What is the standard approach to managing and treating hepatitis B infection, including indications for antiviral therapy and first‑line agents for acute, chronic, and special populations such as pregnant women and patients with renal insufficiency?

Treatment of Hepatitis B

For chronic hepatitis B, first-line treatment is entecavir 0.5 mg daily or tenofovir disoproxil fumarate 300 mg daily, both offering potent viral suppression with minimal resistance risk. 1, 2

Treatment Indications

HBeAg-Positive Chronic Hepatitis B

• Treat when HBV DNA ≥20,000 IU/mL AND ALT ≥2× upper limit of normal (ULN), or when liver biopsy shows significant inflammation/fibrosis (≥A2 or ≥F2). 3
• For patients with ALT 1-2× ULN, obtain liver biopsy or non-invasive fibrosis assessment; treat if significant disease is present. 3
• Patients >30 years old with normal ALT but HBV DNA >1,000 IU/mL should undergo biopsy—treat if significant necroinflammation or fibrosis is found. 3

HBeAg-Negative Chronic Hepatitis B

• Treat when HBV DNA ≥2,000 IU/mL AND ALT >ULN, or with evidence of significant histological disease. 3
• For persistent ALT >ULN but <2× ULN with HBV DNA >2,000 IU/mL, treatment is strongly recommended. 3
• Consider biopsy for ALT 1-2× ULN if non-invasive tests suggest fibrosis. 3

Cirrhosis (Highest Priority)

• All patients with compensated or decompensated cirrhosis and ANY detectable HBV DNA must be treated immediately, regardless of ALT levels or HBeAg status. 3, 2
• Even patients with HBV DNA <2,000 IU/mL should receive antiviral therapy if cirrhosis is present. 3
• For decompensated cirrhosis with jaundice (elevated bilirubin), initiate entecavir or tenofovir immediately without delay. 2

First-Line Antiviral Agents

Nucleos(t)ide Analogues (Preferred for Most Patients)

• Entecavir 0.5 mg daily: Achieves 67% HBV DNA <60-80 IU/mL at 48 weeks in HBeAg-positive patients, with only 1.2% resistance after 5 years in treatment-naïve patients. 3, 1
• Tenofovir disoproxil fumarate (TDF) 300 mg daily: Achieves 76% HBV DNA <60-80 IU/mL at 48 weeks in HBeAg-positive patients, with 0% resistance reported after 5-8 years. 3, 1
• Tenofovir alafenamide (TAF): Alternative to TDF with improved bone and renal safety profile. 3, 1

Critical caveat: Never use entecavir in patients with any prior lamivudine exposure, even if brief, due to archived resistance mutations. 2

Peginterferon Alfa-2a (Selected Patients Only)

• Dose: 180 μg subcutaneously once weekly for 48 weeks. 3
• Achieves 32% HBeAg seroconversion and 3% HBsAg loss at 6 months post-treatment in HBeAg-positive patients. 3
• Consider for young patients with mild-moderate disease, high ALT (>2× ULN), low HBV DNA, genotype A or B, and desire for finite treatment duration. 3, 1
• Absolutely contraindicated in decompensated cirrhosis or liver failure—risk of fatal hepatic decompensation. 3, 2

Agents to Avoid as First-Line

• Lamivudine: High resistance rate (70% at 5 years)—not recommended except in pregnancy or short-term use. 3
• Adefovir: Weak antiviral potency and high resistance—not preferred. 3
• Telbivudine: Moderate resistance rates (25% at 2 years)—not preferred. 3

Special Populations

Pregnancy

• For mothers with HBV DNA >200,000 IU/mL at 28-32 weeks gestation, initiate TDF at week 24-28 to prevent mother-to-child transmission. 3
• TDF is preferred over lamivudine or telbivudine due to superior resistance profile. 3, 1
• Continue treatment through delivery; may discontinue postpartum if mother does not otherwise meet treatment criteria. 3

Renal Insufficiency

• Dose adjustment required for TDF and entecavir based on creatinine clearance. 4
• For creatinine clearance 30-49 mL/min: TDF 300 mg every 48 hours; entecavir 0.5 mg every 48 hours. 4
• For creatinine clearance 10-29 mL/min: TDF 300 mg every 72-96 hours; entecavir 0.5 mg every 72 hours. 4
• TAF or entecavir preferred over TDF in patients with baseline renal disease or bone disease. 1
• Monitor renal function (creatinine, phosphate) every 3 months in patients on TDF. 3, 1

