683/716) of patients achieved a sustained virologic response. Treatment effectiveness was significantly affected by advanced liver disease ( p < 0.001), hepatocellular carcinoma ( p < 0.001), higher baseline ALT levels ( p = 0.02), HCV genotype 3 ( p < 0.001), and prior VEL/SOF treatment ( p = 0.01). In a multivariate analysis, only HCV genotype 3, hepatocellular carcinoma and cirrhosis turned out to be independent predictors of treatment failure. Resistance-associated substitutions, as well as the presence of rare genotypes, did not impact treatment outcome. The effectiveness of rescue therapy with glecaprevir/pibrentasvir and SOF, with or without ribavirin, for 12 to 24 weeks was found to be high (100%)., Conclusions: Infection with HCV genotype 3, the presence of liver cancer and cirrhosis are independently associated with failure of VOX/VEL/SOF re-treatment. It is unclear whether the addition of ribavirin and/or extension of treatment duration may be effective to avoid virologic relapse on VOX/VEL/SOF. However, rescue treatment with glecaprevir/pibrentasvir+SOF seems to be effective., Impact and Implications: Representative data on the effectiveness of voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given. Thus, we aimed to analyze treatment effectiveness and predictors of virologic response to VOX/VEL/SOF in an integrative analysis of three large real-word cohorts. The study results, derived from a multicenter cohort consisting of 746 patients, demonstrated that re-treatment with VOX/VEL/SOF is an effective salvage therapy associated with an overall per protocol sustained virologic response rate of 95%. Hepatocellular carcinoma onset, cirrhosis and HCV genotype 3 were identified as independent negative predictors of treatment response, whereas resistance-associated substitutions, as well as rare genotypes and chimera, did not impact sustained virologic response rates following re-treatment with VOX/VEL/SOF., Competing Interests: Christiana Graf reports speaking and/or consulting fees from AbbVie and travel support from AbbVie and Gilead outside the submitted work. Roberta D’Ambrosio reports speaking and/consulting fees from AbbVie, Gilead and Takeda and research grant from AbbVie and Gilead outside the submitted work. Elisabetta Degasperi reports speaking and/or consulting fees from AbbVie, Gilead, MSD; research grants from Gilead and travel support from AbbVie outside the submitted work. Stefania Paolucci: no conflicts to disclose.Jordi Llaneras: no conflicts to disclose. Johannes Vermehren reports speaking and/or consulting fees from Abbott, AbbVie, Bristol-Myers, Squibb, Gilead, Medtronic, Merck/MSD and Roche outside the submitted work. Georg Dultz reports speaking and/or consulting fees from AbbVie and Gilead outside the submitted work. Kai-Henrik Peiffer: no conflicts to disclose. Fabian Finkelmeier: no conflicts to disclose. Eva Herrmann: no conflicts to disclose. Stefan Zeuzem reports speaking and/or consulting fees from Abbvie, BioMarin, Gilead, GSK, Ipsen, Janssen, Madrigal, Merck/MSD, NovoNordisk, SoBi, and Theratechnologies outside the submitted work. Maria Buti reports speaking and/or consulting fees from AbbVie, MSD and Gilead outside the submitted work. Pietro Lampertico reports speaking and/or consulting fees from AbbVie, BMS, Gilead, GSK, Janssen, MSD and Roche outside the submitted work. Julia Dietz reports research grants from Gilead outside the submitted work. Christoph Sarrazin reports speaking and consulting fees from Abbvie, MSD, Gilead, Merck/MSD and research support from AbbVie and Gilead outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Published
2024
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132. Modelling HDV kinetics under the entry inhibitor bulevirtide suggests the existence of two HDV-infected cell populations.

Author

Shekhtman L, Cotler SJ, Degasperi E, Anolli MP, Uceda Renteria SC, Sambarino D, Borghi M, Perbellini R, Facchetti F, Ceriotti F, Lampertico P, and Dahari H

Abstract

Background & Aims: Bulevirtide (BLV) was approved for the treatment of compensated chronic hepatitis D virus (HDV) infection in Europe in 2020. However, research into the effects of the entry inhibitor BLV on HDV-host dynamics is in its infancy., Methods: Eighteen patients with HDV under nucleos(t)ide analogue treatment for hepatitis B, with compensated cirrhosis and clinically significant portal hypertension, received BLV 2 mg/day. HDV RNA, alanine aminotransferase (ALT), and hepatitis B surface antigen (HBsAg) were measured at baseline, weeks 4, 8 and every 8 weeks thereafter. A mathematical model was developed to account for HDV, HBsAg and ALT dynamics during BLV treatment., Results: Median baseline HDV RNA, HBsAg, and ALT were 4.9 log IU/ml [IQR: 4.4-5.8], 3.7 log IU/ml [IQR: 3.4-3.9] and 106 U/L [IQR: 81-142], respectively. During therapy, patients fit into four main HDV kinetic patterns: monophasic (n = 2), biphasic (n = 10), flat-partial response (n = 4), and non-responder (n = 2). ALT normalization was achieved in 14 (78%) patients at a median of 8 weeks (range: 4-16). HBsAg remained at pre-treatment levels. Assuming that BLV completely (∼100%) blocks HDV entry, modeling indicated that two HDV-infected cell populations exist: fast HDV clearing (median t 1/2  = 13 days) and slow HDV clearing (median t 1/2  = 44 days), where the slow HDV-clearing population consisted of ∼1% of total HDV-infected cells, which could explain why most patients exhibited a non-monophasic pattern of HDV decline. Moreover, modeling explained ALT normalization without a change in HBsAg based on a non-cytolytic loss of HDV from infected cells, resulting in HDV-free HBsAg-producing cells that release ALT upon death at a substantially lower rate compared to HDV-infected cells., Conclusion: The entry inhibitor BLV provides a unique opportunity to understand HDV, HBsAg, ALT, and host dynamics., Impact and Implications: Mathematical modeling of hepatitis D virus (HDV) treatment with the entry inhibitor bulevirtide (BLV) provides a novel window into the dynamics of HDV RNA and alanine aminotransferase. Kinetic data from patients treated with BLV monotherapy can be explained by hepatocyte populations with different basal HDV clearance rates and non-cytolytic clearance of infected cells. While further studies are needed to test and refine the kinetic characterization described here, this study provides a new perspective on viral dynamics, which could inform evolving treatment strategies for HDV., Competing Interests: Elisabetta Degasperi: Advisory Board: AbbVie; Speaking and teaching: Gilead, MSD, AbbVie. Pietro Lampertico: Advisor and speaker bureau for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie, Janssen, Arrowhead, Alnylam, Eiger, MYR Pharma, Antios, Aligos, VIR. Other authors have nothing to disclose. The other authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Published
2023
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134. Bulevirtide for patients with compensated chronic hepatitis delta: A review.

