When should hepatitis B antiviral therapy be discontinued in chronic infection, including the specific criteria for HBeAg‑positive and HBeAg‑negative patients?

When to Stop Hepatitis B Treatment

Hepatitis B antiviral therapy should generally be continued indefinitely until HBsAg loss is achieved, as this represents the only universally accepted stopping point across all patient populations; stopping earlier results in relapse rates of 50-75% and risks severe hepatitis flares, particularly in patients with cirrhosis. 1

Universal Stopping Criterion

• HBsAg loss (with or without anti-HBs seroconversion) is the optimal endpoint for discontinuing therapy in all patient categories. 2, 1 This represents functional cure and is the safest stopping point, though it occurs infrequently with current nucleos(t)ide analogue therapy. 3

• After confirmed HBsAg loss, continue antiviral therapy for an additional 6-12 months of consolidation before discontinuation. 2, 1

HBeAg-Positive Patients

Primary Recommendation

• Continue therapy indefinitely until HBsAg loss is achieved. 1 This is the most conservative and safest approach.

Alternative Stopping Point (with significant caveats)

• Therapy may be discontinued after HBeAg seroconversion (to anti-HBe positive) with undetectable HBV DNA, followed by 12 months of consolidation therapy. 2, 1

• However, this approach carries substantial risk: 38% of patients experience ALT flares after stopping, and the majority experience recurrent viremia. 2 Relapse rates reach 24-26% even after prolonged consolidation. 4

• Patients who were HBeAg-positive before treatment should generally NOT be withdrawn from therapy because clinical relapse is frequent and often severe—all patients in one prospective study experienced virological relapse, with 75% requiring retreatment. 5

Critical Requirement Before Stopping

• If patients insist on stopping despite not achieving HBsAg loss, they must undergo liver biopsy or transient elastography to confirm only mild fibrosis (F0-F1). 2 Patients with F2 or greater fibrosis should continue indefinite therapy.

HBeAg-Negative Patients

Standard Approach

• Long-term (indefinite) therapy is required for HBeAg-negative patients; the only accepted stopping point is HBsAg loss. 2, 1 The AASLD explicitly recommends lifelong treatment for this population due to high relapse rates and risk of immune-escape mutants. 1

Conditional Alternative (not routinely recommended)

• Selected HBeAg-negative patients may discontinue therapy after ≥3 years of sustained virological suppression (undetectable HBV DNA on three separate tests ≥6 months apart), but relapse occurs in 70-75% of cases. 2, 1

• This approach requires extremely close monitoring and should only be considered in patients who can guarantee rigorous post-treatment follow-up. 2

• Patients who were HBeAg-negative before starting treatment have better outcomes after withdrawal than those who were initially HBeAg-positive: in one study, 57% of HBeAg-negative patients achieved HBsAg loss after stopping therapy. 5

Predictors of Successful Withdrawal

• Low pre-withdrawal HBsAg levels predict higher rates of HBsAg loss after stopping therapy. 5

• Duration of on-therapy virological remission matters: approximately 50% maintain virological remission 3 years after stopping if they had >2 years of undetectable HBV DNA during treatment. 2

Patients with Cirrhosis

Compensated Cirrhosis

• Lifelong antiviral therapy is mandatory; discontinuation is permissible ONLY after confirmed HBsAg loss. 2, 1 Even after HBsAg loss, these patients require lifelong HCC surveillance. 2

Decompensated Cirrhosis

• Indefinite (lifelong) therapy is absolutely required; stopping is contraindicated unless HBsAg loss plus sustained anti-HBs seroconversion is maintained for 6-12 months. 1 Overt hepatitis flares and life-threatening episodes have been reported in cirrhotic patients who discontinue therapy. 2

Post-Discontinuation Monitoring Protocol

If therapy is stopped (only after meeting appropriate criteria), intensive monitoring is essential:

• ALT and HBV DNA levels monthly for the first 3 months, then every 3 months for the first year. 2, 6

• HBsAg and anti-HBs testing every 3-6 months. 6

• Liver function tests every 1-3 months initially. 1

• Patients who relapse can be retreated with expectation of similar response as treatment-naïve patients. 2

Retreatment Criteria After Stopping

• Restart therapy if HBV DNA rises to ≥2,000 IU/mL with elevated ALT or if there is evidence of hepatic decompensation. 2, 7

• In one study using stringent retreatment criteria, cumulative retreatment rates were 15%, 22%, and 40% at 6,12, and 24 months after discontinuation. 7

Special Populations

Patients on Immunosuppression

• Continue antiviral prophylaxis for at least 12 months after cessation of immunosuppressive therapy (24 months for rituximab), regardless of HBsAg status. 6 Do not stop based on standard chronic hepatitis B criteria during this period.

Older Patients

• Many clinicians continue treatment indefinitely in patients >60 years old unless HBsAg loss occurs, given the risks of severe flares and limited life expectancy to achieve natural HBsAg clearance. 2

Common Pitfalls to Avoid

• Do not stop therapy in patients with significant fibrosis (F3) or any degree of cirrhosis (F4) unless HBsAg loss is achieved. 2, 1 This is the most critical error to avoid.

• Do not assume HBeAg seroconversion guarantees durable response—the majority of patients experience recurrent viremia after stopping. 2

• Do not discontinue abruptly without establishing close monitoring—hepatitis flares can be severe and life-threatening. 2

• Do not confuse virological relapse (HBV DNA >2,000 IU/mL) with the need for immediate retreatment—a substantial proportion may maintain low-level viremia without requiring retreatment if stringent criteria are used. 7