What is the treatment approach for a patient who is Hepatitis B surface antigen (HbsAg) positive?

Management of HBsAg-Positive Patients

All HBsAg-positive patients require immediate comprehensive evaluation to determine disease phase and treatment eligibility, with first-line antiviral therapy using entecavir or tenofovir for those meeting treatment criteria. 1

Initial Diagnostic Workup

When HBsAg is positive, immediately obtain the following tests to classify disease phase and determine treatment need:

• HBV DNA quantification by PCR to assess viral replication level 2
• ALT and AST levels to evaluate hepatic inflammation 1, 2
• HBeAg and anti-HBe status to classify disease phase 1
• Assessment of liver fibrosis via biopsy or transient elastography 1
• Complete blood count, bilirubin, albumin, prothrombin time to assess liver function 3
• Abdominal ultrasound to evaluate for cirrhosis and exclude focal liver lesions 3
• Screen for coinfections: anti-HCV, anti-HDV (if injection drug use history), anti-HIV 2

Treatment Indications

Immediate Treatment Required (Regardless of ALT or HBV DNA)

• Decompensated cirrhosis with any detectable HBV DNA 1
• Compensated cirrhosis with any detectable HBV DNA 1
• Acute liver failure or severe acute hepatitis B (coagulopathy, bilirubin >3 mg/dL, INR >1.5, encephalopathy, or ascites) 1
• HBV-related hepatocellular carcinoma with detectable HBV DNA 1
• Patients requiring immunosuppressive therapy or chemotherapy with detectable HBV DNA or positive HBsAg 1

Treatment for Chronic Hepatitis B (Non-Cirrhotic)

HBeAg-Positive Patients:

• HBV DNA ≥2,000 IU/mL AND elevated ALT (>30 IU/L for men, >19 IU/L for women) 1
• If ALT is normal but HBV DNA ≥2,000 IU/mL, perform liver biopsy or transient elastography; treat if significant fibrosis (≥F2) is present 1

HBeAg-Negative Patients:

• HBV DNA ≥2,000 IU/mL AND elevated ALT 1, 2
• If ALT is normal but HBV DNA ≥2,000 IU/mL, assess liver histology and treat if significant disease is detected 1

Special Consideration for Early Treatment:

• Patients >30 years of age with HBeAg-positive chronic infection should be considered for treatment even with normal ALT, as HBV integration and hepatocarcinogenesis mechanisms are present during this phase 1, 4, 5

Do NOT Treat

• Immune-tolerant phase patients (HBeAg-positive, persistently normal ALT, no significant fibrosis) under age 30 generally do not require immediate treatment 1

First-Line Treatment Options

The preferred first-line treatments are entecavir, tenofovir (TDF), or tenofovir alafenamide (TAF) due to high potency, high barrier to resistance, and favorable safety profiles. 1

Oral Antiviral Therapy (Primary Recommendation)

Entecavir:

• Dose: 0.5 mg daily for treatment-naïve patients; 1 mg daily for lamivudine-refractory patients 6
• Achieves >90% virologic suppression after 3 years in treatment-adherent patients 1
• Resistance rate <1.2% at 5 years in treatment-naïve patients 6
• Preferred for: patients with renal dysfunction, bone disease, or age >60 years 1

Tenofovir (TDF or TAF):

• Dose: TDF 300 mg daily or TAF (dose varies by formulation) 7
• Achieves >90% virologic suppression after 3 years 1
• High barrier to resistance 1
• TDF is the drug of choice for pregnant women requiring treatment 1
• TAF or entecavir preferred over TDF for patients with renal alterations, bone disease, or age >60 years 1

Avoid lamivudine due to high resistance rates (up to 70% at 5 years) 2, 8

Peginterferon Alfa-2a (Alternative Option)

• Finite treatment option: 1 year of therapy 1
• Higher rates of HBeAg seroconversion and HBsAg loss compared to oral antivirals 1
• Administered via subcutaneous injection with more adverse effects 1
• Contraindicated in decompensated cirrhosis 1

Treatment Monitoring

During First Year:

• HBV DNA every 3 months until undetectable, then every 6 months 9, 2
• ALT/AST every 3-6 months 9, 2
• If on TDF: monitor renal function (creatinine clearance) at least every 3 months 1
• If on TDF: monitor bone density in high-risk patients 1

Long-Term:

• HBV DNA every 6 months once undetectable 9, 2
• Annual quantitative HBsAg testing to assess for potential HBsAg loss 9, 2
• Liver enzymes every 3-6 months 9, 2

Duration of Therapy

Lifelong therapy recommended for:

• All patients with decompensated cirrhosis at treatment initiation 1
• Majority of patients with significant fibrosis (F3) or compensated cirrhosis (F4) at baseline 1

May consider discontinuation only if:

• HBsAg loss sustained for 6-12 months or longer, OR HBsAg seroconversion occurs 1
• However, lifelong HCC surveillance still required even after HBsAg loss in patients with prior cirrhosis 1

For HBeAg-positive patients without cirrhosis:

• Long-term therapy is justified even after HBeAg seroconversion due to high risk of recurrent viremia if stopped 1

Special Populations

Pregnant Women

• Continue or switch to TDF if treatment is needed 1
• For pregnant women with HBV DNA >200,000 IU/mL (or HBsAg >4 log₁₀ IU/mL), initiate TDF prophylaxis at 24-32 weeks gestation to prevent mother-to-child transmission 1
• Continue TDF for up to 12 weeks postpartum 1
• Breastfeeding is not contraindicated on TDF 1

Immunosuppression/Chemotherapy

• Initiate prophylactic antiviral therapy (entecavir or tenofovir) before starting immunosuppression if HBsAg-positive 1, 2
• Continue prophylaxis throughout treatment and for 6-12 months after completion 1, 2

Renal Dysfunction

• Entecavir or TAF are first-line options for patients with renal impairment 1
• If using TDF, adjust dosing interval based on creatinine clearance 7

Liver Transplant Recipients

• HBsAg-positive patients undergoing transplantation should receive high-potency NAs (entecavir or tenofovir) with or without HBIG 1

Hepatocellular Carcinoma Surveillance

Ultrasound every 6 months for high-risk patients: 2

• Asian men >40 years
• Asian women >50 years
• Any patient with cirrhosis
• Family history of HCC
• Age >40 years with persistent ALT elevation

Continue HCC surveillance lifelong, even after HBsAg loss in patients with prior cirrhosis 1

Additional Preventive Measures

• Hepatitis A vaccination if anti-HAV negative (coinfection increases mortality 5.6- to 29-fold) 2
• Counsel on complete alcohol abstinence as even limited consumption worsens outcomes 2
• Educate on preventing transmission to household and sexual contacts 3

Management of Treatment Failure

Virologic breakthrough (≥1 log₁₀ increase in HBV DNA above nadir):

• First assess medication adherence, as nonadherence is the most common cause 1
• If confirmed resistance: add tenofovir to entecavir, OR switch to tenofovir/emtricitabine combination 1
• For lamivudine resistance specifically: tenofovir monotherapy is sufficient 1