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Rutledge et al. Hepatoma Res 2019;5:31 I http://dx.doi.org/10.20517/2394-5079.2019.19 Page 9 of 12
[30]
(25% of these cases had vascular invasion or extrahepatic spread). Renzulli et al. found imaging features of
microvascular invasion in 70.7% of HCC nodules after DAA treatment; microvascular invasion was present
in only 33.3% of HCC nodules that occurred before DAA treatment. However, conflicting studies have also
[26]
been published: the large CIR-VIR study found infiltrative HCC in 10.8% ; typically up to 13% of all HCC
[31]
cases are found to be infiltrating and are often associated with background hepatitis B infection . The study
by Zanetto et al. evaluated 9 DAA-treated explanted livers with 14 control (untreated) liver explants and
[32]
found no difference in median number and total tumor volume of HCC nodules, tumor differentiation, or
microvascular invasion. Clearly, more studies evaluating the biology of tumors after DAA treatment are
required before a definitive conclusion can be drawn.

The high efficacy and tolerability of DAAs has resulted in their use in patients who have more intrinsic
risk factors for HCC, including advanced age, diabetes and cirrhosis. Several studies have shown the
patients treated with DAAs have more risk factors than historical IFN-treated cohorts. The US Veterans
[20]
Administration study by Li et al. demonstrated the “warehousing” of HCV-infected patients which
took place in the years leading up to the release of DAAs. They showed that patients who received the first
available DAA agents had the most advanced liver disease and higher rates of HCC as a result, because
HCV treatment had been deferred in anticipation of an efficacious tolerable regimen.

[33]
Fangazio et al. showed that patients who developed de novo or recurrent HCC after DAA treatment were
less likely to achieve SVR (SVR12 rate of 64% in patients with HCC compared to 95% in their counterparts
without HCC, which is much more typical of the DAA viral clearance rates). This finding suggests that
in patients who do not achieve SVR with DAA, clinicians should have heightened levels of suspicion
[34]
for underlying undetected HCC. A study by Beste et al. also found that HCC patients had lower rates
of viral clearance than patients without HCC, even after adjusting for cirrhosis and genotype. It has
been postulated that the virus within tumor cells could be inaccessible to DAAs because of differential
blood supply, which prevents the clearance of virus. Furthermore, HCC arises in the setting of chronic
inflammation with alterations in the hepatic architecture and micro-environment, including cytokine and
[35]
chemokine populations .This altered immune environment may predispose to treatment failure and to
[36]
the development of liver cancer. A study by Tachi et al. revealed that higher total bilirubin levels and
higher liver stiffness measurements (as measured by ARFI elastography) prior to DAA treatment were
positively associated with occurrence of HCC after achievement of SVR with DAA therapy. Clearly a risk
of HCC still exists even after SVR with DAA treatment, so surveillance imaging should not be ceased even
after treatment success.

Even in view of the mixed data, it is evident that the achievement of SVR is the ultimate arbiter of risk
of HCC. While many studies have shown no increased risk of HCC after DAA treatment, multiple
studies have demonstrated a lower risk of HCC in DAA-treated patients who achieve SVR compared to
untreated patients [22,23,37] . Treatment with DAAs also portends other benefits such as a decrease in MELD
and Child-Pugh score (which sometimes results in delisting for liver transplant and the so-called MELD
“purgatory”), and a reduction in the risk of death as demonstrated by the French Hepather cohort [23,38-46] .
[39]
Munoz et al. have estimated that the DAA-induced reduction in MELD score to below the threshold for
liver transplantation listing may occur in 592-993 listed patients/year during the first year after treatment,
and that 213-515 donated livers/year could be redistributed as a result. As more time passes since
their development and additional studies with longer follow-up are published, the benefit of treatment
with DAAs and the lack of a causative effect on carcinogenesis becomes clearer. It is now evident that
withholding DAA treatment denies patients the possibility of a significant improvement in liver disease
and consigns patients to a higher risk of HCC development.

In conclusion, we did not find evidence of increased rates of de novo HCC or recurrence in DAA-treated
compared with IFN-treated patients. Compared to those treated with IFN, older patients with additional