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

Abstract

BackgroundIntracellular 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 designMathematical 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.ResultsHCV-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.ConclusionsOur 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.

Polarization of granulocytic myeloid‐derived suppressor cells by hepatitis C core protein is mediated via IL‐10/STAT3 signalling

“…The significant correlation between G‐MDSC and HCVc suggests that HCVc may drive G‐MDSC expansion, which is in line with a prior report . It is known that HCV infection can lead to inflammation in the liver and the secretion of inflammatory cytokines, which may result in damage to hepatocytes and the release of ALT in the blood . Chronic HCV infection activates Kupffer cells, macrophages and dendritic cells, and these lead to a dysfunction in the immune system which promotes hepatic fibrosis .…”

“…10 It is known that HCV infection can lead to inflammation in the liver and the secretion of inflammatory cytokines, which may result in damage to hepatocytes and the release of ALT in the blood. 32 Chronic HCV infection activates Kupffer cells, macrophages and dendritic cells, and these lead to a dysfunction in the immune system which promotes hepatic fibrosis. 33 In this study, we found that the frequency of G-MDSCs is positively correlated with the levels of ALT and LSM which reflect liver injury, and these results were in agreement with the report conducted by Cai et al 14 A prior study found that the proliferation and IFNγ secretion of CD4 + and CD8 + T cells in the peripheral blood of CHC patients were inhibited by MDSCs.…”

Disentangling the lifespans of hepatitis C virus‐infected cells and intracellular vRNA replication‐complexes during direct‐acting anti‐viral therapy

“…In our study, we simultaneously fit the ALT and HCV RNA kinetics and used a multiscale model that has three decay phases to fit the viral load data. If we separately analysed the ALT data using an exponential model, we found the ALT decayed exponentially at rate 0.26/day (Table ), in agreement with the rate found by Cento et al of 0.27/day for the patients treated with an NS5A containing regime.…”

“…Recently, a study analysing ALT kinetics from adults with genotype‐1a or 1b infection and cirrhosis receiving at least one DAA with or without IFN concluded that there is no association between viral and ALT kinetics, including no correlation between viral load rates of decay and the ALT rate of decay . However, this study was quite different from ours.…”

“…Its elevation above the normal level is commonly used as a marker of the severity of liver damage. During treatment with DAAs, ALT levels decrease . Here, our goal was to determine whether longitudinal ALT measurements could provide quantitative information about HCV‐infected cells and the mechanisms involved in HCV decay under therapy.…”