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Page 10 of 16 Zanetto et al. Hepatoma Res 2018;4:70 I http://dx.doi.org/10.20517/2394-5079.2018.102

On the other hand, albeit in a very different setting, we were able to compare the histopathological features
of HCC on livers explanted from a small cohort of patients transplanted at our center who were treated with
DAAs while listed for a transplant with active HCC, and having HCC bridging treatments at the same time.
We found no histopathological differences in median number and total volume of HCC nodules, tumor dif-
[66]
ferentiation or MVI vis-à-vis a contemporary untreated cohort involving patients and tumors with com-
parable baseline characteristics.

POSSIBLE PATHOGENIC MECHANISMS
Another particular issue that came to light with the first “warning report” concerns the possibility of HCV
clearance from the liver, and the consequent impairment of the local immunological microenvironment,
having an impact on HCC biology [Table 3]. Chronic stimulation of antigens against HCV infection con-
tributes to virus-specific CD8+ T-cell exhaustion, continuative activation of host-mediated liver inflamma-
tion (driven partly by endogenous IFNs), and altered innate immune cell populations [67,68] . IFN can modulate
both innate and adaptive immune system. Different cells and pathways can be involved, including but not
limited to inhibition of CD4+ and CD8+ T-cell proliferation, direct activation of natural killer (NK) cells,
[63]
and suppression of IL-12 production by monocytes . The immune “restoration” that follows IFN-based
antiviral therapy, together with eradication of the virus, was considered to be the pathophysiological ex-
planation for the decrease incidence of HCC in patients achieving SVR with IFN-based antiviral therapies.
There has been speculation that the mechanism by which patients with cirrhosis on IFN-free treatment
might experience a higher HCC rate could relate to a reduced tumor-specific immune surveillance, par-
ticularly as concerns the HCC-specific CD8+ T-cells. In fact, DAA-induced HCV eradication could lead to a
rapid decline in HCV-specific and non-specific T-cells from the liver, with a reduced homing of leukocytes
towards the liver. This weaker infiltration by lymphocytes has been shown to correlate with a higher risk of
[74]
HCC recurrence [69-73] . Debes et al. recently speculated on other potential mechanisms of immune derange-
ment during DAA therapy, involving NK-cell activity and tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) expression. These immune mediators have consistently been found increased during HCV
infection, potentially blocking HCC cell proliferation while attempting to contain the virus [75,76] . The dem-
onstrated DAA-induced normalization of the NK-cell compartment, together with the decrease in TRAIL
receptor 2 expression, could therefore be responsible for a less efficient immune surveillance, and thus favor
HCC recurrence. Whether or not the high HCC recurrence rate could be due to radiologically-undetectable
[40]
tumors growing rapidly remains to be seen, however. Cheung et al. suggested that the rapid recurrence of
HCC noted in DAA-treated patients might be prompted by the enhanced proliferation of a few isolated ma-
lignant cells already present when the treatment started giving rise to a rapid tumor growth, rather than by
any de novo clone development. Indeed, the regeneration mechanisms activated by the rapid cure of inflam-
mation, and differences in the immunological environment compared with IFN-based treatments could be
[50]
responsible for the unrestricted growth of precancerous lesions or small malignant cell clones . The lack of
any continuous IFN stimulation in the liver after eradication of the virus probably has a significant impact
on intrahepatic immune responses too, giving rise to a less efficient neoplastic surveillance and enhancing
neoplastic cell proliferation after an SVR has been achieved [77,78] . The peculiarity of the warning in the Span-
ish report lies in the timing of HCC recurrences, which peaked during antiviral treatment and soon after-
wards: this prompted several groups to investigate molecular changes occurring during this particular time
frame. For instance, miR-122 concentrations were found to correlate with virus-induced liver inflammation
and HCV-RNA levels, and serum levels decreased in patients with a SVR treated with a 12-week course of
[79]
paritaprevir/ritonavir + dasabuvir or ombitasvir . MiR-122 has a central role in suppressing viral replica-
[80]
tion and it reduces tumorigenesis, angiogenesis and intrahepatic metastasis , serving as a marker of disease
status and response to therapy [81-83] . During the first two weeks of the DAA treatment, changes in miR-122
levels were similar across genotypes, and comparable with or without ribavirin. Interestingly, miR-122 re-
mained below the baseline levels throughout post-treatment week-12 in patients who subsequently achieved