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Page 4 of 10 Yapali et al. Hepatoma Res 2018;4:24 I http://dx.doi.org/10.20517/2394-5079.2018.57

infection with HCV, human immunodeficiency virus (HIV), or hepatitis D virus] and environment related
factors (exposure to aflatoxin, excessive alcohol or tobacco consumption).

A population-based study of untreated chronic hepatitis B (CHB) patients from Taiwan named the risk
evaluation of viral load elevation and associated liver disease/cancer-hepatitis B virus (REVAL-HBV), first
reported that high baseline serum HBV DNA level was associated with the risk of cirrhosis and HCC .
[20]
The risk began to increase in a dose‐response relationship from < 300 (undetectable) to ≥ 1,000,000 copies/
mL. Furthermore, patients with persistently high HBV DNA levels had the highest risk of HCC. The role
of viral load on HCC development was also confirmed in several cross-sectional and longitudinal cohort
studies from Taiwan, Hong Kong, and China [21-23] . HBeAg-positivity, which shows active viral replication, is
also associated with the development of HCC . Although long-term suppression of viral replication can be
[24]
achieved with the use of potent oral antiviral therapies, the risk of HCC is not eliminated. This was clearly
demonstrated in a study of 1378 patients comparing the incidence of HCC between patients who received
oral antiviral treatment and inactive carriers . The study found a higher risk of HCC development in
[25]
patients treated with oral antiviral drugs than those with inactive CHB and indicated that the risk of HCC is
not eliminated in patients receiving oral antiviral treatment. These patients should continue to be screened
for HCC.

HBV genotype is also important in determining the risk for HCC [26,27] . The risk is higher in patients with
genotype C than patients with genotype B. High viral load and genotype C have an additive role in increasing
the risk of HCC . Genotype D patients carry a higher risk for HCC than patients with genotype A . HBV
[28]
[28]
genotype D was found to be the most prevalent genotype in studies reported from Turkey, Iran, Pakistan
and Saudi Arabia [29-32] . There is rare evidence to show the association genotypes with the risk of HCC in the
Middle Eastern countries. Studies from Iran have also demonstrated a strong relationship of genotype D and
mutations in basal core promotor (BCP) and precore regions with the disease outcomes [33,34] .

The prevalence of HBV infection is complex and a major public health problem in Eastern Mediterranean
countries. In the early studies, reported HBV prevalence rates ranged from < 2% to 2%-8% in most
countries, reaching up to ≥ 10% in Saudi Arabia, Yemen and Sudan [29,35-38] . In the latest report of World
Health Organization (WHO), Eastern Mediterranean countries have a prevalence of chronic HBV infection
ranging from low intermediate (2%-4%) in most countries to high intermediate (5%-7%) in Somalia and
Sudan [39,40] . The WHO estimates that more than four million people are infected yearly with HBV in this
region . The lifetime risk of HBV infection in the pre-vaccination era ranged from 25% to > 75%, with
[41]
continued transmission from the perinatal period throughout early children and adult life. It was estimated
that around 100,000 persons from each birth cohort in the region would die from HBV-related liver disease
and HCC during their lifetime. In these high-risk regions, the primary transmission routes are perinatal,
child-to-child, sexual contact and percutaneous exposures (e.g., unsafe injections and blood transfusions).

Despite the introduction of hepatitis B vaccination programs, HBV continues to be transmitted among
unvaccinated older children and adults. Therefore, in 2009 WHO Eastern Mediterranean regional committee
implemented a regional target, to reduce the prevalence of CHB infection to less than 1% among children
below 5 years of age by 2015 . The national health agencies in the region supported the program with
[39]
hepatitis B vaccination of newborns. By the end of 2014, 68% of the countries achieved the target. The rate
of hepatitis B birth dose vaccination coverage in the region increased to 24% in 2014 compared to 14% in
2000 . In 2014, 71% of newborns received a birth dose within 24 h in the countries, which had < 80% birth
[39]
dose coverage .
[39]
A systematic review examining the viral etiologies of HCC in the Eastern Mediterranean countries indicated
HBV as a major cause in 35%, 42.5%, 55% and 52% of HCC cases in Saudi Arabia, Yemen, Turkey and Iran,