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Yoo et al. Hepatoma Res 2020;6:9 I http://dx.doi.org/10.20517/2394-5079.2019.49 Page 7 of 9

[14]
95%CI: 1.01-1.39, P = 0.03) were significant factors prone to experience HCC recurrence . A study from Japan
reported on the impact of DAA on early recurrence of HCC and higher alpha-fetoprotein (AFP)-L3 level (HR:
1.47, 95%CI: 1.02-2.11, P = 0.04), larger number of HCC treatments (HR: 1.65, 95%CI: 1.16-2.35, P = 0.007), and
shorter interval between the last HCC treatment and initiation of antiviral therapy (P = 0.007) were associated
[35]
with the risk of HCC recurrence . In the comparative study for occurrence and recurrence of HCC in IFN-
based and IFN-free therapies, AFP and WFA*M2BP levels were significantly associated with HCC occurrence
[20]
after achieving an SVR . This study suggested that AFP > 5.4 ng/mL and WFA*M2BP > 1.8 COI could be
helpful markers of HCC occurrence. A prospective cohort study including 2249 patients with HCV-associated
cirrhosis reported that albumin level < 3.5 g/dL (HR: 1.77, 95%CI: 1.12-2.82, P = 0.01), platelet count < 120 ×
10 /L (HR: 3.89, 95%CI: 2.11-7.15, P < 0.001), and absence of SVR (HR: 3.40, 95%CI: 1.89-6.12, P < 0.001) were
9
[18]
associated with an increased risk of HCC occurrence .
The retrospective cohort study using national data of 22,500 patients revealed that the patients with SVR (HR:
0.24, 95%CI: 0.19-0.31, P < 0.0001) and African American patients (HR: 0.56, 95%CI: 0.39-0.81, P = 0.02) were
[17]
associated with low risk of HCC . Patients with cirrhosis (HR: 4.73, 95%CI: 3.34-6.68, P < 0.0001) and alcohol
abuse (HR: 1.56, 95%CI: 1.11-2.18, P = 0.01) were associated with high incidence of HCC. A large, prospective,
population-based study from Italy including 3917 patients with fibrosis stage ≥ F3 revealed that DAA
treatment failure (HR: 9.09, 95%CI: 5.2-16.1, P = 0.0001), HBV coinfection (HR: 3.99, 95%CI: 1.24-12.91,
P = 0.021), and APRI score > 2.5 (HR: 2.03, 95%CI: 1.14-3.61, P = 0.016) were significantly associated with
[19]
HCC occurrence . A comparative study including DAA group, SVR-IFN group, and non-SVR group
suggested that increased age, alcohol consumption, HCV genotype 1, and impaired liver function were
[21]
statistically significantly associated with risk of HCC . There was no significant association between DAA
use and risk of HCC. In our study, we compared the rates of HCC between DAA group and IFN group,
and alpha-fetoprotein > 9.5 ng/mL at the time of end-of treatment response was the only significant risk
[22]
factor for HCC occurrence . Moreover, in a prospective study in France, exposure to DAA was strongly
associated with a decrease in all-cause mortality (adjusted HR: 0.34, 95%CI: 0.22-0.55, P < 0.0001) and risk
[24]
of HCC (adjusted HR: 0.57, 95%CI: 0.40-0.81 P = 0.016) . A study including HCV patients with received
DAAs and who achieved SVR showed that male gender (HR: 2.40, 95%CI: 1.46-3.96, P = 0.0006), older
age (HR: 1.51, 95%CI: 1.20-1.91, P = 0.0005), higher FIB-4 index (HR: 1.12, 95%CI: 1.07-1.17, P < 0.0001),
and higher GGTP level (HR: 1.04, 95%CI: 1.02-1.06, P < 0.0001) were independently associated with HCC
[25]
occurrence .

CONCLUSION
Since the initial reports about the unexpected high rate of early recurrence of HCC were published, most
recent reports showed favorable effects of DAA treatment in regard to HCC occurrence/recurrence.
Several published studies have indicated that non-SVR, older age, advanced liver disease, combined liver
disease (chronic hepatitis B and alcohol abuse), higher AFP, and history of previous HCC may play roles
in increasing HCC risk. Accordingly, the Asian Pacific Association for the Study of the Liver guidelines
suggest that surveillance be performed every six months for patients with SVR and liver cirrhosis and
[38]
every four months for patients with SVR and previous history of HCC . Achieving SVR in patients with
HCV improved their outcomes in terms of deaths, Child-Pugh Class, and model for end-stage liver disease
of advanced liver disease, as well as the incidence of HCC. In addition, patients with previous HCC after
achieving SVR had significantly better survival than untreated patients, thus patients eligible for HCC
[39]
therapy should be considered for DAA treatment . However, the risk of HCC is not completely eliminated
by achieving SVR after DAA treatment, and regular surveillance of HCC including biomarkers for tumor
should be considered in patients with cirrhosis, combined liver disease, and previous history of HCC [40,41] .