Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure
Por:
Chen, Q, Perales, C, Soria, ME, Garcia-Cehic, D, Gregori, J, Rodriguez-Frias, F, Buti, M, Crespo, J, Calleja, JL, Tabernero, D, Vila, M, Lazaro, F, Rando-Segura, A, Nieto-Aponte, L, Llorens-Revull, M, Cortese, MF, Fernandez-Alonso, I, Castellote, J, Niubo, J, Imaz, A, Xiol, X, Castells, L, Riveiro-Barciela, M, Llaneras, J, Navarro, J, Vargas-Blasco, V, Augustin, S, Conde, I, Rubin, A, Prieto, M, Torras, X, Margall, N, Forns, X, Marino, Z, Lens, S, Bonacci, M, Perez-del-Pulgar, S, Londono, MC, Garcia-Buey, ML, Sanz-Cameno, P, Morillas, R, Martro, E, Saludes, V, Masnou-Ridaura, H, Salmeron, J, Quiles, R, Carrion, JA, Forne, M, Rosinach, M, Fernandez, I, Garcia-Samaniego, J, Madejon, A, Castillo-Grau, P, Lopez-Nunez, C, Ferri, MJ, Durandez, R, Saez-Royuela, F, Diago, M, Gimeno, C, Medina, R, Buenestado, J, Bernet, A, Turnes, J, Trigo-Daporta, M, Hernandez-Guerra, M, Delgado-Blanco, M, Canizares, A, Arenas, JI, Gomez-Alonso, MJ, Rodriguez, M, Deig, E, Olive, G, del Rio, O, Cabezas, J, Quinones, I, Roget, M, Montoliu, S, Garcia-Costa, J, Force, L, Blanch, S, Miralbes, M, Lopez-de-Goicoechea, MJ, Garcia-Flores, A, Saumoy, M, Casanovas, T, Baliellas, C, Gilabert, P, Martin-Cardona, A, Roca, R, Barenys, M, Villaverde, J, Salord, S, Camps, B, di Yacovo, MS, Ocana, I, Sauleda, S, Bes, M, Carbonell, J, Vargas-Accarino, E, Ruzo, SP, Guerrero-Murillo, M, Von Massow, G, Costafreda, MI, Lopez, RM, Gonzalez-Moreno, L, Real, Y, Acero-Fernandez, D, Viroles, S, Pamplona, X, Cairo, M, Ocete, MD, Macias-Sanchez, JF, Estebanez, A, Quer, JC, Mena-de-Cea, A, Otero, A, Castro-Iglesias, A, Suarez, F, Vazquez, A, Vieito, D, Lopez-Calvo, S, Vazquez-Rodriguez, P, Martinez-Cerezo, FJ, Rodriguez, R, Macenlle, R, Cachero, A, Mereish, G, Mora-Moruny, C, Fabregas, S, Sacristan, B, Albillos, A, Sanchez-Ruano, JJ, Baluja-Pino, R, Fernandez-Fernandez, J, Gonzalez-Portela, C, Garcia-Martin, C, Sanchez-Antolin, G, Andrade, RJ, Simon, MA, Pascasio, JM, Romero-Gomez, M, del-Campo, JA, Domingo, E, Esteban, R, Esteban, JI, Quer, J
Publicada:
1 feb 2020
Resumen:
A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients.
A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) alpha-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers.
Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received.
HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions.
