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Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52 Page 11 of 14

hepatic decompensation and HCC development, with a lower likelihood of liver related death at 10 years, in
[49]
association with achievement of SVR . Similar findings were reported in the Hepatitis Testers cohort from
[50]
North America . In the multivariable model, SVR was associated with reduced liver cancer risk (HR: 0.20;
95%CI: 0.13-0.30) in a median follow-up of 5.6 years.

DISCUSSION
The main points of strength of the previously mentioned studies are their prospective design and the large
number of patients enrolled and the long follow-up. The largest studies included patients treated with IFN-
based regimes and therefore a confirmation with DAA-based treatment only is needed.

[51]
Camma et al. considered Reig’s observations as premature, affirmed that a comparison with untreated
[16]
controls is mandatory to solve the issue without generating excessive alarm on DAAs; Nault and Colombo ,
at the same time, did not consider the data published solid enough to confirm the increased risk in treated
patients, even though they could recommend HCC surveillance after viral eradication; Alberti and
[52]
Piovesan underlined the great variability in occurrence and in recurrence rates, reflecting the extreme
heterogeneity of the different clinical settings and patient cohorts on which studies were based; finally,
[53]
Blanco and Rivero-Juarez specified that prospective studies targeted on this problem are necessary before
even considering a different therapeutic approach to patients with HCV-related liver disease.

[42]
Furthermore, the development of an aggressive tumor has been reported in some of patients , although
the authors cannot exclude that what they observed in these patients merely reflects the natural history
of their liver disease. It is important to point out that the current clinical practice does not include IFN-
based treatment any more, due to the important improvement in HCV-treatment made by DAAs. As
a consequence, to compare DAA treatments with pre-DAA treatments or no treatment is meaningless.
Nevertheless, the lack of randomized control trials is an important clinical and methodological issue. In
conclusion, the risk reduction in hepatic decompensation as well as in HCC incidence in patients achieving
SVR is the only proven evidence. The reports about the increased risk of HCC occurrence/recurrence in
DAA treated patients are afflicted by selection and methodologic biases, that weaken the impact of these
studies. We strongly believe that is mandatory to treat HCV-infected patients with DAAs but also to
maintain an active surveillance for liver cancer as the guidelines suggest; the previously presented data must
be considered with caution.

DECLARATIONS
Authors’ contributions
Wroted the review and approved the final version: Russo FP, Tessari M, Imondi A
Edited the English: Lynch EN
Edited the manuscript and approved the final version: Farinati F

Availability of data and materials
Not applicable.

Finacial support and sponsorship
None.

Conflicts of interest
The authors declare no conflicts of interest in association with this study.

Ethical approval and consent to participate
Not applicable.