Factors Linked to Hepatocellular Carcinoma Development Beyond 10 Years After Viral Eradication in Patients With Hepatitis C Virus

Takashi Kumada; Hidenori Toyoda; Satoshi Yasuda; Takanori Ito; Kunihiko Tsuji; Shinichi Fujioka; Atsushi Hiraoka; Kazuya Kariyama; Kazuhiro Nouso; Toru Ishikawa; Tsutomu Tamai; Toshifumi Tada; Junko Tanaka


J Viral Hepat. 2022;29(10):919-929. 

In This Article

Abstract and Introduction


The risk factors for hepatocellular carcinoma (HCC) development in patients whose duration of sustained virological response (SVR) is over 10 years are not fully understood. We compared the incidence of HCC development within and beyond 10 years after SVR. A total of 1384 patients who achieved SVR (714, interferon-based therapy; 670, direct-acting antiviral therapy) were enrolled. Factors associated with HCC development were analysed within and beyond 10 years after SVR by Cox proportional hazards models. The annual incidence rates of HCC development were 0.568% within 10 years after SVR and 0.190% beyond 10 years, and there was a significant difference in the incidence of HCC development between the 2 periods (p = 0.0242, log-rank test). Male gender (adjusted hazard ratio [aHR] 2.930; 95% confidence interval [CI] 1.508–5.693, p = 0.0015), fibrosis-4 (FIB-4) score > 3.25 (aHR 4.364; 95%CI 2.206–8.633, p < 0.0001) and alpha-fetoprotein ≥5.0 ng/ml (aHR 2.381; 95%CI 1.325–4.280, p = 0.0037) were independently associated with HCC development within 10 years after SVR. Male gender (aHR 4.702; 95%CI 1.366–16.190, p = 0.0141), presence of diabetes mellitus (aHR 2.933; 95%CI 1.240–6.935, p = 0.0143) and gamma-glutamyl transpeptidase (GGT) ≥ 56 U/l (aHR 4.157; 95%CI 1.400–12.350, p = 0.0103) were independently associated with HCC development beyond 10 years after SVR. The incidence of HCC development beyond 10 years after SVR was very low, and the associated factors were mainly extrahepatic, including DM and elevated GGT. Annual routine check-ups with abdominal ultrasound may be sufficient for such patients. (242 words).


Chronic hepatitis C (HCV) infection is one of the major causes of chronic liver disease, and it can lead to cirrhosis, hepatocellular carcinoma (HCC) and end-stage liver disease.[1] Eradication of HCV by either interferon (IFN)-based therapies or direct-acting antivirals (DAAs) has been shown to slow the progression to decompensation and reduce the risk of hepatocellular carcinoma (HCC) development.[2–4] However, despite the eradication of HCV, a substantial absolute risk of HCC persists after sustained virological response (SVR), especially in patients with advanced fibrosis; therefore, continued surveillance is necessary.[5,6] The rising number of patients with HCV eradication has placed a significant burden on clinicians due to the increased need for monitoring.

When the early results of DAA treatment were published, several sentinel European reports raised concerns about potentially increased rates of HCC in patients treated with IFN-free DAA regimens.[7–10] However, many subsequent studies have shown that there is no difference in the cumulative incidence of HCC development after SVR between patients who receive IFN-based therapies versus DAAs after matching for background factors.[11–17]

In the early 1990s, the introduction of IFN-based therapies presented clinicians with many new challenges regarding the management of HCV infection in Japan. Many patients who remain HCV positive beyond 10 years after achieving SVR are being followed up at our institution. In most cases, HCC occurs within 10 years after SVR. There has been no analysis of patients who develop HCC later than 10 years after SVR, and only case reports are available.[18–21] Therefore, the risk factors for HCC development in this population are not fully understood.

The aims of this study were to compare the incidence of HCC development within and beyond 10 years after SVR, and to determine the risk factors associated with HCC development beyond 10 years after SVR.