Hepatitis B: Comprehensive Diagnostic and Management Approach
Diagnostic Testing
All patients suspected of hepatitis B infection require a systematic serological and virological workup to establish diagnosis, determine disease phase, and guide treatment decisions.
Initial Screening Panel
- HBsAg (Hepatitis B surface antigen): The hallmark marker of HBV infection; persistence beyond 6 months defines chronic infection 1, 2
- Anti-HBs (Hepatitis B surface antibody): Indicates immunity from vaccination or resolved infection 2
- Anti-HBc (Hepatitis B core antibody): Distinguishes current/past infection from vaccination-induced immunity 3
- HBeAg and anti-HBe: Essential for disease phase classification and treatment decisions 1, 2
Quantitative Viral and Biochemical Assessment
- HBV DNA quantification by PCR: Critical for determining viral replication level, treatment indication, and monitoring response 1, 4
- ALT/AST levels: Assess hepatic inflammation and guide treatment thresholds 1, 2
- Complete blood count and comprehensive liver panel: Evaluate for cirrhosis complications 1
Additional Essential Testing
- Hepatitis A antibody (anti-HAV): Screen for immunity; vaccinate if negative 1
- Hepatitis C antibody and RNA: Rule out coinfection 1
- Hepatitis D antibody (anti-HDV): Test in all HBsAg-positive patients, especially those with severe disease 1
- HIV testing: Mandatory in all chronic HBV patients due to management implications 1, 2
- Alpha-fetoprotein (AFP) baseline: Initial HCC screening 1
Liver Disease Severity Assessment
- Liver ultrasound: Baseline imaging for cirrhosis and HCC surveillance 1
- Transient elastography (FibroScan) or other non-invasive fibrosis markers: Assess fibrosis stage when available 1, 5, 2
- Liver biopsy: Consider when non-invasive tests are inconclusive or in patients with HBV DNA ≥2,000 IU/mL, elevated ALT, and uncertain fibrosis stage 1
Treatment Indications
Treatment decisions are based on HBV DNA level, ALT elevation, and liver disease severity, with the goal of preventing cirrhosis, hepatocellular carcinoma, and liver-related mortality.
Immediate Treatment (No Biopsy Required)
- HBV DNA ≥20,000 IU/mL AND ALT ≥2× ULN: Start treatment immediately 1, 6, 2
- Any cirrhotic patient with detectable HBV DNA: Treat regardless of ALT level 1, 6, 2
- Decompensated cirrhosis with any detectable HBV DNA: Immediate treatment and liver transplant evaluation 6, 2
Treatment with Disease Assessment
- HBV DNA ≥2,000 IU/mL with elevated ALT (>ULN) and moderate-to-severe necroinflammation or at least moderate fibrosis on biopsy or non-invasive testing: Initiate treatment 1, 5, 2
- HBV DNA ≥2,000 IU/mL with at least moderate fibrosis: May treat even with normal ALT 1, 2
Special Populations Requiring Prophylactic Treatment
- Pregnant women with HBV DNA >200,000 IU/mL: Start tenofovir DF at 24-32 weeks gestation to prevent mother-to-child transmission 6, 2
- Patients requiring immunosuppression or chemotherapy who are HBsAg-positive: Prophylactic antiviral therapy before starting treatment 1, 6
- Liver transplant candidates: Achieve undetectable HBV DNA pre-transplant 2
Observation Rather Than Immediate Treatment
- **HBeAg-positive patients <30 years with persistently normal ALT and high HBV DNA (immune-tolerant phase)**: Monitor every 3-6 months; consider treatment if >30-35 years old or family history of HCC/cirrhosis 1, 2
- HBeAg-negative patients with persistently normal ALT and HBV DNA 2,000-20,000 IU/mL (inactive carriers): Monitor ALT every 3 months for 1 year, then every 6-12 months; assess fibrosis non-invasively 1, 2
First-Line Treatment Options
Potent nucleos(t)ide analogues with high genetic barrier to resistance are the preferred first-line agents for chronic hepatitis B.
