HBV-Induced Carcinogenesis: Mechanisms, Correlation With Viral Suppression, and Implications for Treatment

Abstract

Background: Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection.

Aims: To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development.

Materials and methods: We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy.

Results: We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention.

Conclusion: Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.

Keywords: HBV infection; antiviral therapy; chronic hepatitis B virus; hepatocellular carcinoma.

FIGURE 1

Old vs. new paradigm of the stages of chronic HBV infection. Phases may be referred to as follows: (1) HBeAg‐positive chronic infection or “immune tolerant”; (2) HBeAg‐positive chronic hepatitis or “immune active”; (3) HBeAg‐negative chronic infection or “inactive carrier”; and (4) HBeAg‐negative chronic hepatitis or “reactivation.” HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

FIGURE 2

Relationship of HBV DNA integration to HCC development [79]. It is often the case that a mutation is either lethal to the cell or results in a survival disadvantage for the cell. In this case, the mutant cell will disappear or have limited expansion and will ultimately be outcompeted by wild‐type (nonmutant) hepatocytes and disappear over time. Another possibility is a mutant without a change to its survival probability as compared to the original hepatocyte, in which case the mutant cell will expand clonally at the same rate as wild‐type hepatocytes turn over/expand. Lastly, a mutation may result in a survival advantage to the cell, in which case the mutant cell population will expand more quickly than wild‐type hepatocytes. In these later two scenarios, if the mutation moves the cell further along the continuum towards malignant transformation, the odds of a similar subsequent event increase as the clone expands, increasing the probability that a second mutation or chromosomal translocation can occur, further increasing the risk for cancer. Red indicates cellular mutation. Yellow indicates cell death. Orange represents a red cell with an additional mutation that further improves survival. HBV, hepatitis B virus; HBx, hepatitis viral protein; HCC, hepatocellular carcinoma.