Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study

J Hepatol. 2018 Aug;69(2):345-352. doi: 10.1016/j.jhep.2018.03.009. Epub 2018 Mar 16.


Background & aims: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs.

Methods: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days.

Results: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment.

Conclusions: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors.

Lay summary: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure.

Keywords: Advanced liver disease; Direct-acting antiviral agents; Hepatitis C; Hepatocellular carcinoma; Risk factor.

MeSH terms

  • Aged
  • Antiviral Agents / therapeutic use*
  • Carcinoma, Hepatocellular* / diagnosis
  • Carcinoma, Hepatocellular* / pathology
  • Female
  • Hepacivirus* / drug effects
  • Hepacivirus* / isolation & purification
  • Hepatitis C, Chronic* / complications
  • Hepatitis C, Chronic* / drug therapy
  • Hepatitis C, Chronic* / epidemiology
  • Humans
  • Incidence
  • Italy / epidemiology
  • Liver Cirrhosis* / diagnosis
  • Liver Cirrhosis* / etiology
  • Liver Neoplasms* / diagnosis
  • Liver Neoplasms* / pathology
  • Male
  • Middle Aged
  • Prospective Studies
  • Risk Assessment / methods
  • Risk Factors
  • Sustained Virologic Response
  • Treatment Outcome


  • Antiviral Agents