The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

Background: Hepatitis C virus (HCV) effectively establishes persistent infection in human livers. The nonstructural (NS) 3/4A complex participates in this process by cleavage of interferon b (IFNb) promoter stimulator-1 (IPS-1; also termed Cardif/MAVS/VISA), which inhibits responses to double stranded (ds) RNA. However, it is not known whether this effect extends beyond innate responses. Aims: To test if HCV NS3/4A affects innate and adaptive immune responses in vivo. Methods: NS3 levels were semi-quantified in human liver biopsies, transfected cells, and in transgenic (Tg) mouse livers by western blot. The effect of NS3/4A on dsRNAmediated signalling and on the integrity of IPS-1 was analysed using in vitro translation, transfected cells and Tg mice. Cytotoxic T cell (CTL)-mediated clearance of transient firefly luciferase (FLuc)-and/or NS3/4A-Tg hepatocytes was determined using in vivo imaging and western blot. Results: NS3 protein levels were in a comparable range (0.1-49 mg/g tissue) in infected human livers and Tg mouse livers. Importantly, these levels of NS3/4A reduced murine innate responses to synthetic dsRNA in vivo, supporting the possibility that this occurs also in infected humans. The likely explanation for this was the NS3/4A-mediated cleavage of mouse IPS-1, albeit less efficiently than human IPS-1. Despite this, FLuc-and/or NS3/4A-expressing murine hepatocytes were effectively eliminated by hepatic CTLs, utilising the classical molecules for virus-infected cell lysis, including CD8, IFNc, perforin and FasL. Conclusions: Although HCV NS3/4A inhibits the innate immunity, this does not prevent CTL-mediated clearance of NS3/4A-expressing hepatocytes in vivo. Thus, other HCV proteins are most likely responsible for interfering with the adaptive immunity.Hepatitis C virus (HCV) is highly efficient in establishing persistent infections in human hepatocytes in vivo, but not in vitro.

SVR rates found in our study, in particular for genotype 1 patients (13%), were lower than those generally found in randomized controlled studies. For cirrhotic patients, new treatment alternatives are urgently needed to improve treatment outcome.

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