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Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52 Page 3 of 14

should be undertaken by all prescribers and regulators involved in this issue. The above-mentioned study
also led to the hypothesis that HCV eradication mediated by DAAs may induce a sudden modification in
HCV-dependent inflammatory status and immune surveillance, dysregulating the anti-tumor response
and boosting the growth of still undetected HCC foci. Recurrence after initial complete response may be
explained by the dissemination of cells prior to treatment, and by the development of new oncogenic clones
within a cirrhotic liver that has already suffered genetic damage. Immune surveillance plays a major role
in regulating survival and growth of metastatic cells; DAA-based antiviral treatment, as a consequence of
the inhibition of HCV replication and the abrupt resolution of chronic inflammation, may disrupt cancer
immunosurveillance. This may lead to tumor progression.

A similar report on the management of patients with HCC undergoing DAA treatment was elaborated by
[11]
Conti et al. . Their data suggested that DAA-induced resolution of HCV infection did not decrease the
occurrence of HCC in the short term and that HCC curative treatments, in patients undergoing antiviral
therapy, do not reduce the risk of recurrence. In their study the recurrence rate of patients with a history
of previous liver cancer was around 30% (17 of 59 patients) within 24 weeks. In contrast with the study by
[10]
Reig et al. , the patients who experienced HCC recurrence were younger and had a more severe liver
[12]
stiffness. Another study, published by Kozbial et al. , reported an unexpected high incidence of HCC
occurrence and recurrence in patients treated with DAAs. Even though the study included a small number
of patients, the authors concluded that decreasing inflammation could have a role in modulating liver
regeneration and that the change in the immunological environment could induce the progression of pre-
existing pre-cancerous changes [12,13] . The authors also noticed the reduction of miR-22 levels in patients
treated with DAAs, which could play a possible role in tumor development, since miR-22 is involved in
[14]
suppressing the replication of virus-infected cells and controlling carcinogenesis .
[15]
As suggested by Reig et al. , tumor dormancy derives from a dynamic equilibrium between cancer cells
growth and immune cells infiltration; several conditions and DAA treatment could disturb this equilibrium
by causing immunological changes, connected to the fall of the antigenic load due to HCV eradication.
This phenomenon was not observed in patients who underwent IFN-based therapy, probably because of
[16]
the immune-modulatory and anti-proliferative properties of IFN . Moreover, chronic HCV infection
activates the most prevalent innate cells in the liver, the NK cells, as well as increases the expression of
IFN-stimulated genes, suggesting that infection activates an intrahepatic immune response. In fact, DAA-
mediated HCV eradication is characterized by decreased levels of CXCL10 and CXCL11 and normalization
of NK-cell phenotype and function, a fact that could explain the association between HCV clearance and
loss of intrahepatic immune reactivation [17,18] .

[19]
Cardoso et al. in a study of a cohort of 54 patients successfully treated with IFN-free antiviral therapy,
reported an HCC incidence of 7.4% after a median time of 7.6 months (IQR 6.3-10.6 months), in a median
[15]
follow-up of 12 months (IQR 9.4-12.5 months). The authors, in agreement with Reig et al. , speculated that
an oncogenic effect of the antiviral therapy was highly unlikely, but at the same time, due to the coincidence
with viral elimination, the mechanisms responsible could be those previously hypothesized.

[20]
A recent report by Abdelaziz et al. distinguished de novo vs. recurrent HCC following DAA treatment
and evaluated their behaviour. No difference was found regarding patient baseline and tumor characteristics
(age, gender, hepatic function assessed by Child Pugh Score, performance status, number or size of lesions)
or their response to DAAs. On the opposite, a significantly different time before detection of HCC emerged
between the two groups. De novo lesions developed later than recurrent tumors (14 ± 16.02 vs. 6.7 ±
5.1 months, P = 0.008) and showed a better response to ablation (P = 0.03). The above-mentioned studies
represent the current bulk regarding the evidence of DAAs promoting liver carcinogenesis.