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Tai et al. Hepatoma Res 2020;6:74 I http://dx.doi.org/10.20517/2394-5079.2020.54 Page 3 of 12

Figure 1. Summary of hepatitis B virus (HBV) and host interactions. When humans are exposed to HBV, either acute hepatitis with
subsequent virus clearance or persistent infection may develop. Those who are infected in the early stages of life, and via vertical
transmission, are prone to progress to persistent infection. HLA-DP and -DQ loci are associated with persistent HBV infection in East
Asians. Chronic persistent HBV infection starts with the presence of hepatitis B e-antigen (HBeAg), known as the immune tolerance
stage. In this phase, Africans tend to clear HBeAg before puberty while East Asians tend to clear HBeAg between the second and fourth
decades of life. About 5% of HBeAg-negative patients still present with active viral replication. Many immune-related genes participate
in HBV clearance. Inability to effectively clear HBV may result in liver cirrhosis and increased HBV mutations and integrations into
the human genome. All of these events and some genetic polymorphisms in the host may promote hepatocarcinogenesis. HCC:
hepatocellular carcinoma

Persistent HBV infection
Chronic persistent HBV infections start with the presence of the hepatitis B e-antigen (HBeAg). During
the HBeAg-positive immune tolerance phase, the HBV DNA level is high with low levels of liver
[25]
inflammation . Due to some unclear triggering factors, immune clearance of HBV will develop between
the second and fourth decades of life in East Asians. There is a difference between Africans and East Asians
regarding the duration of the HBeAg-positive period [26-29] . A rapid clearance of HBeAg before puberty can
be found in Africans but rarely occurs in East Asians [30,31] . This difference may be associated with variations
[24]
in the HLA-DP and -DQ genotypes . Certain SNPs in HLA-DP and -DQ loci may prolong the HBV
replication phase in adults of East Asian descent. A high HBV DNA level in parents will increase the risk of
persistent infection in their offspring (submitted for publication).

[28]
HBV genotypes C and D are associated with a more persistent liver necroinflammation . Many immune-
related genes may participate in this immune clearance phase [Figure 1]. Patients either in the HBeAg-
positive or -negative phase who are unable to suppress HBV replication may develop liver cirrhosis due to
repeated liver inflammation and fibrogenesis.

HBV integration and host interaction
[25]
A prolonged HBV replication phase and liver cirrhosis increases the risk of HCC . The mechanism may
be related to hepatitis Bx proteins , increased endoplasmic reticulum stress , HBV integration [10,33] and
[9]
[32]
inflammation-related chromosome damage.