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.
Improvement of ALT decay kinetics by all-oral HCV treatment : role of NS5A inhibitors and differences with IFN-based regimens / V. Cento, T.H.T. Nguyen, D. Di Carlo, E. Biliotti, L. Gianserra, I. Lenci, D. Di Paolo, V. Calvaruso, E. Teti, M. Cerrone, D. Romagnoli, M. Melis, E. Danieli, B. Menzaghi, E. Polilli, M. Siciliano, L.A. Nicolini, A. Di Biagio, C.F. Magni, M. Bolis, F.P. Antonucci, V.C. Di Maio, R. Alfieri, L. Sarmati, P. Casalino, S. Bernardini, V. Micheli, G. Rizzardini, G. Parruti, T. Quirino, M. Puoti, S. Babudieri, A.D. Monforte, M. Andreoni, A. Craxì, M. Angelico, C. Pasquazzi, G. Taliani, J. Guedj, C.F. Perno, F. Ceccherini-Silberstein. - In: PLOS ONE. - ISSN 1932-6203. - 12:5(2017 May 18), pp. e0177352.1-e0177352.13.
|Titolo:||Improvement of ALT decay kinetics by all-oral HCV treatment : role of NS5A inhibitors and differences with IFN-based regimens|
PERNO, CARLO FEDERICO (Corresponding)
|Parole Chiave:||Administration, Oral; Aged; Alanine Transaminase; Antiviral Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Humans; Interferons; Kinetics; Male; Middle Aged; Oligopeptides; RNA, Viral; Ribavirin; Simeprevir; Sofosbuvir; Treatment Outcome; Viral Nonstructural Proteins; Biochemistry, Genetics and Molecular Biology (all); Agricultural and Biological Sciences (all)|
|Settore Scientifico Disciplinare:||Settore MED/07 - Microbiologia e Microbiologia Clinica|
|Data di pubblicazione:||18-mag-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1371/journal.pone.0177352|
|Appare nelle tipologie:||01 - Articolo su periodico|
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