HIV/HBV Coinfection

• Use TDF or TAF combined with emtricitabine or lamivudine as part of antiretroviral therapy (ART) regimen. 3
• Never use HBV monotherapy in HIV-coinfected patients—risk of HIV resistance. 3
• Lamivudine dose for HIV coinfection: 150 mg twice daily (not 100 mg daily). 3

HCV/HBV Coinfection

• Treat HBV using same criteria as mono-infected patients. 3
• Monitor HBV DNA during and after HCV treatment—risk of HBV reactivation with HCV clearance. 3

HDV/HBV Coinfection

• If HBV DNA is elevated, use entecavir, TDF, or TAF. 3
• Consider peginterferon alfa for 12-18 months if HDV is dominant virus. 3

Immunosuppression/Chemotherapy

• All HBsAg-positive patients receiving chemotherapy or immunosuppressive therapy (including rituximab, anti-TNF agents) require prophylactic antiviral therapy with entecavir or TDF, regardless of HBV DNA level. 3
• For HBsAg-negative, anti-HBc-positive patients: monitor HBV DNA monthly; initiate treatment if detectable. 3

Treatment Duration and Monitoring

Duration

• HBeAg-positive patients: Minimum 1 year; continue at least 6-12 months after HBeAg seroconversion is confirmed on two occasions 2 months apart. 3
• HBeAg-negative patients: Indefinite treatment typically required; optimal endpoint is HBsAg loss. 3, 1
• Cirrhosis patients: Lifelong therapy recommended; discontinuation only if HBsAg loss occurs and is sustained for 6-12 months. 3, 2

Monitoring During Treatment

• Months 0-6: Check ALT, HBV DNA, HBeAg/anti-HBe every 1-3 months. 3
• After month 6: Check ALT and HBV DNA every 3-6 months; HBeAg/anti-HBe every 6 months. 3
• Renal monitoring: Creatinine and phosphate every 3 months if on TDF or adefovir. 3, 1
• Virological breakthrough: Confirmed HBV DNA increase >1 log₁₀ IU/mL from nadir indicates resistance or non-adherence—switch to alternative agent immediately. 3

Patients NOT Requiring Treatment (Monitor Only)

Immune Tolerant Phase

• HBeAg-positive, HBV DNA >1,000 IU/mL, ALT <ULN, age <30 years, no fibrosis on biopsy. 3
• Monitor ALT every 3-6 months, HBV DNA every 6-12 months. 3
• Exception: Consider treatment if age >30-40 years or family history of HCC/cirrhosis, even with normal ALT. 3

Inactive Carrier Phase

• HBeAg-negative, anti-HBe-positive, HBV DNA <2,000 IU/mL, persistently normal ALT for ≥1 year. 3
• Confirm with ALT every 3 months for first year, then every 6-12 months lifelong. 3

Treatment Goals

Short-Term Goals

• HBV DNA suppression to undetectable levels (<20 IU/mL). 1
• ALT normalization. 1
• HBeAg seroconversion (in HBeAg-positive patients). 1

Long-Term Goals

• Prevention of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. 1, 2
• Optimal endpoint: HBsAg loss (functional cure), achieved in 3-7% with peginterferon and 1-2% with long-term nucleos(t)ide analogue therapy. 3, 1

Hepatocellular Carcinoma Surveillance

• All cirrhotic patients require ultrasound every 6 months, regardless of treatment status. 3
• Also screen: Asian men >40 years, Asian women >50 years, Africans >20 years, family history of HCC, or any patient >40 years with elevated ALT/HBV DNA >2,000 IU/mL. 3

Acute Hepatitis B

• No evidence that antiviral treatment is effective for acute hepatitis B—supportive care only. 5
• Exception: Severe acute hepatitis with total bilirubin >3 mg/dL, prolonged PT/INR, or signs of liver failure—initiate entecavir or TDF immediately. 2

Critical Warning

Severe acute exacerbation of hepatitis B can occur upon discontinuation of antiviral therapy, potentially leading to hepatic decompensation and death. Monitor ALT, bilirubin, and HBV DNA every 1-3 months for at least 6 months after stopping treatment. 4