Filiaciones:
Chen, Q:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Perales, C:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Soria, ME:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Garcia-Cehic, D:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Gregori, J:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Roche Diagnost SL, Barcelona, Spain
Rodriguez-Frias, F:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Buti, M:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Crespo, J:
Hosp Univ Marques Valdecilla, Inst Invest IDIVAL, Gastroenterol & Hepatol Dept, Santander, Spain
Calleja, JL:
Hosp Univ Puerta Hierro, Liver Unit, Madrid, Spain
Tabernero, D:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Vila, M:
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Lazaro, F:
Hosp Univ La Paz, Microbiol Dept, Madrid, Spain
Rando-Segura, A:
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Nieto-Aponte, L:
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Llorens-Revull, M:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Cortese, MF:
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Fernandez-Alonso, I:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Castellote, J:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Niubo, J:
Hosp Univ Bellvitge, Microbiol Dept, Barcelona, Spain
Imaz, A:
Hosp Univ Bellvitge, Infect Dis Dept, HIV & STI Unit, Barcelona, Spain
Xiol, X:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Castells, L:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Riveiro-Barciela, M:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Llaneras, J:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Navarro, J:
HUVH, Infect Dis Unit, Barcelona, Spain
Vargas-Blasco, V:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Augustin, S:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Conde, I:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ La Fe, Liver Unit, Valencia, Spain
Rubin, A:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ La Fe, Liver Unit, Valencia, Spain
Prieto, M:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ La Fe, Liver Unit, Valencia, Spain
Torras, X:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ Santa Creu & St Pau, Microbiol Dept, Barcelona, Spain
Margall, N:
Hosp Univ Santa Creu & St Pau, Digest Pathol Unit, Barcelona, Spain
Forns, X:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Clin Barcelona, Liver Unit, Inst Invest Biomed August Pi & Sunyer IDIBAP, Barcelona, Spain
Marino, Z:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Clin Barcelona, Liver Unit, Inst Invest Biomed August Pi & Sunyer IDIBAP, Barcelona, Spain
Lens, S:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Clin Barcelona, Liver Unit, Inst Invest Biomed August Pi & Sunyer IDIBAP, Barcelona, Spain
Bonacci, M:
Hosp Clin Barcelona, Liver Unit, Inst Invest Biomed August Pi & Sunyer IDIBAP, Barcelona, Spain
Perez-del-Pulgar, S:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Clin Barcelona, Liver Unit, Inst Invest Biomed August Pi & Sunyer IDIBAP, Barcelona, Spain
Londono, MC:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Clin Barcelona, Liver Unit, Inst Invest Biomed August Pi & Sunyer IDIBAP, Barcelona, Spain
Garcia-Buey, ML:
Hosp Univ Princesa, Liver Unit, Madrid, Spain
Sanz-Cameno, P:
Hosp Univ Princesa, Liver Unit, Madrid, Spain
Morillas, R:
Hosp Badalona Germans Trias & Pujol, Liver Unit, Barcelona, Spain
Martro, E:
Hosp Badalona Germans Trias & Pujol, Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Inst Recerca Germans Trias & Pujol IGTP, Microbiol Dept, Barcelona, Spain
Saludes, V:
Hosp Badalona Germans Trias & Pujol, Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Inst Recerca Germans Trias & Pujol IGTP, Microbiol Dept, Barcelona, Spain
