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Page 4 of 8 Abbas et al. Hepatoma Res 2018;4:43 I http://dx.doi.org/10.20517/2394-5079.2018.26

HCV patients . Moreover, the reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) gene,
[51]
a novel transformation suppressor gene, has also been linked to HCC amongst several other malignancies.
However, a study conducted on an Egyptian cohort concluded that the RECK gene rs10814325 TT genotype
could not be considered a risk factor for HCC development in hepatitis C patients, but may be related to the
disease progression and metastasis .
[52]

Furthermore, the GG and GG + GA genotypes of IL17A gene may also serve as a risk factor for HCC
development by increasing IL17 and IgE levels . WT IL-23R GG , transforming growth factor-β1
[53]
[54]
(TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms may also serve as risk factors
for cirrhosis and HCC in chronic hepatitis C patients .
[55]

NON-RESPONSE TO THE THERAPY
Antiviral therapy reduces the development of HCC and complications of cirrhosis in patients with chronic
hepatitis C . A risk scoring system has been developed to predict HCC development for HCV patients
[56]
following antiviral therapies. The system includes age, gender, platelets count, alpha-fetoprotein levels,
fibrotic stage, HCV genotype and response to the antiviral therapy .
[10]
The cumulative risk of HCC development is higher in subjects with high HCV RNA titer than subjects
with low titer . SVR results in significantly more favorable long-term outcomes, and decreased risk of
[45]
progression to cirrhosis and HCC [13,57] . Indeed, a meta-analysis showed that SVR after treatment at any stage
of fibrosis is associated with reduced HCC risk . The risk of developing HCC diminishes significantly 2 years
[58]
after SVR .
[44]
The risk of HCC after HCV eradication, though considerably reduced, remains relatively high at 0.33% per
year . Compared to subjects with spontaneous viral clearance, subjects with antiviral treatment-induced HCV
[47]
viral clearance are at higher risk for HCC development, especially if they have significant hepatic fibrosis .
[12]
Antiviral therapy for patients with normal ALT levels can also lower the HCC incidence in responders,
particularly for elderly and male patients . Moreover, even in patients who have developed HCC within
[59]
the Milan criteria and have undergone curative treatment for HCC, elimination of HCV and SVR inhibits
recurrence and contributes to a preferential prognosis .
[60]

DIRECTLY ACTING ANTIVIRAL AGENTS
The role of DAAs (used in the treatment of HCV) in the development of HCC is controversial, with several
early studies demonstrating a tenuous link. However, a retrospective population-based cohort study of 17,836
patients treated with either an interferon-based regimen or DAA, showed that the risk of HCC was the same
in both groups . A meta-analysis of 41 studies further clarified the issue and concluded that the risks of
[40]
HCC development after HCV eradication were similar between patients treated with peginterferon plus
ribavirin and direct-acting antiviral therapy and that there was no evidence to suggest that DAAs promoted
HCC [8,61] . The seemingly higher incidence of HCC following SVR with DAA therapy was related to baseline
risk factors and patient selection, and not the use of interferon-free therapy per se. The cohort of patients
treated with DAAs in earlier studies included older patients and patients with more advanced cirrhosis who
were already predisposed to a higher risk for HCC at baseline. In a cohort study of 857 patients, individuals
receiving interferon-free therapy were more likely to be older, of white ethnicity, Child-Turcotte-Pugh B/C vs.
Child-Turcotte-Pugh A; thrombocytopenic, non-genotype 3, and treatment experienced. HCC occurrence
was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated
with a significantly increased risk of HCC (HR: 2.48; P = 0.021). However, after multivariate adjustment for
baseline factors, no significant risk attributable to interferon-free therapy persisted .
[41]