Best Practices in the Diagnosis and Management of Hepatitis B
The diagnosis and management of hepatitis B should follow a structured approach with screening of high-risk populations, comprehensive serological and virological testing, and treatment decisions based on disease phase, viral load, ALT levels, and evidence of liver damage, with entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide as first-line treatments for those meeting therapy criteria. 1, 2
Diagnosis and Screening
HBsAg testing is the primary tool for screening and diagnosis of hepatitis B virus (HBV) infection and should be widely available 1
Screening is recommended for:
Initial diagnostic workup should include:
- HBsAg - indicates current infection 4
- HBeAg and anti-HBe - indicates viral replication status 4
- Anti-HBc (total and IgM) - distinguishes acute from chronic infection 4
- Anti-HBs - indicates immunity from vaccination or resolved infection 4
- HBV DNA quantification - determines viral load and replication 1
- Liver function tests (ALT, AST, bilirubin, albumin, prothrombin time) 1
- Assessment of liver fibrosis using non-invasive methods or liver biopsy when indicated 2
Natural History and Disease Classification
Chronic HBV infection consists of four dynamic phases 1:
- Immune tolerance phase: HBeAg-positive, high HBV DNA, normal ALT, minimal liver damage 1
- Immune clearance phase: HBeAg-positive, fluctuating HBV DNA and ALT levels 1
- Inactive carrier phase: HBeAg-negative, anti-HBe-positive, low HBV DNA, normal ALT 1
- Reactivation phase: HBeAg-negative, elevated HBV DNA and ALT, active liver disease 1
Current classification system by the American Association for the Study of Liver Diseases includes five phases 2:
- HBeAg-positive chronic infection (formerly immune tolerant)
- HBeAg-positive chronic hepatitis
- HBeAg-negative chronic infection (formerly inactive carrier)
- HBeAg-negative chronic hepatitis
- HBsAg-negative phase (resolved infection)
Treatment Indications
Immediate treatment is recommended for 1:
- Acute liver failure
- Decompensated cirrhosis
- Severe acute exacerbation of chronic hepatitis B
Treatment for chronic HBV infection is indicated for 1, 2:
- All patients with compensated or decompensated cirrhosis and detectable HBV DNA
- HBeAg-positive patients with HBV DNA >20,000 IU/mL and ALT >2× ULN or significant liver inflammation/fibrosis
- HBeAg-negative patients with HBV DNA >2,000 IU/mL and ALT >2× ULN or significant liver inflammation/fibrosis
- Patients with a family history of HCC or cirrhosis may be considered for treatment even with lower viral loads 1
Special populations requiring treatment consideration 1, 2:
- HBV/HIV co-infected patients
- Patients receiving immunosuppressive therapy
- Patients with extrahepatic manifestations of HBV
First-line Treatment Options
Nucleos(t)ide analogues (NAs) with high genetic barrier to resistance are preferred 1, 2:
Pegylated interferon alfa-2a can be considered for a finite duration in selected patients with mild to moderate disease 1, 2
Treatment considerations:
Monitoring During Treatment
- Regular monitoring should include 1, 2:
- HBV DNA levels every 3-6 months
- ALT and other liver function tests every 3-6 months
- Renal function tests for patients on tenofovir
- HBeAg and anti-HBe every 6-12 months in HBeAg-positive patients
- HBsAg quantification where available
- Surveillance for HCC in high-risk patients (cirrhosis, family history of HCC)
Treatment Endpoints and Duration
- Ideal endpoint of therapy is HBsAg loss with or without anti-HBs seroconversion 2, 7
- For HBeAg-positive patients, treatment can be discontinued after:
- HBeAg seroconversion and undetectable HBV DNA with at least 12 months of consolidation therapy 1
- For HBeAg-negative patients, long-term treatment is typically required 2
- For patients with cirrhosis, indefinite treatment is recommended 1, 2
Common Pitfalls and Special Considerations
- Severe acute exacerbations may occur upon discontinuation of antiviral therapy, requiring close monitoring for at least several months 5
- HIV testing should be performed before starting HBV treatment, as some HBV drugs have anti-HIV activity and may lead to HIV resistance if used alone in co-infected patients 5
- Lactic acidosis and severe hepatomegaly with steatosis are rare but serious complications of nucleoside analogues 5, 6
- Patients with decompensated liver disease may be at higher risk for lactic acidosis 5
- Treatment should be suspended in patients who develop clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity 5
Emerging Therapies and Future Directions
- Current research focuses on achieving functional cure (HBsAg loss) or complete cure (clearance of cccDNA) 7
- Novel therapeutic approaches targeting various steps of the HBV lifecycle are in development 7
- Areas of unmet need include 1:
- Improved understanding of natural history and treatment indications
- Better non-invasive markers for liver disease severity
- Clarification of the role of HBsAg levels in management
- Development of new drugs and immunomodulatory therapies
- Long-term impact assessment of therapy on prevention of cirrhosis, HCC, and other complications