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Lee et al. Hepatoma Res 2020;6:21 I http://dx.doi.org/10.20517/2394-5079.2019.44 Page 3 of 8

On the contrary, DAAs have been used on HCV patients with advanced fibrosis and cirrhosis who are at
high risk of HCC. It was speculated that there would be more HCV -associated HCCs after DAA with SVR
than those post-IFN with SVR ones in the United States, given that the largest cohort of chronic hepatitis
[36]
C patients in the United States are baby boomers with advanced age, cirrhosis , and rising prevalence of
[37]
metabolic syndrome-associated co-morbidities .
[38]
Waziry et al. reported a random-effects meta-analysis comparing HCC occurrence and recurrence in
patients treated by DAA and IFN therapy and showed no evidence of difference in HCC risk between the
[34]
two groups after meta-regression adjustment of age and study follow up duration. Ioannou et al. published
a large VA cohort study of 21,498 chronic hepatitis C (CHC) patients with DAA-induced SVR, showing that
it is associated with reduced risk of de novo HCC compared to treatment failure and that the risk for HCC
after DAA therapy is similar to the risk after IFN therapy.

[39]
Singer et al. using administrative claims data demonstrated that the risk of HCC was lower in DAA-treated
patients (adjusted HR = 0.69; 95%CI: 0.59-0.81).

DAAS AND DE NOVO HCC
Earlier studies of first-generation DAAs showed increased risk for de novo and recurrent HCC, which
brought concerns that DAAs might have carcinogenic effects [40-43] . A retrospective multicenter study from
Spain reported a short-term HCC incidence of 3.73 HCC/100 patient-years (95%CI: 2.96-4.70), within a
[44]
median 10.3 months after starting DAA therapy on 1123 HCV patients with cirrhosis .
HCC risk with DAAs is related to the severity of liver histology [33,45,46] . The annual incidence of HCC after
SVR was higher in those with cirrhosis than those without cirrhosis (1.82 vs. 0.34/100 person-years) [14,33] .

[47]
Ioannou et al. reported that an increased risk for HCC in hepatitis C patients with baseline cirrhosis or high
[48]
FIB-4 treated with either IFN-based therapy or DAAs could persist up to 10 years after SVR. Kanwal et al.
also showed that an increased risk for HCC after DAAs with SVR remained for up to 3.6 years of follow up,
and it was particularly high in patients with cirrhosis.

DAAS AND RECURRENT HCC
Hepatitis C virus stimulates immune response. HCV-specific T cells produce cytokines including IFN with
anti-HCC effects [49-52] . The recurrence of HCC was speculated to be due to reduced immune surveillance,
cytokine imbalance, and angiogenesis [50-53] .

[54]
A meta-analysis by Singal et al. demonstrated that IFN-based treatment for HCV patients after curative
[55]
HCC therapy reduced HCC recurrence and improved the outcomes. Nishibatake Kinoshita et al. reported
no significant difference of HCV-related early HCC recurrence after HCC treatment between 156 patients in
the IFN-based group and 147 patients in the DAA group.

Several earlier studies showed different results regarding DAAs and the risk of HCC recurrence [56-58] . Some
studies that reported an increased risk for HCC recurrence with use of DAAs correlated earlier HCC
recurrence with a shorter interval between complete response to HCC treatment and the DAA agent [40,59] .

A meta-analysis of HCC recurrence after DAAs by Saraiya pointed out that some studies lacked a
comparison cohort or had different patient selection criteria, timing of DAA therapy, and follow up
[60]
schedules. Nevertheless, they found no significant difference in HCC recurrence among the study groups .

The benefits of DAA therapy including regression of fibrosis, decrease in portal hypertension, and hepatic
failure are weighed against potential risk for HCC recurrence. A large retrospective study of 793 patients in