Author

Degasperi E, Anolli MP, and Lampertico P

Subjects
Humans, Hepatitis Delta Virus genetics, Interferon-alpha adverse effects, Liver Cirrhosis drug therapy, Hepatitis, Chronic, Antiviral Agents adverse effects, Hepatitis D drug therapy
Abstract

Chronic hepatitis delta (CHD) affects approximately 10-20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end-stage liver disease, hepatocellular carcinoma). In the last 30 years, the only treatment option for CHD has been represented by the off-label administration of Interferon (or Pegylated Interferon)-alpha: antiviral treatment, however, resulted in suboptimal (20-30%) virological response and was burdened by several side effects, de facto contraindicating Interferon (IFN) administration in patients with more advanced liver disease. Recently, Bulevirtide (BLV), a first-in-class HBV-HDV entry inhibitor blocking Na + -taurocholate co-transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real-life reports. In July 2020, BLV has granted conditional approval by EMA for treatment of compensated CHD, at the dose of 2 mg/day by self-administered subcutaneous injections. In Phase II and Phase III trials, BLV was evaluated at different doses (2 vs. 10 mg/day) for 24 or 48 weeks, either in monotherapy or in combination with PegIFN. Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%-83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%-78% ALT normalization. Combination therapy with PegIFN provided synergistic effects. These results were replicated in real-life studies and confirmed also in patients with advanced cirrhosis and clinically significant portal hypertension. BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2023
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135. Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.

Author

Montali I, Ceccatelli Berti C, Morselli M, Acerbi G, Barili V, Pedrazzi G, Montanini B, Boni C, Alfieri A, Pesci M, Loglio A, Degasperi E, Borghi M, Perbellini R, Penna A, Laccabue D, Rossi M, Vecchi A, Tiezzi C, Reverberi V, Boarini C, Abbati G, Massari M, Lampertico P, Missale G, Ferrari C, and Fisicaro P

Subjects
Humans, NAD metabolism, CD8-Positive T-Lymphocytes, Reactive Oxygen Species metabolism, Antiviral Agents therapeutic use, Antiviral Agents metabolism, Hepatitis B virus, Hepatitis B, Chronic, Hepatitis B pathology
Abstract

Background & Aims: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies., Methods: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed., Results: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function., Conclusions: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection., Impact and Implications: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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136. Hepatitis D virus infection: Pathophysiology, epidemiology and treatment. Report from the first international delta cure meeting 2022.

Author

Lampertico P, Degasperi E, Sandmann L, and Wedemeyer H

Abstract

Chronic infection with hepatitis delta virus (HDV) affects between 12-20 million people worldwide and represents the most severe form of viral hepatitis, leading to accelerated liver disease progression, cirrhosis and its complications, such as end-stage-liver disease and hepatocellular carcinoma. From the discovery of HDV in 1977 by Prof. Mario Rizzetto, knowledge on the HDV life cycle and mechanisms of viral spread has expanded. However, little is still known about the natural history of the disease, host-viral interactions, and the role of the immune system in HDV persistence. Diagnosis of HDV is still challenging due to a lack of standardised assays, while accurate viral load quantification is needed to assess response and endpoints of antiviral treatment. Until recently, interferon has represented the only treatment option in patients with chronic hepatitis delta; however, it is associated with low efficacy and a high burden of side effects. The discovery of the entry inhibitor bulevirtide has represented a breakthrough in HDV treatment, by demonstrating high rates of viral suppression in phase II and III trials, results which have been confirmed in real-world settings and in patients with compensated advanced liver disease. In the meantime, other compounds ( i.e. lonafarnib, new anti-hepatitis B virus drugs) are under development to provide alternative or combined strategies for HDV cure. The first international Delta Cure meeting was organised in Milan in October 2022 with the aim of sharing and disseminating the latest data; this review summarises key takeaway messages from state-of-the-art lectures and research data on HDV., Competing Interests: Pietro Lampertico: Advisor and speaker bureau for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie, Janssen, Arrowhead, Alnylam, Eiger, MYR Pharma, Antios, Aligos. Elisabetta Degasperi: Advisory Board: AbbVie, Roche; Speaking and teaching: Gilead, AbbVie; Travel support: Gilead, Advanz Pharma. Lisa Sandmann: Advisory board: Roche; Speaking and teaching: Falk Pharma e.V., Gilead, Roche; Travel support: AbbVie. Heiner Wedemeyer: Grants/research support: AbbVie, Biotest, BMS, Gilead, Merck/MSD, Novartis, Roche; Personal fees: Abbott, AbbVie, Altimmune, Biotest, BMS, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Published
2023
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137. Long-term endoscopic surveillance in HBV compensated cirrhotic patients treated with Tenofovir or Entecavir for 11 years.

