,15 for the ARES Study Group Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 mg/week) from week 24 to 48 (n 5 85) or to continue ETV monotherapy (n 5 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P 5 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P 5 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P 5 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P 5 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P 5 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. Conclusion: Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs. (HEPATOLOGY 2015;61:1512-1522

Adipocytokine profile seems to play a distinct role in the pathogenesis of chronic hepatitis C (CHC). Chemerin and vaspin are recently described adipocytokines with various suggested functions and potential to modulate inflammatory response and insulin resistance (IR). We assessed chemerin, vaspin and leptin serum concentration and studied their association with IR laboratory and morphological features in patients with hepatitis C. The study included 40 patients with hepatitis C and 20 healthy volunteers, similar in age and body mass index (43.6 +/- 11.6 vs 40.9 +/- 11.8 years and 25.0 +/- 4.1 vs 23.9 +/- 3.3 kg/m(2), respectively). Patients had to have a normal lipid profile, and diabetes was an exclusion criteria. Serum chemerin and leptin levels and IR were significantly higher in patients with hepatitis C when compared to the controls (P = 0.02, P = 0.02 and P = 0.02, respectively), whereas vaspin level was significantly decreased (P = 0.01). Serum chemerin was negatively associated with necro-inflammatory grade (r = (-0.49), P = 0.01). The lowest levels of serum chemerin were found in patients with moderate/severe inflammation (P = 0.03). Serum leptin tended to be up-regulated in patients with minimal inflammatory activity. Serum vaspin was higher, although not significantly, when fibrosis was more advanced. IR was positively associated with fibrosis stage (r = 0.33, P = 0.03). Serum chemerin and leptin were related to each other (r = 0.45, P = 0.02).Our findings support a complex interaction between the analysed adipokines and pathogenesis of inflammatory process in CHC. The role of chemerin and vaspin in pathogenesis of inflammatory response should be further investigated.

Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Steatosis, independently of its metabolic or viral origin, leads to liver injury and fibrosis. It is suggested that hepatitis C virus may contribute to a wide spectrum of metabolic disturbances-namely, steatosis, insulin resistance, increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus and lipid metabolism abnormalities. Adipokines, which are produced mainly by adipose tissue, may influence the inflammatory response and insulin sensitivity and contribute to the development of metabolic abnormalities in CHC and also regulate fibrogenesis and angiogenesis. Visfatin was described as an adipokine with immunomodulating and proinflammatory properties that promotes B-cell maturation and enhances activation of leukocytes, synthesis of adhesion molecules and production of proinflammatory cytokines. Visfatin exerts insulin-mimetic effects, decreases plasma glucose levels and regulates cell energy balance. Chemerin stimulates chemotaxis of dendritic cells, macrophages and natural killer (NK) cells toward the site of inflammation. On the other hand, it inhibits synthesis of proinflammatory mediators and enhances adiponectin production, influences adipocyte differentiation and maturation and regulates glucose uptake in adipocytes. Vaspin expression in human adipose tissue seems to be a compensatory mechanism associated with obesity and insulin resistance. Vaspin suppresses leptin, tumor necrosis factor (TNF)-α and resistin expression. Leptin protects against liver steatosis but accelerates fibrosis progression and exacerbates the inflammatory process. In contrast, adiponectin exerts a hepatoprotective effect. In this report, data indicating a possible role of these adipokines in the pathogenesis of chronic hepatitis are summarized.

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Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.