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

In contrast, neonates born to HBV-infected mothers should receive the vaccine along with hepatitis B
[66]
immunoglobulins within 12 h . Suboptimal immunoprophylaxis in neonates can occur and is related to
mothers with positive serum HBeAg or high viral load. Suboptimal immunoprophylaxis can also be due to
the delivery of less than the recommended three doses of vaccine, an event which occurs in 60% of HBV
vaccine recipients. In adulthood, failure to achieve 95% immunization rates is mostly seen in persons older
than 60 years of age and patients with morbidities like cancer, immunosuppression, renal failure, HIV,
and organ transplantation. Mammalian cell-derived recombinant vaccines incorporating preS1 and preS2
antigens have shown enhanced immunogenicity and might be used to overcome non-response to second-
generation recombinant vaccines.

While HBV vaccination stands as the only pragmatic approach to prevent mortality from the HDV, a
recent report from WHO sheds a dark light on the other pillar of the WHO campaign of viral hepatitis
elimination, being the prolonged treatment of the HBV infected population with NAs. Currently, less than
10% of all patients chronically infected with HBV have been identified and successfully linked to care with
anti-HBV antivirals. This constraint might have important consequences as chemoprevention of HCC is
[67]
more likely to be successful when antiviral therapy is started before the development of cirrhosis . The
advent of a safe, effective, and user-friendly third-generation NAs, such as tenofovir disoproxil fumarate
and entecavir, overrode the constraints represented by first- and second-generation anti-HBV NAs that
caused studies to be flawed by referral biases, high rates of treatment failures, and ultimately by suboptimal
percent suppression of HBV. Collectively, both population and cohort studies that have been carried out in
both hemispheres of the globe showed that the incidence and mortality of HCC could have been prevented
in a majority of patients if they received NAs for more than five years [68,69] . Given the differences in patient
access (entecavir is contraindicated in lamivudine-experienced patients), market distribution, and genetic
sequences of HBV polymerase targeted by the two NAs, non-randomized studies comparing the HCC
risk reduction following HBV suppression were unable to conclusively demonstrate the superiority of
one regimen over the other . Both NAs fail to clear the nuclei of infected hepatocytes from HBV DNA
[70]
sequences integrated into chromosomes and from free viral cccDNA, two events that are known to play
[67]
a role in the neoplastic transformation of the liver in HBV carriers . More recently, both cohort and
population studies provided some evidence that statins and aspirin may confer protection against HCC in
HBV carriers. This effect was described to result in their ability to interfere with liver cell metabolism and
inflammatory processes engaged in cell carcinogenesis. In a cohort of more than 7000 patients with CHB,
statins were associated with a cumulative dose-response reduction of HCC risk of 74% over an observation
period of 7 years, after adjustment for important confounders like age, sex, cirrhosis, antiviral therapy, and
[71]
correlates of metabolic syndrome . These observations confirm previous observations and aligned with
other studies of statins showing potential anticancer activity in other cancer types (i.e., breast, colon, and
prostate cancer) through inhibition of the downstream products of the mevalonate pathway, which are
crucial for malignant cell proliferation while inhibiting hepatic fibrogenesis, another significant risk factor
of HCC [72-74] . Last but not least, statins may also counteract HBV by slowing down cholesterol synthesis
[75]
and HBV replication . In Taiwan, a nationwide cohort study of more than 10,000 patients with CHB
showed a statistically significant risk reduction of HCC in patients who received daily aspirin compared
[76]
with 1:4 matched controls . Prevention of HCC by aspirin is biologically plausible, considering that this
drug may prevent the progression of liver disease and liver carcinogenesis through different mechanisms
involving blockade of platelets, modulation of bioactive lipids, and inhibition of the proinflammatory
cyclooxygenase-2 enzyme [77-79] .

HEPATITIS C
While HBV is the most common underlying HCC etiology worldwide, HCV is responsible for most cases
[1]
in Western countries . In patients with a chronic HCV infection, the risk of HCC gradually increases as
liver fibrosis progresses. Once cirrhosis is established, the annual incidence of HCC is high, at 1% to 7%