Hepatitis B Workup and Management
Begin with a three-test serological panel (HBsAg, anti-HBc, and anti-HBs) for all adults aged ≥18 years, as this is the foundation for determining infection status, immunity, and need for further evaluation. 1
Initial Serological Testing
The workup starts with three essential markers that define HBV status:
- HBsAg (Hepatitis B surface antigen): The primary marker for active infection; positivity for >6 months defines chronic HBV infection 2
- Anti-HBc (Hepatitis B core antibody, total): Indicates current or previous HBV exposure 2
- Anti-HBs (Hepatitis B surface antibody): Indicates recovery from infection or successful vaccination 2
Interpretation of Initial Serological Patterns
- Chronic HBV infection: HBsAg positive, anti-HBc positive, anti-HBs negative 2
- Past infection with immunity: HBsAg negative, anti-HBc positive, anti-HBs positive 3, 2
- Vaccine-induced immunity: HBsAg negative, anti-HBc negative, anti-HBs positive 3, 2
- Acute infection: HBsAg positive with IgM anti-HBc positive 3, 2
Common pitfall: The "window period" during acute infection may show negative HBsAg but positive IgM anti-HBc, which can lead to missed diagnoses if only HBsAg is ordered 2. Isolated anti-HBc positivity requires repeat testing in 3-6 months and may necessitate HBV DNA testing to rule out occult infection 3, 2.
Additional Testing for Chronic HBV Infection
Once chronic HBV is confirmed (HBsAg positive >6 months), proceed with:
Virological Assessment
- HBV DNA quantification: Essential for assessing viral replication, disease activity, and treatment decisions 2
- HBeAg and anti-HBe: HBeAg indicates high viral replication; anti-HBe typically indicates lower replication 2
Liver Function and Synthetic Capacity
- ALT/AST: Assess liver inflammation 2
- Alkaline phosphatase and GGT: Additional markers of liver injury 2
- Bilirubin, albumin, and PT/INR: Evaluate synthetic liver function and severity 2
Coinfection Screening
- Anti-HCV: Rule out hepatitis C coinfection 2
- Anti-HDV: Test in patients with injection drug use history or from endemic areas 2
- Anti-HIV: Test in high-risk groups 2
- Anti-HAV IgG: Determine immunity status; vaccinate if negative 2
Disease Severity Assessment
- Non-invasive fibrosis assessment or liver biopsy: Evaluate inflammation and fibrosis when treatment decisions are uncertain 2
- Ultrasound and alpha-fetoprotein (AFP): Baseline HCC screening in high-risk patients 2
Monitoring Strategy for Chronic HBV
Patients NOT on Treatment
For patients with chronic HBV who do not meet treatment criteria:
For patients in the "grey area" (uncertain treatment indication):
- ALT and HBV DNA: Every 1-3 months 4
- HBeAg/anti-HBe: Every 2-6 months 4
- Consider non-invasive fibrosis assessment or liver biopsy if uncertainty persists 4
Patients on Antiviral Treatment
- Liver function tests: Every 3-4 months during the first year, then every 6 months 4
- HBV DNA: Every 3-4 months during the first year, then every 6-12 months 4
- HBsAg: Check at 12-month intervals if HBV DNA remains undetectable 4
- Renal monitoring (eGFR and serum phosphate): Every 3 months during the first year, then every 6 months for patients on tenofovir or at high renal risk 4
HCC Surveillance
All high-risk patients require:
High-risk groups include Asian men >40 years, Asian women >50 years, patients with cirrhosis, and those with family history of HCC 1.
Treatment Indications
Clear Treatment Indications
Treat immediately if:
- Cirrhosis (compensated or decompensated) with detectable HBV DNA 4
- HBV DNA >2000 IU/mL with liver stiffness >9 kPa (or >12 kPa if ALT ≤5x ULN) 4
- HBV DNA >2000 IU/mL with at least moderate histological lesions, regardless of ALT 4
- HBV DNA >20,000 IU/mL with ALT >2x ULN 4
- HBeAg-positive patients >30 years old with HBV DNA >20,000 IU/mL 4
Special Populations Requiring Prophylaxis
High-risk patients requiring antiviral prophylaxis regardless of HBsAg status:
- Anti-CD20 monoclonal antibody therapy 4, 1
- Hematopoietic stem cell transplantation 4, 1
- CAR-T cell therapy 1
- High-dose corticosteroids 1
For these patients:
- Start prophylaxis before or at treatment initiation (do not delay cancer therapy for HBV testing) 4, 1
- Continue prophylaxis during therapy and for at least 12 months after completion 4, 1
- Monitor ALT and HBV DNA at baseline and every 6 months during prophylaxis 4, 1
Monitoring vs. Prophylaxis for Past HBV Infection
For patients with past HBV (HBsAg-negative, anti-HBc-positive) receiving systemic anticancer therapy (excluding anti-CD20 or stem cell transplant):
- Check HBsAg and ALT at baseline and every 3 months during therapy 4
- If HBsAg becomes positive, start antiviral therapy immediately 4
- Alternative approach: Preemptive prophylaxis if adherence to frequent monitoring is uncertain 4
Common pitfall: Patients with past HBV receiving anti-CD20 therapy or stem cell transplantation require prophylaxis, not just monitoring, due to high reactivation risk 4.
Post-Treatment Monitoring
After stopping antiviral therapy:
- Monitor ALT for hepatitis flares (defined as ALT >100 U/mL and 3x baseline) 4
- Continue monitoring for at least several months, as severe acute exacerbations can occur after discontinuation 5
- Consider long-term antiviral therapy in consultation with an HBV specialist for patients with cirrhosis or high-risk features 4
Treatment Options
First-line agents with high genetic barrier to resistance:
- Entecavir: 0.5 mg once daily (1 mg for lamivudine-resistant or decompensated liver disease) 5
- Tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF): TAF demonstrates superior renal and bone safety profiles compared to TDF 4
For patients at high renal risk or with underlying renal/bone disease on TDF, switch to entecavir or TAF 4.
Peginterferon alfa: Consider for finite-duration therapy in compensated disease, but contraindicated in decompensated cirrhosis 4. Combination therapy with peginterferon plus nucleos(t)ide analogue offers no significant advantage over monotherapy 4.