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Zanetto et al. Hepatoma Res 2018;4:70 I http://dx.doi.org/10.20517/2394-5079.2018.102 Page 11 of 16

a SVR, whereas they began to return to baseline levels after the second week of treatment in patients who
[84]
[79]
did not . Villani et al. also observed an early rise in serum levels of vascular endothelial growth factor
(VEGF) and a change in the inflammatory pattern 4 weeks after initiating DAA treatment, suggesting an
increased liver cancer angiogenesis and tumor growth during this time. These changes returned to normal
[85]
after the end of treatment, however. In this regard, Faillaci et al. recently reported the result of a prospec-
tive study that confirmed the role of VEGF pathways in HCC occurrence and recurrence. In a cohort of 183
patients with cirrhosis, 14/28 (50.0%) with previous HCC recurred while 21/155 (13.5%) developed de novo
HCC. DAA therapy was associated with a significant increase of VEGF expression and this was significantly
correlated with an increased rate of HCC occurrence/recurrence in “high-risk” patients. These patients were
characterized by a baseline elevated and abnormal activation in liver tissues of neo-angiogenetic pathways,
as shown by increased level of angiopoietin-2. From a clinical perspective, they presented a greater severity
of baseline liver disease, as shown by higher portal collateralization and liver fibrosis scores. VEGF increased
during DAA therapy, remaining elevated during follow-up, and significantly correlated with serum angio-
poietin-2. Furthermore, angiopoietin-2 expression in the primary HCC or in cirrhotic tissue before DAAs
was independently related with risk of HCC recurrence [odds ratio (OR), 1.137; 95% CI, 1.044-1.137; P = 0.003]
or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019).

[86]
Debes et al. found 12 different soluble tumor markers (out of 22 tested, including markers of apoptosis, cy-
tokines and growth factors) that were significantly higher before DAA treatment in patients who developed
de novo HCC than in matched controls who did not. This raises the possibility of patients who eventually
develop HCC already having a more aggressive immunological pattern, even before any immune changes
due to DAAs occur, suggesting that the immune profile modulating HCC growth is attributed more to pa-
tients’ prior individual characteristics than to changes induced by DAA-mediated HCV clearance. Epigen-
etic effects could be affected by DAA-mediated HCV eradication too. It was recently found that the marked
changes in histone methylation induced by chronic HCV infection were only partially reversed by eradicat-
[87]
ing the virus with DAAs . An abnormal transcription could contribute to driving HCC tumorigenesis,
alongside the other mechanisms already discussed. What is clear is that immune system plays a crucial role
[88]
in terms of neoplastic surveillance . Trying to translate this concept into clinical practice, different prog-
nostic scores that include also immunological variables have been conceived and successfully implemented
in different types of tumor, including HCC. In this regard, systemic immune-inflammation index, neutro-
phil to lymphocyte ratio, platelet to lymphocyte ratio, aspartate aminotransferase-lymphocyte ratio index
(ALRI), and albumin/bilirubin score (ALBI) have been shown to predict both survival and recurrence risk
[92]
in patients with HCC [89-91] . Recently, Casadei Gardini et al. tested the applicability of these scores in the
specific setting of HCC recurrence after DAA, showing that ALBI and ALRI scores are promising practical
tools able to stratify the risk of HCC development/recurrence in DAA treated patients. More particularly, at
multivariate analysis, increase in ALBI grade (P = 0.038, HR = 2.35, 95% CI: 1.05-5.25) and ALRI (P = 0.008,
HR = 1.05, 95% CI: 1.01-1.09) were independently associated with HCC development and recurrence, respec-
tively. Importantly, risk of recurrence was adjusted for the time from HCC treatment.

CONCLUSION
In summary, the available data are not consistent enough to judge the risk of HCC occurrence/recurrence
after IFN-free HCV eradication treatment. To better understand the reportedly diverse rates of liver cancer
development, several factors should be taken into account, such as the achievement of a SVR, and the sever-
ity of liver dysfunction (the higher the Child-Pugh score, the higher the risk of HCC). We should consider
patients’ comorbidities and lifestyles too, particularly factors that might have an additional procarcinogenic
potential, such as diabetes, smoking, alcohol abuse, and so on. Another important issue in assessing HCC
recurrence risk is the time frame between tumor eradication and starting DAA treatment: this is not always
taken into account, but it could well help to explain the contrasting results between different studies. Large
cohort studies and meta-analyses suggest that there is no direct correlation between these two events. Addi-