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Original research
Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis
  1. Victor Sapena1,
  2. Marco Enea2,
  3. Ferran Torres3,4,
  4. Ciro Celsa2,5,
  5. Jose Rios3,4,
  6. Giacomo Emanuele Maria Rizzo2,
  7. Pierre Nahon6,
  8. Zoe Mariño7,
  9. Ryosuke Tateishi8,
  10. Tatsuya Minami8,
  11. Angelo Sangiovanni9,10,
  12. Xavier Forns7,
  13. Hidenori Toyoda11,
  14. Stefano Brillanti12,
  15. Fabio Conti12,
  16. Elisabetta Degasperi9,10,
  17. Ming-Lung Yu13,14,
  18. Pei-Chien Tsai13,
  19. Kevin Jean15,16,
  20. Mohamed El Kassas17,
  21. Hend Ibrahim Shousha18,
  22. Ashraf Omar18,
  23. Claudio Zavaglia19,
  24. Hiroko Nagata20,
  25. Mina Nakagawa21,22,
  26. Yasuhiro Asahina23,
  27. Amit G Singal24,
  28. Caitlin Murphy24,
  29. Mohamed Kohla25,
  30. Chiara Masetti26,
  31. Jean-François Dufour27,28,
  32. Nicolas Merchante29,
  33. Luisa Cavalletto30,
  34. liliana LC chemello30,
  35. Stanislas POL31,
  36. Javier Crespo32,33,
  37. Jose Luis Calleja34,35,
  38. Rosanna Villani36,
  39. Gaetano Serviddio36,
  40. Alberto Zanetto37,
  41. Sarah Shalaby37,
  42. Francesco Paolo Russo37,
  43. Rob Bielen38,39,
  44. Franco Trevisani40,
  45. Calogero Cammà2,
  46. Jordi Bruix1,
  47. Giuseppe Cabibbo2,
  48. Maria Reig1
  1. 1 Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD, Hospital Clinic de Barcelona, Barcelona, Spain
  2. 2 Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Sicilia, Italy
  3. 3 Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
  4. 4 Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
  5. 5 Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Palermo, Sicilia, Italy
  6. 6 AP-HP, Hôpital Jean Verdier, Service d’Hépatologie, Bondy; Université Paris 13, Sorbonne Paris Cité, “Equipe labellisée Ligue Contre le Cancer”, F-93206 Saint-Denis; Inserm, UMR-1162, “Génomique fonctionnelle des tumeurs solides”, F-75000, Bondy, France
  7. 7 Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, University of Barcelona, CIBEREHD, Barcelona, Spain
  8. 8 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  9. 9 Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Maggiore Hospital, University of Milan, Milan, Italy
  10. 10 CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy
  11. 11 Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
  12. 12 Department of Medical and Surgical Sciences (DIMEC), Research Centre for the Study of Hepatitis, University of Bologna, Bologna, Italy
  13. 13 Hepatobiliary Division, Department of Internal Medicine and Hepatitis, Center Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
  14. 14 Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
  15. 15 Laboratoire MESuRS (EA 4628), Conservatoire National Des Arts et Métiers, Paris, France
  16. 16 Unité PACRI, Institut Pasteur, Conservatoire National des Arts et Métiers, Paris, France
  17. 17 Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt
  18. 18 Endemic Medicine and Hepato-Gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt
  19. 19 Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milano, Lombardia, Italy
  20. 20 Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  21. 21 Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  22. 22 Institute of Education, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  23. 23 Department of Gastroenterology and Hepatology, Liver Disease Control, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
  24. 24 Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
  25. 25 Hepatology, National Liver Institute, Shebin El-Kom, Egypt
  26. 26 Liver and Transplant Unit, Policlinico Tor Vergata, Rome, Italy
  27. 27 Hepatology, Department of Clinical Research, University Clinic for Visceral Surgery and Medicine Inselspital, Bern, Switzerland
  28. 28 Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland
  29. 29 Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Seville, Spain
  30. 30 Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases, Padova, Italy
  31. 31 l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France
  32. 32 Gastroenterology and Hepatology Service, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Spain
  33. 33 Facultad de Medicina, Universidad de Cantabria, Santander, Cantabria, Spain
  34. 34 Gastroenterology and Hepatology, IDIPHIM, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain
  35. 35 (CIBEREHD), Instituto de Salud Carlos III, Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Madrid, Spain
  36. 36 Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
  37. 37 Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, University of Padova, Padova, Italy
  38. 38 Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Limburg, Belgium
  39. 39 Department of Gastro-Enterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Limburg, Belgium
  40. 40 Department of Medical and Surgical Sciences, Semeiotics Unit, Alma Mater Studiorum—University of Bologna, Bologna, Italy
  1. Correspondence to Dr Maria Reig, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain; MREIG1{at}clinic.cat; Dr Giuseppe Cabibbo, Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy; giuseppe.cabibbo78{at}gmail.com

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, 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; 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.

