What is the treatment indication for a patient with Hepatitis B (HBV) infection, considering factors such as active viral replication, liver damage, and overall health?

Treatment Indications for Hepatitis B Virus Infection

Treat chronic hepatitis B when HBV DNA is >2000 IU/mL combined with ALT above the upper limit of normal AND evidence of at least moderate liver inflammation or fibrosis on biopsy or non-invasive assessment. 1, 2

Core Treatment Criteria (Three-Factor Assessment)

The decision to initiate antiviral therapy requires evaluation of three key parameters 1:

• HBV DNA level: Threshold >2000 IU/mL 1, 2
• ALT level: Above upper limit of normal (typically >40 IU/L) 1, 2
• Liver disease severity: Moderate to severe necroinflammation and/or at least moderate fibrosis on liver biopsy or validated non-invasive markers 1

Important caveat: If HBV DNA >2000 IU/mL with documented moderate-to-severe liver disease on biopsy or imaging, treatment may be initiated even when ALT levels are normal. 1, 2

Immediate Treatment Without Biopsy

Start treatment immediately without requiring liver biopsy in these scenarios 1:

• Obviously active hepatitis: HBV DNA >20,000 IU/mL AND ALT >2× upper limit of normal (both HBeAg-positive and HBeAg-negative patients) 1, 2
• Any compensated cirrhosis: Any detectable HBV DNA, regardless of ALT level 1, 2
• Decompensated cirrhosis: Any detectable HBV DNA requires urgent treatment with nucleos(t)ide analogues and simultaneous liver transplant evaluation 1, 2

Non-invasive fibrosis assessment (such as transient elastography/FibroScan) should still be performed when starting treatment without biopsy to confirm or exclude cirrhosis. 1

Special Populations Requiring Different Thresholds

Immunotolerant Patients (Do NOT Treat)

• Age <30 years with persistently normal ALT, high HBV DNA, no liver disease evidence, and no family history of HCC or cirrhosis: observe with monitoring every 3-6 months 1
• Age ≥30 years OR family history of HCC/cirrhosis: Consider liver biopsy and treatment even with normal ALT 1

HBeAg-Negative Patients with Minimal Activity (Do NOT Treat)

• Persistently normal ALT (monitored every 3 months for ≥1 year) AND HBV DNA 2000-20,000 IU/mL without liver disease evidence: close monitoring only 1
• Follow ALT every 3 months and HBV DNA every 6-12 months for at least 3 years 1

Pregnancy

• Tenofovir disoproxil fumarate is the preferred agent during pregnancy 3
• Prophylactic treatment starting at 24-32 weeks gestation for women with HBV DNA >200,000 IU/mL to prevent mother-to-child transmission 3
• Pegylated interferon is absolutely contraindicated in pregnancy 3

Additional High-Risk Scenarios Requiring Treatment

Treat regardless of standard thresholds in 2, 3, 4:

• Patients requiring immunosuppression or chemotherapy (prophylaxis to prevent reactivation) 4
• Healthcare workers with HBV DNA ≥2000 IU/mL performing exposure-prone procedures 3
• Extrahepatic manifestations of HBV (e.g., polyarteritis nodosa, glomerulonephritis) 1, 4
• Severe acute hepatitis B with coagulopathy or hepatic encephalopathy 3, 4
• HIV-HBV coinfection (must use tenofovir- or TAF-based antiretroviral therapy regardless of CD4 count) 3

Preferred First-Line Treatment Agents

Entecavir 0.5 mg daily OR tenofovir (disoproxil fumarate 245 mg or alafenamide 25 mg) daily are the preferred first-line treatments due to potent antiviral activity and high genetic barrier to resistance. 2, 5, 3, 6

• For lamivudine-refractory patients or those with decompensated liver disease: entecavir 1 mg daily 6
• Pegylated interferon alfa is an alternative for selected patients desiring finite therapy (48 weeks), but has more side effects and is contraindicated in cirrhosis 2, 3
• Lamivudine, adefovir, and telbivudine are not preferred due to weak antiviral potency and high resistance rates 1, 3

Common Pitfalls to Avoid

Do not delay treatment in cirrhotic patients: Any detectable HBV DNA in compensated or decompensated cirrhosis mandates immediate treatment, as viral suppression prevents hepatic decompensation and reduces HCC risk. 1, 2, 3

Do not rely solely on traditional ALT cutoffs: Normal ALT by conventional laboratory criteria does not exclude significant necroinflammation or fibrosis—consider non-invasive fibrosis assessment or biopsy in patients with HBV DNA >2000 IU/mL even when ALT appears normal. 1, 3

Do not use entecavir monotherapy in HIV-HBV coinfection without concurrent antiretroviral therapy: This risks development of HIV resistance to nucleoside reverse transcriptase inhibitors. 6

Monitor closely after treatment discontinuation: Severe acute exacerbations of hepatitis B can occur after stopping antiviral therapy—hepatic function must be monitored with clinical and laboratory follow-up for at least several months. 6

Treatment Duration

Long-term or indefinite treatment is typically required, as HBsAg loss (the optimal endpoint) occurs in only 1-12% of patients even after years of therapy. 5, 3 Treatment may be discontinued in select HBeAg-positive patients who achieve HBeAg seroconversion with undetectable HBV DNA after at least 12 months of consolidation therapy, but close monitoring for relapse is mandatory. 3