Page 25 - Read Online

Burlone et al. Hepatoma Res 2020;6:3 I http://dx.doi.org/10.20517/2394-5079.2019.37 Page 7 of 10

in cirrhotic vs. non-cirrhotic patients, which - combined with the low number of cirrhotic patients who
develop HCC - may create a bias. However, the results logistic regression analysis strongly support the
independence of these two variables in predicting the development of HCC (it should also be noted that
the test is not designed to compare the relative strength of each variable in the model).

A different way to reconcile these findings is to hypothesize that the apparent increase of HCC incidence/
recurrence rates might be due to the difficulties of identifying small HCC foci by current screening
methods. Not surprisingly, compared to explant pathology, ultrasound is insufficiently sensitive in detecting
[54]
HCC in obese patients and obesity hampers the quality of HCC surveillance [55-57] . Thus, one may
speculate that, especially in obese patients, what is observed as de novo HCC is in fact missed HCC, hence
the low SVR rate among those who “develop” HCC in our cohort. Most of the DAA failures in patients with
previous HCC diagnosis occurred among patients with active cancers, where DAA failed in almost half of
[9]
the cases , possibly because HCC may serve as a sanctuary for HCV. In agreement with these findings, in a
preliminary report from our group, we did observe unusually low SVR rates among de novo and recurrent
HCC cases, leading us to suggest that treatment failure should be considered a clue of a yet undetected
HCC [58,59] .

We must acknowledge several limitations of our work. First, it is a single-center study, with a short follow-
up, during which - luckily enough - only a relatively small number of patients went on to develop HCC.
Being a retrospective analysis of data generated in clinical practice, we screened our patients before and
after DAA treatment with ultrasound, thus we are unable to provide pre-treatment data on higher level
dynamic imaging (CT or MRI), which was performed only in the presence of suspicious focal liver lesions.
Finally, we do not have reliable data about current and past alcohol intake in our study population, which
are traditionally quite difficult to obtain. Nevertheless, at least in our opinion, the study conveys two
messages worth considering: (1) given the extremely high SVR rates obtainable today in all subgroups of
HCV infected patients, when DAA treatment fails, the possibility that the patient harbors HCC should
come to mind; and (2) in male, obese, cirrhotic HCV-infected patients, a second level imaging technique
should confirm that they are free of HCC before starting a DAA regimen.

In conclusion, the present study indicates virologic failure as a strong independent predictor for de novo
HCC identification early after treatment of hepatitis C with DAA. Clearly, all patients with cirrhosis
regardless of SVR response should be monitored at regular six-month intervals, since cirrhosis - either in
the presence or in the absence of HCV - is the dominant risk factor for HCC. However, lack of achieving
SVR should further alert clinicians to the possibility of this dreadful complication, especially among HCV
carriers who are male, obese, and cirrhotic.

DECLARATIONS
Authors’ contributions
Conceptualization, data curation, formal analysis, supervision, investigation, validation, visualization,
writing - original draft, writing - review & editing: Burlone ME
Conceptualization, data curation, formal analysis, supervision, validation, visualization, writing -review &
editing: Fangazio S
Data curation, investigation, validation, visualization: Croce A, Ceriani E, Rapetti R, Rigamonti C, Smirne C
Data curation, investigation, supervision, validation, visualization: Tonello S
Supervision, validation, visualization: Ravanini P
Data curation, investigation, supervision, validation, visualization: Minisini R
Conceptualization, data curation, formal analysis, investigation, methodology, project administration,
supervision, validation, visualization, writing - review & editing: Pirisi M