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Page 4 of 9 Gitto et al. Hepatoma Res 2020;6:22 I http://dx.doi.org/10.20517/2394-5079.2019.50

HCC OCCURRENCE AFTER SVR ASSOCIATED WITH DAA THERAPY
[4]
Chronic viral hepatitis is the most important predisposing factor for the occurrence of HCC . Indeed, viral
eradication is a main goal to decrease the incidence of HCC and, more in general, to lessen liver-related
[3,8]
mortality .

[26]
Considering the IFN era, Van der Meer et al. , compared long-term outcomes of IFN monotherapy, IFN +
ribavirin and PEG IFN + ribavirin, in 5 Liver Units. Recruited patients displayed advanced fibrosis and were
followed up for a mean period of 8.4 years. Ten-year cumulative HCC incidence rate was 5.1% for the SVR
subgroup and 21.8% for non-responders.

[27]
Ogawa et al. conducted a prospective national multicenter study on the effect of PEG IFN + ribavirin
treatment on chronic HCV infection, focusing on HCC occurrence. The authors enrolled 1013 patients
and demonstrated that 5-year cumulative incidence of HCC was 1.7% in the SVR and 7.6% in the non-SVR
group with a weakening of this effect considering only cirrhotic subjects (18.9% vs. 39.4%).

[28]
Morgan et al. carried out a meta-analysis including 30 observational studies, with 31,528 patients enrolled.
The authors confirmed that patients with SVR due to IFN-based protocol showed a lower HCC occurrence
with respect to the others: 0.33 per person-year in SVR and 1.67 in non-responders.

[11]
Regarding the role of DAA therapy in favoring HCC occurrence, Conti et al. published in 2016 a regional
multicenter study of 344 consecutive cirrhotic patients treated with DAAs, including 285 subjects who did
not show previous HCC. The authors reported that after the end of DAA treatment (follow-up of 24 weeks),
9 patients (3.16%) developed HCC in a higher percentage than IFN responders. The key point of discussion
should be about the main clinical patterns of enrolled patients who displayed more advanced liver disease in
comparison with the classical IFN cohort. Additionally, enrolled patients were screened for HCC exclusively
by ultrasound with a certain probability of small undiagnosed HCC nodules at the beginning of antiviral
therapy.

Some of the previously cited meta-analyses examined the whole risk of HCC occurrence after DAAs.

[22]
Waziry et al. , comparing IFN regimens and DAAs, demonstrated that HCC occurrence following SVR was
1.14/100 per year for patients treated with IFN and 2.96/100 per year in subjects receiving DAAs. Notably,
the authors showed that occurrence rate decreased with longer follow-up and was lower in younger subjects.
Finally, the authors proposed a meta-regression after adjusting data for follow-up and age, demonstrating
that SVR due to DAA was not related to significantly more HCC occurrence.

[23]
Singh et al. analyzed a total of 39,145 patients treated with DAA (data from uncontrolled studies). Among
them, 542 developed de novo HCC after achievement of SVR. Incident HCC showed an overall occurrence
of 1.5% with substantial statistical heterogeneity among the studies included. The authors examined the
HCC occurrence rate associated with DAA considering only controlled cohorts. Among five studies, the
proportion of HCC occurrence was 3.3%, again with considerable statistical heterogeneity. Therefore, authors
concluded that data derived from their study should be considered non-conclusive regarding the possible
relationship between DAAs and increased risk of HCC occurrence.

[24]
A recently published meta-analysis examined 81 studies of HCC occurrence after DAA. In particular,
the authors compared the following subgroups of studies: 31 involving 71,443 IFN-treated subjects, 44
comprising 91,249 of DAA-treated patients and 6 on 9944 untreated subjects.

The authors reported that, considering only patients with SVR due to DAA and not all the DAA population,
HCC occurrence rate was 3.57 per 100 per year vs. 0.70 per 100 per year in the IFN-treated SVR group