Recommended First-Line Monotherapy
- Entecavir 0.5 mg daily: High potency with <1% resistance at 5 years 1, 6, 5, 2
- Tenofovir disoproxil fumarate (TDF) 245 mg daily: High potency with no resistance detected after 8 years 1, 6, 5, 2
- Tenofovir alafenamide (TAF) 25 mg daily: High potency with improved renal and bone safety profile compared to TDF 1, 6, 2
Alternative Finite-Duration Therapy
- Pegylated interferon alfa-2a: May be considered in non-cirrhotic patients with mild-to-moderate disease, particularly those seeking finite therapy; contraindicated in decompensated cirrhosis and pregnancy 1, 2
Agents to Avoid as First-Line
- Lamivudine: NOT recommended due to 70% resistance rate at 5 years 1, 6
- Adefovir: Inferior to tenofovir; not recommended as first-line 1, 6
- Telbivudine: Moderate resistance rates; not preferred 1, 6
Special Population Considerations
- Pregnancy: Tenofovir DF is the ONLY recommended agent; pegylated interferon is absolutely contraindicated 6, 2
- Decompensated cirrhosis: Entecavir or tenofovir (TDF/TAF) immediately; pegylated interferon is absolutely contraindicated 2
- HIV-HBV coinfection: TDF- or TAF-based antiretroviral therapy mandatory regardless of CD4 count 2
Treatment Monitoring Protocol
Regular monitoring ensures virological response, detects resistance, and identifies disease progression or hepatocellular carcinoma development.
Virological and Biochemical Monitoring
- HBV DNA: Every 3 months until undetectable, then every 6 months 6, 2
- ALT/AST: Every 3-6 months throughout treatment 6, 2
- Quantitative HBsAg: Annually to assess for potential functional cure 6
Renal and Bone Monitoring (for Tenofovir)
- Serum creatinine and estimated GFR: Baseline, then periodically based on risk factors 5, 7
- Bone mineral density: Consider in patients with osteoporosis risk factors on TDF 2
Hepatocellular Carcinoma Surveillance
- Liver ultrasound every 6 months: For all cirrhotic patients, Asian men >40 years, Asian women >50 years, Africans >20 years, and any patient with family history of HCC 1, 6
- AFP every 6 months: Adjunct to ultrasound in high-risk patients 1
Monitoring for Non-Treated Patients
- Initial year: ALT and HBV DNA every 3 months to ensure stability 1, 2
- After stabilization: ALT every 3-6 months, HBV DNA every 6-12 months, non-invasive fibrosis assessment every 12 months 1, 2
Treatment Duration and Endpoints
Long-term, potentially indefinite treatment is typically required with nucleos(t)ide analogues, as HBsAg loss (functional cure) is rarely achieved.
Treatment Goals
- Primary endpoint: Undetectable HBV DNA by sensitive PCR assay (<10-15 IU/mL) 1, 2
- Optimal endpoint: HBsAg loss with or without anti-HBs seroconversion (functional cure) 1, 2
- Biochemical response: ALT normalization 1, 2
Duration of Therapy
- Most patients: Long-term, potentially indefinite treatment until HBsAg loss 1, 6, 5, 2
- HBeAg-positive patients achieving HBeAg seroconversion: Continue treatment for at least 12 months after seroconversion with undetectable HBV DNA, then may consider stopping in non-cirrhotic patients with close monitoring 1, 6
- Cirrhotic patients: Lifelong treatment mandatory 2
Stopping Criteria (Non-Cirrhotic Patients Only)
- HBeAg-positive: HBeAg seroconversion to anti-HBe, undetectable HBV DNA, and 12 months consolidation therapy completed 6, 2
- Post-treatment monitoring: Close follow-up required due to high relapse rates, especially in HBeAg-negative patients (80-90% relapse if stopped at 1-2 years) 1
Common Pitfalls and Caveats
Critical Warnings
- Severe acute exacerbation after discontinuation: Monitor hepatic function closely for at least several months after stopping treatment; risk of fulminant hepatic failure 8
- HIV coinfection: Entecavir is NOT recommended unless patient is receiving HAART; use TDF- or TAF-based regimens 2, 8
- Lactic acidosis risk: Rare but serious complication; suspend treatment if suspected 8
Diagnostic Pitfalls
- Normal ALT does not exclude significant liver disease: Traditional ALT cutoffs miss many patients with moderate-to-severe necroinflammation or fibrosis; consider non-invasive fibrosis assessment 2
- Occult HBV infection: HBsAg-negative but HBV DNA-positive patients exist; test HBV DNA in high-risk individuals with negative HBsAg 9
Treatment Decision Pitfalls
- Do not delay treatment in cirrhotic patients: Any detectable HBV DNA in cirrhosis requires immediate treatment regardless of ALT 1, 6, 2
- Avoid lamivudine, adefovir, and telbivudine as first-line: High resistance rates lead to treatment failure and disease progression 1, 6
- Never use pegylated interferon in decompensated cirrhosis or pregnancy: Absolute contraindications 2