What is the treatment approach for hepatitis B infection?

Treatment Approach for Hepatitis B Infection

For chronic hepatitis B infection, first-line treatment consists of entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) as nucleos(t)ide analogue monotherapy, with treatment decisions based on HBV DNA levels ≥2,000 IU/mL, elevated ALT, presence of cirrhosis, or significant fibrosis. 1, 2

Initial Diagnostic Evaluation

Before initiating treatment, all patients require comprehensive assessment:

• Measure HBsAg, HBeAg/anti-HBe, and quantitative HBV DNA by PCR to determine infection status and viral replication activity 1
• Assess liver enzymes (ALT/AST), complete blood count, and liver function panel (bilirubin, albumin, prothrombin time) to evaluate disease activity and severity 1, 3
• Screen for coinfections: anti-HCV, anti-HDV (if injection drug use history), anti-HIV, and anti-HAV (vaccinate if negative) 1, 2
• Perform baseline alpha-fetoprotein (AFP) and liver ultrasound to assess for hepatocellular carcinoma, particularly in high-risk patients 1, 2
• Consider liver biopsy or non-invasive fibrosis assessment (transient elastography) when treatment indication is uncertain or to assess disease severity 1

Treatment Indications

Immediate Treatment Required

All patients with cirrhosis and any detectable HBV DNA must be treated immediately, regardless of ALT levels. 1, 2

Patients with decompensated cirrhosis require urgent nucleos(t)ide analogue therapy (entecavir or tenofovir) and simultaneous liver transplantation evaluation. 1, 2

Standard Treatment Criteria

Initiate antiviral therapy in the following scenarios:

• HBV DNA ≥2,000 IU/mL AND elevated ALT (>ULN for men 30 IU/L, women 19 IU/L) 1, 2
• HBV DNA ≥20,000 IU/mL AND ALT >2× ULN (can treat without liver biopsy) 2
• HBV DNA ≥2,000 IU/mL with significant fibrosis demonstrated by biopsy or liver stiffness ≥9 kPa (normal ALT) or ≥12 kPa (ALT <5× ULN) 1, 2
• HBeAg-positive patients over age 30 with persistently normal ALT and high HBV DNA may be treated regardless of histology 2

Special Populations Requiring Prophylaxis

All HBsAg-positive patients undergoing chemotherapy or immunosuppressive therapy must receive entecavir, TDF, or TAF as prophylaxis. 1

• Continue prophylaxis for at least 12 months (18 months for rituximab-based regimens) after cessation of immunosuppression 1
• HBsAg-negative, anti-HBc positive patients at high risk (>10%) for reactivation (rituximab therapy, stem cell transplantation) also require prophylaxis 1

Pregnant women with HBV DNA >200,000 IU/mL should receive tenofovir DF prophylaxis beginning at 24-32 weeks gestation to prevent mother-to-child transmission 2

First-Line Treatment Options

Nucleos(t)ide Analogues (Preferred)

Entecavir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) are the preferred first-line agents due to high genetic barrier to resistance. 1

Dosing:

• Nucleoside-naïve patients: Entecavir 0.5 mg daily OR tenofovir (TDF or TAF) 1, 4
• Lamivudine-resistant patients: Entecavir 1 mg daily OR tenofovir 1, 4
• Decompensated cirrhosis: Entecavir 1 mg daily OR tenofovir 1, 4

Critical pitfall: Avoid lamivudine, emtricitabine, and telbivudine monotherapy due to high resistance rates (lamivudine resistance up to 70% at 5 years) 1, 2

Peginterferon Alfa-2a (Alternative)

Peginterferon alfa-2a for 48 weeks can be considered in selected non-cirrhotic patients who desire finite-duration therapy and have compensated disease 1, 2

• Contraindicated in decompensated cirrhosis 1
• Higher rates of HBeAg seroconversion and HBsAg loss compared to nucleos(t)ide analogues, but more side effects and parenteral administration 1
• Consider early discontinuation if inadequate virological response or intolerable side effects 1

Monitoring During Treatment

Virological and Biochemical Monitoring

• HBV DNA every 3 months until undetectable, then every 6 months 1, 2
• ALT/AST every 3-6 months 2
• Annual quantitative HBsAg testing to assess for potential HBsAg loss 2
• Renal function monitoring if on tenofovir (baseline and every 6 months: creatinine, spot urine protein/creatinine ratio) 1, 2

Hepatocellular Carcinoma Surveillance

Ultrasound examination every 6 months is mandatory for high-risk patients:

• Asian men >40 years, Asian women >50 years 1, 2
• Any patient with cirrhosis 1, 2
• Family history of HCC 1
• Age >40 years with persistent ALT elevation and/or high HBV DNA 1

Treatment Duration and Endpoints

Long-term, potentially indefinite treatment is typically required with nucleos(t)ide analogues. 1, 2

Optimal Treatment Endpoint

HBsAg loss (functional cure) is the optimal endpoint but is rarely achieved with current therapies. 1, 2

Potential Stopping Criteria (Selected Cases Only)

In HBeAg-positive patients who achieve HBeAg seroconversion with undetectable HBV DNA, stopping therapy may be considered after at least 12 months of consolidation therapy. 2

• Continue monitoring HBV DNA and liver function tests every 3-6 months for at least 12 months after treatment discontinuation due to high relapse risk 1
• HBeAg-negative patients have 80-90% relapse rates if treatment stopped within 1-2 years, making indefinite therapy necessary for most 1

Special Considerations

HIV/HBV Coinfection

All HIV-HBV coinfected patients should receive antiretroviral therapy including tenofovir (TDF or TAF) plus emtricitabine or lamivudine, regardless of CD4 count. 1, 2

• Never use entecavir alone in HIV/HBV coinfection without concurrent HAART due to risk of HIV resistance 1, 4

Renal Impairment

Dose adjustment required for entecavir when creatinine clearance <50 mL/min:

• CrCl 30-49: 0.5 mg every 48 hours (or 0.5 mg daily for lamivudine-refractory) 4
• CrCl 10-29: 0.5 mg every 72 hours (or 1 mg every 72 hours for lamivudine-refractory) 4
• CrCl <10 or hemodialysis: 0.5 mg every 7 days (or 1 mg every 7 days for lamivudine-refractory) 4

Acute Severe Hepatitis B

Nucleos(t)ide analogue therapy (entecavir or tenofovir) is recommended for patients with severe acute hepatitis B (coagulopathy, severe jaundice, or liver failure), with concurrent liver transplantation evaluation 1, 2