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in 2011 . However, a recent epidemiological study observed that the rate of increase in HCC incidence has
[4]
slowed down in recent years . The study included data acquired from the surveillance, epidemiology, and
[5]
end results (SEER) program and noted that although HCC incidence increased by 4.5% per year from 2000
to 2009, it only increased by 0.7% annually from 2010 to 2012 . Variations in HCC incidence by gender,
[5]
age, ethnicity, race and geographical location were also noted. Men had a higher average annual percentage
increase of 3.7% compared to the 2.7% increase in women. In spite of the overall plateauing of HCC incidence,
the incidence in some sub-groups such as men aged 55-64 years continued to rise, corresponding to the baby
boomer population with peak rates of hepatitis C virus (HCV) infection. By 2012, the rate of incidence in
Hispanics was higher than that among Asians within the United States. Amongst the states included in
the SEER database, Texas had the highest age-adjusted HCC incidence . An earlier study based on SEER
[5]
data showed similar results . Thus, for the first time in four decades, there was no significant increase in
[6]
the incidence or incidence-based overall mortality of HCC. The studies indicated a deceleration of HCC
incidence around the year 2006 .
[4]

Worldwide, HCC is still amongst the top three leading causes of cancer-related deaths. In the Asia-Pacific
region, HCC incidence remains high because of the high prevalence of hepatitis B virus (HBV) infection .
[7]
Except for Japan, Australia, Singapore and New Zealand, where HCV is more prevalent, HBV accounts for
almost 80% of HCC in this region . HBV and HCV are also the most common risk factors for HCC in China
[7]
that leads the world by accounting for more than half of the HCC cases world-wide .
[7]

ETIOLOGY: ROLE OF HCV IN THE DISEASE BURDEN OF HCC
Hepatitis C virus is a single-stranded RNA virus from the family Flaviviridae . Along with HBV, it accounts
[8]
for more than 70% of the HCC cases worldwide . However, it is quite distinct from HBV with regards to its
[9]
mechanisms of hepatocarcinogenesis [9,10] . Being a DNA virus, HBV has the ability to incorporate into the
host genome and to intrinsically affect DNA replication and induce carcinogenesis. In contrast, HCV cannot
integrate within the host genome and uses other mechanisms to promote carcinogenesis. Those mechanistic
pathways invariably stem from chronic inflammation, which is the hallmark of HCV infection. HCV
proteins have been implicated to play a role in hepatocarcinogenesis and some of the proposed mechanisms
include induction of oxidative stress, modulation of cell regulation pathways and interaction with tumor
suppressor proteins. In addition to the HCV core protein, other proteins such as E2, NS3 and NS5A have also
been studied for their potential role in carcinogenesis . The high rate of replication errors in the HCV RNA
[11]
leads to the formation of quasispecies which are adept at evading the immune system and in establishing
chronic infection . Hepatitis C viral infection thus results in chronic hepatitis in nearly 80% of cases in
[10]
comparison to 5% of HBV-infected patients who develop chronic disease . Chronic hepatitis C progresses
[10]
to liver fibrosis in 60%-70% of patients, cirrhosis in 10%-20% and eventually HCC in 1%-5% within two
decades of harboring the virus. The ability of HCV to promote cirrhosis is 10- to 20-fold higher than HBV .
[10]
Therefore, unlike HBV, almost all HCV-infected persons who develop HCC have underlying cirrhosis [12,13] .
An additional important factor for the high burden of HCV-induced HCC is the lack of a preventative
vaccine like the HBV vaccine which has been instrumental in reducing the global incidence of HBV .
[9]

HCV PREVALENCE - USA AND GLOBAL
The World Health Organization (WHO) estimated the global prevalence of HCV to be around 3%, amounting
to more than 170 million people worldwide [14-16] . There is a lot of geographic variation in the prevalence of HCV,
with African and the Middle Eastern countries such as Egypt, Cameroon, Saudi Arabia, Iraq and Syria topping
the list . Egypt has the highest prevalence of HCV in the world with endemic levels of infection, and that is
[15]
reflected in the high incidence of HCC . Along with Egypt, the Asian countries of China, India, Pakistan and
[17]
Indonesia also carry a heavy burden of HCV and together make up half of the global HCV population [14,15] .