Author

Farina E, Loglio A, Tosetti G, Degasperi E, Viganò M, Gentile C, Monico S, Perbellini R, Borghi M, Facchetti F, Uceda Renteria SC, Ceriotti F, Cerini F, Primignani M, and Lampertico P

Subjects
Male, Humans, Middle Aged, Female, Tenofovir, Antiviral Agents, Hepatitis B virus genetics, Cohort Studies, Liver Cirrhosis diagnosis, Liver Cirrhosis drug therapy, Liver Cirrhosis complications, Treatment Outcome, Carcinoma, Hepatocellular complications, Esophageal and Gastric Varices etiology, Esophageal and Gastric Varices complications, Liver Neoplasms etiology, Liver Neoplasms complications, Varicose Veins complications
Abstract

Background: Long-term administration of TDF/ETV in patients with HBV-related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown., Aim: To assess the risk of EV development/progression in this population., Methods: A total of 186 Caucasian HBV-monoinfected compensated cirrhotics were enrolled in a long-term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development/progression of oesophageal/gastric varices over time., Results: At TDF/ETV start, median age was 61 years, 80% males, 60% HBV-DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets <150,000/mmc and 25 (13%) with low-risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11-year cumulative probability of 5.1% (95% CI 3-10%); no patient bled. Out of 161 patients without EV at baseline, the 11-year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11-year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p = 0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset., Conclusions: In compensated cirrhotic patients under long-term effective TDF/ETV treatment, the 11-year risk of developing/progressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline., (© 2023 John Wiley & Sons Ltd.)

Published
2023
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138. Bulevirtide-based treatment strategies for chronic hepatitis delta: A review.

Author

Degasperi E, Anolli MP, and Lampertico P

Subjects
Adult, Humans, Treatment Outcome, Hepatitis, Chronic drug therapy, Antiviral Agents adverse effects, Hepatitis Delta Virus
Abstract

Chronic hepatitis Delta (CHD) is a rare and severe form of chronic viral hepatitis. Until recently, the only therapeutic approach has been the off-label use of a 48 weeks course of PegInterferon alpha (PegIFNα), that was characterized by suboptimal efficacy and burdened by significant side effects that limited treatment applicability in patients with advanced liver disease. In July 2020, European Medicines Agency (EMA) conditionally approved the entry inhibitor Bulevirtde (BLV) at the dose of 2 mg/day for the treatment of adult patients with compensated CHD. Efficacy and safety of BLV in CHD have been evaluated in clinical trials either as monotherapy or in combination with PegIFNα. These results were confirmed by real-life studies, which also evaluated long-term BLV monotherapy in patients with advanced compensated cirrhosis. Notwithstanding these promising results there are still several issues to be addressed, such as the optimal duration of the treatment, the rates of off-therapy responses, as well as the long-term clinical benefits. This review summarizes updated and current literature data about clinical trials and real-life studies with BLV monotherapy and/or in combination with PegIFNα., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Published
2023
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139. Spike-specific humoral and cellular immune responses after COVID-19 mRNA vaccination in patients with cirrhosis: A prospective single center study.

Author

Iavarone M, Tosetti G, Facchetti F, Topa M, Er JM, Hang SK, Licari D, Lombardi A, D'Ambrosio R, Degasperi E, Loglio A, Oggioni C, Perbellini R, Caccia R, Bandera A, Gori A, Ceriotti F, Scudeller L, Bertoletti A, and Lampertico P

Subjects
Humans, Antibodies, Antibodies, Viral, BNT162 Vaccine, Breakthrough Infections, Immunity, Cellular, Liver Cirrhosis, Prospective Studies, RNA, Messenger, SARS-CoV-2, Vaccination, Carcinoma, Hepatocellular, COVID-19 prevention & control, COVID-19 Vaccines adverse effects, Liver Neoplasms
Abstract

Background and Aims: COVID-19 mRNA vaccines were approved to prevent severe forms of the disease, but their immunogenicity and safety in cirrhosis is poorly known., Method: In this prospective single-center study enrolling patients with cirrhosis undergoing COVID-19 vaccination (BNT162b2 and mRNA-1273), we assessed humoral and cellular responses vs healthy controls, the incidence of breakthrough infections and adverse events (AEs). Antibodies against spike- and nucleocapsid-protein (anti-S and anti-N) and Spike-specific T-cells responses were quantified at baseline, 21 days after the first and second doses and during follow-up., Results: 182 cirrhotics (85% SARS-CoV-2-naïve) and 38 controls were enrolled. After 2 doses of vaccine, anti-S titres were significantly lower in cirrhotics vs controls [1,751 (0.4-25,000) U/mL vs 4,523 (259-25,000) U/mL, p=0.012] and in SARS-CoV-2-naïve vs previously infected cirrhotics [999 (0.4-17,329) U/mL vs 7,500 (12.5-25,000) U/mL, (p<0.001)]. T-cell responses in cirrhotics were similar to controls, although with different kinetics. In SARS-CoV-2-naïve cirrhotics, HCC, Child-Pugh B/C and BNT162b2 were independent predictors of low response. Neither unexpected nor severe AEs emerged. During follow-up, 2% turned SARS-CoV-2 positive, all asymptomatic., Conclusion: Humoral response to COVID-19 vaccines appeared suboptimal in patients with cirrhosis, particularly in SARS-CoV-2-naïve decompensated cirrhotics, although cellular response appeared preserved, and low breakthrough infections rate was registered., Competing Interests: Conflict of interest MI: Speaking/Teaching, consultant and advisory board for Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, Guerbet, EISAI, Roche. BA: A patent for a method to monitor SARS-CoV-2-specific T-cells in biological samples pending. PL: Advisory Board/Speaker Bureau for BMS, ROCHE, GILEAD SCIENCES, GSK, ABBVIE, MSD, ARROWHEAD, ALNYLAM, JANSSEN, SBRING BANK, MYR, EIGER, ALIGOS, ANTIOS, VIR., (Copyright © 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Published
2023
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140. A 3-Year Course Of Bulevirtide Monotherapy May Cure Hdv Infection In Cirrhotics.