  • hepatocellular carcinoma
  • antiviral therapy
  • meta-analysis

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Footnotes

  • Twitter @Sbrillanti, @policlinicoMI, @kvn_jean, @docamitgs, @dufour_jf, @nicomerchante;@AGSSurSevilla;@GEHEP_;@SEIMC_;@SAEI_tweets;@hepavir, @DRJLCalleja;@DigestivoPdH;@IDIPHIM, @fprusso73;@ServizioRicerc, @bruixj;@BCLC_group;@hospitalclinic;@CIBERehd, @cabibbo78;@PROMISEUnipaHCC, @ma5RN;@BCLC_group;@hospitalclinic;@CIBERehd

  • VS and ME contributed equally.

  • FT and CC contributed equally.

  • Collaborators Alejandro Forner (Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD, Barcelona, Spain), A. Brega (Tor Vergata University Hospital, Department of Infectious Disease), A. De Santis (Sapienza University of Rome, Gastroenterology Unit), Antonio Facciorusso (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), A. Mario (Tor Vergata University Hospital, Liver and Transplant Unit), A. Pellicelli (Policlinico Tor Vergata, Department of Infectious Disease), A. Picardi (University Campus Biomedico, Internal Medicine and Hepatology Unit), Alberto Masotto (Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar, Italy), Annamaria Piscazzi (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), Antonio Gasbarrini (Internal Medicine and Gastroenterology Unit, Policlinico Gemelli, Università Cattolica del Sacro Cuore, Roma, Italy), Adel El Tahan (New Cairo Viral Hepatitis Treatment Unit, Cairo, Egypt), Agustin Albillos (Hospital Universitario 12 de octubre, Madrid, Spain), Ahmad T. Sweedy (New Cairo Viral Hepatitis Treatment Unit, Cairo, Egypt), Ahmed A. Cordie (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Ahmed H. Abdelmaksoud (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Alba Díaz (Department of Pathology, BCLC Group, Hospital Clínic Barcelona, IDIBAPS, University of Barcelona, Spain), Alberto Ferrarese (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), Alessandra Biasiolo (Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases), Alessandra Scuteri (Department of Digestive Diseases, Policlinico S. Orsola-Malpighi, Bologna, Italy), Alessandro Vitale (Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology Unit), Alessio Aghemo (Department of Internal Medicine, Humanitas Clinical and Research Center IRCCS, Rozzano-Milan, Italy), Andrea Ribeiro (Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Universidad de Barcelona, CIBEREHD Barcelona, Spain), Andrea Mega (Gastroenterology Unit, Bolzano Regional Hospital, Bolzano, Italy), Anna Darnell (Department of Radiology, BCLC Group, Hospital Clinic Barcelona, University of Barcelona, Spain), Anna Funk (Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France), Anna Licata (Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy), Anna Ludovica Fracanzani (Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy), Antonietta Romano (Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases), Antonio Ciaccio (Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy), Antonio Craxì (Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy), Antonio Rivero-Juárez (Instituto Maiomónides de Investigación Biomédica de Córdoba (IMIBIC). Hospital Universitario Reina Sofía, Córdoba, Arnaud Fontanet (Unité PACRI, Institut Pasteur, Conservatoire National des Arts et Métiers, Paris, France, Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France), Ayako Sato (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Begoña Sacristán (Hospital San Pedro, Logroño, Spain), Belén Ruiz-Antorán (Hospital Universitario Puerta de Hierro, Madrid, Spain), Boris Revollo (Hospital German Trias i Pujol, Badalona), Bruno Sangro (Unidad de Hepatología, Clínica Universidad de Navarra, IDISNA, CIBEREHD Pamplona, Spain), C. Dell’unto (University Campus Biomedico, Internal Medicine and Hepatology Unit), C. Taibi (National Institute for Infectious Diseases Spallanzani, Infectious Diseases-Hepatology), Camillo Aliberti (Department of Interventistic Radiology, Oncologic Istitute of Veneto Region, IOV), Carmen Alvarez Navascues (Hospital Universitario Central de Asturias, Oviedo, Spain), Céline Dorival (l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France), Chantal de Galocsy (Department of Gastro-Enterology and Hepatology, Hôpital HIS Bracops, Anderlecht, Brussels, Belgium), Chiara Mazzarelli (Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milan, Italy), Christian Brixco (Department of Gastroenterology and Digestive Oncology, CHR