目的 观察长期核苷(酸)类似物(NUC)治疗未达到慢性乙型肝炎防治指南(2010年)停药标准的HBeAg阳性CHB患者加用聚乙二醇干扰素(peg-INF)-α-2a联合治疗的疗效,并探讨HBeAg/HBsAg消失的预测因素.方法 回顾性分析83例接受NUC治疗≥1年未实现病毒学或血清学应答的HBeAg阳性CHB患者,加用(peg-INF)-α-2a联合治疗48周,记录治疗12周和24周时HBV血清学标志物等指标值,停药后随访24周.以加用peg-INF的时间点定义为基线,探讨基线HBsAg水平和治疗过程中HBsAg下降程度对HBeAg/HBsAg消失的预测价值.受试者工作特征(ROC)曲线用于确定基线HBsAg水平对联合治疗后HBsAg消失的预测价值,Cox回归模型用于分析与联合治疗后HBeAg/HBsAg消失相关的因素;计算每个变量的风险比(HR),并纳入单因素和多因素分析.结果 peg-INF-α-2a停药24周后,50例患者HBeAg消失,占60.2％;27例HBeAg血清学转换,占32.5％;23例HBsAg消失,占27.7％;12例HBsAg血清学转换,占14.5％.基线HBsAg＜1 000 IU/mL的11例患者均HBeAg消失,与基线HBsAg 1 000～3 000 IU/mL(共12例,8例HBeAg消失;HR=0.215,95％CI:0.078～0.591; P=0.003)和＞3 000 IU/mL(共60例,31例HBeAg消失;HR=0.251,95％CI:0.120～0.526;P=0.000)的患者比较,更易实现HBeAg消失.结论 对于长期NUC治疗未取得病毒学或血清学应答的患者,加用peg INF-α-2a时的血清HBsAg水平对HBeAg和HBsAg消失具有预测价值.基线HBsAg＜1 000 IU/mL者,联合治疗后可获得高HBeAg和HBsAg阴转率;而HBsAg＞1 000 IU/mL(包括HBsAg＞3 000 IU/mL)者,联合治疗12周时的HBsAg较基线下降水平可预测HBeAg/HBsAg的阴转.%Objective To investigate the efficacy of add-on peginterferon α-2a in patients with hepatitis B e antigen (HBeAg)-positive hepatitis who failed to achieve virological or serological response to long-term treatment of nucleos(t)ide analogues and to explore the predictive value of hepatitis B surface antigen (HBsAg) quantification on the HBeAg and HBsAg loss.Methods Eighty-three HBeAg-positive chronic hepatitis B (CHB) patients who failed to achieve virological or serological response after more than one-year nucleos(t) ide analogues treatment were added with peginterferon α-2a for 48 weeks and were further followed up for 24 weeks after treatment.HBsAg was quantified at baseline and throughout the antiviral therapy (week 12 and 24) and its predictive value on the HBeAg and HBsAg loss was explored.Receiver operating characteristics (ROC) curve was used to identify the predictive value of baseline HBsAg level on HBsAg loss.Cox regression model was used to analyze the factors associated with HBeAg and HBsAg loss.Multivariable-adjusted hazard ratios (HR) were derived for each factor using univariate and multivariate analysis.Results Twenty-four weeks after drug withdrawal,50(60.2％) patients achieved HBeAg loss,27 (32.5％) achieved HBeAg seroconversion,23 (27.7％) achieved HBsAg loss while 12 (14.5％) achieved HBsAg seroconversion.In patients with an HBsAg level of ＜ 1 000 IU/mL,11 (100.0％) patients achieved HBeAg loss.Compared to patients with an HBsAg level of ＜1 000 IU/mL,the rates of HBeAg loss were lower in those with HBsAg level of 1 000-3 000 IU/mL (8/12,66.7％) and ＞3 000 IU/mL (31/60,51.7％),with hazard ratios (HR) of 0.215 (95％CI:0.078-0.591) and 0.251 (95％ CI:0.120-0.526),respectively.As to HBsAg loss,10 patients (90.9％) achieved HBsAg loss with an HBsAg level of ＜1 000 IU/mL,compared with only 8 patients (13.3％) achieved HBsAg loss with an HBsAg level of ＞3 000 IU/mL.An HBsAg level of ＞ 3 000 IU/mL was found to be associated with a lower possibility of HBsAg loss (HR=0.155,95％CI:0.055-0.439; P=0.000).Conclusions Baseline HBsAg level predicts HBeAg and HBsAg loss in patients treated with add-on peginterferon after a long-term treatment of nucleos (t)ide analogues.The efficacy is better in patients with a baseline HBsAg level of ＜1 000 IU/mL.Patients with a baseline HBsAg level of ＞1 000 IU/mL (including those with a baseline HBsAg level of ＞3 000 IU/mL) who achieve a significant HBsAg decline at week 12 during treatment still have a chance to achieve HBeAg or HBsAg loss,while those with mild HBsAg decline should be advised to discontinue the combination therapy.
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