Author

Anolli MP, Degasperi E, Allweiss L, Sangiovanni A, Maggioni M, Scholtes C, Oberhardt V, Neumann-Haefelin C, Dandri M, Zoulim F, and Lampertico P

Abstract

Bulevirtide has been recently conditionally approved by the European Medicines Agency for the treatment of Chronic Hepatitis Delta, but the ideal duration of therapy is unknown. Here we describe the first case of cure of Hepatitis Delta following 3 years of Bulevirtide monotherapy in a patient with compensated cirrhosis and esophageal varices. During the 72-week off-Bulevirtide follow-up, virological and biochemical responses were maintained. In the off-therapy liver biopsy, intrahepatic HDV RNA and Hepatitis D antigen were undetectable, <1% hepatocytes were Hepatitis B surface antigen positive while hepatitis B core antigen was negative. Grading and staging improved compared to pre-treatment biopsy., (Copyright © 2022. Published by Elsevier B.V.)

Published
2023
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141. Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients.

Author

Wong YJ, Zhaojin C, Tosetti G, Degasperi E, Sharma S, Agarwal S, Chuan L, Huak CY, Jia L, Xiaolong Q, Saraya A, and Primignani M

Subjects
Humans, Liver Cirrhosis complications, Liver Cirrhosis diagnosis, Liver Cirrhosis pathology, Adrenergic beta-Antagonists therapeutic use, Esophageal and Gastric Varices complications, Hypertension, Portal complications, Hypertension, Portal diagnosis, Carcinoma, Hepatocellular complications, Carcinoma, Hepatocellular diagnosis, Liver Neoplasms complications, Liver Neoplasms diagnosis, Elasticity Imaging Techniques adverse effects
Abstract

Background/aims: The utility of Baveno-VII criteria of clinically significant portal hypertension (CSPH) to predict decompensation in compensated advanced chronic liver disease (cACLD) patient needs validation. We aim to validate the performance of CSPH criteria to predict the risk of decompensation in an international real-world cohort of cACLD patients., Methods: cACLD patients were stratified into three categories (CSPH excluded, grey zone, and CSPH). The risks of decompensation across different CSPH categories were estimated using competing risk regression for clustered data, with death and hepatocellular carcinoma as competing events. The performance of "treating definite CSPH" strategy to prevent decompensation using non-selective beta-blocker (NSBB) was compared against other strategies in decision curve analysis., Results: One thousand one hundred fifty-nine cACLD patients (36.8% had CSPH) were included; 7.2% experienced decompensation over a median follow-up of 40 months. Non-invasive assessment of CSPH predicts a 5-fold higher risk of liver decompensation in cACLD patients (subdistribution hazard ratio, 5.5; 95% confidence interval, 4.0-7.4). "Probable CSPH" is suboptimal to predict decompensation risk in cACLD patients. CSPH exclusion criteria reliably exclude cACLD patients at risk of decompensation, regardless of etiology. Among the grey zone, the decompensation risk was negligible among viral-related cACLD, but was substantially higher among the non-viral cACLD group. Decision curve analysis showed that "treating definite CSPH" strategy is superior to "treating all varices" or "treating probable CSPH" strategy to prevent decompensation using NSBB., Conclusion: Non-invasive assessment of CSPH may stratify decompensation risk and the need for NSBB in cACLD patients.

Published
2023
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142. Bulevirtide monotherapy for 48 weeks in patients with HDV-related compensated cirrhosis and clinically significant portal hypertension.

Author

Degasperi E, Anolli MP, Uceda Renteria SC, Sambarino D, Borghi M, Perbellini R, Scholtes C, Facchetti F, Loglio A, Monico S, Fraquelli M, Costantino A, Ceriotti F, Zoulim F, and Lampertico P

Subjects
Aged, Female, Humans, Male, Middle Aged, Hepatitis Delta Virus genetics, Liver Cirrhosis complications, Liver Cirrhosis drug therapy, Adult, Antiviral Agents therapeutic use, Hepatitis D complications, Hepatitis D drug therapy, Hypertension, Portal complications, Hypertension, Portal drug therapy, Liver Neoplasms, Lipopeptides therapeutic use
Abstract

