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


To our knowledge, this is the first study to investigate the effect of DAA therapy on the progression of HCC and describe the details of repeated recurrences in patients with HCC at BCLC stage 0/A using a tailored statistical method. We observed that the DAA-induced SVR significantly reduced the risk of tumour progression and the rate of HCC treatment until tumour progression.

DAA therapy should benefit patients infected with HCV.[9] DAA-induced SVR reduces HCC incidence by approximately 70%,[7,17,18] and is expected to revert fibrosis, decrease portal hypertension,[19–21] and reduce the risk of liver-related and all-cause death.[8] However, the benefits of DAA-induced SVR for HCC recurrence are controversial. Two small uncontrolled studies with short follow-up periods reported a high recurrence rate in patients with DAA therapy, which indicated that DAA therapy unexpectedly made HCC more aggressive.[22,23] Large controlled prospective studies showed no increased risk of HCC recurrence following DAA therapy.[10,24,25] On the contrary, other studies showed that DAA therapy reduced the risk of recurrence.[26–28]

The results among previous studies were different because of the unique HCC characteristics, and varied types of HCC treatment and statistical methods used. Some studies included patients with recurrent HCC, HCC with BCLC stage B, or patients who received palliative treatment for HCC. In some studies, the effect of different timings of DAA therapy was not considered because the authors performed time-fixed analysis. To assess the impact of DAA-induced SVR clearly, we limited our selection criteria to patients with HCC in BCLC stage 0/A, diagnosed at first time and managed by curative treatment and analysed the risk using a time-varying analysis. In our study, DAA-induced SVR was not associated with recurrence at new foci.

A meta-analysis demonstrated that 77.8% of HCC recurrences were detected at an early stage,[29] whereas in our study cohort, 75% of recurrences at new foci were in the BCLC stage 0/A. Even after the detection of HCC recurrence, most cases were expected to be cured again. Therefore, we investigated a new outcome, tumour progression, which was defined as HCC in BCLC stage 0/A progressing to BCLC stage B-D. We believe this outcome to be important because if HCC progresses to BCLC stage B-D, the median survival time is decreased to less than 2 years and[30,31] because tumour progression directly worsens the patients' quality of life and survival.[32]

Our study noted an interesting finding that DAA-induced SVR resulted in a 72% reduction in the risk of tumour progression (p = .001), whereas DAA-induced SVR did not reduce the risk of recurrence at new foci (p = .10). To assess the rate of repeated recurrence until tumour progression, we investigated the rate of HCC treatment until tumour progression. We found that DAA-induced SVR resulted in a 58.9% reduction in the annual incidence of HCC treatment (p < .001).

Usually, cancer cells grow over long time periods into a tumour mass that can be detected on imaging. Hence, cancer cells could already be present when DAA therapy is initiated, which could explain the different recurrence rates obtained after DAA therapy in previous studies. Our study showed that DAA-induced SVR strongly reduced the risk of tumour progression and dramatically decreased the rate of HCC treatment until tumour progression, indicating that DAA-induced SVR suppresses the tumorigenesis and metastasis. We also found that DAA-induced SVR strongly reduced the risk of liver-related death. Some recent multicentre studies reported that DAA therapy reduces the risk of death.[33,34] We suggest that a reduction in the risk of tumour progression contributes to this survival.

Our study had several limitations. First, this was a single-centre retrospective study, and there could be some bias and confounding factors. Multivariate analysis was used to adjust for the factors that were suggested to affect outcomes. There was a selection bias since doctors would prescribe DAAs only for patients who could have a long survival. Thus, to reduce the selection bias, we collected data before the DAA regimen was permitted. Patients who survived longer without recurrence had more chances to receive DAA therapy; this introduced the immortal time bias. Thus, it was important to apply the timing of DAA therapy as a time-varying covariate.[16] Second, we excluded patients with Child-Pugh class B/C, because DAA therapy was not permitted for patients with Child-Pugh class B/C until February 2019 in Japan. Therefore, we were not able to assess the impact of DAA-induced SVR in patients with Child-Pugh class B/C. Lastly, the data on the patient's alcohol consumption were lacking, and we were not able to assess the effect of alcohol consumption on outcomes.

In summary, 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.