Page 20 - Read Online

Page 2 of 10 Burlone et al. Hepatoma Res 2020;6:3 I http://dx.doi.org/10.20517/2394-5079.2019.37

the independent predictors of HCC were male sex (P = 0.031), cirrhosis (P = 0.004), obesity (P = 0.006), and failure
to achieve an SVR (P < 0.001).

Conclusion: Lack of achieving SVR is a strong independent predictor of development of HCC early after treatment of
hepatitis C with DAA. Treatment failure should further alert clinicians to the possibility of this dreadful complication.

Keywords: Chronic hepatitis C, direct antiviral agent, sustained viral response, hepatocellular carcinoma, obesity,
cirrhosis

INTRODUCTION
Clearance of hepatitis C virus (HCV) infection, a major health problem, is obtainable by treating infected
[1]
patients with one of several combinations of direct antiviral agents (DAA) . Today, this desirable outcome
can be reached so predictably and safely that HCV eradication is considered by many an achievable goal
both on a local scale and on a global scale. Indeed, in 2016, the World Health Organization launched
a campaign that - if successful - would eliminate viral hepatitis as a major threat to global health, with
substantial economic benefits. Most importantly, putting HCV infection under control would prevent
[2]
over 1.2 million deaths annually . For sure, DAA treatment allows curing HCV infection in patients
with advanced liver disease, including those who had undergone curative treatments for hepatocellular
carcinoma (HCC).

Soon after DAA were introduced in practice, however, surprisingly high HCC incidence and/or recurrence
[3]
rates were reported, an observation that generated alarm and dismay among clinicians . In fact, among
HCV-related complications, HCC is the most fearsome; furthermore, in the last few years, its incidence
[4]
appears to be increasing . Doubts that viral clearance by DAA might favor emergence of HCC clones by
[2]
reducing immune pressure on HCV have been dispelled : In fact, recent studies demonstrate convincingly
that the opposite is true, i.e., DAA-induced sustained viral response (SVR) reduces the risk for de novo
[5-7]
HCC . The current interpretation is that the controversy - which has had the merit of highlighting the
need to continue HCC surveillance in patients with cirrhosis, despite their achievement of an SVR - might
have been generated mainly by inconsistencies and methodological limitations that flawed earlier studies .
[8]

Conceivably, among patients “cured” of HCC, so-called “recurrences” may actually represent prevalent
tumors, whose presence is recognized only after DAA treatment is started. Could the same explanation
apply to the apparent increase of HCC de novo diagnosed after DAA treatment? By definition, the presence
of HCC foci should have been excluded to call these HCCs de novo; however, surveillance of HCC relies on
ultrasonography, whose sensitivity is limited. A clue - if not definitive proof - in favor of the hypothesis that
hidden HCC foci might have already been present when DAA were started would be to observe lower than
expected SVR among DAA-treated patients later found to have an incident HCC, since patients with active
[9]
HCC respond sub-optimally to DAA . In the present study, we aimed to substantiate this hypothesis.

METHODS
Patients
The study population included a cohort of consecutively recruited patients attending an academic liver
clinic in Northern Italy to receive interferon-free treatment for chronic hepatitis in accordance to the
[10]
European Association for Liver Diseases (EASL) guidelines . Inclusion criteria were: (1) no previous
diagnosis of HCC; and (2) minimum follow-up after the end of treatment of 180 days. Figure 1 presents the
flow chart of the study.