Background & Aims: Bulevirtide (BLV) has recently been conditionally approved for the treatment of chronic hepatitis delta (CHD) in Europe, but its effectiveness and safety in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) are unknown., Methods: Consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2 mg/day were enrolled in this single-center study. Clinical/virological characteristics were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. HDV RNA was quantified by Robogene 2.0 (lower limit of detection 6 IU/ml)., Results: Eighteen Caucasian patients with compensated cirrhosis and CSPH under nucleos(t)ide analogue treatment were enrolled: median (IQR) age was 48 (29-77) years, and 67% were male. Median (IQR) platelet count was 70 (37-227) x10 3 /μl, liver stiffness measurement (LSM) 16.4 (7.8-57.8) kPa, alanine aminotransferase (ALT) 106 (32-222) U/L, HBsAg 3.7 (2.5-4.3) log IU/ml, HDV RNA 4.9 (3.3-6.6) log IU/ml. During 48 weeks of BLV monotherapy, HDV RNA declined by 3.1 (0.2-4.3) log IU/ml (p <0.001 vs. baseline), becoming undetectable in 5 patients (23%). A virological response was observed in 14 (78%) patients while a non-response was observed in 2 (11%). ALT decreased to 35 (15-86) U/L (p <0.001 vs. baseline), normalizing in 83% of patients. A combined response was observed in 67% of patients. Aspartate aminotransferase and gamma-glutamyltransferase levels significantly improved. Concerning liver function parameters, albumin values significantly increased and bilirubin remained stable. LSM significantly improved in patients with virological response, while platelet count was unchanged. None of the patients developed decompensating events or hepatocellular carcinoma. BLV was well tolerated, no patient discontinued treatment and the increase in bile acids was fully asymptomatic., Conclusions: A 48-week course of BLV 2 mg/day monotherapy is safe and effective even for difficult-to treat patients with HDV-related compensated cirrhosis and CSPH., Lay Summary: Hepatitis delta virus (HDV) is associated with the most severe form of viral hepatitis. A new treatment for HDV called bulevirtide has recently received conditional approval for patients with chronic HDV infection. However, its safety and effectiveness in patients with more advanced liver disease is not known. Herein, we show that it is safe and effective in patients with HDV-related cirrhosis and clinically significant portal hypertension., Competing Interests: Conflict of interest Elisabetta Degasperi: Advisory Board: AbbVie; Speaking and teaching: Gilead, MSD, AbbVie; Alessandro Loglio: Travel grant for MYR Pharma, Speaker bureau for Gilead Sciences; Fabien Zoulim: Advisor for Aligos, Antios, Arbutus, Assembly, Gilead, GSK, MYR Pharma, Roche Pietro Lampertico: Advisor and speaker bureau for BMS, Roche, Gilead Sciences, GSK, MSD, Abbvie, Janssen, Arrowhead, Alnylam, Eiger, MYR Pharma, Antios, Aligos. Other authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2022
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143. RESIST-HCV Criteria to Monitor Progression of Low-Risk Esophageal Varices in Patients With Compensated Cirrhosis After HCV Eradication: The SIMPLE Study: SIMPLE: Scoring Index to Monitor Progression of Low-risk Esophageal varices.

Author

Calvaruso V, Celsa C, D'Ambrosio R, Simone F, Petta S, Cacciola I, Enea M, Battaglia S, Pandolfo A, Licata M, Degasperi E, Cabibbo G, Di Marco L, Pennisi G, Borghi M, Di Martino V, Filomia R, Abdel-Hadi Y, Crapanzano L, Raimondo G, Lampertico P, Craxì A, Cammà C, and Di Marco V

Subjects
Male, Humans, Aged, Female, Hepacivirus, Antiviral Agents therapeutic use, Platelet Count, Liver Cirrhosis diagnosis, Serum Albumin, Esophageal and Gastric Varices diagnosis, Esophageal and Gastric Varices etiology, Esophageal and Gastric Varices drug therapy, Hepatitis C, Chronic complications, Hepatitis C, Chronic drug therapy, Elasticity Imaging Techniques
Abstract

Introduction: Noninvasive criteria to predict the progression of low-risk esophageal varices (EV) in patients with compensated hepatitis C virus (HCV) cirrhosis after sustained virological response (SVR) by direct-acting antivirals (DAAs) are lacking. Our aim was to assess the diagnostic performance of Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) criteria for EV progression compared with elastography-based criteria (Baveno VI, Expanded Baveno VI, and Baveno VII-HCV criteria)., Methods: All consecutive patients observed at 3 referral centers with compensated HCV cirrhosis with or without F1 EV who achieved sustained virological response by DAAs were classified at last esophagogastroduodenoscopy (EGDS) as RESIST-HCV low risk (i.e., low probability of high-risk varices [HRV]) if platelets were >120 × 10 9 /L and serum albumin >3.6 g/dL or RESIST-HCV high risk (i.e., high probability of HRV) if platelets were <120 × 10 9 /L or serum albumin <3.6 g/dL. The primary outcome was the progression to HRV. The area under the receiver operating characteristic curve and decision curve analysis of noninvasive criteria were calculated., Results: The cohort consisted of 353 patients in Child-Pugh class A (mean age 67.2 years, 53.8% males). During a mean follow-up of 44.2 months, 34 patients (9.6%, 95% CI 6.7%-13.5%) developed HRV. At the last EGDS, 178 patients (50.4%) were RESIST-low risk, and 175 (49.6%) were RESIST-high risk. RESIST-HCV criteria showed the highest area under the receiver operating characteristic curve (0.70, 95% confidence interval 0.65-0.75), correctly sparing the highest number of EGDS (54.3%), with the lowest false-positive rate (45.7%), compared with elastography-based criteria. Decision curve analysis showed that RESIST-HCV had higher clinical utility than elastography-based criteria., Discussion: Biochemical-based RESIST-HCV criteria are useful to easily predict HRV development after HCV eradication by DAAs in patients with compensated cirrhosis and low-risk EV., (Copyright © 2022 by The American College of Gastroenterology.)

Published
2022
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144. Towards a Functional Cure for Hepatitis B Virus: A 2022 Update on New Antiviral Strategies.

