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

Materials and Methods

Study Design and Patient Population

We conducted a retrospective cohort study of patients with HCV-related HCC who were admitted to the Department of Hepatology at Osaka City University Hospital from 2010 to 2019. HCC was diagnosed based on the American Association for the Study of Liver Disease (AASLD) criteria.[12,13] HCV infection was diagnosed by positive HCV-RNA or positive HCV core antigen. Patients were included if HCC was diagnosed for the first time, in BCLC stage 0/A, cured with resection or ablation (curative treatment), with Child-Pugh class A, and if they were followed up for more than 90 days after HCC treatment. Patients were excluded if they were positive for hepatitis B surface antigen, had autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), achieved SVR with interferon (IFN)-based therapy, failed HCV treatment with DAA therapy or received DAA therapy before HCC diagnosis (Figure 1). Cured HCC was defined as the presence of no residual tumour by computed tomography (CT) or magnetic resonance imaging (MRI) after curative treatment.

Figure 1.

Flowchart showing the study design for a retrospective cohort of patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). Overall, 165 patients were analysed, 72 received direct-acting antivirals (DAA) after HCC treatment (DAA-treated group) and 93 did not (untreated group)

We classified the patients into untreated and DAA-treated groups. The untreated group included patients who did not receive DAA therapy after HCC treatment. The DAA-treated group included patients who received DAA therapy and achieved SVR after HCC treatment.

This retrospective cohort study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Committee of Osaka City University Hospital.


Patients were followed up with three-monthly physical examinations and laboratory evaluations and abdominal ultrasonography, dynamic computed tomography (CT), or magnetic resonance imaging (MRI) every 3–6 months following HCC treatment. HCC recurrence was diagnosed using dynamic CT/MRI, contrast-enhanced ultrasonography or histological examination. HCC recurrences were treated per the AASLD guidelines.[13]


The main outcome of this study was the estimation of the risk of tumour progression. Tumour progression was defined as progression of HCC to BCLC stage B-D, which is characterized by more than 4 nodules of HCC, portal invasion, or extrahepatic metastasis on follow-up imaging, or by Child-Pugh C hepatic reserve.

We also estimated the risk of liver-related death, recurrence at new foci, and the frequency of HCC treatment until tumour progression. Recurrence at new foci was defined as the appearance of a new HCC lesion at a different part from the HCC lesion that was initially diagnosed. The frequency of HCC treatment until tumour progression was calculated from the number of treatments performed for recurrent HCC during the follow-up period. We counted the combination therapy, such as ablation following transarterial chemoembolization (TACE), as one treatment.

The follow-up began from the date of curative treatment for HCC and continued until the date of death or date of last follow-up.

Statistical Analysis

Baseline characteristics of the patients just before the first HCC treatment were analysed using a chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. We estimated the cumulative incidence using the Kaplan-Meier method and hazard ratio (HR) using time-varying Cox regression. We used multivariate analysis to adjust for the following variables: the variables in multivariate 1 analysis included age, number of tumours, Child-Pugh score, fibrosis-4 (FIB-4) index, α-fetoprotein (AFP) and type of treatment (resection or ablation), and the variables in multivariate 2 analysis included age, number of tumours, ALBI score, FIB-4 index, AFP and type of treatment (resection or ablation). The ALBI score was calculated using serum albumin and total bilirubin: (log10 bilirubin [μmol/L] ×0.66) + (albumin [g/L] × −0.085), which assesses liver function in HCC.[14] FIB-4 index was calculated using age, platelet, aspartate aminotransferase (AST) and alanine aminotransferase (ALT): age (year) × AST (IU/L)/(platelet count [109/L] × √ALT [IU/L]), which is an accurate marker of fibrosis in HCV infection.[15] Event rates were reported as annual incidence rates. The timing of DAA therapy after HCC treatment differed among patients, which means the status could change during the follow-up period. Therefore, we assigned DAA therapy as a time-varying covariate, by which the time from HCC treatment to the initiation of DAA therapy was statistically treated as the untreated group (Figure S1).[16] All data analyses were performed using R statistical software (version 3.6.0). All reported P values were two-sided, and a P value of less than 0.05 was considered statistically significant.