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Page 2 of 18 Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49

INTRODUCTION
Chronic infections with blood-borne hepatitis B (HBV), hepatitis C (HCV), and hepatitis D (HDV)
viruses are the dominant causes of hepatocellular carcinoma (HCC) worldwide. In 2018, the death toll of
HCC was 810,000 persons, and the attributable fractions of HCC due to HBV and HCV were 33% and
[1,2]
21%, respectively . In selected regions of Eurasia, the Far East, and Africa, HDV stands as a significant
[3]
risk factor for HCC and liver-related mortality . While this cancer is on the rise globally, reflecting the
continuing growth of the world population, the threat is not annulled by the lifestyle changes of people
at risk, and many hopes are posed on the delivery of effective sanitation interventions. Mirroring the
frequency and geographical distribution of blood-borne viral hepatitis, the prevalence of HCC has long
been lower in developed regions than in developing regions. Yet, more recently, some peculiar changes
in disease trends have emerged. Based on the 2012 data of the World Health Organization (WHO),
HCC mortality was on the rise in northern Europe, North America, and some parts of Asia (China,
India, and Korea), mainly as a consequence of epidemics of blood-borne viral hepatitis due to such
parenteral risk behaviors, such as drug injections, tattoos, and unsafe sex. Conversely, HCC is declining in
traditionally high-risk countries, including the Mediterranean European nations, Japan, and Hong Kong,
as a consequence of improved sanitation, screening of blood donors, and mass vaccination of newborns
against HBV. Of note, the latter also prevents the spread of HDV, another important player in the arena
[4-6]
of HCC known to enhance cancer risk in HBV carriers . While projections have predicted a decline of
HCC mortality following massive access of infected patients to antiviral therapy against HBV and HCV,
currently, only a minority of individuals with chronic hepatitis B (CHB) or C have been diagnosed, and an
even smaller percentage of them has received effective antiviral therapy. The global goal of eliminating viral
hepatitis as a public health threat by 2030 is expected to prevent HCC-related mortality by 65%. It would
require a 7% annual decline of the global burden of viral hepatitis, a goal that has been reached by only a
[7]
dozen countries to date .

HEPATITIS B
HBV is a small, partially double-stranded DNA virus and a major contributor to chronic liver disease.
The virus has a specific predilection for the liver, where it persists in hepatocyte nuclei in the form of
[8]
chromosomal insertions of HBV DNA sequences and episomal covalently-closed circular DNA (cccDNA) .
[9]
Approximately 15%-40% of HBV carriers develop CHB . The 5-year cumulative incidence of cirrhosis in
[10]
untreated CHB is 8%-20%, with an annual risk of HCC in cirrhotic patients of 2%-5% . At the beginning
of the 1980s, a highly effective HBV vaccine was developed, and it proved to be very successful in reducing
the disease burden. Nevertheless, the global number of HBV infections remains to be high, in part due
to ineffective vaccination implementation programs in many less-developed countries and a high rate of
[11]
perinatal transmission in certain parts of the world .
HBV is generally considered to be the strongest epidemiologic factor associated with HCC. Worldwide,
CHB is responsible for almost half of all HCC cases, but the importance of this risk factor varies
[12]
significantly between regions (e.g., critical in East Asia, but less so in Europe) .Many studies have revealed
that HBV-infected patients have a 15- to 20-fold increased risk for the development of HCC compared
to non-infected individuals [13,14] . However, several effective antiviral therapies (e.g., nucleoside/nucleotide
analogs (NAs) have been developed for patients with HBV over the last decade, and these agents were
[15]
shown to reduce the rate of HCC occurrence in cirrhotic HBV patients .

Risk factors for HCC in HBV patients
A long list of risk factors for disease progression to HCC in CHB patients have been described. Firstly,
several host-related factors have been shown to influence the HCC risk, with a higher risk in older
patients and HBV carriers of African American origin [16-19] . Additionally, HCC is known to have a male