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




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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.



Author: Valeria Cento, Thi Huyen Tram Nguyen, Domenico Di Carlo, Elisa Biliotti, Laura Gianserra, Ilaria Lenci, Daniele Di Paolo, Vincenz

Source: http://plos.srce.hr/



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