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Page 2 of 9 Gitto et al. Hepatoma Res 2020;6:22 I http://dx.doi.org/10.20517/2394-5079.2019.50

[5]
HCV leads to chronic hepatitis C and cirrhosis in about 20% of subjects within 20 years of infection and
[6]
HCC occurs in around 3.5% of cases per year .

[7]
For many years, interferon (IFN)-based protocols have represented the cornerstone of antiviral therapy .
Achievement of sustained virological response (SVR) with IFN is infrequent (especially in cirrhotics), and
the drug leads to low compliance and high toxicity. However, viral clearance due to IFN is associated with
[8]
decreased incidence of HCC and overall reduction of other liver-related events .
[9]
In the last few years, new antiviral molecules with a direct action against the virus have been developed .
[10]
Today, many direct-acting antivirals (DAAs) are available with amazing results in terms of SVR and safety .
A few years after the introduction of DAAa, two noteworthy and innovative studies reported first that SVR
due to DAA might increase the risk of both HCC occurrence and recurrence [11,12] .

Later, other authors suggested the unexpected high incidence of HCC after DAA treatment, describing the
[13]
onset of extraordinarily aggressive tumors a few weeks after the end of antiviral therapy .
Following the publication of these studies, many other groups reported the increased occurrence of HCC
[14]
after DAA use , whereas others rebutted this notion [15-17] .
The exact biological mechanisms by which oral DAAs might enhance the risk of HCC are largely
[18]
unknown . Modifications in immune surveillance may potentiate the risk of HCC by accelerating the
process of regeneration. Moreover, DAAs seem to increase levels of vascular endothelial growth factor
[19]
(VEGF) and to modify the balance between pro- and anti-inflammatory reactions .

The aim of the present review was to analyze the main evidence about the relationship between DAA and
HCC onset, privileging meta-analyses and original real-life controlled trials. Moreover, we tried to identify
high-risk subpopulations that can benefit from personalized post-eradication follow-up. We analyzed the
state-of-the-art about this debated matter offering a critical point of view and underlining potential future
perspectives.

HCC RECURRENCE AFTER SVR DUE TO DAA THERAPY
In the last years, there has been particular concern about the rates of HCC recurrence following DAA
treatment [11,12,20] .

Notably, many studies about HCC recurrence are single-arm and retrospective cohort studies. Moreover,
they show relevant heterogeneity in the following patterns: tumor burden, HCC treatments leading to whole
[21]
response, and follow-up periods . Indeed, it is questionable whether HCC recurrence might be part of
the natural history of patients with advanced liver disease or whether DAAs can have a chief role in cancer
pathogenesis. Fortunately, in the last 2 years, some meta-analyses have been proposed, and these are the ideal
instruments to obtain solid answers.

[22]
In 2017, Waziry et al. compared, using systematic review, meta-analysis, and meta-regression approaches,
15 studies on HCC recurrence after SVR. Seven studies included patients treated with IFN-based therapy
and 10 comprising patients cured with DAA. The incidence of HCC recurrence was 9.21/100 per year and
12.16/100 per year in IFN and DAA subgroups, respectively. Through a meta-regression analysis and an
adjustment for age and follow-up length, the authors demonstrated that patients in the DAA group did not
show higher HCC recurrence in comparison with those treated with IFN.