HCC occurrence after DAA treatments: molecular tools to assess the post-treatment risk and surveillance.

The perspective of hepatitis C virus (HCV) therapy has dramatically changed over the years after the introduction of direct-acting antiviral (DAA) therapy, which increased the sustainable viral response rate (SVR) up to 90% with better tolerance and effectiveness in clinical practice as compared with interferon-based regimens [1]. However, despite the excellent efficacy and extensive studies, alarming reports from two retrospective studies, conducted in 2016 in Spain and Italy [2,3], suggested an increased risk of hepatocellular carcinoma (HCC) occurrence and recurrence after DAA treatment in patients, triggering the debate on the safety profile of DAA and its correlation to HCC development. Nonetheless, some criticisms regarding the absence of control groups, sample size or short-follow-up periods have been raised in some studies. A meta-analysis conducted by Waziry et al. in 2017 estimated no significant HCC occurrence cases in both DAA-treated or interferon-treated patients following SVR [4]. Indeed, several reports underlined the efficacy of DAA in significantly reducing the risk of HCC in patients with SVR as compared with those with either treatment failure or no treatment [1,5,6]. However, what emerges from those studies is that the DAA-induced SVR reduces the risk of HCC occurrence, without eliminating it. This includes patients with other risk factors, such as age, gender and cirrhosis. In particular, patients with cirrhosis with long exposure to the virus, can still be considered at risk, even after the achievement of SVR. Hamdane et al. described how epigenetic alterations induced by chronic HCV infection persist even after viral clearance and were further associated with HCC risk [7]. Liver alteration was also evident in early studies conducted by Kono et al., observing sustained abnormal ALT and AFP levels, especially in F3–F4 patients (F3: severe fibrosis, characterized by fibrotic bridging across lobules, between portal areas and between portal areas and central veins; F4: cirrhosis), even after the achievement of SVR. Multivariate analysis identified pre-treatment low albumin levels and fibrosis 4 (FIB-4) index as independent predictive factors for the sustained AFP after SVR. At the same time, the fatty liver presence was associated with both sustained abnormal AFP and ALT levels after SVR [8] suggesting that the persistence of hepatocyte damage and regeneration mechanisms might lead to HCC development. The oxidative stress present in the fatty liver might also be responsible for DNA damage that foster carcinogenesis [8]. Confirming the results of Kono et al., Watanabe et al. identified FIB-4 index ≥4.0 and albumin ≤3.8 g/dl at the beginning of DAA treatment and a FIB-4 index ≥4.0 and AFP ≥6.0 at the end of DAA treatment as independent predictors for HCC occurrence [9]. Moreover, despite the correlation between HCC risk with fibrosis index, recent data suggested the presence of liver steatosis in HCV patients as a major predictor of mortality and HCC occurrence in patients who achieved SVR following DAA treatment regardless of fibrosis [10].