HBV-Integration Studies in the Clinic: Role in the Natural History of Infection

Abstract

Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.

HBeAg Levels Vary across the Different Stages of HBV Infection According to the Extent of Immunological Pressure and Are Associated with Therapeutic Outcome in the Setting of Immunosuppression-Driven HBV Reactivation

“…In particular, it is plausible that in the setting of HBeAg positivity, the synthesis of both HBeAg and HBsAg is mainly sustained by the transcriptional activity of cccDNA with a limited contribution of integrated HBV-DNA to the HBsAg production. This is in line with different studies supporting that integrated HBV-DNA can represent a major source of HBsAg, mostly in HBeAg-negative patients [22,23].…”

Quantitative HBsAg versus HBV DNA in Predicting Significant Hepatitis Activity of HBeAg-Positive Chronic HBV Infection

“…The quantitative standard for HBsAg in predicting the significant hepatitis activity phase of HBeAg-positive chronic HBV infection has not been formed [ 2 , 3 , 4 ]. HBsAg is produced by both HBV covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome [ 18 , 19 , 20 ]. HBV DNA integration begins at the very early stage of chronic HBV infection [ 19 , 20 ], and the frequency of the integration in HBeAg-negative patients is significantly higher than that of HBeAg-positive patients [ 18 , 19 , 20 ].…”

“…HBsAg is produced by both HBV covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome [ 18 , 19 , 20 ]. HBV DNA integration begins at the very early stage of chronic HBV infection [ 19 , 20 ], and the frequency of the integration in HBeAg-negative patients is significantly higher than that of HBeAg-positive patients [ 18 , 19 , 20 ]. Nevertheless, HBsAg in patients with HBeAg-positive chronic HBV infection was significantly positively correlated with HBV DNA [ 13 , 14 , 21 ].…”

Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

“…In particular, the risk was increased following HBsAg loss after treatment (within a median 4.8 years follow up) [ 101 ], likely due to the increased rate of associated cirrhosis in treated patients in comparison to treatment-naïve patients that spontaneously clear HBsAg. Surface antigen levels during infection do not always correlate with viral replicative activity, as integrated HBV DNA is a source of HBsAg expression, particularly in HBeAg-negative patients [ 102 ] ( Figure 1 ). Furthermore, mutations within the PreS1, PreS2 or HBsAg coding regions may result in altered HBsAg quantification due to secretion or expression defects [ 103 , 104 ].…”