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Gitto et al. Hepatoma Res 2020;6:22 I http://dx.doi.org/10.20517/2394-5079.2019.50 Page 3 of 9

[21]
Sometime later, Saraiya et al. conducted a further meta-analysis examining data from 1820 patients
with SVR due to DAA treatment. A vast part of the studies considered involved less than 100 patients with
consequent inexact estimates of HCC recurrence. Notably, many but not all patients were treated for HCC
with radical therapy (surgical resection or ablation). In fact, a substantial percentage of subjects (25%-50%)
received non-curative therapies such as transarterial chemoembolization, showing by definition a high risk
of recurrence regardless of antiviral therapy.

The authors correctly underlined other methodological differences among the studies analyzed. The extent of
follow-up to evaluate HCC recurrence varied among the studies (from 3 to 36 months). Furthermore, some
groups defined HCC recurrence from date of cancer treatment, while others assessed recurrence from start
of DAAs.

According to reported data, the HCC recurrence rate was 21.9% (with high statistical heterogeneity). Nine
studies compared HCC recurrence in DAA-treated (n = 947), IFN-treated (n = 210) and/or untreated (n =
641) patients. The authors demonstrated that DAA-treated patients displayed lower pooled recurrence risk
than did untreated patients and similar rate in comparison with subjects treated with IFN-based protocols.

[23]
In the same year (2018), another meta-analysis was published . The authors selected studies better with
respect to the previous meta-analysis, since they restricted patient enrollment to those with HCC previously
treated with a curative approach (surgical resection or percutaneous ablation). The authors subdivided
uncontrolled and controlled studies. The pooled proportion of recurrent HCC in uncontrolled cohorts was
16.7% (with evidence of substantial statistical heterogeneity) with follow-up that highly varied (from 12
to 280 weeks). Considering controlled cohorts, the pooled proportion was 20.1% (again with substantial
statistical heterogeneity) with a follow-up range that was up to 416 weeks. Remarkably, the authors
themselves reported that the global quality of the evidence was low for each of the outcomes considered,
suggesting the need for further studies with longer follow-up periods.

[24]
Recently, Rutledge et al. made strong suggestions about the complex matter of HCC recurrence after DAA
therapy. The meta-analysis conducted by these authors is not only the widest among the available studies
but is also particularly solid from a methodological point of view. In fact, the authors included only patients
with previous curative cancer therapy and excluded studies with less than one year of follow-up. Notably,
this rigorous approach allowed avoiding any rise in early HCC recurrence that could definitely be associated
with the presence of small subclinical HCC at the beginning of antiviral therapy. The authors analyzed and
compared 57 studies, which involved 16 IFN-treated, 33 DAA-treated and 8 untreated patients. DAA-treated
patients who achieved SVR displayed a recurrence rate of 18.17/100 per year. Patients with SVR due to IFN
therapy showed a similar recurrence rate (11.01/100 per year). The rate of HCC recurrence was comparable
between untreated patients (25.69/100 per year) and IFN-treated patients without virological response
(16.89/100 per year); subjects not responding to DAA showed a higher rate of recurrence, but the small
number of patients made the value not statistically significant (44.16/100 per year).

Notably, the authors performed a subanalysis adjusting data according to HCC consolidated risk factors such
as age and cirrhosis. They demonstrated that the DAA-treated group showed a lower rate of recurrent HCC
(although without statistical significance).

[25]
Since overall mortality represents the most important clinical outcome, the recent findings of Singal et al.
should be pointed out. The authors demonstrated with a multicenter cohort study (n = 797), that patients
who achieved both complete response to any HCC treatment (resection, local ablation, transarterial chemo-
or radioembolization, or radiation therapy) and SVR due to DAAs, showed a significant reduction of
mortality risk in comparison with non-responders and untreated subjects.