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Page 2 of 16 Zanetto et al. Hepatoma Res 2018;4:70 I http://dx.doi.org/10.20517/2394-5079.2018.102

complications, while sustained virological response (SVR) rates were often not very high. The prescription
of IFN was also constrained by disease stage and a patient’s comorbidities, making any attempt to eradicate
HCV unfeasible in the case of end-stage disease.

The last few years have seen a major step forward in the treatment of HCV with the introduction of all-oral
therapies. Direct-acting antiviral agents (DAAs) have since revolutionized the management of HCV patients,
[1]
achieving high eradication rates with an excellent safety profile . The restrictions that IFN treatments im-
posed have been consigned to history and SVR rates have consistently exceeded 90%, regardless of the cho-
[2-5]
sen antiviral schedule . These unexpected, striking results led to the assumption that HCV could be virtu-
ally eradicated and on a global level, interrupting the natural history of the disease without incurring any
severe side effects. In fact, it has been demonstrated that liver function can improve after the virus has been
[6-8]
eradicated, with a significant reduction in the hepatic venous pressure gradient in most patients . This im-
provement has prompted the delisting of some patients with advanced disease [9,10] , but the greatest benefit is
[11]
seen in cases of well-compensated cirrhosis with no clinically significant portal hypertension .

Bearing in mind that chronic HCV infection is one of the main risk factors for the onset of hepatocellular
carcinoma (HCC), lower rates of the latter’s occurrence/recurrence were expected in the HCV-eradicated
population, whatever the stage of their liver disease was. Accordingly as previously seen for patients suc-
[12]
cessfully treated with IFN , the incidence rate of HCC dropped from 7.2/1000 person-years among patients
[13]
with no SVR to 1.1/1000 person-years among those who achieved a SVR, as recently reported by Janjua et al. .
The widespread use of DAAs is clinically and economically cost-effective for society in the short and long
term, justifying the provision of this treatment for patients with all stages of liver disease [14-17] . In fact, cur-
rent treatment guidelines issued by the European and American Associations for the study of the liver
recommend a timely treatment for all infected patients in order to prevent not only hepatic but also extra-
[21]
hepatic HCV-related complications [18-20] , and thereby contain tumor-unrelated mortality .
Solid data on the long-term outcome of cirrhotic patients treated with these new regimens are still unavail-
able, however, and DAA registration trials did not distinguish between patients with and without a history
of HCC [3,22-34] . Patients with HCC were treated with DAAs regardless of any presence of concomitant or prior
[35]
HCC, or any other cancer. Great concern was raised, however, by the unexpected report from Reig et al.
of a presumable time-related association between DAA treatment and recurrent HCC with an aggressive
pattern. This prompted several groups to analyze their results in an effort to establish whether this red flag
raised on DAAs was justifiable.

To date, controversial data have emerged on HCC occurrence/recurrence after HCV eradication with IFN-
free treatment regimens. Most reports come from single-center, often retrospective, observational studies,
with differences in patients’ characteristics and length of follow-up [Tables 1 and 2]. The picture consequent-
ly remains unclear for now, with a marked heterogeneity, even in terms of the control groups considered:
some authors compared DAA-treated patients with those treated with IFN-based regimens; others compared
them with untreated patients; and retrospective cohorts belonging to different eras were often involved. This
might be partly attributable to several factors. For a start, HCC onset was not an endpoint in the initial DAA
registration studies. Secondly, trials included patients with both chronic hepatitis C (CHC) and cirrhosis,
with or without a history of HCC, and usually with a follow-up after treatment too short for the purpose of
assessing HCC onset or recurrence. The incidence of HCC is also difficult to compare between patients given
DAAs as opposed to IFN-based regimens because the former group also includes patients with decompen-
[36]
sated cirrhosis, who are at higher risk of developing HCC . The present review summarizes all the latest
and most relevant literature regarding this issue, providing evidence on the occurrence and recurrence of
HCC after HCV antiviral treatment with the new DAAs. Retaining the distinction between HCC occurrence
and recurrence, we also provide a distinction between those studies comparing DAAs and no treatment, and