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Page 6 of 8 Yang et al. Hepatoma Res 2020;6:31 I http://dx.doi.org/10.20517/2394-5079.2019.45

Other studies compared the risk of HCC in DAAs-cured patients with DAAs-failed patients [22,27,29,30,33-35] . All
of these studies showed that DAAs-induced SVR decreased the incidence of HCC. The HCC risk reduction
by DAAs treatment was evident not only in patients without cirrhosis, but also in patients with cirrhosis.
[27]
Romano et al. reported that the incidence of HCC was higher during the first year (0.46% in F3, 1.49%
in CTP-A and 3.61% in CTP-B cirrhosis, respectively), and declined in the second year (0% in F3, 0.2% in
CTP-A, and 0.69% in CTP-B cirrhosis, respectively). But some studies reported that in cirrhotic patients
with DAAs-induced SVR, the incidence of HCC was usually still higher than 1.5% above which HCC
[37]
surveillance is cost-effective. Kanwal et al. reported the quarterly incidence rate of HCC remained stable
between 1.5 to 2.3 per 100 person-years in patients with cirrhosis, which indicated HCC risk of cirrhotic
[38]
patients cured with DAAs did not progress or regress during follow-up. Ide et al. found the one, two, and
three-year cumulative incidences of HCC in patients with cirrhosis were 2.5%, 5.2%, and 10.0% respectively.
Recently, Ioannou et al. reported that in DAAs-treated patients with cirrhosis and a fibrosis index based
[39]
on four factors (FIB-4) with scores ≥ 3.25, the annual HCC incidence decreased from 3.8% in the first year
after SVR to 2.4% by the fourth year, which was still at high risk of developing HCC. Although these studies
with more than three years follow-up have confirmed HCC risk is not increased after SVR by DAAs [37-39] ,
the changes in HCC incidence over time deserve to be further clarified in longer-term studies.

Physicians are most interested in which patients should undergo HCC surveillance after achieving SVR
by DAAs. Male gender, older age, alcohol abuse, diabetes mellitus, the existence of advanced fibrosis (F3)
or cirrhosis, higher alpha-fetoprotein and no SVR are risk factors for HCC occurrence. The existence
of cirrhosis is the most important risk factor for HCC development. Therefore, guidelines recommend
patients with advanced liver fibrosis or cirrhosis at the time of DAAs treatment should stay in HCC
surveillance even after DAA-induced SVR. FIB-4 and aspartate aminotransferase to platelet ratio index
(APRI) are easily accessible non-invasive indicators which can be used as stratification risk factors for HCC
[37]
development, alongside cirrhosis. Kanwal et al. divided cirrhotic patients who achieved SVR with DAAs
into three groups: patients who had persistently high FIB-4/APRI over time, patients who experienced
a decline in FIB-4/APRI, and patients who had persistently low FIB-4/APRI. Annual HCC incidence
remained below 1.5% in the third subgroup, suggesting that it might be possible to exclude these cirrhotic
patients from HCC surveillance programs. On the contrary, the annual HCC incidence was between 0.4%
to 1.6% in non-cirrhotic patients but with high FIB-4/APRI subgroup (FIB-4>3.25/APRI >1.5), which was
high enough to recommend HCC surveillance in these patients.

Although the impact of DAAs treatment and HCC has been extensively published, our review has some
strengths. Firstly, we divide the studies not supporting high rates of HCC occurrence after DAAs treatment
into three categories, which facilitates easy comparison between studies. Secondly, we include the most
recent published evidence on this topic up to April, 2020, with the majority of studies published in 2019
and 2020, with follow-up of three to five years. Thirdly, we discuss the changes in HCC incidence over time
following DAAs-induced HCV eradication. Fourthly, we emphasize FIB-4/APRI as the stratification factors
besides cirrhosis, which is more useful for the patients with F3 fibrosis.

CONCLUSION
DAAs treatment doesn’t appear to increase the occurrence of HCC, even in the cirrhotic patients.
DAAs treatment should be considered in all HCV patients. Cirrhotic patients should be monitored for
development of HCC during and after DAAs treatment.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study and performed data acquisition and
interpretation: Yang M, Ma R
Made manuscript revision: Wei L, Huang Y