白细胞介素-21与HBeAg阳性慢性乙型肝炎患者恩替卡韦停药后复发的相关性

The correlation between interleukin-21 and the recurrence of chronic hepatitis B after entecavir discontinuation

目的了解IL-21表达水平与HBeAg阳性CHB患者恩替卡韦（Entecavir，ETV）停药后复发的相关性。 方法入选接受ETV治疗的CHB患者112例，分别于停药0、12、24、52周检测血清IL-21水平，Cox模型分析IL-21与患者停药复发的相关性，受试者工作特征曲线确定IL-21对恩替卡韦停药后复发的预测价值。比较IL-21在病毒学持续应答（sustained viral response，SVR）组和病毒学复发（viral relapse，VR）组的表达差异。统计学处理采用t检验和χ2检验。 结果停药0、12、24、52周SVR组患者血清IL-21水平分别为（60.0±10.8）、（60.2±14.7）、（60.6±19.5）和（61.2±15.4） ng/L，均显著高于VR组的（47.5±10.7）、（47.3±12.9）、（46.9±12.2）和（46.4±12.8） ng/L（t值分别为6.153、4.926、4.382、5.515，均P〈0.01）。受试者工作特征曲线下面积为0.811（95%CI：0.728～0.893，P〈0.01），最佳Cut-off值为49.8 ng/L。停药时IL-21≥49.8 ng/L和〈49.8 ng/L患者的病毒学复发率分别为25.4%（16/63）和77.6%（38/49），差异有统计学意义（χ2＝30.027，P〈0.01）。多因素Cox模型分析结果显示，与ETV停药复发相关的影响因素依次为：停药时血清IL-21水平（P＝0.005）、发生HBeAg血清学转换时HBsAg水平（P＝0.008）和年龄（P＝0.016）。停药后12、24、52周SVR组患者ALT、HBV DNA、HBeAg和HBsAg水平均显著低于VR组（t值分别为－5.968、－7.691、－8.093；－3.047、－9.477、－28.900；－2.872、－10.424、－18.330；－4.633、－4.030、－5.032，均P〈0.01）。停药后SVR组患者血清IL-21水平与血清HBsAg水平呈负相关（r＝－0.241，P〈0.01），而VR组患者呈正相关（r＝0.286，P〈0.01）。 结论停药时血清IL-21水平是停药后复发的影响因素；IL-2l作为免疫调节因子在HBeAg阳性CHB患者ETV停药后维持病毒学应答中起到一定的作用。

ObjectiveTo study the correlation between interleukin （IL）-21 and the recurrence of chronic hepatitis B （CHB） in hepatitis B e antigen （HBeAg）-positive patients after discontinuation of entecavir （ETV）. MethodsA total of 112 HBeAg-positive CHB patients treated with ETV were enrolled. Serum levels of IL-21 at week 0, 12, 24 and 52 after ETV discontinuation were detected. The Cox regression model was used to analyze the correlation between IL-21 and the recurrence after ETV discontinuation. The receiver operating characteristic （ROC） curve was applied to determine the predictive value of IL-21 for CHB recurrence after ETV discontinuation. The expression differences of IL-21 were compared between sustained viral response （SVR） group and viral relapse （VR） group. The t test and Chi-square test were used for statistical analysis. ResultsThe serum levels of IL-21 in SVR group at week 0, 12, 24 and 52 after ETV withdrawal were （60.0±10.8）, （60.2±14.7）, （60.6±19.5） and （61.2±15.4） ng/L, respectively, which were all significantly higher than those in VR group （47.5±10.7）, （47.3±12.9）, （46.9±12.2） and （46.4±12.8） ng/L, respectively （t=6.153, 4.926, 4.382 and 5.515, respectively, all P〈0.01）. The area under curve （AUC） was 0.811 （95%CI： 0.728~0.893, P〈0.01） and the best cut-off value of serum IL-21 level was 49.8 ng/L. The recurrence rates of patients with serum IL-21 level ≥49.8 ng/L and 〈49.8 ng/L at time of ETV withdrawal was 25.4% （16/63） and 77.6% （38/49）, respectively. The difference was statistically significant （χ2=30.027, P〈0.01）. The serum IL-21 level at the time of drug withdrawal （P=0.005）, serum hepatitis B surface antigen （HBsAg） level at the time of HBeAg seroconversion （P=0.008） and age （P=0.016） were factors associated with CHB recurrence after ETV withdrawal by multivariate Cox model analysis. The serum levels of ALT, HBV DNA, HBeAg and HBsAg in SVR group were significantly lower than those of VR group at week 12, 24 and 52 after ETV withdrawal （t=-5.968, -7.691, -8.093; -3.047, -9.477, -28.900; -2.872, -10.424, -18.330; -4.633, -4.030 and -5.032, respectively; all P〈0.01）. Serum level of IL-21 was negatively correlated with HBsAg in SVR group after ETV withdrawal （r=-0.241, P〈0.01）, while positively correlated with HBsAg in VR group （r=0.286, P〈0.01）. ConclusionsThe serum IL-21 level at the time of drug withdrawal is associated with the recurrence after ETV discontinuation. IL-2l may play an important role as an immunomodulatory factor in maintaining virological responses in HBeAg-positive CHB patients after ETV withdrawal.