Impact of Hepatitis B Virus Genetic Variation, Integration, and Lymphotropism in Antiviral Treatment and Oncogenesis

Abstract

Chronic Hepatitis B Virus (HBV) infection poses a significant global health burden. Although, effective treatment and vaccinations against HBV are available, challenges still exist, particularly in the development of curative therapies. The dynamic nature and unique features of HBV such as viral variants, integration of HBV DNA into host chromosomes, and extrahepatic reservoirs are considerations towards understanding the virus biology and developing improved anti-HBV treatments. In this review, we highlight the importance of these viral characteristics in the context of treatment and oncogenesis. Viral genotype and genetic variants can serve as important predictive factors for therapeutic response and outcomes in addition to oncogenic risk. HBV integration, particularly in coding genes, is implicated in the development of hepatocellular carcinoma. Furthermore, we will discuss emerging research that has identified various HBV nucleic acids and infection markers within extrahepatic sites (lymphoid cells). Intriguingly, the presence of hepatocellular carcinoma (HCC)-associated HBV variants and viral integration within the lymphoid cells may contribute towards the development of extrahepatic malignancies. Improved understanding of these HBV characteristics will enhance the development of a cure for chronic HBV infection.

Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability

“…In addition, BCP double mutation T1762/A1764 is more frequent in genotype C compared to genotype B increasing the risk for HCC [ 47 ]. In those patients infected with genotype B, non-cirrhotic HCC early onset is more common; whereas, genotype C is associated with cirrhotic HCC late-onset [ 48 ]. Nonetheless, chronically HBV-infected Japanese patients treated with NAs indicated that those infected with genotype B had a higher probability of HBsAg loss during treatment than those infected with genotype C [ 46 ].…”

“…Besides BCP and pre-core mutations, viral variants within the X and pre-S1 region are also associated with the risk of HCC development. Failure in NAs treatment associated with HBV mutations allows the replicative state of HBV raising the viral load and, together with the previously mentioned mutations, increases the risk of HCC development [ 48 ]. Teng et al demonstrated that the presence of deletions into the pre-S region is related to the risk or recurrence of HCC [ 50 ].…”

Diagnostic performance of elastography on liver fibrosis in antiviral treatment-naive chronic hepatitis B patients: a meta-analysis

“…Despite the availability of effective drug interventions that reduce or prevent complications in most cases, chronic hepatitis B (CHB) remains a major public health issue worldwide that poses a significant health burden [ 1 ]. As the causative agent of CHB, human hepatitis B virus (HBV) is a hepatotropic DNA virus that can trigger acute and chronic hepatitis, contributing to HBV-related cirrhosis and even hepatocellular carcinoma [ 2 ].…”

Advances in Nanoparticle Drug Delivery Systems for Anti-Hepatitis B Virus Therapy: A Narrative Review

“…The inability of existing drugs to enter the nucleus and clear the cccDNA is the main cause of CHB infection and recurrence in “functional cure” patients with negative HBsAg findings after drug withdrawal [ 10 , 11 , 12 ]. In addition, integration of the HBV and host cell genomes occurs during the process of viral replication, which is closely related to chronic infection and the occurrence of hepatoma [ 13 , 14 ]. In recent years, several studies have been performed to research and analyze the life cycle of HBV, through which many novel promising drug targets have been unveiled ( Figure 1 ) [ 15 ].…”