When can nucleos(t)ide analogue therapy be safely stopped in chronic hepatitis B patients (both HBeAg‑positive and HBeAg‑negative) without advanced liver disease?

When to Stop Nucleos(t)ide Analogue Therapy in Chronic Hepatitis B

For HBeAg-positive patients without cirrhosis, nucleos(t)ide analogue therapy can be stopped after achieving HBeAg seroconversion (loss of HBeAg and gain of anti-HBe) with undetectable HBV DNA, followed by at least 12 months of consolidation therapy, though relapse rates remain substantial at 50-70%. 1, 2, 3

HBeAg-Positive Chronic Hepatitis B

Stopping Criteria:

• Nucleos(t)ide analogues should be continued for at least 12 months after achieving both HBeAg seroconversion AND undetectable serum HBV DNA by real-time PCR 1
• Viral suppression can be sustained in 50-90% of patients when treatment is stopped after HBeAg seroconversion is achieved 1
• Extending consolidation therapy beyond 3 years significantly reduces persistent virological relapse rates (25% vs 54% at 1 year for <1 year consolidation), making longer consolidation preferable when feasible 2

Important Caveats:

• Even with adequate consolidation, approximately 49-74% of patients will develop virological relapse (HBV DNA >2000 IU/mL) within 3 years after stopping therapy 2, 3
• Approximately 33% of patients who stop therapy will require retreatment based on virological or biochemical relapse 3
• ALT flares >10× upper limit of normal occur in 31% of patients after stopping, though hepatic decompensation is rare in non-cirrhotic patients 3

HBeAg-Negative Chronic Hepatitis B

The optimal stopping point for HBeAg-negative patients is HBsAg loss, as relapse is extremely common (70-75%) even after prolonged viral suppression. 1

Stopping Criteria:

• Treatment should ideally continue until HBsAg loss is achieved 1
• If stopping before HBsAg loss, treatment discontinuation can be considered only after undetectable serum HBV DNA has been documented on three separate occasions 6 months apart 1
• The Asian Pacific Association for the Study of the Liver suggests at least 2-3 years of consolidation therapy (treatment after achieving undetectable HBV DNA) before considering discontinuation 4, 5

Relapse Rates and Outcomes:

• Virological relapse occurs in approximately 70% of HBeAg-negative patients, with clinical relapse in 43% 4
• Only 22-29% of HBeAg-negative patients maintain sustained disease remission at 72 weeks after stopping therapy 3, 4
• Consolidation therapy ≥3 years reduces 1-year persistent relapse rates from 57% to 24% compared to <1 year consolidation 2
• HBsAg loss rates increase substantially after stopping therapy, reaching 20-39% at 5 years, particularly in patients with low quantitative HBsAg levels at discontinuation 4, 5

Patients with Compensated Cirrhosis

For patients with compensated cirrhosis, long-term treatment is required, but discontinuation can be considered in specific circumstances with intensive monitoring. 1

• In HBeAg-positive cirrhotic patients, treatment discontinuation can be considered when nucleos(t)ide analogues have been administered for at least an additional 12 months after HBeAg seroconversion 1
• In HBeAg-negative cirrhotic patients, treatment should continue until HBsAg loss is achieved 1
• Two cirrhotic patients in one study developed hepatic decompensation after stopping therapy, though both recovered, highlighting the need for extreme caution in this population 2

Monitoring After Discontinuation

Mandatory close monitoring is essential after stopping therapy to detect relapse early and prevent complications:

• HBsAg should be tested at 6-month intervals after HBeAg seroconversion 1
• Serum HBV DNA should be monitored every 3-6 months 1
• ALT monitoring is critical as biochemical breakthrough typically follows virological breakthrough 1
• Patients must be counseled that deterioration of liver disease may occur after discontinuation 6

Populations Who Should NOT Stop Therapy

Treatment must continue indefinitely in:

• Patients with decompensated cirrhosis 1
• Patients who have not achieved the stopping criteria outlined above 1
• Patients who cannot commit to intensive post-treatment monitoring 3

Key Clinical Pitfall

The most critical error is stopping therapy in HBeAg-negative patients after achieving only viral suppression without HBsAg loss, as this leads to relapse in the majority of patients. 1, 4 While finite therapy is emerging as an option in carefully selected HBeAg-negative patients, the high relapse rates (70-75%) mean this approach requires exceptional patient selection, prolonged consolidation (≥3 years), and intensive post-treatment monitoring. 2, 3, 5