When can antiviral treatment be stopped in a patient with hepatitis B (HBV) infection and normalized liver function tests, who has achieved a sustained virological response with undetectable HBV DNA level?

When to Stop Antiviral Treatment for Hepatitis B Infection

The safest and most definitive endpoint for stopping nucleos(t)ide analogue (NA) therapy in chronic hepatitis B is confirmed HBsAg loss, regardless of HBeAg status or cirrhosis presence. 1, 2, 3

Primary Stopping Criteria

HBsAg Loss (Functional Cure) - The Gold Standard

• Discontinue NA therapy after confirmed HBsAg loss, defined as two negative HBsAg tests at least 6 months apart. 1, 2
• This represents the optimal treatment endpoint with significantly lower risk of HCC development and rare virological relapse. 1
• Continue treatment for at least 12 months after confirmed HBsAg loss in non-cirrhotic patients before discontinuation. 2
• Even after HBsAg loss, cirrhotic patients should continue indefinite therapy due to persistent HCC risk and potential for severe hepatitis flares. 2, 3

Conditional Stopping Criteria (Higher Relapse Risk)

HBeAg-Positive Patients

• Discontinuation may be considered in non-cirrhotic patients who achieve HBeAg seroconversion with undetectable HBV DNA on three separate occasions 6 months apart, followed by at least 12 months of consolidation therapy. 1, 3
• However, relapse rates remain high (41-74% at 3 years) even with 12 months consolidation. 4, 5
• Extending consolidation therapy to ≥3 years significantly reduces persistent virological relapse rates (from 54% to 25% at 1 year). 4
• Younger patients (≤40 years) with consolidation treatment ≥15 months show better durability. 5

HBeAg-Negative Patients

• EASL and AASLD recommend continuing treatment indefinitely until HBsAg loss in HBeAg-negative patients. 1
• APASL allows consideration of discontinuation after ≥2 years of treatment with undetectable HBV DNA documented on three separate measurements 6 months apart, though this is primarily cost-driven. 1
• Virological relapse occurs in 70-75% of HBeAg-negative patients at 3 years after stopping therapy. 4, 6
• Low quantitative HBsAg levels (<2 log IU/mL or <100 IU/mL) may identify patients more likely to achieve sustained response, though optimal cutoffs remain unclear. 1, 7

Absolute Contraindications to Stopping Treatment

Cirrhotic Patients

• Never discontinue NA therapy in patients with cirrhosis (compensated or decompensated) unless HBsAg loss is achieved. 1, 3
• Lifelong treatment is mandatory for decompensated cirrhosis due to risk of fatal hepatic decompensation. 3
• Cirrhosis is associated with lower virological relapse rates (22.2% vs 86.1% in non-cirrhotic), but the consequences of relapse are catastrophic. 6

Older Patients

• Continue treatment indefinitely in patients >60 years old unless HBsAg loss occurs. 1

Mandatory Post-Discontinuation Monitoring Protocol

Close monitoring is critical as relapse can lead to acute hepatitis flare, decompensation, or fulminant hepatitis. 1

First Year After Stopping

• Measure HBV DNA and liver function tests every 1-3 months. 1, 3, 8
• Check HBeAg/anti-HBe every 3-6 months. 1, 3
• Monitor ALT monthly for first 3 months, then every 3 months. 2

Beyond First Year

• Continue HBV DNA and liver function tests every 3-6 months. 1, 3, 8
• Check HBsAg/anti-HBs every 6-12 months to monitor for HBsAg loss or reversion. 1, 2
• Maintain HCC surveillance every 6 months indefinitely, even after HBsAg loss. 1, 2

Critical Pitfalls to Avoid

• Do not stop therapy based solely on undetectable HBV DNA without meeting other criteria - most patients will relapse. 1, 7
• Do not use HBeAg seroconversion alone as an endpoint without adequate consolidation therapy - this is an imperfect endpoint with high relapse rates. 1, 5
• Never discontinue in cirrhotic patients without HBsAg loss - life-threatening decompensation can occur. 3
• Do not assume HBsAg loss is permanent - HBsAg reversion can occur, requiring continued monitoring. 1

Emerging Biomarkers for Decision-Making

• Quantitative HBsAg levels may help predict sustained response or relapse before stopping therapy. 1, 7
• HBcrAg and HBV RNA testing can be performed when considering cessation, though specific thresholds are not yet standardized. 1
• Baseline HBV DNA <2000 IU/mL before stopping is associated with 72% sustained response vs 23.5% for higher levels. 9

Special Populations

Patients on Immunosuppressive Therapy

• Continue antiviral prophylaxis for at least 12 months after cessation of immunosuppressive therapy (24 months for rituximab), regardless of HBsAg status. 2

Patients Unable to Afford Long-Term Treatment

• If discontinuation is unavoidable after ≥5 years of treatment with undetectable HBV DNA for past 3 years, most patients maintain low HBV DNA and normal ALT levels despite virological relapse. 1
• However, this approach requires intensive monitoring and willingness to promptly restart treatment. 1