V.C. Di Maio

Hepatitis C Virus Genetic Variability and the Presence of NS5B Resistance-Associated Mutations as Natural Polymorphisms in Selected Genotypes Could Affect the Response to NS5B Inhibitors

ABSTRACT Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed the NS5B polymerase genetic variability in circulating HCV genotypes/subtypes and its impact on the genetic barrier for the development of resistance to clinically relevant nucleoside inhibitors (NIs)/nonnucleoside inhibitors (NNIs). The study included 1,145 NS5B polymerase sequences retrieved from the Los Alamos HCV database and GenBank. The genetic barrier was calculated for drug resistance emergence. Prevalence and genetic barrier were calculated for 1 major NI and 32 NNI resistance variants (13 major and 19 minor) at 21 total NS5B positions. Docking calculations were used to analyze sofosbuvir affinity toward the diverse HCV genotypes. Overall, NS5B polymerase was moderately conserved among all HCV genotypes, with 313/591 amino acid residues (53.0%) showing ≤1% variability and 83/591 residues (14.0%) showing high variability (≥25.1%). Nine NNI resistance variants (2 major variants, 414L and 423I; 7 minor variants, 316N, 421V, 445F, 482L, 494A, 499A, and 556G) were found as natural polymorphisms in selected genotypes. In particular, 414L and 423I were found in HCV genotype 4 (HCV-4) (n = 14/38, 36.8%) and in all HCV-5 sequences (n = 17, 100%), respectively. Regardless of HCV genotype, the 282T major NI resistance variant and 10 major NNI resistance variants (316Y, 414L, 423I/T/V, 448H, 486V, 495L, 554D, and 559G) always required a single nucleotide substitution to be generated. Conversely, the other 3 major NNI resistance variants (414T, 419S, and 422K) were associated with a different genetic barrier score development among the six HCV genotypes. Sofosbuvir docking analysis highlighted a better ligand affinity toward HCV-2 than toward HCV-3, in agreement with the experimental observations. The genetic variability among HCV genotypes, particularly with the presence of polymorphisms at NNI resistance positions, could affect their responsiveness to NS5B inhibitors. A pretherapy HCV NS5B sequencing could help to provide patients with the full efficacy of NNI-containing regimens.

166 HCV DIVERSITY AND FIBROSIS PROGRESSION: NS5A AND CORE VARIANTS CORRELATE WITH SEVERITY OF HCV RECURRENCE AFTER LIVER TRANSPLANTATION

Results: The overall 1-, 5and 10-year posttransplant survival rates, stratified by the composite risk score are presented in table 1. More than half (53.6%) of patients had at least one of the risk factors (obesity, renal dysfunction or advanced age). Patients with two or more risk factors (score ≥2) experienced a significantly higher covariate-adjusted risk of death compared to patients with zero (HR: 5.9, 95%CI: 2.3–14.3; p < 0.001) or one (HR: 2.6, 95%CI: 1.3–5.6; p = 0.009) risk factor.

63 CORRELATION OF EARLY DETECTION OF HCV NS3-RESISTANCE AND VIROLOGICAL FAILURE IN PATIENTS TREATED WITH TRIPLE THERAPY INCLUDING TELAPREVIR OR BOCEPREVIR

63 CORRELATION OF EARLY DETECTION OF HCV NS3-RESISTANCE AND VIROLOGICAL FAILURE IN PATIENTS TREATED WITH TRIPLE THERAPY INCLUDING TELAPREVIR OR BOCEPREVIR V. Cento, V.C. Di Maio, D. Di Paolo, F. De Luca, V. Micheli, M. Tontodonati, M.C. Bellocchi, L. Carioti, D. Armenia, F. De Leonardis, F.P. Antonucci, G. Madeddu, C. Magni, C. Sarrecchia, S. Babudieri, G. Parruti, M. Angelico, G. Rizzardini, C.F. Perno, F. Ceccherini-Silberstein. University of Rome Tor Vergata, University Hospital of Rome Tor Vergata, Roma, Hospital Sacco of Milan, Milan, Infectious Disease Clinic of Chieti, Chieti, University of Sassari, Sassari, Pescara General Hospital, Pescara, Italy E-mail: ceccherini@med.uniroma2.it

430 KEY GENETIC SIGNATURES IN THE WHOLE pre-S1/Pre-S2/S GENE CORRELATE WITH HBV-INDUCED CARCINOGENESIS BY AFFECTING HBsAg SECRETION AND RELEASE

430 KEY GENETIC SIGNATURES IN THE WHOLE pre-S1/Pre-S2/S GENE CORRELATE WITH HBV-INDUCED CARCINOGENESIS BY AFFECTING HBsAg SECRETION AND RELEASE V. Svicher, M. Neumann-Fraune, C. Mirabelli, R. Salpini, V. Cento, V.-C. Di Maio, A. Bertoli, C. Alteri, M. Aragri, C. Gori, V. Micheli, G. Gubertini, P. Trimoulet, H. Fleury, J. Vecchiet, N. Iapadre, A. Barlattani, T. Mari, C. Pasquazzi, C. Sarrecchia, F. Ceccherini-Silberstein, M. Andreoni, M. Angelico, J. Verheyen, C.-F. Perno. University of Rome Tor Vergata, Rome, Italy; University of Cologne, Cologne, Germany; National Institute for Infectious Diseases ‘L. Spallanzani’, Rome, “L. Sacco” Hospital, Milan, Italy; Hopital Pellegrin Tripode, Bordeaux, France; “SS Annunziata” Hospital, Chieti, “S Salvatore” Hospital, L’Aquila, “S Giacomo” Hospital, “Regina Margherita” Hospital, “S Andrea” Hospital, Rome, Italy; University of Essen, Essen, Germany E-mail: valentina.svicher@uniroma2.it