Masnou-Ridaura, H:
Hosp Badalona Germans Trias & Pujol, Liver Unit, Barcelona, Spain
Salmeron, J:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Complejo Hosp Granada, Liver Unit, Granada, Spain
Quiles, R:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Complejo Hosp Granada, Liver Unit, Granada, Spain
Carrion, JA:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Mar, Liver Unit, Parc Salut Mar, Barcelona, Spain
Forne, M:
Hosp Univ Mutua Terrassa, Gastroenterol Unit, Barcelona, Spain
Rosinach, M:
Hosp Univ Mutua Terrassa, Gastroenterol Unit, Barcelona, Spain
Fernandez, I:
Univ 12 Octubre, Liver Unit, Madrid, Spain
Garcia-Samaniego, J:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ La Paz, Liver Unit, Inst Invest Hosp Univ La Paz IdiPAZ, Madrid, Spain
Madejon, A:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ La Paz, Liver Unit, Inst Invest Hosp Univ La Paz IdiPAZ, Madrid, Spain
Castillo-Grau, P:
Hosp Univ La Paz, Liver Unit, Inst Invest Hosp Univ La Paz IdiPAZ, Madrid, Spain
Lopez-Nunez, C:
Hosp Univ Doctor Josep Trueta, Gastroenterol Dept, Girona, Spain
Ferri, MJ:
Hosp Univ Doctor Josep Trueta, Clin Lab, Girona, Spain
Durandez, R:
Hosp Santa Caterina, Lab Terr, Girona, Spain
Saez-Royuela, F:
Hosp Univ Burgos, Gastroenterol & Hepatol Dept, Burgos, Spain
Diago, M:
Hosp Gen Valencia, Liver Unit, Valencia, Spain
Gimeno, C:
Hosp Gen Valencia, Microbiol Unit, Valencia, Spain
Medina, R:
Hosp Gen Valencia, Microbiol Unit, Valencia, Spain
Buenestado, J:
Hosp Arnau Vilanova, Med Dept, Med Sch, Lleida, Spain
Bernet, A:
Hosp Arnau Vilanova, Microbiol Dept, Lleida, Spain
Turnes, J:
Complejo Hosp Pontevedrq, Gastroenterol & Hepatol Dept, IISGS, Pontevedra, Spain
Trigo-Daporta, M:
Complejo Hosp Pontevedra, Microbiol & Parasitol Dept, Pontevedra, Spain
Hernandez-Guerra, M:
Hosp Univ Canarias, Liver Unit, San Cristobal la Laguna, Santa Cruz De T, Spain
Delgado-Blanco, M:
CHUAC, Liver Unit, La Coruna, Spain
Canizares, A:
CHUAC, Microbiol Dept, Inst Invest Biomed A Coruna INIBIC, La Coruna, Spain
Arenas, JI:
Hosp Univ Donostia, Gastroenterol, San Sebastian, Spain
Gomez-Alonso, MJ:
Hosp Univ Puerta Hierro, Liver Unit, Madrid, Spain
Rodriguez, M:
Cent Univ Hosp Asturias HUCA, Gastroenterol Depart, Oviedo, Spain
Deig, E:
Granollers Gen Hosp, Barcelona, Spain
Olive, G:
St Jaume de Calella Cty Hosp, Barcelona, Spain
del Rio, O:
St Jaume de Calella Cty Hosp, Barcelona, Spain
Cabezas, J:
Hosp Univ Marques Valdecilla, Inst Invest IDIVAL, Gastroenterol & Hepatol Dept, Santander, Spain
Quinones, I:
Dr Negrin Univ Hosp Gran Canaria, Gastroenterol Dept, Las Palmas Gran Canaria, Spain
Roget, M:
Hosp Terrassa, Consorci Sanitari Terrassa, Liver Unit, Terrassa, Spain
Montoliu, S:
Joan XXIII Univ Hosp, Gastroenterol Unit, Tarragona, Spain
Garcia-Costa, J:
CHUO, Microbiol Dept, Virol & Mol Biol Unit, Orense, Spain
Force, L:
Hosp Mataro, Barcelona, Spain
Blanch, S:
Hosp Univ St Pau & Santa Tecla, Tarragona, Spain
Miralbes, M:
Hosp Univ Santa Maria Lleida, Gastroenterol Dept, Lleida, Spain
Lopez-de-Goicoechea, MJ:
Hosp Univ Galdakao, Microbiol Unit, Vizcaya, Spain
Garcia-Flores, A:
Cty Hosp Blanes, Girona, Spain
Saumoy, M:
Hosp Univ Bellvitge, Infect Dis Dept, HIV & STI Unit, Barcelona, Spain
Casanovas, T:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Baliellas, C:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Gilabert, P:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Martin-Cardona, A:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Roca, R:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Barenys, M:
Hosp Viladecans, Liver Unit, Barcelona, Spain
Villaverde, J:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Salord, S:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Camps, B:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