Author

Degasperi E, Anolli MP, and Lampertico P

Subjects
Humans, Hepatitis B virus genetics, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Hepatitis B Surface Antigens, Hepatitis B Antibodies, Virus Replication, DNA, Viral, Hepatitis B, Chronic drug therapy, Hepatitis B drug therapy
Abstract

Chronic infection with hepatitis B virus (HBV) represents one of the main causes of the development of cirrhosis and its complications. Treatment with potent third-generation nucleos(t)ide analogues (NUCs) results in >99% HBV DNA undetectability, and prevents fibrosis progression and liver-related complications. However, NUCs are not able to induce the so-called functional cure, which is hepatitis B surface antigen (HBsAg) loss and anti-HBs seroconversion. Consequently, NUC treatment is currently intended as being long-term or lifelong, resulting in the need for clinical monitoring and potentially suffering from compliance issues. Consequently, drug development in HBV has the goal of developing new agents in order to achieve a functional cure for HBV. Currently, the three main strategies include the following: inhibition of viral replication, inhibition of viral antigens, and immune modulation. This review summarizes the most recent updates concerning HBV compounds among these three main classes.

Published
2022
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145. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study.

Author

Valenti L, Pelusi S, Aghemo A, Gritti S, Pasulo L, Bianco C, Iegri C, Cologni G, Degasperi E, D'Ambrosio R, Del Poggio P, Soria A, Puoti M, Carderi I, Pigozzi MG, Carriero C, Spinetti A, Zuccaro V, Memoli M, Giorgini A, Viganò M, Rumi MG, Re T, Spinelli O, Colombo MC, Quirino T, Menzaghi B, Lorini G, Pan A, D'Arminio Monforte A, Buscarini E, Autolitano A, Bonfanti P, Terreni N, Aimo G, Mendeni M, Prati D, Lampertico P, Colombo M, and Fagiuoli S

Subjects
Antiviral Agents therapeutic use, Cohort Studies, Humans, Liver Cirrhosis diagnosis, Sustained Virologic Response, Carcinoma, Hepatocellular epidemiology, Cardiovascular Diseases complications, Diabetes Mellitus drug therapy, Hepatitis C, Chronic complications, Liver Neoplasms epidemiology
Abstract

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m 2 , 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20-3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16-6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11-0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi-disciplinary management approach may improve cardiovascular and possibly liver-related outcomes., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Published
2022
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146. Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

Author

Sapena V, Enea M, Torres F, Celsa C, Rios J, Rizzo GEM, Nahon P, Mariño Z, Tateishi R, Minami T, Sangiovanni A, Forns X, Toyoda H, Brillanti S, Conti F, Degasperi E, Yu ML, Tsai PC, Jean K, El Kassas M, Shousha HI, Omar A, Zavaglia C, Nagata H, Nakagawa M, Asahina Y, Singal AG, Murphy C, Kohla M, Masetti C, Dufour JF, Merchante N, Cavalletto L, Chemello LL, Pol S, Crespo J, Calleja JL, Villani R, Serviddio G, Zanetto A, Shalaby S, Russo FP, Bielen R, Trevisani F, Cammà C, Bruix J, Cabibbo G, and Reig M

Subjects
Humans, Neoplasm Recurrence, Local diagnosis, Propensity Score, Antiviral Agents therapeutic use, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular therapy, Liver Neoplasms epidemiology, Liver Neoplasms therapy, Neoplasm Recurrence, Local epidemiology
Abstract

Objective: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration., Design: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson., Results: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I 2 =74.6%) and 5.7 (2.5 to 15.3, I 2 =54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1)., Conclusion: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified., Competing Interests: Competing interests: VS: travel funding from Bayer. FT: DSMB fees from Basilea Pharmaceutica International and ROVI; educational fees from Janssen and Ferrer. PN: consults for AbbVie, AstraZeneca, Bayer, BMS, Eisai, Gilead, Ipsen, Roche. He received grants from AbbVie and BMS. ZM: speaker fees and consultancy for Gilead and AbbVie. RT: personal fees from Merk Sharp & Dorme, Giliad Sciences and AbbVie GK. TM: personal fees from Merk Sharp & Dorme, Giliad Sciences and AbbVie GK. XF: consultancy fees for AbbVie and Gilead Sciences. HT: speaker fees from AbbVie, Gildead, MSD and Bayer. SB: consultancy fees and educational grants from: Gilead Sciences, MSD, Intercept. ED: advisory board from AbbVie; speaking and teaching from Gilead, MSD, AbbVie. M-LY: research grant from Abbott, BMS, Gilead and Merck; consultant of AbbVie, Abbott, BMS, Gilead, Merck and Roche; speaker of AbbVie, Abbott, BMS, Gilead and Merck. YA: donation-funded department funded by Toray Industries Inc., Gilead Sciences, AbbVie GK and Fuji Rebio Inc. AS: has received research funding from AbbVie and Gilead. He has served as a consultant for Wako Diagnostics, Glycotest, Exact Sciences, Roche, GRAIL, Genentech, Bayer, Eisai, Exelixis, AstraZeneca, BMS and TARGET Pharmasolutions. MK: lecture fees from Abott and AstraZeneca. J-FD: advisory committees: AbbVie, Bayer, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, Novartis. Speaking and teaching: Bayer, Bristol-Myers Squibb, Intercept, Genfit, Gilead Sciences, Novartis, Roche. NM: research founding, lecture fees, advisory committees and travel grants from MSD. Lecture fees, advisory committees and travel grants from AbbVie and Gilead. SP: consulting and lecturing fees from Janssen, Gilead, MSD, AbbVie, Biotest, Shinogui, Viiv and grants from Bristol-Myers Squibb, Gilead, Roche and MSD, without relation to this manuscript. JC: grants and research support from Gilead Sciences, AbbVie, MSD, Shionogi and Intercept Pharmaceuticals (all outside the submitted work). Is a speaker for Gilead Sciences and AbbVie. JLC: reports grant support and/or consultancy and lecture fees from AbbVie, Gilead Sciences, Bristol-Myers Squibb, Janssen and MSD. RV: research grant from AbbVie. GS: consultancy fees and lecture fees from Gilead and AbbVie. FPR: lecture fees AbbVie, Gilead, MSD, Biotest; travel funds AbbVie, Biotest, Kedrion; research funds AbbVie, Gilead, MSD. RB: research grants from MSD, AbbVie and Gilead. JR: educational grants from Amgen, Grüenenthal Pharma, Boehringer Ingelheim España, Janssen-Cilag, Ferrer International, Lilly, Merck Sharp & Dohme and Roche Farma. FT: consultancy fees from AstraZeneca, Bayer, BMS, Eisai and Sirtex. Lecture fees from AlfaSigma and Bayer. Research grants from Bayer. CC: consultancy fees from Bayer, EISAI, MSD, Gilead, ABV. JB: consultancy fees from Arqule, Bayer, Novartis, BMS, BTG-Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance/Onxeo, Roche, AbbVie, Merck, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, Basilea, Nerviano. Research grants from Bayer and BTG. Educational grants from Bayer and BTG. Lecture fees from Bayer, BTG-Biocompatibles, Eisai, Terumo, Sirtex, Ipsen. GC: consultancy fees from Bayer, Ipsen. MR: consultancy fees from Bayer, BMS, Roche, Ipsen, AstraZeneca and Lilly. Lecture fees from Bayer, BMS, Gilead, Lilly and Roche. Research grants from Bayer and Ipsen., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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147. Prothrombin induced by vitamin K absence or antagonist-II and alpha foetoprotein to predict development of hepatocellular carcinoma in Caucasian patients with hepatitis C-related cirrhosis treated with direct-acting antiviral agents.

