What is the first-line treatment for chronic Hepatitis B (HBV) infection?

First-Line Treatment for Chronic Hepatitis B Infection

Entecavir (0.5 mg daily) or tenofovir (either tenofovir disoproxil fumarate 300 mg daily or tenofovir alafenamide 25 mg daily) are the recommended first-line treatments for chronic hepatitis B, with tenofovir alafenamide preferred in patients with renal dysfunction, bone disease, or age >60 years. 1, 2

Treatment Selection Algorithm

For Treatment-Naïve Patients Without Comorbidities

• Entecavir 0.5 mg daily or tenofovir disoproxil fumarate 300 mg daily are equally effective first-line options, both achieving >90% virologic suppression after 3 years with minimal resistance 3, 1, 4
• Both drugs demonstrate comparable rates of HBV DNA suppression, ALT normalization, and HBeAg loss in head-to-head comparisons 4
• The choice between these agents can be based on cost, availability, and patient preference when no risk factors are present 5

For Patients With Renal or Bone Disease Risk Factors

• Entecavir or tenofovir alafenamide are strongly preferred over tenofovir disoproxil fumarate 3, 2
• Risk factors requiring this preference include: age >60 years, pre-existing chronic kidney disease (eGFR <60 mL/min/1.73 m²), bone disease, history of fragility fracture, or hemodialysis 3
• Tenofovir alafenamide has demonstrated improved renal and bone safety compared to tenofovir disoproxil fumarate while maintaining equal antiviral efficacy 2, 6
• For patients already on tenofovir disoproxil fumarate who develop renal dysfunction, switch to tenofovir alafenamide or entecavir 3

For Lamivudine-Experienced Patients

• Avoid entecavir completely due to high risk of cross-resistance from archived lamivudine-resistant mutations in HBV cccDNA 3, 2, 7
• Use tenofovir (disoproxil fumarate or alafenamide) as the only appropriate first-line option 2, 8
• Entecavir monotherapy is contraindicated even if lamivudine resistance mutations are not currently detected 8

For Patients With Cirrhosis

• Compensated cirrhosis: Entecavir or tenofovir are preferred; treat if HBV DNA ≥2,000 IU/mL regardless of ALT level 2, 9
• Decompensated cirrhosis: Use entecavir 1 mg daily or tenofovir; peginterferon is contraindicated 1, 7
• Indefinite therapy is required for all cirrhotic patients 3

Agents to Avoid as First-Line Therapy

• Never use lamivudine, adefovir, or telbivudine as first-line therapy due to high resistance rates (lamivudine resistance reaches 70% over 5 years) 2, 10
• These older agents should only be considered when entecavir and tenofovir are completely unavailable 3

Alternative Option: Peginterferon Alfa-2a

• Peginterferon alfa-2a 180 mcg weekly subcutaneously for 48 weeks is an alternative first-line option for select patients 3, 1
• Best candidates: HBeAg-positive patients with genotype A or B, high ALT (>2× ULN), low HBV DNA, younger age, and no cirrhosis 3, 1
• Advantages: Finite treatment duration (48 weeks), no resistance development, higher rates of HBsAg loss (3-7% vs 1-3% with nucleos(t)ide analogues) 3, 10
• Disadvantages: Poor tolerability, bone marrow suppression, exacerbation of depression, contraindicated in decompensated cirrhosis 1, 10
• Consider stopping if no HBsAg decline at week 12 1

Treatment Duration

HBeAg-Positive Patients

• Continue nucleos(t)ide analogue until HBeAg seroconversion occurs, then continue for an additional 6-12 months of consolidation therapy 1, 2, 9
• If HBeAg seroconversion does not occur, long-term indefinite therapy is required due to high relapse risk 3, 9

HBeAg-Negative Patients

• Long-term or indefinite treatment is typically required, as relapse rates reach 80-90% if stopped within 1-2 years 2, 10
• Treatment may only be discontinued after HBsAg loss with or without anti-HBs seroconversion 2, 9

Monitoring During Treatment

• HBV DNA and ALT every 3-6 months to assess virologic and biochemical response 1, 2, 9
• HBeAg status every 6 months in HBeAg-positive patients 1, 2
• Renal function monitoring: Serum creatinine every 6 months for all patients; baseline and every 3 months if using tenofovir disoproxil fumarate in high-risk patients 3
• Bone density monitoring should be considered in patients on tenofovir disoproxil fumarate with risk factors 2

Special Populations

Pregnant Women

• Tenofovir disoproxil fumarate is the drug of choice for pregnant women requiring treatment 3
• For prevention of mother-to-child transmission in women with HBV DNA >200,000 IU/mL, start tenofovir at 24-32 weeks gestation and stop 2-12 weeks after delivery 3

HBV-Related Hepatocellular Carcinoma

• Initiate antiviral therapy if serum HBV DNA is detected 3
• Prophylactic antiviral therapy should be given at least 1-2 weeks before and continued during and after chemotherapy, locoregional therapies, resection, or liver transplantation 3

Immunosuppression or Chemotherapy

• All HBsAg-positive patients should receive entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide as prophylaxis before starting immunosuppressive therapy 3

Common Pitfalls to Avoid

• Do not use entecavir in any patient with prior lamivudine exposure, even if currently HBV DNA undetectable—archived resistance mutations will emerge 3, 2, 8
• Do not use tenofovir disoproxil fumarate in elderly patients (>60 years) or those with renal/bone disease without considering tenofovir alafenamide or entecavir first 3, 2
• Do not stop treatment in HBeAg-positive patients who achieve undetectable HBV DNA but remain HBeAg-positive—they require continued long-term therapy 3, 9
• Do not use peginterferon in patients with decompensated cirrhosis, active psychiatric disease, or autoimmune conditions 1, 10
• Ensure medication is taken on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal) for entecavir to optimize absorption 7