Stopping Nucleos(t)ide Analogues in Chronic Hepatitis B Using HBsAg Thresholds: A Meta-Analysis and Meta-Regression

Background and aims Recommendations for stopping nucleoside analogue(NA) therapy in HBeAg-negative Chronic Hepatitis B(CHB) are unclear. End-of-treatment quantitative HBsAg(EOTqHBsAg) thresholds<100IU/ml or <1000IU/ml have been proposed as stopping criterion. We assessed this by meta-analysis and meta-regression. Design We searched PubMed, EMBASE and conference abstracts for studies of HBeAg-negative CHB NA discontinuation. Extracted studies were analysed for risk-of-bias, pooled risk of HBsAg loss, virological(VR) and biochemical relapse(BR). Significant heterogeneity(I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariables, including EOTqHBsAg thresholds, ethnicity, duration of therapy and followup. Results We found 24 papers(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<100IU/ml were 41.8%, 33.4% and 17.3%, versus 4.6%, 72.1% and 34.6% respectively for EOTqHBsAg≥100IU/ml. The pooled risks of HBsAg loss, VR and BR for stopping therapy at EOTqHBsAg<1000IU/ml were 22.0%, 52.7% and 15.9%, versus 3.4%, 63.8% and 26.4% respectively for EOTqHBsAg≥1000IU/ml. Multivariable analysis for HBsAg loss showed ethnicity, followup duration and EOTqHBsAg<100≥IU/ml explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg<100IU/ml had 28.2%, while non-Asians with EOTqHBsAg<1000IU/ml had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg<100≥IU/ml and other covariables 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 followup duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.