Citadelle, Liège, Belgium), Christie Perelló (Liver Unit, Hospital Universitario Puerta de Hierro, CIBEREHD IDIPHIM, Madrid, Spain), Christophe Moreno (Department of Gastro-Enterology and Hepatopancreatology, Erasme Hospital, Brussels, Belgium), Christophe Van Steenkiste (Department of Hepatology and Gastro-Enterology, University Hospitals Gent, Gent, Belgium, Department of Gastro-Enterology and Hepatology, AZ Maria Middelares, Gent, Belgium), Chung-Feng Huang (Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan), Claudia Mescoli (Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy), Conrado Fernández Rodriguez (Hospital Universitario Fundación Alcorcón, Madrid, Spain), Cristina Crespi (Department of Digestive Diseases, Policlinico S.Orsola-Malpighi, Bologna, Italy), Dalia A. Omran (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Daniel M. Forton (Department of Gastroenterology and Hepatology, St. George’s University Hospitals National Health Service Foundation Trust, London, UK), David Semela (Division of Gastroenterology and Hepatology, Cantonal Hospital St Gallen, St Gallen, Switzerland), Diego Rincón (Complejo Hospitalario de Huelva, Huelva, Spain), E. Teti (Tor Vergata University Hospital, Department of Infectious Disease), Edoardo G. Giannini (Department of Internal Medicine, Gastroenterology Unit, University of Genova, IRCCS Policlinico San Martino, Genova, Italy), Eleonora Alimenti (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology—CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy), Elia Biganzoli (Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico—University of Milan, Milan, Italy), Elisabetta Parente (Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy), Eman M. Hassan (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Enas Maged (Epidemiology, National Liver Institute, Shebeen El-Kom, Egypt), Enrica Franceschet (Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, Padua University Hospital, Padua, Italy), Erica Villa (Gastroenterology Unit, Azienda Ospedalie-ro-Universitaria Policlinico di Modena, Modena, Italy), Esperanza Merino (Hospital General Universitario de Alicante, Alicante), Eugenio Caturelli (Department of Medical and Surgical Sciences, Internal Medicine–Zoli Unit, Alma Mater Studiorum—University of Bologna, Bologna, Italy), F. Ponziani (A. Gemelli Hospital, Gastroenterology and Hepatology), Fabio Cartabellotta (Medicina Interna, Ospedale Buc-cheri La Ferla, Palermo, Italy), Fabio Farinati (Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy), Fabio Marra (Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Firenze, Italy), Fabio Piscaglia (Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Internal Medicine–Piscaglia Unit, Bologna, Italy), Fabio Tinè (Gastroenterologia, A.O. Villa Sofia-Cervello, Palermo, Italy), Fabrice Carrat (l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France), Federica Buonfiglioli (Research Centre for the Study of Hepatitis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Federica Cerini (Division of Hepatology, Ospedale San Giuseppe, Università degli Studi di Milano, Milano, Italy), Filip Janssens (Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium, Department of Gastro-Enterology and Hepatology, Jessa Hospital, Hasselt, Belgium), Filippo Oliveri (Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine, University of Pisa, Pisa, Italy), Filomena Morisco (Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Napoli "Federico II", Napoli, Italy), Francesco Bellanti (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), Francesco Benanti (Malattie Infettive, A.O. Cannizzaro, Catania, Italy), Francesco Giuseppe Foschi (Department of Internal Medicine, Ospedale per gli Infermi of Faenza, Faenza, Italy), Francesco Azzaroli (Department of Surgical and Medical Sciences, Gastroenterology Unit, Alma Mater Studiorum—University of Bologna, Bologna, Italy), Francisco Gea (Hospital Universitario Ramon y Cajal, Madrid, Spain), Francisco J. Vera-Méndez (Hospital General Universitario de Santa Lucía, Cartagena), Francisco Jorquera (Complejo Asistencial Universitario León, León, IBIOMED and CIBEREHD Spain), Francisco Rodríguez-Arrondo (Hospital Universitario de Donostia, San Sebastián), Francisco Téllez (Hospital Universitario de Puerto Real, Hospital de La Línea, Instituto de Investigación e Innovación en Ciencias Biomédicas de la provincia de Cádiz (INiBICA), Cádiz), Francois D’Heygere (Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium, Department of Gastro-Enterology and Hepatology, AZ Groeninge, Kortrijk, Belgium), Frederik Nevens (Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium), Fukiko Kawai-Kitahata (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), G. D’offizi (National Institute for Infectious Diseases Spallanzani, Infectious Diseases-Hepatology), G. Galati (University Campus Biomedico, Internal Medicine and Hepatology Unit), Gabriella Verucchi (Research Centre for the Study of Hepatitis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Gabriele Missale (Infectious Diseases and Hepatology Unit, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy), Gaetano Bertino (Medicina Interna e d’Urgenza, A.O.U.P Vittorio Emanuele, Catania, Italy), Gaetano Scifo (Malattie Infettive, Ospedale di Siracusa, Siracusa, Italy), Gaia Pellegatta (Department of Internal Medicine, Gastroenterology Unit, University of Genova, IRCCS Policlinico San Martino, Genova, Italy), Gamal Esmat (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Gasser El-Azab (Hepatology, National Liver Institute, Shebeen El-Kom, Egypt), Geert Robaeys (Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium, Department of Gastro-Enterology and Hepatology, Ziekenhuis-Oost Limburg, Genk, Belgium, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium), Gerardo Nardone (Department of Clinical Medicine and Surgery, Hepato‐Gastroenterology Unit, University of Napoli "Federico II", Napoli, Italy), Giacomo Germani (Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, Padua University Hospital, Padua, Italy), Gian Ludovico Rapaccini (Gastroenterology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy), Gianluca Svegliati-Baroni (Gastroenterology Unit, Polytechnic University of Marche, Ancona, Italy), Gianluigi Vendemiale (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), Gianpolo Vidili (Department of Medical, Surgical and Experimental Sciences. Clinica Medica Unit, University of Sassari, Azienda Ospedaliero-Universitaria of Sassari, Sassari, Italy), Giovanna Lunghi (Microbiology and Virology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy), Giovanni Mazzola (Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy), Giovanni Raimondo (Department of Clinical and Experimental Medicine, Clinical and Molecular Hepatology Unit, University of Messina, Messina, Italy), Giovanni Squadrito (Department of Clinical and Experimental Medicine, Clinical and Molecular Hepatology Unit, University of Messina, Messina, Italy), Giuseppe Mazzella (Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Guglielmo Borgia (Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Napoli ‘Federico II', Napoli, Italy), Guillermo Ojeda-Burgos (Hospital Virgen de la Victoria, Málaga), Hans Van Vlierberghe (Department of Hepatology and Gastro-Enterology, University Hospitals Gent, Gent, Belgium), Hayato Nakagawa (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), Helene Fontaine (l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France), Hideki Sakai (Kashiwa Municipal Hospital, Chiba, Japan), Ignazio Scalisi (Medicina Interna, Ospedale di Castelvetrano, Castelvetrano, Italy), Ilaria Serio (Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy), Inmaculada Fernandez (Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy), Irene Cacciola (Department of Internal Medicine, University of Messina, Messina, Italy), Isabelle Vögeli (University Clinic for Visceral Surgery and Medicine Inselspital Bern, Bern, Switzerland), Javier Ampuero (Hospital Universitario Virgen del Rocío, IBIS and CIBEREHD, Spain), Javier García-Samaniego (Hospital Universitario La Paz, CIBEREHD IdiPAZ, Madrid, Spain), Jean-Pierre Mulkay (Department of Gastro-Enterology and Hepatology, Hôpital Saint-Pierre, Brussels, Belgium), Jochen Decaestecker (Department of Gastro-Enterology and Hepatology, AZ Delta, Roeselare, Belgium, Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium), Johannes Vermehren (Department of Medicine I, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt am Main, Germany), Jordi Llaneras (Hospital Universitario Vall D’Hebrón, Barcelona, Spain), Joseba Portu (Hospital Txagorritxu, Vitoria), Juan A. Pineda (Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla), Juan Arenas (Hospital Universitario Donostia, San Sebastian, Spain), Juan Macías (Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla), Juan Manuel Pascasio (Hospital Universitario Virgen del Rocío and