Cento, Valeria and Nguyen, Thi Huyen Tram and Di Carlo, Domenico and Biliotti, Elisa and Gianserra, Laura and Lenci, Ilaria and Di Paolo, Daniele and Calvaruso, Vincenza and Teti, Elisabetta and Cerrone, Maddalena and Romagnoli, Dante and Melis, Michela and Danieli, Elena and Menzaghi, Barbara and Polilli, Ennio and Siciliano, Massimo and Nicolini, Laura Ambra and Di Biagio, Antonio and Magni, Carlo Federico and Bolis, Matteo and Antonucci, Francesco Paolo and Di Maio, Velia Chiara and Alfieri, Roberta and Sarmati, Loredana and Casalino, Paolo and Bernardini, Sergio and Micheli, Valeria and Rizzardini, Giuliano and Parruti, Giustino and Quirino, Tiziana and Puoti, Massimo and Babudieri, Sergio and D'Arminio Monforte, Antonella and Andreoni, Massimo and Craxì, Antonio and Angelico, Mario and Pasquazzi, Caterina and Ceccherini-Silberstein, Francesca (2017) Improvement of ALT decay kinetics by all-oral HCV treatment: role of NS5A inhibitors and differences with IFN-based regimens. PLoS One, Vol. 12 (5), e0177352. ISSN 1932-6203. Article.
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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.
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