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Regardless of these discrepancies, it is possible to review the published results to draw some conclusions, but
a few statements need to be addressed at first: (1) the concept of incidence; (2) the characteristics of the study
population; (3) the starting point and the ending point of the observation period; and (4) the distribution of
events during the follow-up.

Incidence is a measure of the probability of occurrence of a given condition in a population within a
specified period. The incidence rate is the number of new cases per population at risk in a given time period.
From this concept derives that to analyse the incidence rate of HCC after DAA therapy it is fundamental to
define both the exact starting point and the exact ending point of the observation period. Only if these time
points are comparable, different study results can be compared.

The study population should be at risk of developing the medical condition. Therefore, the risk should be
comparable among different study groups before performing any comparison. Since in HCV-related liver
disease HCC occurs almost exclusively in patients with liver cirrhosis, the population at risk should include
only patients with advanced liver fibrosis (F4 according to the METAVIR classification).

In analysing the incidence rate of HCC after DAA therapy, we must distinguish between analysing the new
de novo occurrence of HCC and the recurrence of a new HCC in patients with prior history of successfully
treated HCC. In the former situation, the starting point should be the end of DAA therapy, in the latter, we
must distinguish between considering as a starting point the time of the previous HCC treatment or the end
of DAA treatment. In all cases, the ending point should be defined after DAA therapy end, and the interval
from the starting point must be clearly assessed.

Another important point is the distribution of events (HCC) during the follow-up. It is known that during
the natural history of liver cirrhosis the development of de novo incident HCC is not clustered around any
[12]
specific time point . Similarly, HCC recurrence is generally not clustered around specific time points, even
[6]
if recurrence rate is higher during the first two years after curative treatment of the neoplastic nodule . For
this reason, the median interval between DAA therapy and HCC diagnosis needs to be analysed to assess the
latency period between exposure to DAA therapy and HCC development.

WHAT PUBLISHED STUDIES TELL US
In Table 1, we have summarized the results of the principal studies addressing the de novo occurrence and/or
recurrence of HCC in HCV-infected patients, with compensated liver cirrhosis, who have been treated with
DAA therapy. Due to the heterogeneity of the study populations and the different observation periods, any
formal meta-analysis seems of limited utility to draw any sound conclusion. It seems more important to note
some common and peculiar aspects of the results.

At first, we must differentiate between the de novo occurrence of new HCC in cirrhotic patients without
prior history of HCC and recurrence of HCC in patients with previously treated HCC. In studies analysing
the former group of patients, the observation period after DAA therapy ranged a median of 6 to 14 months,
indicating a relatively short follow-up. Despite this short observation period, de novo HCC occurred in 1.5%
to 3.9% of patients. If we consider an expected annual rate of 2% to 3% in these subjects, we can conclude
that HCC occurrence is certainly not reduced after DAA treatment. On the other hand, we have not strong
elements to assume that the occurrence rate is increased, without a control group. Therefore, the argument
of the incidence rate of new HCC after DAA therapy remains unsettled without a definite conclusion. In any
case, a real increased annual incidence rate of HCC does not seem to happen after DAA treatment.

More intriguing data come from the studies on the recurrence of HCC after DAA treatment. The analysis
of the recurrence rate must take into account the interval since previous HCC treatment, due to the higher