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Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49 Page 7 of 18
[17]
per year . Overall, it has been established that HCV infected patients have a 15-20 fold increased risk of
developing HCC compared with HCV negative patients [14,80,81] .

Risk factors for HCC in HCV patients
The rate of HCC progression varies greatly among patients with chronic HCV infection, and this is due to
the existence of a complex interplay between host, viral, and environmental factors. Similar to what was
described for HBV, the most important risk factor for the development of HCC in patients with a chronic
[82]
HCV infection is the underlying liver disease . Apart from that, several other concurrent risk factors that
impact the HCC risk in patients with HCV have been identified. To begin, male sex and older age have
universally been described as independent risk factors for the development of HCC in patients with a
chronic HCV infection [82-84] . Also, a coinfection with HBV or HIV seems to influence the course of an HCV
infection. Several studies have demonstrated that coinfection with HIV promotes the progression of fibrosis
and cirrhosis in patients with HCV, resulting in a significantly increased risk for severe liver disease [85-88] .
As a result, it is widely accepted that an HIV coinfection in HCV patients also increases the risk of
[89]
HCC compared to HCV mono-infected patients . However, recent data from two prospective French
cohorts demonstrate that this is no longer the case in the current context of more effective combination
antiretroviral therapies and increased access to HCV therapy. In this analysis, the 5-year cumulative
incidence of HCC and liver decompensation did not differ significantly between HIV/HCV coinfected and
[90]
HCV mono-infected patients (8.5% vs. 13.2%, P = 0.12 and 12.8% vs. 15.6%, P = 0.40, respectively) . Also,
patients with a dual HBV/HCV infection have a higher risk of progression to cirrhosis and decompensated
liver disease compared to patients with an HCV mono-infection [91,92] . Already in 1998, a meta-analysis of
more than 30 case-control studies demonstrated a synergistic effect of HCV and HBV on the incidence of
[14]
HCC . This observation was later confirmed by a second, Chinese meta-analysis indicating that a dual
infection by HBV and HCV was associated with a higher risk of HCC than each infection alone [odds ratio
[13]
(OR) for the development of HCC for coinfected patients: 35.7] . Similarly, an Italian study reported a
yearly HCC incidence of 6.4% in HBV/HCV coinfected patients as compared to 2.0% and 3.7% in HBV
and HCV mono-infected patients, respectively. At 10-years, this translated into a cumulative HCC rate of
[93]
45%, 16%, and 28%, respectively . For HBV/HCV dual infection, the research data suggest that the HBV
replication status is the crucial factor affecting the risk for HCC. HCV patients with active HBV replication
have twice the risk of HCC compared to those with latent HBV and HCV, while the risk in coinfected
[83]
patients with undetectable HBV DNA levels is similar to that of mono-infected HCV patients . As
discussed in the section on HBV, more research is needed to shed light on the potential effect of OBI on the
[40]
risk for HCC in HCV-infected patients . Intriguingly, certain HCV genotypes seem to be associated with a
higher risk of HCC, particularly genotype 3 which is associated with an 80% higher risk of HCC compared
[94]
to genotype 1 , contradicting a previous meta-analysis that associated genotype 1 with a 78% increased
risk of HCC relative to all other genotypes and a 60% increased risk among patients with cirrhosis .
[95]
Similar to what was described for HBV, there are significant associations between lifestyle factors and the
HCC risk in HCV patients. A meta-analysis has shown a significant increase in the relative risk of HCC
[24]
in smokers (relative risk 23) compared to non-smokers (relative risk 7.9) with HCV . Also, alcohol
consumption was shown to accelerate liver fibrosis in HCV-infected patients, resulting in an increased risk
for progression to cirrhosis and HCC. In a study evaluating the natural history of liver fibrosis progression
in 2,235 HCV patients, daily alcohol consumption of at least 50 g resulted in a 34% increase in the rate
of fibrosis progression . In line with this, a meta-analysis involving more than 15,000 HCV patients
[96]
demonstrated that heavy alcohol intake (210-560 g per week) was associated with a 3.54 relative risk for
the development of decompensated cirrhosis . A study that specifically looked into the effect of alcohol
[97]
on the development of HCC in HCV patients revealed a 2-fold increase in HCC risk for drinkers of more
[98]
than 60 g per day . Similarly, a case-control study revealed an OR for HCC development of 26.1 in HCV-
carriers with an alcohol intake of 0-40 g/day, rising to 62.6 and 126 among patients drinking a daily dose of