What is the approach to managing a patient who is hepatitis B surface antigen (HBsAg) positive?

Management of HBsAg-Positive Patients

All HBsAg-positive patients require immediate comprehensive evaluation including HBV DNA quantification, HBeAg status, liver enzyme testing, and assessment for cirrhosis, with first-line treatment using entecavir or tenofovir for those meeting specific criteria based on viral load, ALT elevation, and fibrosis stage. 1

Initial Diagnostic Workup

Upon confirming HBsAg positivity, the following tests must be obtained immediately:

• HBV DNA quantification by PCR to determine viral replication level (the single most important test) 1, 2
• HBeAg and anti-HBe antibodies to distinguish disease phase 3, 2
• Complete metabolic panel including ALT, AST, bilirubin, albumin, and prothrombin time to assess liver function 3, 4
• Complete blood count 3
• Coinfection screening: anti-HCV, anti-HDV, and anti-HIV antibodies 3, 2
• Anti-HAV antibody with vaccination if negative 3, 2
• Baseline alpha-fetoprotein (AFP) 3
• Liver ultrasound to assess for cirrhosis and exclude focal lesions 3, 4
• Fibrosis assessment via liver biopsy or transient elastography if HBV DNA ≥2,000 IU/mL 3, 1, 2

Treatment Decision Algorithm

Immediate Treatment Required (Regardless of ALT or HBV DNA Level):

• Decompensated cirrhosis with any detectable HBV DNA 3, 1, 2
• Compensated cirrhosis with any detectable HBV DNA 3, 1, 2
• Acute liver failure or severe acute hepatitis B 1
• HBV-related hepatocellular carcinoma with detectable HBV DNA 1
• Patients requiring immunosuppressive therapy or chemotherapy (prophylactic treatment regardless of HBV DNA level) 3, 2

Treatment Based on HBeAg Status and Laboratory Values:

For HBeAg-Positive Patients:

• HBV DNA ≥20,000 IU/mL + ALT >2× ULN: Treat immediately 3
• HBV DNA ≥20,000 IU/mL + ALT normal but >ULN: Consider liver biopsy, especially if age >35-40 years; treat if moderate/severe inflammation or fibrosis present 3
• HBV DNA <2,000 IU/mL: No treatment; monitor every 6-12 months (initially every 3 months for first year) 3

For HBeAg-Negative Patients:

• HBV DNA ≥2,000 IU/mL + ALT >2× ULN: Treat immediately 3, 5
• HBV DNA ≥2,000 IU/mL + ALT normal but >ULN: Consider liver biopsy or transient elastography; treat if disease present 3, 5
• HBV DNA <2,000 IU/mL + ALT normal: No treatment (inactive carrier phase); monitor ALT and HBV DNA every 3-6 months 3, 2

Important caveat: Use lower ALT upper limit of normal (ULN) thresholds: 30 IU/L for men and 19 IU/L for women 3

First-Line Treatment Options

Preferred oral antiviral agents (high potency with high barrier to resistance):

• Entecavir 0.5 mg daily (achieves >90% virologic suppression after 3 years) 3, 1, 6
• Tenofovir disoproxil fumarate (TDF) 300 mg daily 3, 1, 7
• Tenofovir alafenamide (TAF) 25 mg daily (improved renal and bone safety profile) 1, 2

Alternative for selected patients:

• Peginterferon alfa-2a for finite treatment duration (1 year), with higher rates of HBeAg seroconversion and HBsAg loss compared to oral agents, but more side effects and contraindicated in decompensated cirrhosis 3

Critical note: Lamivudine is no longer recommended as first-line therapy due to high resistance rates, except for short-term use in specific circumstances (e.g., pregnancy third trimester, short immunosuppression courses with low HBV DNA) 3

Treatment Monitoring Protocol

• HBV DNA levels: Every 3 months until undetectable, then every 6 months 1, 2, 5
• ALT/AST: Every 3-6 months 1, 2
• Annual quantitative HBsAg testing to assess for potential HBsAg loss (functional cure) 2, 5
• Renal function monitoring for patients on tenofovir: creatinine clearance, serum phosphate, urine glucose, and protein at baseline and at least annually 2, 7
• Bone density monitoring for patients on tenofovir 1

