In chronic hepatitis B patients receiving antiviral therapy, when is it appropriate to discontinue treatment versus continue it?

Treatment Continuation vs. Discontinuation in Chronic Hepatitis B

In chronic hepatitis B patients on antiviral therapy, treatment should generally be continued indefinitely until HBsAg loss is achieved, as stopping therapy before this endpoint leads to high relapse rates (50-75%) and risks clinical decompensation, particularly in HBeAg-negative patients and those with cirrhosis. 1, 2

Decision Algorithm Based on Patient Category

HBeAg-Positive Patients

Continue treatment until one of these endpoints is reached:

• Primary endpoint: HBsAg loss (with or without anti-HBs seroconversion) 1, 2
• Alternative endpoint: HBeAg seroconversion with undetectable HBV DNA, followed by at least 12 months of consolidation therapy 1, 3

Critical caveat: Even with HBeAg seroconversion and consolidation, relapse occurs in 50-70% of patients who stop treatment 3, 4. The AASLD and EASL recommend treating until HBsAg loss as the preferred strategy 1.

HBeAg-Negative Patients

Continue treatment indefinitely in most cases 1, 2:

• Preferred stopping criterion: HBsAg loss only 1
• Alternative (not routinely recommended): May consider stopping after ≥3 years of virological suppression with undetectable HBV DNA on three separate occasions 6 months apart, but relapse rates reach 70-75% 1, 5

Key pitfall: The AASLD explicitly recommends indefinite treatment for HBeAg-negative patients due to immune escape mutants and high relapse rates 1. Research confirms that patients initially HBeAg-negative before treatment have better outcomes if therapy is stopped, but those initially HBeAg-positive experience frequent and severe relapses 4.

Patients with Cirrhosis

Never stop treatment except under very specific circumstances 1:

• Compensated cirrhosis: Long-term (potentially lifelong) treatment required; discontinuation only after HBsAg loss 1, 2
• Decompensated cirrhosis: Indefinite (lifelong) treatment mandatory; stopping only after HBsAg loss and anti-HBs seroconversion maintained for 6-12 months 1, 2, 3

Critical warning: Hepatic decompensation, jaundice, and death have been documented in cirrhotic patients after treatment discontinuation 6.

When Continuation is Absolutely Required

Do not stop treatment in these populations:

• Patients with decompensated cirrhosis (indefinite therapy required) 3
• Patients without HBsAg loss who remain HBeAg-negative 1, 2
• Patients with compensated cirrhosis who have not achieved HBsAg loss 1, 2
• Patients who were initially HBeAg-positive before treatment (high risk of severe relapse) 4

Management of Suboptimal Response (When to Switch, Not Stop)

If patients show partial virological response, switch therapy rather than stop 1:

• Low genetic barrier drugs (lamivudine, telbivudine): Switch to high genetic barrier drugs (entecavir, tenofovir) 1
• Entecavir partial response: Switch to tenofovir 1
• Virological breakthrough: Confirm resistance testing and add or switch to non-cross-resistant agent 1

Post-Discontinuation Monitoring (Only After Meeting Stopping Criteria)

If treatment is stopped after achieving HBsAg loss 2, 3:

• Liver function tests: Every 1-3 months initially 2
• HBV DNA: Every 2-6 months (or every 3-6 months per some guidelines) 2, 3
• HBsAg and anti-HBs: Every 6-12 months 2, 3
• ALT monitoring: Regular checks as biochemical breakthrough follows virological breakthrough 3

Evidence Strength and Guideline Consensus

The 2020 international guideline comparison demonstrates strong consensus 1:

• KASL, EASL, AASLD, APASL all agree: HBsAg loss is the ideal endpoint 1
• AASLD is most conservative, recommending indefinite treatment for HBeAg-negative patients 1
• EASL allows consideration of stopping after ≥3 years suppression in select HBeAg-negative patients, but acknowledges high relapse risk 1

Recent prospective research confirms these recommendations: a 2018 study showed 70-72% cumulative relapse rates at 18 months after stopping effective ≥4-year entecavir/tenofovir therapy in HBeAg-negative patients 7. A 2021 prospective study demonstrated that patients initially HBeAg-positive experienced universal virological relapse (8/8 patients) with frequent severe clinical relapses requiring retreatment 4.

Special Considerations for Switching (Not Stopping)

Switch to alternative agents if adverse effects develop 1, 2:

• Tenofovir-associated renal dysfunction or bone disease: Switch to entecavir or tenofovir alafenamide 1, 2
• Drug resistance: Switch or add agents without cross-resistance 1

The fundamental principle: In chronic hepatitis B, the default is to continue treatment until HBsAg loss, as premature discontinuation compromises the ultimate goals of preventing liver disease progression, hepatocellular carcinoma, and death 5, 6.