Direct-acting Antivirals Reduce the Risk of Tumour Progression of Hepatocellular Carcinoma After Curative Treatment

Hiroko Ikenaga; Sawako Uchida-Kobayashi; Akihiro Tamori; Naoshi Odagiri; Kanako Yoshida; Kohei Kotani; Hiroyuki Motoyama; Ritsuzo Kozuka; Etsushi Kawamura; Atsushi Hagihara; Hideki Fujii; Masaru Enomoto; Norifumi Kawada


J Viral Hepat. 2022;29(1):52-59. 

In This Article

Abstract and Introduction


Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on HCC progression remains uninvestigated. We conducted a retrospective cohort study of patients with hepatitis C virus-related HCC with BCLC stage 0/A diagnosed for the first time and treated by curative resection or ablation. Using a time-varying method, we estimated the risk of tumour progression (defined as progression to BCLC stage B-D) and liver-related death and the characteristics of repeated recurrence. Overall, 165 patients were enrolled. Following curative HCC treatment, 72 patients received DAA therapy (DAA-treated group), whereas 93 did not (untreated group). Approximately 75% of the recurrences were at an early stage and expected to be disease-free by retreatment. We recorded 56 tumour progressions, of which 60.7% were observed after second recurrence. Multivariate adjusted time-varying Cox regression analysis showed that the DAA-induced SVR significantly reduced the risk of tumour progression (hazard ratio [HR] 0.28; p = .001) and liver-related death (HR 0.12; p < .001). The annual incidence of HCC treatment until tumour progression was 82.8% and 23.9% in the untreated and DAA-treated groups, respectively (HR 0.30; p < .001). DAA-induced SVR significantly reduced the risk for tumour progression and liver-related death and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A.


The hepatitis C virus (HCV) infection affects 71 million people worldwide[1] and is a major risk factor for hepatocellular carcinoma (HCC). HCC is the sixth most common tumour worldwide and the fourth leading cause of cancer-related death.[2] Approximately 31% of the HCC cases can be attributed to HCV infection, and this increases up to 64% in Japan.[3,4] HCC is well known for its high recurrence rate, with nearly 70% of the patients developing recurrence within 5 years of curative HCC resection.[5]

Direct-acting antiviral (DAA) therapy regimens are effective at eradicating HCV infections.[6] DAA-induced sustained virologic response (SVR) results in reduced HCC incidence, risk of liver-related and all-cause death.[7,8] However, evidence for the benefit of DAA therapy for HCC recurrence is deemed low or inconclusive.[9] Furthermore, recent multicentre prospective cohort studies reported no significant difference in the HCC recurrence rates between DAA-treated and DAA-untreated patients.[10,11]

The Barcelona Clinic Liver Cancer (BCLC) staging system is recommended for prognostic prediction and treatment allocation.[3] In BCLC stage 0/A, curative treatment (resection, ablation and transplantation) is recommended, and median survival surpasses more than 5 years following curative treatment. However, curative treatment is not recommended following progression to BCLC stage B, when the median survival reduces to below 2 years. The progression of BCLC stage strongly affects the patients' quality of life and prognosis.

Although the risk of HCC recurrence following DAA therapy has been investigated in many previous studies, the timing of progression remains uninvestigated. According to previous reports, most HCC recurrences were BCLC stage 0/A, which were expected to be disease-free after retreatment following HCC recurrence. Some HCC recurrences are treated several times without progression. Therefore, assessment of the risk of tumour progression is important. Thus, this study aimed to assess the impact of DAA-induced SVR on the HCC progression and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A.