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Ayoub et al. Nucleos(t)ide therapy for hepatitis B impacts HCC incidence

the incidence of HCC is vaccination against HBV. A the western world and Asia; the 5-year cumulative
recent analysis of two Taiwanese HCC registries of incidences of HCC in Asia among inactive carriers
1,509 patients diagnosed with HCC from 1983-2011 and those with compensated cirrhosis are 1% and
5
demonstrated an incidence per 10 person-years 17%, respectively. In Europe and the United States,
[8]
of 0.92 in the unvaccinated cohort and 0.23 in the those incidences are 0.1% and 10% . A recent meta-
[2]
vaccinated cohort . Another appealing strategy to analysis evaluated 66 studies with a total of 347,859
decrease the incidence of HCC in patients with chronic patients using multivariate regression analysis, and
hepatitis B is inhibition of viral replication. In the after adjusting for age, there were no significant
[3]
seminal study by Liaw et al. , the chemopreventive differences in HCC incidence between Western and
effect of nucleos(t)ides was first suggested as the European studies. The analysis showed that age,
suppression of HBV replication led to decreased rates symptomatic carrier status, chronic hepatitis, or
of cirrhosis, liver failure, and the development of HCC. compensated cirrhosis were the greatest risk factors
for development of HCC when compared to inactive
[9]
THE RELATIONSHIP BETWEEN HBV AND carriers .
HCC
GOALS OF HBV THERAPY
Chronic hepatitis B (CHB) stimulates the immune
system to release cytokines and reactive oxygen There are 7 drugs currently approved for the treatment
species, which cause damage to genes, results in of CHB and they can be divided into 2 groups. The
cell death and initiates a cascade of fibrosis. As a immune-modulators include pegylated interferon
result, the hepatocyte cell cycle is accelerated and alfa-2a and interferon alfa-2b. The NA are oral
leads to accumulation of genetic alterations, which medications, which include lamivudine, telbivudine,
[4]
leads to malignant transformation of hepatocytes . In adefovir, tenofovir and entecavir. The oral agents have
addition, HBV integrates into the host DNA where it a better side effect profile and thus, most patients
modifies the expression of certain oncogenes. Certain are treated with oral therapy. Goals of treating CHB
mutations have been implicated in contributing to in the short term include suppressing replication
a higher incidence of HCC. These include the HBV with induction of hepatitis B e-antigen (HBeAg)
protein known as HBx, infection with HBV genotype C, seroconversion in patients with HBeAg-positive CHB
the hepatitis B genome mutations pre-S deletions and and normalization of alanine aminotransferase. In
core promoter mutations (V1735, T1762 and A1764) [4,5] . the long term, the goal is to achieve seroconversion
Another risk factor is the level of the hepatitis B of HBsAg to hepatitis B surface antibody. However,
surface antigen (HBsAg) titer. Levels of HBsAg that HBsAg seroconversion is not common with currently
are greater than 1,000 IU/mL may independently available therapies. It is seen in 1% and 1.5% of
predict increased risk for developing HCC in Asians patients after 52 weeks of lamivudine or telbivudine
[6]
in HBeAg negative patients with low HBV viral load . therapy respectively. Furthermore, 5 years of adefovir
One retrospective study examined the cumulative therapy results in HBsAg loss in only 3% of patients.
probability of HCC development over time despite The rates of HBsAg seroconversion are slightly better
long-term nucleos(t)ide analog (NA) therapy. The study with entecavir and tenonfovir. Ninety-six weeks of
included treatment-naive CHB patients (n = 524) who entecavir results in 5% seroconversion rate and 4
received treatment with NAs between January 2003 years of tenofovir yields a 10% seroconversion rate.
and December 2007 for longer than 48 weeks. The The best HBsAg seroconversion rate (15%) is seen
study revealed a cumulative probability of developing after 72 weeks of treatment with pegylated interferon
HCC at 1, 2, 3, 4 and 5 years of 0.2%, 1.8%, 3.6%, alfa-2a and lamivudine [10-12] . Although seroconversion
5.8%, and 9.3% respectively. In multivariate analysis, of HBsAg doesn’t occur frequently, multiple studies
age greater than 50 years [hazard ratio (HR) 1.05], show that treatment favorably impacts fibrosis, survival
family history of HCC (HR 5.48), and the presence and reduces HCC development in patients who are
of cirrhosis (HR 17.16) were significant predictors of treated for CHB.
HCC development. Importantly, maintaining a virologic
response or HBV DNA < 20 IU/mL for longer than 12 The first nucleoside approved for the treatment of HBV
months reduced the risk of HCC development (HR was lamivudine. However, development of resistance
[7]
0.09) . These studies suggest that persistent HBV with prolonged treatment has limited its use. After 5
viral replication and subsequent liver injury are major years of therapy, resistance is reported to be as high
risk factors for developing HCC. as 75% [13] . Telbivudine and adefovir have a moderate
genetic barrier to resistance and are considered to
The incidence of HBV-related HCC varies between be are second line therapies. Currently, entecavir and

Hepatoma Research ¦ Volume 3 ¦ December 20, 2017 303