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Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression
Seng Gee Lim1, Ada Ee Der Teo2, Edwin Shih-Yen Chan3
1Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore.
Insights
Stopping nucleoside analogue therapy for chronic hepatitis B is complex. Lower hepatitis B surface antigen levels (<100 IU/mL) before stopping therapy increase the chance of losing the antigen but not necessarily preventing relapse.
Area of Science:
- Hepatology
- Virology
- Clinical Medicine
Background:
- Nucleoside analogue (NA) therapy is used for chronic hepatitis B (CHB).
- Stopping criteria for NA therapy in hepatitis B e antigen-negative CHB are not well-defined.
- End-of-treatment quantitative hepatitis B surface antigen (EOTqHBsAg) levels are proposed as predictors for treatment cessation.
Purpose of the Study:
- To assess the efficacy of EOTqHBsAg thresholds (<100 IU/mL and <1000 IU/mL) as criteria for stopping NA therapy in CHB.
- To evaluate the risk of hepatitis B surface antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR) based on EOTqHBsAg levels.
- To identify factors influencing treatment outcomes after NA discontinuation through meta-regression.
Main Methods:
- A meta-analysis and meta-regression of studies on NA discontinuation in CHB.
- Searched PubMed, EMBASE, and conference abstracts for relevant studies.
- Analyzed risk of bias, pooled risks of HBsAg loss, VR, and BR, and performed subgroup analysis and meta-regression with covariates like EOTqHBsAg thresholds, ethnicity, therapy duration, and follow-up.
Main Results:
- Pooled risks for stopping NA therapy at EOTqHBsAg <100 IU/mL were 41.8% for HBsAg loss, 33.4% for VR, and 17.3% for BR.
- Pooled risks for stopping NA therapy at EOTqHBsAg <1000 IU/mL were 22.0% for HBsAg loss, 52.7% for VR, and 15.9% for BR.
- Multivariable analysis indicated EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predicted HBsAg loss, explaining 85% of heterogeneity.
Conclusions:
- EOTqHBsAg thresholds, ethnicity, and follow-up duration are significant predictors of HBsAg loss.
- The predictive power of these factors for virological and biochemical relapse is less pronounced.
- Caution is advised when considering stopping NA therapy due to potential for relapse.
Background And Aims:
Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression.
Methods:
We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up.
Results:
We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse.
Conclusions:
While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.
