Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis

Background & Aim: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. Patients and methods: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. Results: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47–6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23–7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05–3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08–4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35–6.09; p = 0.006) were associated with HCC recurrence. Conclusion: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAAtreated patients; this was not accompanied by increased tumor aggressiveness.