Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: relevance of non-characterized nodules

Abstract Background & Aims Despite the very high efficacy of direct acting antivirals (DAA) to eradicate hepatitis C virus infection, the impact on hepatocellular carcinoma development remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing hepatocellular carcinoma. Methods Retrospective, multicenter study focusing on cirrhotic patients treated with direct acting antivirals until December 2016. Clinical and radiologic characteristics before starting antiviral therapy, at follow-up and at hepatocellular carcinoma development were collected. Diagnosis of hepatocellular carcinoma was centrally validated and its incidence was expressed as HCC/100 patients-year. Results 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved sustained virological response. Median time of follow-up was 19.6 months. Seventy-two patients developed hepatocellular carcinoma within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 patients-year (95% CI 2.96;4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated to higher risk. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95%CI 1.55;5.16) vs absence of non-characterized nodules. When excluding these patients, the risk remained increased. Conclusion These data expose a clear-cut time association between interferon-free treatment and HCC. There is need to further investigate the mechanisms involved in the increased risk of hepatocellular carcinoma emergence at short term. Lay summary In this cohort of cirrhotic patients, interferon-free therapies achieved a high rate of sustained virological response (>95%); however, a 3.73% risk of developing de novo hepatocellular carcinoma per 100 persons/year with a clear-cut time association with antiviral therapy was registered. The presence of non-characterized nodules in radiologic assessments before starting DAA was associated to a 9.6% risk of developing hepatocellular carcinoma per 100 persons/year among cirrhotic patients treated with DAA. Thus, patients who started DAA and had indeterminate nodules have up to almost 3 times higher risk of developing HCC than those patients without or with well-defined benign nodules. The time association between starting DAA and developing HCC, together with the association with the presence of non-characterized nodules at the baseline ultrasound, suggests that antiviral therapy elicits a mechanism (probably immune-related) that primes the growth and clinical recognition of hepatocellular carcinoma early during follow-up. As a result, liver cancer risk at short term is significantly increased.