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

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 delta 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., 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.