What are the indications for initiating antiviral therapy in chronic hepatitis B and what are the recommended first‑line treatment options?

Hepatitis B Treatment: Indications and First-Line Options

Initiate antiviral therapy immediately in patients with HBV DNA ≥2,000 IU/mL and ALT >2× ULN, or in any patient with cirrhosis and detectable HBV DNA, using entecavir or tenofovir as first-line agents. 1

Treatment Indications by Disease Phase

Immune Active Chronic Hepatitis B (Non-Cirrhotic)

HBeAg-Positive Patients:

• Treat immediately if HBV DNA ≥20,000 IU/mL AND ALT ≥2× ULN 1
• Consider liver biopsy if HBV DNA ≥20,000 IU/mL but ALT is only 1–2× ULN; treat if moderate-to-severe necroinflammation (≥A2) or significant fibrosis (≥F2) is present 1
• Consider treatment in patients >30–40 years old with normal ALT but HBV DNA >1,000 IU/mL if liver biopsy shows significant disease 1

HBeAg-Negative Patients:

• Treat immediately if HBV DNA ≥2,000 IU/mL AND ALT ≥2× ULN 1
• Perform fibrosis assessment if HBV DNA ≥2,000 IU/mL but ALT is 1–2× ULN; treat if liver stiffness ≥9 kPa (with normal ALT) or ≥12 kPa (with ALT <5× ULN), or if biopsy shows ≥A2 or ≥F2 1, 2
• The EASL guideline recommends treating all patients with HBV DNA >2,000 IU/mL and ALT >ULN (40 IU/L), representing a more aggressive threshold than AASLD or KASL 1

Cirrhosis (Compensated or Decompensated)

Compensated Cirrhosis:

• Treat all patients with HBV DNA ≥2,000 IU/mL, regardless of ALT level 1
• Some guidelines recommend treatment with any detectable HBV DNA in cirrhotic patients 1

Decompensated Cirrhosis:

• Treat immediately if HBV DNA is detectable at any level 1
• Refer urgently for liver transplantation evaluation while initiating antiviral therapy 1, 2
• Never use pegylated interferon in decompensated cirrhosis due to risk of hepatic decompensation 1

Immune Tolerant Phase

• Monitor without treatment in patients with very high HBV DNA (≥10^7 IU/mL) and persistently normal ALT (male <34–35 IU/mL, female <25–30 IU/mL) if age <30 years 1
• Consider liver biopsy to determine treatment need if age ≥30–40 years, HBV DNA <10^7 IU/mL, noninvasive tests suggest significant fibrosis, or family history of HCC/cirrhosis 1
• This remains the most controversial area, with recent data suggesting potential benefit of early treatment, though guidelines remain conservative 1

Immune Inactive Carriers

• Monitor without treatment in HBeAg-negative patients with HBV DNA <2,000 IU/mL and normal ALT 1
• Consider treatment even without typical indications if family history of HCC or cirrhosis, or extrahepatic manifestations present 1

First-Line Treatment Options

Preferred Nucleos(t)ide Analogues (High Genetic Barrier to Resistance)

Entecavir:

• Dose: 0.5 mg once daily in treatment-naïve patients 2, 3, 4
• FDA-approved for chronic HBV with active viral replication and elevated ALT or histologically active disease 3
• Preferred due to potent antiviral activity and high barrier to resistance 1, 2, 4

Tenofovir Disoproxil Fumarate (TDF):

• Dose: 300 mg once daily 1, 2, 4
• Equivalent efficacy to entecavir with high barrier to resistance 1, 4
• Monitor renal function during treatment due to potential nephrotoxicity 2, 5

Tenofovir Alafenamide (TAF):

• Dose: 25 mg once daily with food 1, 5
• FDA-approved for adults and pediatric patients ≥6 years weighing ≥25 kg with compensated liver disease 5
• Improved renal and bone safety profile compared to TDF 5, 4
• Not recommended in decompensated cirrhosis (Child-Pugh B or C) 5

Alternative Agent (Finite Duration)

Pegylated Interferon Alfa:

• Dose: 180 mcg subcutaneously weekly for 48 weeks 1, 2
• Consider in selected patients desiring finite-duration therapy with mild-to-moderate disease 2
• Contraindicated in decompensated cirrhosis, pregnancy, severe psychiatric disease 1
• Higher rates of HBeAg seroconversion but poor tolerability limit use 4

Agents to Avoid as First-Line

Lamivudine and Adefovir:

• Not recommended as first-line due to high resistance rates (lamivudine: up to 70% at 5 years; adefovir: lower potency) 1, 2, 4
• Reserve for situations where preferred agents unavailable 1

Treatment Monitoring Protocol

During Therapy:

• HBV DNA every 3 months until undetectable, then every 6 months 1, 2
• ALT/AST every 3–6 months 1, 2
• Annual quantitative HBsAg to assess for functional cure (HBsAg loss) 2
• Renal function monitoring if on tenofovir (creatinine, estimated GFR, urine protein) 2, 5
• Serum phosphorus in patients with chronic kidney disease on tenofovir 5

Hepatocellular Carcinoma Surveillance:

• Ultrasound every 6 months in high-risk patients: Asian men >40 years, Asian women >50 years, any cirrhosis, family history of HCC, age >40 with persistent ALT elevation 2, 6
• Continue surveillance even after HBsAg loss if cirrhosis or significant fibrosis was present 6

Special Populations Requiring Treatment

Pregnancy:

• Tenofovir DF starting at 24–32 weeks if HBV DNA >200,000 IU/mL to prevent mother-to-child transmission 1, 2

Immunosuppression/Chemotherapy:

• Start prophylactic nucleos(t)ide analogue 2–4 weeks before high-risk immunosuppression (rituximab, anthracyclines, high-dose steroids) in HBsAg-positive patients 2, 6
• Continue through treatment and 12–24 months after completion 2, 6

HIV/HBV Coinfection:

• Use tenofovir-based antiretroviral therapy (TDF or TAF with emtricitabine or lamivudine) regardless of CD4 count 1, 2, 6
• Never use entecavir or tenofovir monotherapy due to risk of HIV resistance 1, 5

Critical Pitfalls to Avoid

• Do not use tenofovir alafenamide alone in HIV/HBV coinfection—it will cause HIV resistance 5
• Do not stop nucleos(t)ide analogues abruptly—severe hepatitis flares occur in 20–50% of cases 2, 6, 5
• Do not delay treatment in decompensated cirrhosis—immediate antiviral therapy is life-saving 1
• Do not use pegylated interferon in cirrhosis—risk of fatal hepatic decompensation 1
• Do not overlook renal monitoring with tenofovir—assess creatinine clearance before and during treatment 5

Treatment Duration and Endpoints

• Optimal endpoint: HBsAg loss (functional cure), achieved in only 1–12% with nucleos(t)ide analogues and 3–7% with pegylated interferon 1, 2, 4
• Most patients require indefinite therapy with nucleos(t)ide analogues 2, 4
• Consider stopping only after HBsAg loss maintained for 12 months, with close monitoring for at least several months after discontinuation 1, 2, 5