What is the management for a patient with hepatitis B who was initially hepatitis B surface antigen (HBsAg) reactive and now shows a non-reactive result after a few months of antiviral treatment with medications such as entecavir (entecavir) or tenofovir (tenofovir)?

Management of Non-Reactive HBsAg After Initial Reactivity

If a patient's repeat HBsAg becomes non-reactive after a few months of antiviral treatment with entecavir or tenofovir, this represents HBsAg loss (functional cure), which is the optimal treatment endpoint—you should confirm this result, continue antiviral therapy for at least 12 months after confirmed HBsAg loss in non-cirrhotic patients, then consider discontinuation with close monitoring. 1, 2

Immediate Confirmation Steps

• Confirm HBsAg loss by repeating the test within 1-3 months to ensure this is not a laboratory error or transient fluctuation 1
• Measure HBV DNA levels to verify virologic suppression (should be undetectable) 2, 3
• Check anti-HBs (hepatitis B surface antibody) to determine if the patient has developed protective immunity 4
• Verify liver enzymes (ALT/AST) remain normal 1

Treatment Duration After HBsAg Loss

For Non-Cirrhotic Patients

• Continue antiviral therapy for at least 12 months after confirmed HBsAg loss before considering discontinuation 1, 2
• This consolidation period reduces the risk of virologic relapse, though HBsAg loss itself represents the best predictor of sustained remission 5, 6

For Cirrhotic Patients

• Continue indefinite antiviral therapy even after HBsAg loss due to the persistent risk of hepatocellular carcinoma and potential for severe hepatitis flares 1, 2

Post-Discontinuation Monitoring Protocol

After stopping antiviral therapy following the consolidation period:

• Monitor ALT levels monthly for the first 3 months, then every 3 months thereafter to detect hepatitis flares early 1
• Check HBsAg and HBV DNA every 3 months for the first year, then every 6 months indefinitely 1
• Immediate retreatment is indicated if HBsAg becomes positive again or HBV DNA exceeds 2,000 IU/mL with elevated ALT 2, 4

Critical Considerations Based on Patient Context

If Patient Was on Chemotherapy/Immunosuppression

• Continue antiviral prophylaxis for at least 12 months after cessation of immunosuppressive therapy (24 months for rituximab), regardless of HBsAg status 1
• HBV reactivation can occur even after HBsAg loss in immunosuppressed patients 1, 3

Predictors of Sustained Response

The likelihood of maintaining HBsAg loss after discontinuation is higher when:

• End-of-treatment HBsAg level was <40 IU/mL before it became non-reactive (5-year virologic relapse rate of only 17.3% vs 67.6% for levels ≥40 IU/mL) 5
• Baseline HBV DNA was <50,000 IU/mL before starting treatment 5, 7
• Patient received tenofovir rather than entecavir (7-year HBsAg loss maintenance rate of 35.4% vs 22.6%) 6
• Treatment duration exceeded 5 years before HBsAg loss occurred 5, 6

Hepatocellular Carcinoma Surveillance

• Continue ultrasound screening every 6 months indefinitely for high-risk patients (Asian men >40 years, Asian women >50 years, any patient with cirrhosis, family history of HCC) even after HBsAg loss 2, 3, 4
• The risk of HCC persists despite functional cure, particularly in those with prior cirrhosis or advanced fibrosis 2

Common Pitfalls to Avoid

• Do not stop antiviral therapy immediately upon first non-reactive HBsAg result—confirm the result and complete the consolidation period 1, 2
• Do not assume permanent cure—approximately 25-30% of patients may experience HBsAg seroreversion after discontinuation, particularly if end-of-treatment HBsAg was detectable but low 5, 8
• Do not discontinue HCC surveillance—the cancer risk remains elevated even after functional cure 2, 3
• Do not miss hepatitis flares after discontinuation—these can be severe and require immediate retreatment; monthly ALT monitoring in the first 3 months is essential 1

Coordination of Care

• Refer to or coordinate with a hepatologist experienced in HBV management to determine the optimal timing of treatment discontinuation and long-term monitoring strategy 1
• This is particularly important for patients with cirrhosis, prior decompensation, or those who required immunosuppressive therapy 1, 2