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Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006–2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006–2010; 2011–2015; 2016–2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia,

Direct-acting antivirals (DAAs) revolutionized the treatment of chronic HCV-related disease achieving high rates of sustained virological response (SVR), even in advanced cirrhosis, with modest contraindications and a low rate of adverse events. However, the risk of hepatocellular carcinoma (HCC) persists due to the underlying chronic liver disease, both in patients with and without history of HCC. Although some initial studies reported a presumptive high risk of HCC development after DAA therapy, more recent observational studies denied this hypothesis. The residual risk for HCC occurrence after HCV eradication seems being progressively reduced with time after SVR. Data on recurrence of HCC after DAA exposure in patients with previously treated carcinoma initially reported conflicting results too, this being also due to methodological issues in analysis of retrospective multicenter studies. Anyway, current evidence support the use of DAAs in HCV-HCC treated patients, without any higher risk of tumor recurrence linked to antiviral therapy. Less effort has been made to evaluate the efficacy of DAA therapy in patients with untreated active HCC and it has been questioned whether a lower rate of SVR would be obtained among patients with active HCC. Studies conducted in this perspective concluded that HCC status does not influence the likelihood to obtain SVR with DAAs, making DAAs appropriate in HCC-active patients. As far as survival is concerned, recent studies conducted in cirrhotic HCV-related early-stage HCC found that DAAs improved overall survival, a benefit probably due to the reduction of hepatic decompensation.