What are the indications for antiviral therapy in a patient with a high Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) titre?

HBV DNA Titre and Indications for Antiviral Therapy

Antiviral therapy should be initiated when HBV DNA ≥2,000 IU/mL in HBeAg-negative patients or ≥20,000 IU/mL in HBeAg-positive patients, combined with elevated ALT ≥2× ULN, or when any detectable HBV DNA is present in patients with cirrhosis regardless of ALT level. 1

Critical HBV DNA Thresholds by Clinical Context

HBeAg-Positive Chronic Hepatitis B

• Treat immediately if HBV DNA ≥20,000 IU/mL AND ALT ≥2× ULN 1
• For ALT 1-2× ULN with HBV DNA ≥20,000 IU/mL, perform liver biopsy or non-invasive fibrosis testing; treat if moderate-to-severe necroinflammation or significant fibrosis (≥F2) is present 1
• Population-based cohort studies demonstrate increased risks of cirrhosis and HCC when HBV DNA exceeds 2,000 IU/mL, establishing this as the widely accepted treatment threshold 1

HBeAg-Negative Chronic Hepatitis B

• Treat immediately if HBV DNA ≥2,000 IU/mL AND ALT ≥2× ULN 1, 2
• This lower DNA threshold (compared to HBeAg-positive patients) reflects the fact that HBeAg-negative patients have already experienced immune-active disease and may harbor significant fibrosis 1
• For HBV DNA ≥2,000 IU/mL with normal or mildly elevated ALT (1-2× ULN), assess fibrosis via liver biopsy or non-invasive tests (liver stiffness ≥9 kPa with normal ALT or ≥12 kPa with ALT <5× ULN); treat if significant fibrosis is present 1

Cirrhosis (Compensated or Decompensated)

• All patients with cirrhosis and ANY detectable HBV DNA must be treated immediately, regardless of ALT level 1, 3, 2
• This represents the most critical indication, as even low-level viremia drives disease progression in cirrhotic patients 4
• Patients with decompensated cirrhosis require urgent antiviral treatment with entecavir or tenofovir AND simultaneous evaluation for liver transplantation 3, 5

Special Clinical Scenarios Requiring Treatment

Immune-Tolerant Phase (DO NOT TREAT)

• Antiviral therapy is NOT indicated for patients in the immune-tolerant phase (HBeAg-positive, persistently normal ALT, very high HBV DNA ≥10^7 IU/mL) despite high viral load 1
• The natural course is benign with minimal histologic changes, and treatment yields minimal benefit 1
• Monitor these patients every 3-6 months without treatment if age <30 years 2

Severe Acute Exacerbation or Acute-on-Chronic Liver Failure

• Initiate immediate antiviral therapy if ALT ≥5-10× ULN with signs of liver failure (jaundice, INR ≥1.5, ascites, hepatic encephalopathy) 1
• This scenario requires emergent treatment regardless of HBV DNA level 1
• Consider emergent liver transplantation if MELD score is high or hepatic encephalopathy worsens despite treatment 1

Pregnancy

• Treat in third trimester if HBV DNA ≥200,000 IU/mL (≥10^6 IU/mL) to prevent mother-to-child transmission 3, 2
• Tenofovir disoproxil fumarate is the preferred agent during pregnancy 3

Immunosuppression/Chemotherapy

• All HBsAg-positive patients receiving immunosuppressive therapy or chemotherapy require prophylactic antiviral therapy starting 2-4 weeks before treatment to prevent HBV reactivation (risk 12-50%) 3
• Continue prophylaxis through treatment and for 12-24 months after completion (24 months for rituximab) 3

First-Line Treatment Options

Entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) are the ONLY recommended first-line therapies due to potent antiviral activity and high genetic barrier to resistance 1, 2

Specific Regimens

• Entecavir 0.5 mg daily (oral, without regard to food) 1, 2, 6
• Tenofovir DF 245 mg daily (oral, without regard to food) 1, 2, 6
• Tenofovir AF 25 mg daily 1, 2

Agents to AVOID

• Do NOT use lamivudine or telbivudine as first-line therapy due to high resistance rates (up to 70% at 5 years for lamivudine) 1, 3, 7
• Lamivudine should only be considered when first-line agents are unavailable 1

Treatment Duration and Monitoring

Duration

• Long-term, potentially indefinite treatment is required in most patients as HBV eradication is rarely achieved with current therapies 1, 3
• Treatment can be discontinued after confirmed HBsAg loss with or without anti-HBs seroconversion 1
• In HBeAg-positive patients without cirrhosis, consider stopping after HBeAg seroconversion with undetectable HBV DNA documented on 3 separate occasions over at least 2 years 1

Monitoring Protocol

• Monitor HBV DNA every 3 months until undetectable, then every 6 months 1, 3
• Monitor ALT/AST every 3-6 months 1, 3
• Annual quantitative HBsAg testing to assess for functional cure (HBsAg loss) 3
• Ultrasound surveillance for HCC every 6 months in high-risk patients (Asian men >40 years, Asian women >50 years, any patient with cirrhosis, family history of HCC) 3, 2

Critical Pitfalls to Avoid

• Do NOT delay treatment in cirrhotic patients with any detectable HBV DNA, even if ALT is normal 3, 2
• Do NOT wait for ALT >2× ULN if non-invasive tests show significant fibrosis (≥F2) 1, 2
• Do NOT discontinue therapy in cirrhotic patients without achieving HBsAg loss, as viral rebound can cause acute-on-chronic liver failure 2
• Do NOT treat immune-tolerant patients <30 years old unless biopsy shows significant disease 1, 2
• Virologic breakthrough in patients on entecavir/tenofovir is almost always due to nonadherence rather than resistance; ensure medication adherence 2

Treatment Goals and Expected Outcomes

The primary goal is undetectable HBV DNA (<20 IU/mL by sensitive PCR assay) with ALT normalization 1, 2

Long-term viral suppression:

• Reduces mortality and prevents progression to cirrhosis and HCC 1, 8
• Can reverse fibrosis and even cirrhosis (typically requires 3-5 years of viral suppression) 1, 2, 9
• Achieves >90% virologic suppression after 3 years with minimal resistance (<1% for entecavir at 4 years) 2

The ideal treatment goal is HBsAg clearance (functional cure), but this is rarely achieved with current therapies and requires long-term maintenance of undetectable HBV DNA 1, 3