Hepatitis B, a significant cause of cirrhosis and hepatocellular carcinoma worldwide, affects an estimated 800,000 to 1.4 million people in the United States. While progress has been made in the prevention, diagnosis, and treatment of chronic hepatitis B, challenges remain in identifying persons affected by the virus and in determining recommendations for management and treatment. The Hepatitis B Research Network (HBRN) was a multicenter network to investigate the etiology and progression of the disease, and to test the safety and efficacy of current treatment approaches.

Hepatitis B virus (HBV) is largely a non-cytopathic virus. Therefore, liver disease pathogenesis and viral clearance in HBV infection is believed to be immune-mediated. At the same time, HBV persists with impaired antiviral immune effector responses that are potentially regulated by multiple immune pathways, including the CD28 costimulatory receptors and immune regulatory T cells. The Immune Regulation and Costimulation in Natural History of Chronic Hepatitis B (HBRN Immunology Cohort) study aimed to assess whether the balance between immune regulatory and effector responses in HBV-infected individuals defines the level of viremia, liver inflammation, and treatment outcomes.

The clinical and virological status of chronic HBV infection is defined by distinct patterns of immune effector and regulatory responses. This study examined:

• The immune effector and regulatory responses relative to serum HBV DNA, alanine aminotransferase (ALT), Hepatitis B e antigen (HBeAg), Hepatitis B surface antigen (HBsAg), and liver histology for participants with chronic HBV and in control groups
• Clinical hepatitis flares that reflect altered balance between immune regulatory and effector responses for chronic HBV participants

Outcome measures included immune regulatory and effector responses relative to HBV DNA, ALT, and clinical outcomes. In addition, HBV-specific lymphoproliferative, IFN-gamma and IL 10 responses, T cell activation and costimulatory markers (PD1, CTLA4, CD28, CD127), FoxP3+ Treg frequency, and NK frequency and expression of activating/inhibitory receptors and Dendritic cell frequency.

Inclusion criteria:

• 18 years and older
• Providing informed consent for this ancillary study

Exclusion criteria:

• Children under 18 years of age, participants with anemia
• Hgb < 10 or Hct < 30, congestive heart failure or chronic lung disease requiring oxygen, active coronary artery disease with unstable angina, sepsis or renal failure, other significant medical conditions, autoimmune disease or immunosuppression

Compared to controls, participants with chronic hepatitis B had weak T cell proliferative, interferon-γ, and interleukin-10 responses to HBV, with increased frequency of circulating FOXP3+CD127− regulatory T cells and CD4+ T cell expression of PD1 and CTLA4. T cell measures did not clearly distinguish between clinical chronic hepatitis B phenotypes, although the HBV core-specific T cell response was weaker in HBeAg+ than HBeAg− participants. Although in vitro blockade of PD1 or CTLA4 increased T cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg− participants. Furthermore, T cell responses to influenza and lipopolysaccharide were weaker in chronic hepatitis B participants than controls.