di Yacovo, MS:
Hosp Univ Bellvitge, Liver Unit, Barcelona, Spain
Ocana, I:
HUVH, Infect Dis Unit, Barcelona, Spain
Sauleda, S:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
BST, Barcelona, Spain
Bes, M:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
BST, Barcelona, Spain
Carbonell, J:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Vargas-Accarino, E:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Ruzo, SP:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Guerrero-Murillo, M:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Von Massow, G:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Costafreda, MI:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
BST, Barcelona, Spain
Lopez, RM:
VHIR HUVH, Biochem & Microbiol Dept, Barcelona, Spain
Gonzalez-Moreno, L:
Hosp Univ Princesa, Liver Unit, Madrid, Spain
Real, Y:
Hosp Univ Princesa, Liver Unit, Madrid, Spain
Acero-Fernandez, D:
Hosp Univ Doctor Josep Trueta, Gastroenterol Dept, Girona, Spain
Viroles, S:
Hosp Univ Doctor Josep Trueta, Gastroenterol Dept, Girona, Spain
Pamplona, X:
Hosp Univ Doctor Josep Trueta, Gastroenterol Dept, Girona, Spain
Cairo, M:
Hosp Univ Mutua Terrassa, Gastroenterol Unit, Barcelona, Spain
Ocete, MD:
Hosp Gen Valencia, Microbiol Unit, Valencia, Spain
Macias-Sanchez, JF:
St Jaume de Calella Cty Hosp, Barcelona, Spain
Estebanez, A:
Hosp Univ Marques Valdecilla, Inst Invest IDIVAL, Gastroenterol & Hepatol Dept, Santander, Spain
Quer, JC:
Joan XXIII Univ Hosp, Gastroenterol Unit, Tarragona, Spain
Mena-de-Cea, A:
CHUAC, Liver Unit, La Coruna, Spain
Otero, A:
CHUAC, Liver Unit, La Coruna, Spain
Castro-Iglesias, A:
CHUAC, Liver Unit, La Coruna, Spain
Suarez, F:
CHUAC, Liver Unit, La Coruna, Spain
Vazquez, A:
CHUAC, Liver Unit, La Coruna, Spain
Vieito, D:
CHUAC, Liver Unit, La Coruna, Spain
Lopez-Calvo, S:
CHUAC, Liver Unit, La Coruna, Spain
Vazquez-Rodriguez, P:
CHUAC, Liver Unit, La Coruna, Spain
Martinez-Cerezo, FJ:
Hosp Univ St Joan de Reus, Tarragona, Spain
Rodriguez, R:
CHUO, Microbiol Dept, Virol & Mol Biol Unit, Orense, Spain
Macenlle, R:
CHUO, Microbiol Dept, Virol & Mol Biol Unit, Orense, Spain
Cachero, A:
Hosp Igualada, Liver Unit, Barcelona, Spain
Mereish, G:
Hosp Igualada, Liver Unit, Barcelona, Spain
Mora-Moruny, C:
Hosp Figueres, Fundacio Salut Emporda, Girona, Spain
Fabregas, S:
Hosp Figueres, Fundacio Salut Emporda, Girona, Spain
Sacristan, B:
Hosp San Pedro CIBIR, Logrono, Spain
Albillos, A:
Hosp Univ Ramon & Cajal, Madrid, Spain
Sanchez-Ruano, JJ:
Hosp Univde Toledo, Gastroenterol & Hepatol Dept, Toledo, Spain
Baluja-Pino, R:
Hosp Povisa, Vigo, Spain
Fernandez-Fernandez, J:
Hosp Povisa, Vigo, Spain
Gonzalez-Portela, C:
Hosp Povisa, Vigo, Spain
Garcia-Martin, C:
Lab Referencia Catalunya, Barcelona, Spain
Sanchez-Antolin, G:
Hosp Univ Rio Ortega, Valladolid, Spain
Andrade, RJ:
Hosp Virgen de la Victoria, Gastroenterol Unit, Malaga, Spain
Simon, MA:
Hosp Univ Miguel Servet, Liver Unit, Zaragoza, Spain
Pascasio, JM:
Hosp Univ Virgen del Rocio, Liver Unit, Seville, Spain
Romero-Gomez, M:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ Virgen de Valme, Liver Unit, Seville, Spain
del-Campo, JA:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Univ Virgen de Valme, Liver Unit, Seville, Spain
Domingo, E:
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Univ Autonoma Madrid, CBMSO, Madrid, Spain
Esteban, R:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Esteban, JI:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Quer, J:
HUVH, VHIR, Liver Unit, Liver Dis Viral Hepatitis, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Joan XXIII Univ Hosp, Gastroenterol Unit, Tarragona, Spain
Green Accepted
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