CIBEREHD, Seville, Spain), Juan Turnes (Complejo Hospitalario Universitario de Pontevedra and IISGS, Spain), Junko Tanaka (Department of Epidemiology, Infectious Disease Control and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan), Kazuyuki Mizuno (Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki Japan), Katrien Wuyckens (Faculty of Medicine and Life sciences, Hasselt University, Hasselt, Belgium, Department of Gastro-Enterology and Hepatology, Ziekenhuis-Oost Limburg, Genk, Belgium), Kazuhiko Koike (Department of Gastroenterology, Juntendo University, Japan), Kenichiro Enooku (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), Koldo Aguirrebengoa (Hospital de Cruces, Bilbao), Laura Virginia Forzenigo (Unit of Radiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy), Licia Larocca (Malattie Infettive, ARNAS Garibaldi-Nesima, Catania, Italy), Lode Van Overbeke (Department of Gastro-Enterology and Hepatology, AZ Sint Maarten, Mechelen, Belgium), Luca Saverio Belli (Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milan, Italy, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy), Luca Valenti (Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy), Luca Marzi (Gastroenterology Unit, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.), Lucia Cesarini (Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milan, Italy), Luigi Bolondi (Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Luis Metola (Hospital de San Pedro, Logroño), Lydia Giannitrapani (Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy), M. Andreoni (Policlinico Tor Vergata, Department of Infectious Disease), Matteo Landriscina (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), M. Lupo (National Institute for Infectious Disease Spallanzani, Infectious Diseases- Hepatology), M. Montalbano (National Institute for Infectious Diseases Spallanzani, Infectious Diseases-Hepatology), M. Pompili (A. Gemelli Hospital, Internal Medicine, Gastroenterology and Hepatology), M. Siciliano (Internal Medicine and Gastroenterology Unit, Policlinico Gemelli, Università Cattolica del Sacro Cuore, Roma, Italy), Makoto Tomita (Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan), Mamoru Watanabe (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Marcial Delgado-Fernández (Hospital Regional Universitario de Málaga, Málaga), Marco Barbàra (Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy), Marco Distefano (Malattie Infettive, Ospedale di Siracusa, Siracusa, Italy), Marco Lenzi (Research Centre for the Study of Hepatitis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Marco Senzolo (Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, Padua University Hospital, Padua, Italy), Marco Zoli (Department of Medical and Surgical Sciences, Internal Medicine–Zoli Unit, Alma Mater Studiorum—University of Bologna, Bologna, Italy), María A. García (Complejo Hospitalario de Huelva, Huelva, Spain), Maria Di Marco (Medicine Unit, Bolognini Hospital, Seriate, Italy), María García-Eliz (Hospital Universitario La Fe and CIBEREHD, Valencia, Spain), María J. Galindo (Hospital Clínico Universitario de Valencia), María J. Ríos-Villegas (Hospital Universitario Virgen Macarena, Sevilla), María Remedios Aleman-Valls (Hospital Universitario de Canarias, San Cristóbal de La Laguna, Tenerife), Maria Rita Cannavò (Epatologia, A.O. Cannizzaro, Catania, Italy), María Varela (IUOPA.ISPA, Liver Unit, Hospital Universitario Central de Asturias, Oviedo, Spain), Mario Strazzabosco (Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy), Marion Willaime (l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France), Marta Borghi (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology—CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy), Marta Montero (Hospital General de Valencia, Valencia), Martina Gambato (Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy), Masato Miyoshi (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Masaya Sato (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), Massimo Colombo (Department of Internal Medicine, Humanitas Clinical and Research Center IRCCS, Rozzano-Milan, Italy), Massimo Iavarone (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology—CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy), Massimo Rugge (Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy), Matteo Brunacci (Department of Internal Medicine, Gastroenterology Unit, University of Genova, IRCCS Policlinico San Martino, Genova, Italy), Maurizia