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Page 2 of 14 Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52

treated with Peg-interferon (Peg-IFN) and ribavirin, demonstrated a reduction in LRD and non-LRD, with
patients achieving sustained virological response (SVR) showing nearly the same life expectancy as the
[3,4]
general population . Patients with compensated cirrhosis, and without the clinical manifestations of portal
hypertension, are those who experience the greater clinical benefits of HCV eradication, as they do not
[5]
develop LD and rarely HCC .

This was confirmed in a meta-analysis of 12 studies including 25,497 patients that demonstrated a relative
risk reduction for HCC at all stages of liver disease [hazard ratio (HR): 0.24; 95%CI: 0.18-0.31; P = 0.001] and
an absolute risk reduction of 4.6% (95%CI: 4.2%-5.0%) in patients who achieved SVR compared to those who
[6]
did not respond .

DIRECT-ACTING ANTIVIRAL THERAPY: A NEW STORY HAS STARTED
The more widely extended indication criteria and the greater affordability of direct-acting antiviral
(DAA) therapy is leading to higher rates of HCV eradication and is expected to reduce the risk of HCC
by preventing, at least in part, liver cirrhosis. Nevertheless, in cirrhotic patients, particularly in those with
concurrent pro-carcinogenic co-factors, such as diabetes and/or advanced age, the risk of HCC remains
elevated for several years after SVR. This underlines the importance of HCC surveillance even after
SVR in cirrhotic patients and highlights the need for early initiation of DAA therapy, before cirrhosis is
[7]
[8]
established . Cabibbo et al. published a meta-analysis of the HCV-untreated arms of the studies evaluating
the outcomes of patients with early HCC who, after a successful treatment of the tumour, did not receive any
antiviral treatment. This study provides a benchmark for indirect future comparisons aimed to determine
the actual benefit of HCV eradication by antiviral treatment. They found an extremely variable 2 and 3-year
HCC recurrence rate, respectively at 47% and 79.8%, in patients HCV-infected who did not receive antiviral
therapy, and this heterogeneity was not completely explained by any single patient or study characteristic.

DAA AND HCC: HIGHER OCCURRENCE/RECURRENCE
In 2014, the introduction of DAAs has revolutionized the standard of care of HCV infection, allowing
to reach SVR rates of over 90% in patients with genotype 1. Multiple oral interferon-free HCV regimes
are now available and, although there is some evidence of response variability, related to specific patient
characteristics and HCV genotypes, the SVR rates are high for all approved DAAs. Due to their high
efficacy, tolerability and the relatively short treatment duration, DAAs are now the standard care for patient
[9]
populations that were historically considered difficult to cure , even though data on the long-term outcome
of patients with advanced liver disease treated with DAAs are still lacking.

The assumption that HCV eradication would translate into a reduced incidence of newly developed tumours
in HCV patients as well as into a reduced HCC recurrence rate, is to be considered in the context of the
controversy about a potential association between DAA treatment and an increased HCC risk, overall [Table 1].

[10]
In fact, in 2016 a report described a totally unexpected early tumor recurrence in patients with HCV-
related HCC undergoing DAA treatment.

In a cohort of patients who achieved a complete HCC radiological response before starting antiviral
[10]
treatment with DAAs, Reig et al. described an HCC recurrence rate of 28% (16 of 58 patients), with a
median follow-up of only 6 months, recurrence rate that was extremely higher than expected and previously
observed. Furthermore, the pattern of relapse was described as infiltrative or multinodular in 25% cases,
this also being an unexpected finding. Even though the authors concluded that their data should only be
taken as a “note of caution”, and that large-scale studies were necessary to confirm their results, this report
raised a debate about the risk of DAA treatment and suggested that a stricter pharmacovigilance action