Liver Angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after HCV direct-acting antivirals

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC).In Study 1,we studied the proangiogenic liver microenvironment in 242 DAAs-treated chronic Hepatitis C patients with advanced fibrosis.Angiopoietin-2 expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent,de novo,non-recurrent HCC or patients never developing HCC.Circulating Angiopoietin-2,vascular-endothelial growth factor (VEGF),and C-reactive protein were also measured. In Study 2,we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical,clinical,hemodynamic,endoscopic, elastographic,and echo-Doppler work-up was performed in both studies.In Study 1,none without cirrhosis developed HCC.Of 183 patients with cirrhosis,14/28 (50.0%) with previous HCC recurred while 21/155 (13.5%) developed de novo HCC.Recurrent and de novo HCCs had significantly higher liver fibrosis scores,portal pressure,and systemic inflammation than non-recurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients,tumor and non-tumor Angiopoietin-2 showed an inverse relationship with portal vein velocity (r=-0.412,p=0.037 and r= -0.409,p=0.047,respectively) and a positive relationship with liver stiffness (r=0.526,p=0.007;r=0.525,p=0.003,respectively).Baseline circulating VEGF and cirrhotic liver Angiopoietin-2 were significantly related (r=0.414,p=0.044).VEGF increased during DAAs, remaining stably elevated at 3 months follow-up, when it significantly related with serum Angiopoietin-2 (r=0.531,p=0.005).Angiopoietin-2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with the risk of HCC recurrence (OR 1.137,95%CI 1.044-1.137,p=0.003) or occurrence (OR 1.604,95% CI 1.080-2.382;p=0.019).In Study 2,DAA treatment (OR 4.770,95%CI 1.395-16.316,p=0.013) and large varices (OR 3.857,95%CI 1.127-13.203,p=0.032) were independent predictors of de novo HCC.