Rossana Brunetto (Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine, University of Pisa, Pisa, Italy), Maurizio Russello (Epatologia, A.O. Cannizzaro, Catania, Catania, Italy), Medhat Assem (Hepatology, National Liver Institute, Shebeen El-Kom, Egypt), Mercedes Iñarrairaegui (Unidad de Hepatología, Clínica Universidad de Navarra, IDISNA, CIBEREHD Pamplona, Spain), Michele Barone (Gastroenterology Unit, Department of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Bari, Italy), Miguel A. López-Ruz (Hospital Universitario Virgen de las Nieves, Granada), Miguel A. Serra (Hospital Clínico de Valencia, Valencia, Spain), Miguel A. Simon (Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain), Miguel García-Deltoro (Hospital General de Valencia, Valencia), Miguel Raffo (Complejo Hospitalario de Huelva, Huelva, Spain), Mike Cool (Department of Gastro-Enterology and Hepatology, University Hospitals KULeuven, Leuven, Belgium, Department of Gastro-Enterology and Hepatology, AZ Damiaan, Oostende, Belgium), Miyako Murakawa (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan, Department of Clinical Laboratory, Tokyo Medical and Dental University, Japan), Mobolaji Odewole (Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, USA), Mohamed M. Nabil (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Mohamed Omar (Complejo Hospitalario de Jaén, Jaén), Mohammed Eltabbakh (Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt), Mohammed Salaheldin Abdelhamid (Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt), Moises Diago (Hospital Universitario General de Valencia, Valencia, Spain), Naglaa FA Youssef (Medical Surgical Nursing Department, Faculty of Nursing, Cairo University, Cairo, Egypt), Naoto Fujiwara (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), Natalia M. Terreni (Division of Gastroenterology, Valduce Hospital, Como, Italy), Nicola Alessi (Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy), Nicole Rich (Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, USA), Oliver Waidmann (Department of Medicine I, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt am Main, Germany), Paolo Angeli (Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases), Paolo Caraceni (Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Patrizia Burra (Gastroenterology/Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology Unit, Padua University Hospital, Padua, Italy), Patrizia Pontisso (Department of Medicine-DIMED, Padua University, University Hospital, Clinica Medica 5, Refering Center for Liver Diseases), Pietro Andreone (Research Centre for the Study of Hepatitis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Italy), Pietro Lampertico (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology—CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy), R. Lionetti (National Institute for Infectious Disease Spallanzani, Infectious Diseases-Hepatology), Rafael Bañares (Hospital General Universitario Gregorio Marañón, Facultad de Medicina de la Universidad Complutense and CIBEREHD Madrid, Spain), Ramón Vilana (Department of Radiology, BCLC Group, Hospital Clinic Barcelona, University of Barcelona, Spain), Rania Leithy (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Raquel Muñoz (Hospital Universitario 12 de octubre, Madrid, Spain), Riccardo Gattai (Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine, University of Pisa, Pisa, Italy), Roberta D’Ambrosio (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology—CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy), Roberta Soffredini (Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology—CRC “A.M. and A. Migliavacca” Center for Liver Disease, Milan, Italy), Roberto Filomia (Department of Clinical and Experimental Medicine, Clinical and Molecular Hepatology Unit, University of Messina, Messina, Italy), Rodolfo Sacco (Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy), Rosa Maria Morillas (Hospital Germans Trias I Pujol and CIBEREHD, Badalona, Spain), Rosanna Tamborra (Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy), Ryo Nakagomi (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), S. Francioso (Tor Vergata University Hospital, Department of Infectious Disease), Sabela Lens (Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, CIBEREHD, Barcelona, Spain), Salvatore Madonia (Medicina Interna, A.O. Villa Sofia-Cervello, Palermo, Italy), Salvatore Petta (Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy), Satoshi