What are the indications for treatment of chronic Hepatitis B (HBV)?

Treatment Indications for Chronic Hepatitis B

All patients with chronic hepatitis B who have HBV DNA ≥2,000 IU/mL, ALT above the upper limit of normal (>40 IU/L for men, >30 IU/L for women), and evidence of at least moderate liver necroinflammation or fibrosis should be treated. 1, 2

Core Treatment Criteria

The decision to initiate antiviral therapy is based on three key parameters that must be assessed together:

1. HBV DNA Thresholds

• HBeAg-positive patients: Treat if HBV DNA ≥20,000 IU/mL with ALT ≥2× ULN 1
• HBeAg-negative patients: Treat if HBV DNA ≥2,000 IU/mL with ALT ≥2× ULN 1
• Any patient with cirrhosis: Treat if HBV DNA ≥2,000 IU/mL regardless of ALT level 1
• Decompensated cirrhosis: Treat immediately if HBV DNA is detectable at any level 1

2. ALT Level Interpretation

• ALT ≥2× ULN: Clear indication for treatment when combined with elevated HBV DNA 1
• ALT 1-2× ULN: Liver biopsy or non-invasive fibrosis assessment required to determine if moderate-to-severe inflammation (≥A2) or significant fibrosis (≥F2) is present 1, 2
• Normal ALT with elevated HBV DNA: Treatment may still be indicated if non-invasive tests show liver stiffness ≥9 kPa (normal ALT) or ≥12 kPa (ALT <5× ULN) 1, 3

Critical pitfall: Traditional ALT thresholds (>40 IU/L) may be too high; studies show the 95th percentile for healthy individuals is 30 IU/L for men and 19 IU/L for women 1. Two-thirds of patients with mildly elevated ALT (1-2× ULN) have significant hepatic fibrosis 1.

3. Liver Disease Severity Assessment

• Liver biopsy findings: Treat if moderate-to-severe necroinflammation (≥A2) or significant fibrosis (≥F2) is present 1
• Non-invasive alternatives: Liver stiffness measurement by transient elastography can substitute for biopsy when values suggest advanced fibrosis 1, 2
• Compensated cirrhosis: Always treat if HBV DNA is detectable, regardless of ALT 1

Specific Clinical Scenarios

Immune Tolerant Phase (Do NOT Treat)

• Definition: HBeAg-positive with persistently normal ALT and very high HBV DNA (≥10^7 IU/mL) 1
• Age <30 years: Monitor every 3-6 months without treatment 1
• Age ≥30-40 years: Consider liver biopsy or non-invasive assessment; treat if significant disease is found 1
• Exception: Treat patients >30 years old with family history of HCC or cirrhosis even without typical indications 1

Immune Active Phase (Treat)

• HBeAg-positive: HBV DNA ≥20,000 IU/mL + ALT ≥2× ULN 1
• HBeAg-negative: HBV DNA ≥2,000 IU/mL + ALT ≥2× ULN 1
• Patients can start treatment without liver biopsy if these criteria are met 1

Inactive Carrier Phase (Monitor, Do NOT Treat)

• Definition: HBeAg-negative with persistently normal ALT and HBV DNA <2,000 IU/mL 1
• Management: Monitor ALT every 3 months and HBV DNA every 6-12 months for at least 3 years 1
• Exception: Consider treatment if family history of HCC/cirrhosis or extrahepatic manifestations present 1

Cirrhosis (Always Treat)

• Compensated cirrhosis: Treat if HBV DNA ≥2,000 IU/mL, regardless of ALT level 1
• Decompensated cirrhosis: Treat urgently if HBV DNA is detectable at any level; consider liver transplantation simultaneously 1

Special Populations Requiring Treatment

Pregnancy

• Treat in third trimester if HBV DNA ≥4-6 log₁₀ IU/mL (≥10,000-1,000 IU/mL) to prevent mother-to-child transmission 1

Immunosuppression/Chemotherapy

• Prophylactic treatment indicated in all HBsAg-positive patients receiving immunosuppression or chemotherapy to prevent HBV reactivation 3

Liver Transplant Recipients

• All HBsAg-positive patients on transplant waiting list should receive treatment 1

HIV/HBV Co-infection

• Treat with tenofovir-based antiretroviral therapy that covers both viruses 1

First-Line Treatment Options

Preferred agents (per FDA labeling and guidelines):

• Entecavir 0.5 mg daily (nucleoside-naïve patients) 2, 4
• Tenofovir disoproxil fumarate 245 mg daily 2
• Tenofovir alafenamide 25 mg daily 2

These agents achieve viral suppression in >90% of patients at 12 months and have high genetic barriers to resistance 2. Treatment will likely be long-term or indefinite, as HBsAg loss occurs in only 1-12% of patients even after years of therapy 2.

Key Clinical Pitfalls to Avoid

• Do not wait for ALT >2× ULN if non-invasive tests show significant fibrosis (≥F2) 1
• Do not delay treatment in cirrhotic patients with any detectable HBV DNA, even if ALT is normal 1
• Do not use lamivudine or telbivudine as first-line therapy due to high resistance rates 1
• Do not treat immune tolerant patients <30 years old unless biopsy shows significant disease 1
• Do not stop monitoring inactive carriers after initial assessment; they require lifelong surveillance 1