Author

Degasperi E, Perbellini R, D'Ambrosio R, Uceda Renteria SC, Ceriotti F, Perego A, Orsini C, Borghi M, Iavarone M, Bruccoleri M, Rimondi A, De Silvestri A, Sangiovanni A, and Lampertico P

Subjects
Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Female, Humans, Liver Cirrhosis diagnosis, Liver Cirrhosis virology, Male, Middle Aged, Protein Precursors, ROC Curve, Vitamin K, Antiviral Agents therapeutic use, Carcinoma, Hepatocellular diagnosis, Carcinoma, Hepatocellular virology, Hepatitis C, Chronic complications, Hepatitis C, Chronic drug therapy, Liver Neoplasms diagnosis, Liver Neoplasms virology, Prothrombin analysis, alpha-Fetoproteins analysis
Abstract

Background: Prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha fetoprotein (AFP) are biomarkers for hepatocellular carcinoma (HCC). However, their performance in patients with cirrhosis related to hepatitis C virus (HCV) treated with direct-acting antiviral agents (DAA) is unknown., Aim: To evaluate PIVKA-II and AFP as HCC predictors in DAA-treated patients with HCV-related cirrhosis METHODS: In this single centre study, patients with cirrhosis from chronic HCV infection and with a sustained virological response (SVR) to DAA were tested for PIVKA-II and AFP (Fujirebio, Japan) at the start of DAA treatment (baseline), end of treatment (EOT) and at HCC diagnosis., Results: We included 400 patients with mean age 65 (24-92); 56% were men. From baseline to EOT, PIVKA-II did not change (35 vs 35 mAU/mL, P = 0.43) while AFP significantly decreased (12 vs 6 ng/mL, P < 0.0001). After 52 (3-66) months from baseline, 34 (8.5%) patients developed de novo HCC; median AFP 9 (2-12 868) ng/mL and PIVKA-II 80 (22-1813) mAU/mL. EOT-PIVKA-II (HR 3.05, P < 0.0001) and AFP (HR 2.77, P = 0.001) independently predicted HCC together with diabetes (HR 6.12, P < 0.001) and GGT (HR 1.01, P = 0.03). The 4-year cumulative probability of HCC was 24% vs 2% in patients with EOT-PIVKA-II > or ≤41 mAU/mL (P < 0.0001), and 26% vs 9% for EOT-AFP > or ≤15 ng/mL (P = 0.02). By combining EOT-PIVKA-II and AFP, the 4-year probabilities of HCC were 3% in patients testing negative for both markers, 18% in patients positive for both, and 38% in patients positive for at least one (P < 0.0001)., Conclusions: In patients with HCV-related cirrhosis treated with DAA, PIVKA-II and AFP independently predicted HCC, while their combination improved risk stratification., (© 2021 John Wiley & Sons Ltd.)

Published
2022
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148. Incidence of liver- and non-liver-related outcomes in patients with HCV-cirrhosis after SVR.

