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Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

2017; Public Library of Science; Volume: 12; Issue: 5 Linguagem: Inglês

10.1371/journal.pone.0177352

1932-6203

Valeria Cento, Thi Huyen Tram Nguyen, Domenico Di Carlo, Elisa Biliotti, Laura Gianserra, I. Lenci, Daniele Di Paolo, Vincenza Calvaruso, Elisabetta Teti, Maddalena Cerrone, Dante Romagnoli, M. Melis, Elena Danieli, Barbara Menzaghi, Ennio Polilli, Massimo Siciliano, Laura Ambra Nicolini, Antonio Di Biagio, C. Magni, Matteo Bolis, F.P. Antonucci, V.C. Di Maio, Roberta Alfieri, Loredana Sarmati, Paolo Casalino, Sergio Bernardini, Valeria Micheli, Giuliano Rizzardini, Giustino Parruti, Tiziana Quirino, Massimo Puoti, Sergio Babudieri, Antonella d’Arminio Monforte, Massimo Andreoni, Antonio Craxı̀, M. Angélico, C. Pasquazzi, Gloria Taliani, Jérémie Guedj, Carlo Federico Perno, Francesca Ceccherini‐Silberstein,

Systemic Lupus Erythematosus Research

Background Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis.