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Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52 Page 5 of 14

and 3% in the IFN-free treatment group and 1% and 2.2% in the Peg-IFN/RBV group, with no statistically
[32]
[31]
significant differences . A European multicentre study by Kolly et al. assessed the HCC recurrence rate
after DAA treatment, reported as the cumulative disease-free survival during the follow-up. In 47 patients
previously treated for HCC, the time between tumor treatment and the initiation of DAAs was a predictor
of recurrence, but whether this effect was due to the anti-viral therapy, or due to foci of HCC which were
[33]
undetectable before treatment was undefined. Petta et al. , using the ITA.LI.CA liver cancer collaborative
database, demonstrated that the eradication achieved by both IFN-based therapy and DAAs resulted in an
increased time before tumour recurrence in patients with HCC curatively treated by radical ablation. Data
deriving from their observation showed 16 (28%) and 22 cases (39%) of HCC, after a median follow-up of 18
months in DAA, and 34 months in IFN-based SVR, respectively.

[34]
Also, the retrospective large cohort study performed by Kanwal et al. on DAA-treated patients from
129 Veterans Health Administration centres confirmed the lack of evidence that DAAs promote HCC
and the preventive effect of the HCV eradication on HCC occurrence, with a 76% risk reduction. On the
other hand, their analysis confirmed that the HCC risk persists despite SVR in DAA-treated patients, with
an annual HCC incidence after HCV eradication with DAAs of 0.90%, compared to 0.3% in IFN-treated
patients (as reported by previous studies). It must be said that the treated population has changed since the
advent of DAAs, thus giving patients with other independent HCC risk factors, such as advanced cirrhosis,
a chance to be treated. The incidence rate was greater in cirrhotic patients, underlying the importance of
HCC surveillance in this scenario, as well as the need of not delaying treatment in order to avoid liver
deterioration.

A retrospective population-based cohort study using the Electronically Retrieved Cohort of HCV Infected
Veterans (ERCHIVES) investigated whether DAA use was associated with higher rates of incident HCC
compared to treatment with IFN-based regimes, the primary outcome being the development of incident
HCC cases. A series of 17,836 persons was included, and amongst cirrhotic patients DAA treatment was not
associated with higher risk of HCC compared to the IFN-treatment group (HR: 1.07; 95%CI: 0.55-2.08). The
risk of incident HCC was higher, among patients with known HCC risk factors including older age (HR, per
10 years increased: 1.76; 95%CI: 1.26-2.16) and AFP > 20 (HR: 4.1; 95%CI: 2.75-6.10), but when an analysis
in cirrhotics was performed, there were no differences in HCC-free survival between the DAA-treated and
IFN group. According to the authors, this suggests that pre-treatment HCC risk is the factor that determines
post-treatment risk. In contrast, untreated cirrhotic patients had a significantly higher incidence rate of HCC
[35]
compared to both DAA and IFN treated groups (45.31 per 1000 person-years; P = 0.03) .

Very recently large cohort studies using real-world data demonstrated that DAA-based HCV treatment is not
associated with an increased risk of incident liver cancer and suggested that DAA-based HCV treatments
are associated with a reduced risk of incident liver cancer, irrespective of co-medication with interferon.
Male gender, older age and baseline cirrhosis were the strongest predictors independently associated with
[36]
subsequent incident liver cancer . It’s been demonstrated that reaching SVR allows all-cause mortality
reduction, including HCC-related mortality, for all stages of hepatic disease. In advanced liver disease, this
[37]
was first proven when SVR was reached with IFN-based regimens . In the above mentioned study by
[24]
Cheung et al. on DAA treatment in patients with decompensated hepatic disease, HCC incidence in
patients with SVR24 was lower than in those who did not accomplish it (17/317, 5.4% vs. 10/89, 11.2%; P = 0.049;
HR: 0.33; 95%CI: 0.13-0.87). The results were compared to HCC incidence in untreated patients (4.2%). There
[24]
was no evidence of a significant increase in HCC occurrence in treated patients .
Another interesting scenario is liver transplantation, and the clinical impact of viral eradication in patients
on waiting list is still poorly evaluated.