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Page 10 of 14 Russo et al. Hepatoma Res 2018;4:25 I http://dx.doi.org/10.20517/2394-5079.2018.52

with DAAs, comparing them to matched controls without HCC. Each marker was measured before and
after DAA treatment, and very interestingly 12 of them, including apoptosis markers, cytokines and growth
factors, resulted significantly higher before treatment in patients who developed de novo HCC, compared
to controls. The authors suggested that a different immunologic pattern could be already present in patients
who eventually develop HCC, before the immune changes due to DAAs occur. The immune background
could therefore be a decisive factor in HCC development. Individuals who develop HCC may express a
different pattern of immune mediators, that induces ongoing carcinogenic or pre-carcinogenic activity,
prior to the appearing of HCC. In addition, TNF alpha levels remained stable or trended up during the first
month of DAA treatment (with viral load being undetectable in serum) in patients who developed HCC,
while decreasing in controls. TNF alpha could therefore be directly involved in HCC development even if
HCV is absent, or on the other hand its production could be stimulated by the presence of occult tumor foci
in the liver. Finally, this study suggested that tumorigenesis occurred with different characteristics in HCC
recurrence compared to de novo HCC after DAAs, as IL-6 levels, were shown to be increased at the end of
therapy in patients with HCC recurrence, while the levels of the cytokine showed a trend toward reduction
in patients with de novo tumor. Again, these results should be interpreted with caution and additional
studies could help to clarify their interpretation.

HCC AND DAA: POSSIBLE ROLE IN RESPONSE TO ANTIVIRAL THERAPY AND NATURAL
HISTORY OF DISEASE?
Another matter of debate is whether the presence of HCC can influence the response to HCV therapy with
[45]
direct-acting antivirals, and what could be the mechanism behind it. According to Prenner et al. , the
presence of active HCC (and not merely a history of tumor) when starting HCV therapy was the strongest
predictor of treatment failure, with an eight-fold increased risk of failing treatment at multivariate analysis
compared to patients without tumour (OR 8.49; 95%CI: 3.90-18.49; P < 0.001). Interestingly, none of the well-
known factors correlated with a lower SVR, and not even inadequate treatment regimens could explain the
difference between the two groups. A possible explanation could be that HCC may serve as a sanctuary for
HCV, where virus particles can evade DAAs, as already known for HBV cccDNA; it is also possible that
DAAs may be unequally distributed within fibrotic areas, generated for instance after some loco-regional
treatment, radioembolization above all, due to the decreased blood flow.

[46]
Very recently, a review by Konjeti and John on DAAs and HCC presence/occurrence suggested deferring
IFN-free therapy until complete radiological response to HCC curative treatment. Therefore HCV
eradication with DAAs is still recommended in patients with history of treated HCC, until proven otherwise
by future studies.

[45]
Similar data (and similar explanations) to Prenner et al. study was obtained through the analysis of a large
[47]
cohort of HCC identified by Beste et al. in the national Veterans Affairs health care system. This study also
suggested that a greater likelihood of SVR after DAA treatment was reached in patients with HCC history
undergoing LT. This evidence is not fully explained by clinical reasons.

What is the most effective timing to offer HCV treatment in patients listed for LT, whether it is better to do
so before or after LT, still remain open questions. Finally, another matter has been investigated: does SVR
[48]
really matter in in the progression of liver disease? Nahon et al. , in a multi-centre French cohort of 1323
Child A patients, mostly treated with IFN-based therapy, reported that viral eradication and achievement of
SVR was associated with a significant reduction of HCC incidence (HR: 0.29; 95%CI: 0.19-0.43; P < 0.001).
They also noticed that SVR was associated with a reduction in both liver- and non-liver-related mortality (HR:
[49]
0.27; 95%CI: 0.18-0.42; P < 0.001). Petta et al. seem to have come to the same conclusions: in an Italian
study of 535 HCV cirrhotic patients, there was a reduction in disease progression and liver related mortality
with the achievement of SVR. More specifically, the data of this report demonstrated a reduced incidence of