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Page 6 of 10 Burlone et al. Hepatoma Res 2020;6:3 I http://dx.doi.org/10.20517/2394-5079.2019.37
[15]
It is well known that male gender represents a risk factor to develop HCC , although the reasons for the
strong gender difference in HCC remain unclear. In the Italian population, the male to female ratio of HCC
from any cause is 2.2 to 1, similar to what is observed in other western countries. In our cohort, the male to
female ratio was higher, 5.3 to 1, possibly reflecting in part the age-specific sex difference in the incidence
[16]
of HCC, which peaks at a slightly younger age than the one we observed in our study population . The
highest incidence of HCC in men could be related to the higher prevalence of cirrhosis in males due to
more rapid disease progression before age 50 years. In fact, women during their reproductive years have a
better control of HCV replication, possibly due to estrogens, and this fact leads to less necroinflammatory
[17]
response and less fibrosis progression . Others have suggested that estrogens have a direct putative
antifibrogenic activity, or an interference with metabolic parameters and oxidative stress [18-20] . Finally,
[21]
higher, genetically determined expression of interleukin-6 in males may also be a factor .

Most experts would agree that cirrhosis of any etiology is the strongest predictor of HCC. In fact, cirrhosis
can be considered a premalignant condition, independently from the underlying liver disease [22-24] . It is
worth mentioning that we staged liver disease mainly by transient elastography; while this is consistent
with what is recommended by current European guidelines on hepatitis C , consideration must be given
[1]

to the fact that the performance of this test may be suboptimal in obese patients. Hepatocarcinogenesis
represents a multistep process, leading to chronic liver damage through persistent inflammatory damage
that promotes malignant transformation [25-27] . The annual risk of HCC is as high as 3% in patients with
cirrhosis and active HCV infection . Viral hepatocarcinogenesis can be due to direct or indirect
[28]
mechanisms, and is affected by host and environmental factors, such as alcohol intake, smoking, and HBV
or HIV co-infections, which also increase the risk of cirrhosis. Indeed, although the estimated risk of HCC
is increased 15-20-fold among persons infected with HCV in comparison to those who are not infected,
most of the excess risk is limited to those with advanced hepatic fibrosis or cirrhosis .
[29]

In the present study, obesity was a major independent predictor of HCC. This observation is fully
consistent with current literature that suggests the existence of a vicious circle linking cirrhosis/fibrosis,
HCV infection, and lipid metabolism derangement. In the obese, the inactivation of negative regulators
of STAT-1 and STAT-3 signaling drives the development of non-alcoholic steatohepatitis and HCC, not
only in cirrhotic patients, but also in patients with chronic hepatitis [30,31] . Moreover, there is evidence that
HCV-infected patients are prone to develop features of metabolic syndrome (MetS), probably due to the
fact that the replication cycle of HCV depends heavily on the pathways of lipid metabolism in hepatocytes
and considerably alters host lipid hemostasis [32,33] . Interestingly, two large population cohort studies from
Taiwan showed that HCV infection was strongly associated with MetS. The prevalence of MetS in these
patients ranged from 13% to 32%; they had an aggressive and severe liver disease, developing more severe
fibrosis than those without MetS, which contributed to cancer development [34-36] . However, MetS did not
[37]
affect SVR achievement after DAA .

The major novelty of the present study lies in the strong association observed between lack of SVR and
identification of HCC soon after concluding DAA. Overall, the rates of SVR and virologic failure in our
cohort (97.6% and 1.8%, respectively) were comparable with what has been observed in registration
trials [38-40] and in real-life cohorts [25,41,42] . While some authors affirmed in several retrospective studies that
DAA increased the rate of early recurrence/occurrence of HCC, the short follow-up, the small number of
patients, and the study design did not allow definite conclusions [3,43,44] . In contrast, multiple large cohort
studies and meta-analyses have since demonstrated that DAA-induced SVR is associated with reduced risk
of HCC occurrence [45-49] .

One possible explanation for the low SVR in those who develop HCC is that it derives from the sum of
risk factors for HCC, such as older age, high alcohol intake, more severe fibrosis, and co-infections [50-53] .
Although the difference did not reach statistical significance, we did observe a numerically lower SVR rate