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Page 2 of 6 Buonfiglioli et al. Hepatoma Res 2018;4:6 I http://dx.doi.org/10.20517/2394-5079.2017.42

premalignant lesion, it represents a premalignant condition since almost 90% of HCV-related HCC cases
emerge after cirrhosis becomes established. The annual occurrence rate of HCC has been estimated to
[4,5]
be around 3% in HCV-related cirrhosis . Surgical resection, radiofrequency ablation and transarterial
chemoembolization allow effective treatment of single and small HCC in a significant proportion of patients
with compensated liver disease, but recurrence is common, affecting about 35% of treated patients after
[6,7]
2 years .
The aim of this review was to evaluate the effect of antiviral therapy on the de novo occurrence and
recurrence of HCC in patients with chronic hepatitis C. We searched all available publications regarding
“hepatitis C”, “HCC”, “antiviral therapy”, “interferon-free”, “DAA”, “occurrence”, “recurrence” and focused our
review mainly on the data reported in high-quality full-text format.

EFFECT OF INTERFERON-BASED ANTIVIRAL THERAPY ON THE DEVELOPMENT OF HCC
Until 2011, peg-interferon alfa plus ribavirin combination was the only available therapy for chronic hepatitis
C. This treatment had only 40%-50% probability of curing HCV infection, and the significant side effects
contraindicated its use in a significant proportion of patients. Despite these limitations, many patients with
compensated liver cirrhosis had been treated during the last decade, and the effect of treatment on the
development of HCC has been evaluated. In summary, achieving sustained virological response (SVR) was
associated with a reduced risk of developing HCC, in comparison with patients who did not obtain an SVR
after antiviral therapy [8-10] . Despite these positive results, it remains not clear whether SVR was independently
associated with the reduced risk of developing HCC. In fact, a different explanation could be that SVR
occurred in those patients with a lower spontaneous probability of developing HCC, without altering the
cumulative risk of HCC in the entire population of cirrhotic patients. Also, even in patients who obtain SVR,
a residual annual rate of HCC is still present, as high as 2% in different groups of patients.

THE ADVENT OF DIRECT-ACTING ANTIVIRALS AGAINST HCV
Since 2013, the therapy of hepatitis C has dramatically changed. Direct-acting antivirals (DAA) are new
oral drugs, with potent antiviral activity against HCV infection, highly efficacious, relatively safe and well
tolerated, that can be used in all categories of patients with chronic HCV infection, including those with
[11]
more advanced and even complicated liver disease . This has allowed treatment of a huge cohort of patients
with liver cirrhosis, obtaining the eradication of HCV infection in the vast majority of them. Resolution
of HCV infection in these patients leads great expectations about the possibility of preventing the most
serious complications of liver cirrhosis, including the development of HCC. In the following paragraphs, we
try to summarize the best existing evidence regarding the effects of DAA-induced HCV eradication on the
development of HCC in patients with compensated liver cirrhosis.

HCC DEVELOPMENT AFTER DAA THERAPY
The story learned from the interferon era teaches us that eradication of HCV infection is not sufficient
per se to prevent HCC development after cirrhosis has been established. Due to the possibility of treating
patients with more advanced liver disease, it is not surprising to expect that a few of them may develop
HCC despite HCV eradication. This topic became immediately hot after the simultaneous publication
of two papers from Spain and Italy suggesting a possible increased incidence of HCC after successful
DAA treatment [12,13] . Since those publications, more than 100 papers, letters or communications have
been published addressing the problem, without conclusive results. Most of the debate derives from the
heterogeneity of the different studied population, the inclusion and exclusion criteria, the time points used to
analyse the incidence rates, the length of follow-up, and finally the radiologic methods used for the diagnosis
of HCC.