预测核苷（酸）类似物停药后慢性乙型肝炎复发的生化标记筛查及其临床应用

摘要

为探寻核苷（酸）类似物停药后慢性乙型肝炎复发的相关因素及可能血清标记，收集经核苷（酸）类似物治疗的乙型肝炎病毒e抗原（hepatitis B virus e antigen ，HBeAg）阳性或阴性慢性乙型肝炎患者，根据治疗应答对其能否停药进行临床评估，分析达到停药标准患者的临床资料，包括性别，年龄，疗程，HBeAg水平，基线丙氨酸氨基转移酶（alanine aminotransferase ，ALT ）、HBV DNA ，停药时的肝硬度值、HBV 表面抗原（HBV surface antigen ，HBsAg）水平、白细胞介素21（interleukin 21，IL‐21）水平、外周血CD4＋ IL‐21＋ T细胞频数。结果显示，共47例患者符合停药标准，其中 HBeAg阳性26例，HBeAg阴性21例；平均年龄（42．45±14．08）岁。抗病毒疗程平均为（4．60±1．61）年。抗病毒治疗初始ALT值为（174．38±200．84）U／L ；基线HBV DNA为（5．87±1．06）log拷贝／mL；停药时HBsAg精确定量平均为（1104．82±1328．11）IU／mL ，IL‐21平均为（729．82±427．39） pg／mL ，CD4＋ IL‐21＋ T细胞频数平均为（0．79±0．49）％，肝硬度测定F127例、F216例、F34例、F40例。共27例患者复发，1年内累积复发率为57．45％。Logistic回归单因素分析提示，慢性乙型肝炎患者停用核苷（酸）类似物后复发与服药总疗程及停药时 IL‐21水平、CD4＋ IL‐21＋T细胞频数、HBsAg水平有关；Logistic回归多因素分析则提示，停药时 HBsAg和 IL‐21水平与复发有关。因此，停药时HBsAg和IL‐21水平可作为慢性乙型肝炎患者停用核苷（酸）类似物后复发的预测因素。%To evaluate the probable predicting factors and biomarkers associated with the relapse of chronic hepatitis B after withdrawal of nucleos(t)ide analogs ,a clinical assessment of patients with chronic hepatitis B ,either hepatitis B virus e antigen (HBeAg)‐positive or ‐negative ,who had received the treatment of nucleos(t )ide analogs and met the requirement for withdrawal was made . Then the clinical data were collected including sex ,age ,treatment course ,HBeAg level ,baseline alanine aminotransferase (ALT) and HBV DNA levels ,liver stillness ,HBV surface antigen (HBsAg) level ,interleukin 21 (IL‐21) level and frequency of peripheral blood CD4+ IL‐21+ T cells at the time of withdrawal .Forty seven patients met the requirement for withdrawal .Among them ,26 patients were HBeAg‐positive and 21 patients were HBeAg‐negative .The mean age was (42 .45 ± 14 .08) years .The mean treatment course was (4 .60 ± 1 .61) years . The mean baseline ALT level was (174 .38 ± 200 .84) U/L .The mean baseline HBV DNA level was (5 .87 ± 1 .06) log copies/mL .The mean HBsAg level was (1 104 .82 ± 1 328 .11) IU/mL .The mean IL‐21 level was (729 .82 ± 427 .39 ) pg/mL . The mean frequency of peripheral blood CD4+ IL‐21+ T cells was (0 .79 ± 0 .49)% .The liver stillness measurement at the time of withdrawal was F1 in 27 patients ,F2 in 16 patients , and F3 in 4 patients .Twenty seven (57 .45% ) patients relapsed in one year .Single‐factor logistic regression analysis showed that the relapse of chronic hepatitis B after withdrawal of nucleos (t ) ide analogs was associated with treatment course , IL‐21 level , frequency of peripheral blood CD4+ IL‐21+ T cells , and HBsAg level .Multi‐factor logistic regression analysis showed that HBsAg level and IL‐21 level could predict the relapse of chronic hepatitis B after withdrawal of nucleos(t)ide analogs .