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Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49 Page 9 of 18

pathways, and activate TGF-β, PI3K/Akt/mTOR, NF-κB, p53, IL-6/Stat3, and the androgen receptor
pathways. Through these pathways, the HCV core protein could regulate cell growth, differentiation,
apoptosis, transcription, and angiogenesis [62,126] . Similarly, NS5A interacts with multiple pro-oncogenic
pathways, including β-catenin, PI3K/Akt/mTOR, NF-κB, and p53 [62,126] .

Finally, insulin resistance, commonly observed in patients with HCV, plays a crucial role in the
development of HCC in HCV patients. Intensive research identified that cross-talk between the HCV core
[62]
protein and molecules regulating insulin signaling might affect HCV-related hepatocarcinogenesis .

Prevention of HCV-related HCC
Every year, de novo HCV affects 1.75 million persons, and more than 350,000 people die of HCV-related
cirrhosis or liver cancer [66,127] . Since new HCV infections outnumber the sum of people who die of end-
[63]
stage hepatitis C and those pharmacologically cured, HCV elimination is also a priority of the WHO .
This goal is achievable because the virus lacks a non-human reservoir, cannot amplify in the environment
and can be identified with simple and accurate diagnostic tests. At the same time, practical interventions
can be delivered to interrupt transmission and cure both acute and chronic infections [128] . With an
articulated package of interventions similar to the one in place for HBV elimination, except for vaccine
prophylaxis, which is not available, the strategy designed by WHO is expected to provide treatment to 90%
[63]
of all infected individuals by 2030 worldwide . The clinical benefits of HCV elimination are undisputed
and are already well-established since the ages of interferon therapy for HCV. The treatment strategy is
also well acknowledged by all international liver societies, which strongly recommend antiviral treatment
of all HCV infected patients, independent of the severity of the underlying liver disease [129,130] . A sustained
virologic response (SVR) heralds improvement of portal hypertension and fibrosis progression in patients
with chronic hepatitis and may reduce HCC incidence and all-cause mortality [130] . Significant HCC
chemoprevention already surfaced in the interferon studies, where an SVR was found to be associated with
a relative risk reduction of 74% compared to non-responders [131] . This HCC chemoprevention by SVR was
further amplified by the advent of safe and effective DAA against HCV. These agents extended the range
and clinical benefits of antiviral therapy. Also, DAAs can be indicated in patients with decompensated
liver disease who were either ineligible for treatment with interferon or did not respond to the therapy.
HCC chemoprevention by DAA was firmly established through the retrospective scrutiny of large cohorts
of patients in the US, Europe, and Asia. Moreover, this finding was further confirmed by prospective
population studies. In a Veterans Health Administration cohort, which included more than 20,000 patients
with advanced liver disease and multiple comorbidities, DAAs reduced the risk of developing HCC by 72%
compared to non-responders [132] . More recently, an analysis of the Veterans Affair cohorts including more
than 15,000 HCV patients demonstrated that patients who achieved an SVR after DAA treatment had a
significantly lower all-cause mortality (78.9% reduction) and a lower HCC incidence (83.5% reduction)
than those who did not achieve an SVR [Figure 1] [133,134] .

In a prospective population study in Sicily, Italy, the incidence rate of HCC at one year was 2.6% in SVR
patients compared to 8% in non-responders with a clear cut association between HCC risk and liver
disease severity [134] . Importantly, these studies had the additional merit of wiping out any doubt about the
safety of DAA therapy in patients with advanced hepatitis C as they counteracted the initial observations
of high rates of clinically aggressive de novo HCC after an SVR to DAA that were identified in small groups
of cirrhotic patients in Spain and Italy [135-137] . Nowadays, it is clear that early occurrence of de novo HCC is
confined to patients who harbor magnetic resonance imaging (MRI)-undefined liver nodules at the onset
of DAA therapy and is promoted by the imbalance of field immunity caused by the swift eradication of
HCV [136] . Early, aggressive recurrence was also a complication of HCV eradication with DAAs in patients
with a history of HCC [137,138] , where antiviral therapy aims to halt the progression of hepatitis C towards
liver failure and prevent the onset of second primary tumors which result from both direct and indirect