Author

D'Ambrosio R, Degasperi E, Anolli MP, Fanetti I, Borghi M, Soffredini R, Iavarone M, Tosetti G, Perbellini R, Sangiovanni A, Sypsa V, and Lampertico P

Subjects
Aged, Antiviral Agents therapeutic use, Chi-Square Distribution, Cohort Studies, Female, Hepacivirus drug effects, Hepacivirus pathogenicity, Hepatitis C epidemiology, Humans, Incidence, Male, Middle Aged, Outcome Assessment, Health Care methods, Proportional Hazards Models, Hepatitis C complications, Outcome Assessment, Health Care statistics & numerical data, Sustained Virologic Response
Abstract

Background & Aims: As the long-term benefits of a sustained virological response (SVR) in HCV-related cirrhosis following direct-acting antiviral (DAA) treatment remain undefined, we assessed the incidence and predictors of liver-related events (LREs), non-liver-related events (NLREs) and mortality in DAA-treated patients with cirrhosis., Methods: Consecutive patients with cirrhosis and SVR were enrolled in a longitudinal, single-center study, and divided into 3 cohorts: Cohort A (Child-Pugh A without a previous LRE), Cohort B (Child-Pugh B or Child-Pugh A with prior non-hepatocellular carcinoma [HCC] LREs), Cohort C (previous HCC)., Results: A total of 636 patients with cirrhosis (median 65 years-old, 58% males, 89% Child-Pugh A) were followed for 51 (8-68) months (Cohort A n = 480, Cohort B n = 89, Cohort C n = 67). The 5-year estimated cumulative incidences of LREs were 10.4% in Cohort A vs. 32.0% in Cohort B (HCC 7.7% vs. 19.7%; ascites 1.4% vs. 8.6%; variceal bleeding 1.3% vs. 7.8%; encephalopathy 0 vs. 2.5%) vs. 71% in Cohort C (HCC only) (p <0.0001). The corresponding figures for NLREs were 11.7% in Cohort A vs. 17.9% in Cohort B vs. 17.5% in Cohort C (p = 0.32). The 5-year estimated probabilities of liver-related vs. non-liver-related deaths were 0.5% vs. 4.5% in Cohort A, 16.2% vs. 8.8% in Cohort B and 12.1% vs. 7.7% in Cohort C. The all-cause mortality rate in Cohort A was similar to the rate expected for the general population stratified by age, sex and calendar year according to the Human Mortality Database, while it was significantly higher in Cohort B., Conclusions: Patients with cirrhosis and an SVR on DAAs face risks of liver-related and non-liver-related events and mortality; however, their incidence is strongly influenced by pre-DAA patient history., Lay Summary: In this large single-center study enrolling patients with hepatitis C virus (HCV)-related cirrhosis cured by direct-acting antivirals, pre-treatment liver disease history strongly influenced long-term outcomes. In patients with HCV-related cirrhosis, hepatocellular carcinoma was the most frequent liver-related complication after viral cure. Due to improved long-term outcomes, patients with cirrhosis after HCV cure are exposed to a significant proportion of non-liver-related events., Competing Interests: Conflict of interest Roberta D’Ambrosio: Advisory Board: AbbVie, Gilead; Speaking and teaching: AbbVie, Gilead, MSD, BMS; Research support: Gilead. Elisabetta Degasperi: Advisory Board: AbbVie; Speaking and teaching: Gilead, MSD, AbbVie. Massimo Iavarone: Speaking and Teaching: Bayer, Gilead Science, Janssen, BTG, AbbVie; Consultant: BTG. Angelo Sangiovanni: Speaker Bureau: Bayer, Gilead Science, Janssen, BTG, AbbVie, Novartis; Advisory board: Tiziana Life sciences. Pietro Lampertico: Advisory Board/Speaker Bureau for: BMS, ROCHE, GILEAD SCIENCES, GSK, ABBVIE, MSD, ARROWHEAD, ALNYLAM, JANSSEN, SPRING BANK, MYR, EIGER. Other authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2022
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150. The CCR5 and CXCR3 Pathways in Hepatitis C Virus Liver Transplanted Recipients Treated by a Direct Antiviral Agent Regimen: Informative Kinetics Profiles.

Author

Colucci G, Invernizzi F, Uceda Renteria S, Perbellini R, Degasperi E, D'Ambrosio R, Galmozzi E, Lunghi G, Sguazzini E, Lampertico P, and Donato MF

Subjects
Antiviral Agents therapeutic use, Humans, Kinetics, Receptors, CCR5 genetics, Receptors, CXCR3, Retrospective Studies, Hepacivirus genetics, Hepatitis C, Chronic drug therapy
Abstract

The CC5 and CXC3 chemokines (CK) pathways are involved in the pathogenesis and outcome of several disease states, including chronic hepatitis C (CHC). The kinetics of Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) (CCL5) and IP-10 (CXCL10) during direct-acting antivirals (DAA) treatment was retrospectively analyzed in 18 liver transplant recipients (LT-R) compared with 20 patients with CHC and 49 healthy controls (HC). CK levels were determined at baseline, week 4, end of treatment, 24 weeks post-treatment (sustained virological response [SVR]), and later-on during follow-up (FU), 12 and 24 months post-DAA. At baseline, median RANTES levels were higher in HC than in both LT-R ( p  > 0.01) and CHC ( p  > 0.01), whereas IP-10 levels were higher in LT-R and CHC than in HC ( p  > 0.05 and p  = 0.01), respectively. Mean RANTES values increased during DAA therapy to peak at SVR and FU with significantly higher levels than at baseline in LT-R ( p  < 0.01) and in CHC, but only at FU ( p  < 0.003). A subsequent return to baseline or lower levels was observed at extended FU. On the contrary, IP-10 values showed a significant decrease from baseline to SVR and FU in both LT-R ( p  < 0.03) and CHC ( p  < 0.01). RANTES profiles during the first 4 weeks of DAA treatment showed an increase or decrease from baseline according to baseline RANTES levels. CCR5 genotyping in LT-R showed the presence of 1 homozygous Δ32/Δ32 and 2 heterozygous WT/Δ32 haplotypes with a prevalence of 5.5% and 11.1%, respectively. In conclusion, although IP-10 showed the expected kinetics, the CC5 pathway appears extensively altered during CHC infection: monitoring these patients may be indicated as they may be at risk of other infections or immune-mediated disorders.

Published
2021
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