Late Hepatocellular Carcinoma Occurrence in Patients Achieving Sustained Virological Response After Direct-Acting Antiviral Therapy: A Matter of Follow-Up or Something Else?

<b>Background</b>: Despite achieving a sustained virological response (SVR) with direct-acting antivirals (DAAs), an unexpected increase in the occurrence rate of hepatocellular carcinoma (HCC) has been observed among HCV-treated patients. This study aims to assess the long-term follow-up of HCV patients treated with DAAs who achieved an SVR to investigate the potential for late-onset HCC. <b>Methods</b>: In this prospective multicenter study, we enrolled consecutive HCV patients treated with DAAs following Italian ministerial guidelines between 2015 and 2018. Exclusion criteria included active HCC on imaging, prior HCC treatment, HBV or HIV co-infection, or liver transplant recipients. Monthly follow-ups occurred during treatment, with subsequent assessments every 3 months for at least 48 months. Abdominal ultrasound (US) was performed within two weeks before starting antiviral therapy, supplemented by contrast-enhanced ultrasonography (CEUS), dynamic computed tomography (CT), or magnetic resonance imaging (MRI) to evaluate incidental liver lesions. <b>Results</b>: Of the 306 patients completing the 48-months follow-up post-treatment (median age 67 years, 55% male), all achieved an SVR. A sofosbuvir-based regimen was administered to 72.5% of patients, while 20% received ribavirin. During follow-up, late-onset HCC developed in 20 patients (cumulative incidence rate of 6.55%). The pattern of HCC occurrence varied (median diameter 24 mm). Multivariate and univariate analyses identified liver stiffness, diabetes, body mass index, and platelet levels before antiviral therapy as associated factors for late HCC occurrence. <b>Conclusions</b>: Our findings suggest that late HCC occurrence may persist despite achieving SVR. Therefore, comprehensive long-term follow-up, including clinical, laboratory, and expert ultrasonography evaluations, is crucial for all HCV patients treated with DAAs.