Treatment Duration

• HBeAg-positive patients: Continue until HBeAg seroconversion plus at least 12 additional months of consolidation therapy 3
• HBeAg-negative patients: Long-term (indefinite) treatment required; discontinuation only considered after HBsAg loss 3, 5
• Cirrhotic patients: Indefinite treatment even after HBsAg loss due to persistent HCC risk 5

Special Populations

Pregnancy:

• Screen all pregnant women for HBsAg 3
• High viral load (HBV DNA >200,000 IU/mL): Start tenofovir at 24-32 weeks gestation to prevent vertical transmission 3, 2
• Infants of HBsAg-positive mothers: Administer HBIG within 12 hours of birth plus HBV vaccination at birth, 1 month, and 6 months 3
• Monitor mothers every 12 weeks during pregnancy and at 4-6 weeks postpartum for hepatitis flares 3

Immunosuppression/Chemotherapy:

• Screen all candidates for HBsAg, anti-HBs, and anti-HBc before starting therapy 3
• HBsAg-positive patients: Initiate prophylactic entecavir or tenofovir several weeks before, during, and for 12 months after therapy (24 months for rituximab) 3, 5
• HBsAg-negative, anti-HBc-positive patients with detectable HBV DNA: Treat as HBsAg-positive 3
• HBsAg-negative, anti-HBc-positive patients with undetectable HBV DNA: Monitor ALT and HBV DNA every 1-3 months; treat if HBV DNA becomes detectable 3

Liver Transplantation:

• Pre-transplant: Suppress HBV DNA to undetectable levels 3
• Post-transplant: HBIG plus oral antivirals (entecavir or tenofovir) to prevent reinfection 3

Hepatocellular Carcinoma Surveillance

Initiate ultrasound surveillance every 6 months for:

• All patients with cirrhosis (compensated or decompensated) 1, 2
• Asian males >40 years or Asian females >50 years 3, 2
• Africans >20 years 3
• Family history of HCC 3, 1
• Age >40 years with persistent/intermittent ALT elevation or elevated fibrosis markers 3, 2

Continue HCC surveillance lifelong, even after HBsAg loss in patients with prior cirrhosis 1

Patient Counseling and Prevention

Transmission Prevention:

• Counsel household, sexual, and needle-sharing contacts to get tested and vaccinated 3
• Use latex condoms with non-immune sex partners until vaccination and immunity documented 3
• Cover cuts and skin lesions; clean blood spills with bleach solution 3
• Refrain from donating blood, plasma, tissue, or semen 3
• Do not share household articles that could be contaminated with blood (toothbrushes, razors, injection equipment) 3

Liver Protection:

• Complete alcohol abstinence (even limited consumption worsens outcomes) 3, 2
• Hepatitis A vaccination if anti-HAV negative (coinfection increases mortality 5.6- to 29-fold) 3, 2
• Avoid hepatotoxic medications 2
• Referral to hepatologist experienced in chronic hepatitis B management 3, 1

Important Reassurances:

• HBV is NOT spread by breastfeeding, kissing, hugging, coughing, food/water, or sharing eating utensils 3
• No exclusion from school, work, or childcare unless prone to biting 3

Common Pitfalls to Avoid

• Do not use lamivudine as first-line therapy due to high resistance rates (except specific short-term scenarios) 3
• Do not treat immune-tolerant patients (HBeAg-positive, high HBV DNA, normal ALT, age <40) except in clinical trials, as response rates are low 3
• Do not discontinue treatment in HBeAg-negative patients without HBsAg loss, as virologic relapse is nearly universal 5
• Do not stop HCC surveillance after HBsAg loss in cirrhotic patients 1
• Do not use peginterferon in decompensated cirrhosis 3
• Monitor closely for hepatitis flares after stopping antiviral therapy or postpartum 3