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Table 1. Available meta-analyses analyzing the possible association between DAA therapy and HCC
Ref. Year Country N of studies N of patients Increased risk of occurrence Increased risk of recurrence
Waziry et al. [22] 2017 Australia 41 13,875 DAA comparable to IFN DAA comparable to IFN
Saraiya et al. [21] 2018 USA 24 1820 / DAA comparable to IFN
Singh et al. [23] 2018 USA 44 39,145 no conclusive data no conclusive data
Rutledge et al. [24] 2019 USA 138 177,512 DAA comparable to IFN DAA comparable to IFN

DAA: direct-acting antiviral; HCC: hepatocellular carcinoma; IFN: interferon

Regarding the possible relationship between metabolic disorders and risk of HCC in the specific setting
of DAA therapy, Nahon et al. reported interesting results. These authors retrospectively analyzed data
[37]
from 1270 cirrhotic patients comparing the incidence of HCC in patients treated with IFN-based protocols
or DAA therapy. First of all, authors demonstrated that patients treated with DAA were older and had
higher rates of diabetes, suggesting that these patterns might explain the reported higher percentages of
HCC occurrence in this subgroup of patients in comparison with the IFN group. However, the authors
conducted a multivariate analysis, demonstrating that DAA therapy itself did not emerge as a predictor
of HCC occurrence. Other factors such as increased age, past excessive alcohol consumption, virological
parameters [genotype 1 (in contrast with previously reported data)], decreased platelet count and increased
gamma-glutamyl transferase (GGT) levels were independently associated with post-treatment HCC onset.
Concerning the metabolic issue, neither diabetes nor obesity was directly associated with HCC occurrence,
[38]
[39]
but it is well known that GGT increase is a sign of altered metabolism or higher inflammatory activity .
In fact, elevated GGT activity is coupled with traditional cardiovascular risk factors and particularly with
metabolic syndrome .
[38]

CONCLUSIONS AND FUTURE PERSPECTIVES
DAAs have constituted an extraordinary breakthrough in the therapy of hepatitis C. With an 8- to 12-week
course of treatment, SVR occurs in more than 95%-99% of patients, depending on degree of liver fibrosis.
These results were beyond any reasonable expectation until a few years ago. It is therefore quite conceivable
that the report of an increased occurrence or recurrence of HCC during or shortly after stopping DAAs
initiated a series of reactions of concern. With more data accumulating, it is now clear that there is no
such risk on a population basis. In fact, as summarized in Table 1, the available high-quality meta-analyses
categorically demonstrated that the risk of both HCC recurrence and occurrence after SVR is comparable
between patients treated with “old” IFN-based protocols and new DAAs. As recently stated by the American
Association for the Study of Liver Diseases , SVR due to DAAs determine a decrease in all-cause mortality,
[40]
cirrhosis, hepatic decompensation and HCC, an improvement in extra-hepatic manifestations of HCV, and
an amelioration of both productivity and quality of life. Summarizing, we must treat with DAA all patients
without history of HCC and all subjects with complete response to HCC treatment. Notably, as strongly
demonstrated in a recently published meta-analysis , patients with HCC show, for unknown reasons, lower
[41]
pooled SVR rate in comparison with subjects without cancer (88.2% vs. 92.4%).

Although DAAs represent a great therapeutic option, it is possible that some subgroups of subjects may be
at increased risk of HCC onset after DAA treatment. In fact, on an individual basis, administration of DAAs
might be associated with facilitated HCC development in subjects who already have a predisposing hepatic
condition, namely activated neoangiogenesis, as shown by increased levels of angiopoietin-2 in cirrhotic
[29]
tissue . In these patients, a careful evaluation of risk-benefit of DAA treatment should be done, also in
[29]
view of the aggressive features of DAA-associated HCC . Finally, in the long-term management of HCV-
positive patients, it has to be considered that subjects with severe metabolic impairment seem to maintain a
[37]
significant risk of HCC despite antiviral treatment and viral eradication .
Concerning the possible identification of subpopulations at higher risk of HCC, some authors have analyzed
the change in inflammatory balance due to DAAs as a determinant of cancer development [19,42] .