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Page 8 of 16 Zanetto et al. Hepatoma Res 2018;4:70 I http://dx.doi.org/10.20517/2394-5079.2018.102

tion does not reduce HCC recurrence in the short term. The design of this latter study was very similar to
[35]
the Spanish one. The crude HCC recurrence rate was almost identical to the one reported by Reig et al. ,
but the follow-up after starting DAA was longer, thus leading to a lower time-based incidence.

Here again, however, the study design did not allow for the HCC recurrence rate to be defined as higher,
lower or the same as expected in the natural history of the disease.

Other studies analyzing different populations did not confirm such a high risk of HCC recurrence follow-
[56]
ing DAA-based therapy. The largest study concerned a French multicenter cohort in which two different
groups of pre-transplant patients were prospectively followed up: the HCC recurrence rates were similar in
DAA-treated and untreated patients.

A rather similar low rate of HCC recurrence in cirrhotic patients treated with DAAs was also reported by
[40]
[57]
Zavaglia et al. along with Cheung et al. reporting respectively on compensated and decompensated cir-
rhotic patients.

[58]
Similarly, Cabibbo et al. found 6-, 12- and 18-month recurrence rates comparable with the figures reported
in the literature for untreated patients, and the time to recurrence was much the same too. A history of HCC
recurrence and tumor size emerged as two independent risk factors, and the authors suggested they be used
to stratify patients by risk of early HCC recurrence.

Besides the few initial alarming studies, in which probably the HCC recurrence just happened to coincide
with their antiviral treatment follow-up, it is becoming clear that DAAs do not substantially change the risk
of recurrence in patients with advanced liver disease and previous history of HCC. Indeed, in these patients,
in which the neoplastic process did already take place, the risk of recurrence remains high, appearing not
be influenced by viral eradication. It is possible in fact that, contrariwise to patients without any previous
tumoral history, the process, once triggered by active viral replication on a cirrhotic ground, becomes inde-
pendent from the replication status so that recurrence rates and timings remain unmodified after treatment
being modulated by HCC characteristics instead.

DAAs vs. IFN-based regimens
[59]
The experience of the Italian Liver Cancer Group, recently reported by Petta et al. , demonstrated that both
IFN-based and IFN-free HCV clearance result in longer times to tumor recurrence in patients with HCC
radically treated with either resection or ablation, with no significant difference between the two virus eradi-
cation treatments.

[60]
In a European multicenter study by Kolly et al. , the time elapsing between HCC treatment and DAA ini-
[55]
tiation emerged as a predictor of recurrence, in line with the analysis by Cammà et al. .
Obtaining a SVR with DAAs (as opposed to IFN-based treatment or no treatment) does not seem to enhance
the risk of HCC recurrence, which appears to be better predicted, again by other tumor- and patient-related
variables. That said, studies on cancer recurrence should always report the tumors’ baseline characteristics,
the type of treatment administered, and the time elapsing before starting DAA to enable results to be inter-
[61]
preted correctly. In a meta-analysis, Waziry et al. recently confirmed the uncertainty of correlating HCC
occurrence or recurrence with DAAs: they found no evidence for a correlation between IFN-free regimens
and HCC development, and confounders such as a shorter mean follow-up or older age emerged as potential
biases influencing the studies that sounded the alarm. The authors confirmed that HCV eradication reduces
the risk of HCC in patients who achieve a SVR, while older age, advanced cirrhosis, and worse baseline
patient features were independent predictors of HCC onset in the DAA-treated population, which helps to