Otani (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Sayuri Nitta (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Sei Kakinuma (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Seishin Azuma (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Sergio Maimone (Department of Clinical and Experimental Medicine, Clinical and Molecular Hepatology Unit, University of Messina, Messina, Italy), Shimaa Afify (National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt), Shuichiro Shiina (Department of Gastroenterology, Juntendo University, Japan), Shun Kaneko (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Silvia Fargion (Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy), Sofía Ibarra (Hospital de Basurto, Bilbao), Stefan Bourgeois (Department of Gastro-Enterology and Hepatology, ZNA Stuivenberg, Antwerp, Belgium), Stefan Zeuzem (Department of Medicine I, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt am Main, Germany), Stefano Okolicsanyi (Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy), Susana Llerena (Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Cantabria, Spain), Tomoyuki Akita (Department of Epidemiology, Infectious Disease Control, and Prevention, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan), Takashi Kumada (Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan), Toshifumi Tada (Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan), Tamer M. Elbaz (Endemic Medicine and Hepato-Gastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt), Thomas Berg (Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany), Thomas Vanwolleghem (Department of Gastro-Enterology and Hepatology, Antwerp University Hospital, Edegem, Belgium), Tomoyuki Tsunoda (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Toshihiko Nouchi (Showa General Hospital, Tokyo, Japan), Tullio Prestileo (Malattie Infettive, ARNAS Civico-Di Cristina-Benefratelli, Palermo, Italy), U.V. Comandini (National Institute for Infectious Diseases Spallanzani, Infectious Diseases-Hepatology), U.V. Gentilucci (University Campus Biomedico, Internal Medicine and Hepatology Unit), Umberto Cillo (Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology Unit), V. Giannelli (San Camillo Forlanini Hospital, Liver Transplantation), Valerio Pontecorvi (Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy), Ventzislava Petrov Sanchez (l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France), Victor de Ledinghen (l’Agence de recherche ANRS (France REcherche Nord&Sud Sida-HIV Hépatites), Paris, France), Vincenza Calvaruso (Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy), Vito Di Marco (Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy), Wim Verlinden (Department of Gastro-Enterology and Hepatology, Antwerp University Hospital, Edegem, Belgium), Xavier Torras (Hospital Universitario Vall D’Hebrón, Barcelona, Spain), Yasmin Omar (University Campus Biomedico, Internal Medicine and Hepatology Unit), Yasuhiro Sone (Department of Radiology, Ogaki Municipal Hospital, Ogaki, Japan), Yasuhiro Itsui (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan, Department of General Medicine, Tokyo Medical and Dental University, Tokyo, Japan), Yoshinari Asaoka (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), Yu Asano (Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan), Yuji Kondo (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan), Yuji Kaneoka (Department of Surgery, Ogaki Municipal Hospital, Ogaki, Japan), Yusuke Shimakawa (Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France).

  • Contributors Conceptualisation: MR, FT, CC, GC, JB. Investigation: VS, MR, CC, GC, JB, VS, FT, all authors and collaborators. Supervision: MR, JB, FT, CC, GC. Statistical analysis: VS, FT, JR, ME. Writing—original draft: VS, GC, MR. Writing—review and editing: MR, JB, CC, all authors and collaborators. Approval of the final version of the manuscript to be published: MR, GC.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • 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.

  • Patient consent for publication Not required.

  • Ethics approval This study complied with the principles of the Declaration of Helsinki and its later amendments, and local and national laws. It was approved by the Research Ethics Committee of the Hospital Clinic of Barcelona (HCB/2019/0030).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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