暂无摘要。

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed.
Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection.
Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection.
Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.

Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) is highly effective. However, people who inject drugs face significant barriers to DAA access.
We describe a program that colocates HCV management within a syringe service program in New York City. We performed a retrospective chart review of all patients with confirmed HCV viremia.
From 2015 to 2018, 102 patients with viremia completed intake. Fifty-eight patients started DAAs. Nine patients discontinued treatment or were lost to follow-up before completion; 1 is continuing DAA treatment. Of 48 patients who completed therapy, sustained virologic response (SVR) was achieved in 43 (89.6%). Age and established mental health treatment at intake were associated with SVR. Regular cocaine use was negatively associated with SVR in univariate analysis, but this association was not significant after adjustment for age. Of 30 patients completing DAA therapy with active illicit opioid use at intake, 14 (46.4%) engaged in opioid use disorder (OUD) treatment during therapy, and 9 remained in OUD treatment after completion of DAA treatment.
Loss to follow-up is a challenge for people who inject drugs, but among those who completed treatment, SVR was achieved at a high rate. Mental health treatment may facilitate HCV cure. Conversely, HCV therapy may facilitate engagement in OUD treatment and other services.

BACKGROUND: Two kinds of peginterferons, peginterferon-α2a (PEG-IFN-α2a) and peginterferon-α2b (PEG-IFN-α2b), are used in the treatment of chronic hepatitis C virus (HCV) infection. However, it is unclear which is better in terms of virological responses and patient compliance. We conducted a meta-analysis to assess which peginterferon was better when used with ribavirin.
METHODS: Relevant clinical trials were identified through the PubMed and EMBASE databases. Primary outcomes included early virological response (EVR), end of treatment response (ETR) and sustained virological response (SVR). Secondary outcomes included biochemical and histological responses and the discontinuation of treatment after adverse events. Meta-analysis was performed using fixed-effect or random-effect methods, depending on absence or presence of significant heterogeneity. Analyses were performed with Review Manager Version 4.2.2.
RESULTS: Seven clinical trials were included that involved 3,526 patients in total; six were randomized clinical trials (RCTs) and one was nonrandomized. PEG-IFN-α2a plus ribavirin was better than PEG-IFN-α2b plus ribavirin with regards to ETR (relative risk [RR] = 1.21, 95% confidence interval [CI]: 1.14-1.28). This advantage was less obvious for EVR (RR = 1.12, 95% CI: 1.06-1.19) and SVR (RR = 1.10, 95% CI: 1.02-1.18). Patients who received PEG-IFN-α2a were less likely to discontinue treatment for safety reasons (RR = 0.85, 95% CI: 0.52-1.38).
CONCLUSIONS: We demonstrated that PEG-IFN-α2a was a better choice than PEG-IFN-α2b in terms of virological responses.