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

Antonio Craxi, Vincenza Calvaruso, Barbara Menzaghi, Jeremie Guedj, Ilaria Lenci, Elisa Biliotti, Ennio Polilli, Valeria Cento, Antonella D'Arminio Monforte, Mario Angelico, Carlo Federico Perno, Laura Ambra Nicolini, Thi Huyen Tram Nguyen, Laura Gianserra, Elisabetta Teti, Paolo Casalino, Velia Chiara Di Maio, Domenico Di Carlo, Roberta Alfieri, Jeremie GuedjFrancesca Ceccherini-Silberstein, Massimo Siciliano, Giustino Parruti, Michela Melis, Matteo Bolis, Elena Danieli, Dante Romagnoli, Antonio Di Biagio, Antonio Di Biagio, Massimo Puoti, Maddalena Cerrone, Francesco Paolo Antonucci, Daniele Di Paolo, Caterina Pasquazzi, Sergio Babudieri, Carlo Federico Magni, Francesco Paolo Antonucci, Loredana Sarmati, Giuliano Rizzardini, Tiziana Quirino, Massimo Puoti, Valeria Micheli, Massimo Andreoni, Sergio Bernardini, Gloria Taliani

Risultato della ricerca: Articlepeer review

10 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
Numero di pagine13
RivistaPLoS One
Volume12
Stato di pubblicazionePublished - 2017

All Science Journal Classification (ASJC) codes

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  • General

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