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Gitto et al. Hepatoma Res 2020;6:22 I http://dx.doi.org/10.20517/2394-5079.2019.50 Page 5 of 9

(without statistical significance). Afterwards, the authors carried out an additional smaller meta-analysis
evaluating only studies with multivariate-adjusted hazard ratios (for gender, baseline cirrhosis and age).
With this approach, these authors did not find augmented hazard of HCC occurrence in subjects treated
with DAA compared to the IFN-treated subgroup. Notably, the authors also sub-analyzed data according
to follow-up length. Considering occurrence rates in the second year after treatment with DAAs, similar
incidence rates were found (0.88 per 100 per year in the DAA group and 0.55 in the IFN group). Finally,
the authors conducted a sub-analysis excluding any cases of HCC occurrence within six months after end
oftreatment, where they found an incidence rate of 1.12 per 100 per year for the DAA group and 3.01 for the
IFN group (again without statistical significance).

HIGH RISK PATIENTS: POTENTIAL ROLE OF GENETIC SIGNATURE
The data outlined in the previous paragraphs underlined the concepts that on the whole, the risk of
developing HCC after DAAs is small and DAAs represent an extraordinary option for curing hepatitis C.
There is already consistent evidence that on a population basis, DAAs improve survival and decrease long-
term complications such as decompensation. On an individual basis, however, DAAs might constitute a
stimulus associated with higher risk of developing HCCs. In a series of patients with liver cirrhosis enrolled
in a prospective study of HCC development, liver tissue of patients who subsequently developed HCC were
[29]
already primed towards neoangiogenesis well before DAA treatment and ensuing HCC development .
Expression levelsof angiopoietin-2, evaluated by immunohistochemistry, differed significantly in tumor
tissue among patients with recurrent, de novo, and non-recurrent HCC after DAAs (P < 0.0001, Kruskal-
Wallis test). Likewise, hepatic stiffness, spleen size, variceal size, and hepatic venous pressure gradient were
related to HCC risk but only angiopoietin-2 was independently related to both risk of HCC occurrence and
recurrence. Our hypothesis was that the events occurring during the progression of chronic liver disease,
with occurrence of increasing portal hypertension, could be critical in activating angiopoietin-2 expression
[29]
in splanchnic vascular bed hyperplasia . Of further interest, HCC developing after DAAs was often
biologically aggressive, as indicated in a large proportion of them by the presence of five-gene neoangiogenic
[30]
signature identified as a marker of rapidly growing and clinically aggressive HCC .
The intriguing relationship between severe portal hypertension and DAA-mediated carcinogenesis could
[11]
already be glimpsed in a few previously published papers. Conti et al. identified more severe liver fibrosis
[31]
as independently associated with risk of HCC recurrence. Ravaioli et al. recently showdc that the decrease
in spleen stiffness in patients who developed HCC after DAAs was significantly less than in patients who did
[32]
not develop HCC. Similar results were obtained by Ioannou et al. who showed that when FIB-4 remains
higher than 3.25 after SVR, the risk of HCC is so consistent to merit HCC surveillance. This highlights that
severe portal hypertension is a critical predisposing factor for HCC.

IMPACT OF METABOLIC RISK FACTORS ON HCC RISK
Both diabetes and obesity represent consolidated risk factors for HCC exerting a strong carcinogenic effect
[33]
directly by disrupting the insulin-IGF pathway or indirectly by promoting steatosis .
[34]
In a large retrospective cohort study, El-Serag et al. showed that SVR due to effective IFN-based treatment
led to a noteworthy drop in HCC risk. Nevertheless, the authors reported that the annual risk of HCC among
responding patients was not insignificant (overall 0.33%). Interestingly, residual HCC risk was associated
not only with advanced stage of fibrosis and age but also with diabetes and HCV genotype 3. Relative to this
point, other authors also suggested that HCV genotype 3 was correlated not only with higher rates of liver
steatosis (being the more “metabolic” genotype) but also with greater HCC risk in comparison with the other
genotypes [35,36] . These data indicate that metabolic disorders might have a significant role also in determining
HCC occurrence after DAA therapy.