目的:停止核苷类似物(NA)治疗HBeAg阴性慢性乙型肝炎(CHB)的建议尚不清楚。已提出治疗结束定量HBsAg(EOTqHBsAg)阈值<100IU/ml或<1000IU/ml作为停止标准。我们通过荟萃分析和荟萃回归进行了评估。
方法:我们搜索了PubMed,用于HBeAg阴性CHBNA停药研究的EMBASE和会议摘要。对提取的研究进行了偏倚风险分析,合并HBsAg消失的风险,病毒学(VR)和生化复发(BR)。通过亚组分析和具有已知重要协变量的随机效应元回归来解决显著异质性(I2),包括EOTqHBsAg阈值,种族,治疗持续时间和随访。
结果:我们发现了24篇论文(3732名受试者),16人的偏倚风险较低,8人的偏倚风险中等。HBsAg消失的合并风险,在EOTqHBsAg<100IU/ml停止治疗的VR和BR为41.8%,33.4%和17.3%,与4.6%相比,EOTqHBsAg≥100IU/ml分别为72.1%和34.6%。HBsAg消失的合并风险,在EOTqHBsAg<1000IU/ml停止治疗的VR和BR为22.0%,52.7%和15.9%,与3.4%相比,EOTqHBsAg≥1000IU/ml分别为63.8%和26.4%。HBsAg消失的多变量分析显示种族,随访持续时间和EOTqHBsAg<100≥IU/ml解释了异质性差异的85%;EOTqHBsAg<100IU/ml的亚洲人有28.2%,而EOTqHBsAg<1000IU/ml的非亚洲人有38.4%的HBsAg损失。多变量分析显示,EOTqHBsAg<100≥IU/ml和其他共变量仅分别解释了VR和BR异质性方差的43%和63%,提示其他因素对复发也很重要。
结论:虽然EOTqHBsAg阈值,种族和随访持续时间强烈预测HBsAg消失,这对于VR和BR来说是不正确的,因此,应谨慎考虑停止NA治疗.
OBJECTIVE: 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.