Abstract

Background: Direct-acting antiviral (DAA) treatment enables almost all patients with hepatitis C virus (HCV), including those with decompensated cirrhosis to achieve sustained virologic response (SVR), and improves prognosis in SVR patients. However, factors associated with long-term prognosis after SVR are unclear. The aim of this study is to clarify the risk factors for long-term prognosis according to liver-related and non-liver-related death.

Methods: This prospective study included 3,238 HCV patients who started DAA treatment between September 2014 and June 2021 and achieved SVR in Japanese hospitals. Patients who developed hepatocellular carcinoma (HCC) before SVR were excluded. SVR was defined as serum HCV-RNA undetectable at 24 weeks after the end of treatment. The start of the observation period was the time of SVR confirmation. Factors associated with liver-related and non-liver related death after SVR were examined by Cox proportional hazard analysis. Liver-related death was defined as death from HCC, liver failure and varix rupture.

Results: The median age was 69 years, 43% of patients were male, 9% of patients had a history of HCC and 18% of patients had liver cirrhosis. During the median follow-up of 50.4 months from SVR, 24 patients died of liver-related causes, and 103 patients died of non-liver-related causes. Among the 24 patients who died of liver-related causes, 20 patients died of HCC, three died of liver failure and one died of varix rapture. Among the 103 patients who died of non-liver-related causes, the most common causes of death were malignant tumors other than HCC (20 patients), cerebrovascular and cardiovascular events (14 patients) and infections (12 patients). The proportion of patients who died of liver-related causes was significantly higher in patients with a history of HCC than in those without (46% vs. 11%, p < 0.001). Annual liver-related mortality at 3/4/5 years after SVR was 1.5/1.3/3.6% in patients with a history of HCC. Liver-related and non-liver-related mortality at 5 years were 1.1% and 4.4%, respectively. In the multivariate analysis, older age (p = 0.008), history of HCC (p = 0.002) and lower albumin level at SVR (p = 0.014) were significantly associated with liver-related mortality after SVR, and older age (p < 0.001), male sex (p = 0.006) and lower albumin level at SVR (p < 0.001) were significantly associated with non-liver-related mortality after SVR.

Conclusion: Approximately 80% of deaths in SVR patients were non-liver-related cause, and older age, male sex and lower albumin level at SVR were significantly associated with non-liver-related death. In patients with a history of HCC, the risk of liver-related death persists over the long term after SVR.