How do I know if I am cured of Hepatitis B (HBV)?

From the Guidelines

To determine if a patient has been cured of hepatitis B, a combination of clinical and laboratory assessments are employed. Specifically, a patient is considered to have achieved a functional cure if they have undetectable hepatitis B virus (HBV) DNA levels, normalized alanine transaminase (ALT) levels, and loss of hepatitis B e-antigen (HBeAg) with development of anti-HBe antibodies 1.

Key Laboratory Assessments

• HBsAg test: to check for the presence of hepatitis B surface antigen, which indicates an active infection 1
• Anti-HBs test: to check for the presence of hepatitis B surface antibody, which indicates immunity to the infection 1
• HBeAg test: to check for the presence of hepatitis B e-antigen, which indicates high viral replication levels in the liver 1
• Anti-HBe test: to check for the presence of antibody to HBeAg, which indicates a reduction in viral replication levels 1
• HBV DNA test: to check for the presence and quantity of hepatitis B virus DNA in the blood, which indicates the level of viral replication 1

Treatment

Treatment with nucleos(t)ide analogs such as entecavir (0.5-1mg daily) or tenofovir (300mg daily) for a minimum of 12 months, and in some cases up to 24 months or longer, is often required to achieve these outcomes 1.

Monitoring

Regular monitoring of HBV DNA levels, ALT levels, and HBeAg status is necessary to assess the response to treatment and determine if a functional cure has been achieved 1.

Interpretation of Test Results

The interpretation of test results should be done in the context of the patient's clinical presentation and medical history 1. A positive HBsAg test indicates an active infection, while a negative HBsAg test and positive anti-HBs test indicate immunity to the infection 1. A positive HBeAg test indicates high viral replication levels, while a positive anti-HBe test indicates a reduction in viral replication levels 1.

Limitations

It is essential to note that complete eradication of HBV is almost impossible to achieve due to the persistence of covalently closed circular DNA (cccDNA) in the liver, even after successful treatment 1. Therefore, a functional cure is the most realistic goal of treatment.

From the Research

Definition of HBV Cure

• Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment 2
• HBV cure is associated with improved clinical outcomes in patients with chronic HBV infection 3
• Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy 4

Barriers to HBV Cure

• Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA) 2
• High viral burden (HBV DNA and HBsAg) and impaired host innate and adaptive immune responses against HBV also pose challenges to achieving HBV cure 2

Current Therapies and HBV Cure

• Current HBV therapeutics, such as 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure 2
• Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients 2
• Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels 2

Novel Therapies and HBV Cure

• Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials 2
• Novel immunomodulatory approaches, including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses, are being explored 2
• Combinations of direct-acting antivirals and immune modulatory therapies have shown promising results in achieving HBV cure 4

Predictors of Functional Cure

• HBeAg seroconversion at <18 years of age, high-genetic-barrier nucleos(t)ide analogue(s) therapy before HBeAg seroconversion, and a serum HBsAg titer <1000 IU/mL at 18 months after HBeAg seroconversion were significant predictors of functional cure 5
• The annual functional cure rate was 0.55% per person-year, and increased to 0.96% per person-year after HBeAg seroconversion 5

Diagnosis of HBV Cure

• Novel assays with improved sensitivity for detection of very low levels of HBsAg and to determine the source of HBsAg production will be required to measure efficacy of newer antiviral treatments for HBV cure 3
• A functional cure is defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks 5