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Page 2 of 9 Yoo et al. Hepatoma Res 2020;6:9 I http://dx.doi.org/10.20517/2394-5079.2019.49

Recently, an IFN-free regimen as a treatment for CHC including NS3/4A protease inhibitor, NS5A
inhibitor, and NS5B polymerase inhibitor was introduced. There have been several reports indicating that
the SVR rate is up to 97.8% and the adverse event rate at all stages of CHC is lower in patients treated with
direct-acting antivirals than IFN-based therapy [8-12] . Despite expectations of a decrease in the incidence of
[13]
HCC because of the high rate of SVR, Reig et al. reported an unexpected high rate of HCC recurrence
[14]
after treating with direct-acting antivirals (DAA) in patients who experience previous HCC. Conti et al.
also reported a high rate of HCC recurrence (28.81%) 24 weeks after DAAs. Since the two aforementioned
reports were published, much debate has been raised about the recurrence and occurrence of HCC after
treating DAAs.

In this article, we review the pros and cons of the effects of the DAAs on occurrence/recurrence of HCC.

THE INTERPLAY BETWEEN DIRECT-ACTING ANTIVIRALS AND OCCURRENCE OF
HEPATOCELLULAR CARCINOMA
CHC is the most common cause of HCC worldwide. The incidence of HCC is below 1% per year in
[15]
CHC patients without liver cirrhosis . However, the risk of HCC increases by 2%-8% in CHC with liver
[16]
cirrhosis .
The papers on HCC occurrence related to DAAs are listed in Table 1. A negative paper was first published
[14]
on the occurrence of the HCC after the treatment of DAAs. In 2016, Conti et al. published the first
report about early occurrence of HCC in hepatitis C virus-related cirrhosis treated with DAAs. They
retrospectively analyzed 285 consecutive cirrhotic patients who completed antiviral therapy with DAA
regimens and HCC developed in 9 of 285 patients (3.16%, 95%CI: 1.45-5.90) during the 24-week post-
treatment evaluation. The report concluded that DAA-induced resolution of HCV infection does not seem
to reduce occurrence of HCC.

Since the publication of the previous paper, several papers have been published indicating that DAAs are not
[17]
associated with occurrence of HCC. A thesis against the previous study was published by Kanwal et al. in
2017. This retrospective cohort study included 22,500 patients who received DAA treatment; 39.0% of the
patients had cirrhosis and 86.74% achieved SVR. The incidence rate of HCC was 0.90 per 100 person-year
(95%CI: 0.77-1.03) in patients with SVR and 3.45 per 100 person-year (95%CI: 2.73-4.18) in patients without
SVR.

A large prospective study of 2249 patients with HCV-associated cirrhosis was published in Italy by
[18]
Calvaruso and his colleagues . SVR after DAA treatment was achieved in 95.2% of patients and the overall
rate of HCC occurrence was 3.4%. They analyzed the HCC incidence according to achieved SVR, and HCC
occurrence was 3% in SVR group and 12.8% in non-SVR group (P < 0.001). Although this study did not
contain the analysis of control group, they found the SVR to DAA treatment decreased the incidence of
HCC. A similar study in the same country including 3917 patients with fibrosis stage ≥ F3 was published
[19]
by Romano and colleagues . This large, prospective cohort study showed that the incidence of HCC
occurrence was 0.42% in F3, 1.88% in cirrhosis, and 0.97 per 100 person-year (95%CI: 0.73-1.26) in all
patients.

[20]
Nagata et al. compared data between IFN-based and IFN-free regimens for occurrence of HCC. This
report included 1085 patients treated with IFN and 669 patients treated with DAAs. The cumulative
incidence of HCC occurrence after SVR was 2.6% (five-year incidence) in IFN-based and 3.3% (three-
year incidence) in IFN-free therapies. Although the incidence of HCC appears to be higher in IFN-free
group than IFN-based group, there are no significant differences between the two groups after performing