HBeAg阳性慢性乙型肝炎患者经核苷和核苷酸类药物治疗达标停药后复发的相关因素

Risk factors for recurrence after drug withdrawal in HBeAg-positive chronic hepatitis B patients completing pharmacotherapy with nucleos(t) ide analogues

目的探讨影响核苷和核苷酸类药物（NAs）治疗HBeAg阳性的慢性乙型肝炎（CHB）患者达到治疗终点停药后复发的相关因素。方法选取2004年5月-2014年12月于广西医科大学第一附属医院就诊并接受NAs治疗的HBeAg阳性CHB患者60例,达到相关指南治疗停药标准后停药。将性别、年龄、HBV感染家族史、基线HBV DNA载量、基线TBil、基线ALT水平、基线AST水平、病毒学应答时间、HBeAg消失时间、开始用药至发生HBeAg血清学转换时间、HBeAg血清学转换后巩固治疗时间、总疗程、延长疗程、停药时HBsAg水平、药物种类共15个可能影响复发的因素进行单因素、多因素Cox比例风险回归模型分析,累积复发率采用Kaplan-Meier法进行分析。结果 60例患者平均疗程（37.36±12.67）个月,延长疗程7.0（2.0-13.0）个月,48个月的复发率为56.7%。性别、年龄、基线HBV DNA载量、基线TBil、基线ALT水平、基线AST水平、病毒学应答时间、巩固治疗时间、总疗程、延长疗程、药物种类对达标停药后复发无明显影响（P值均〉0.05）。多因素Cox模型分析可以看出,HBV感染家族史[风险比（RR）=1.583,P=0.047）]、HBeAg血清学转换时间（RR=1.205,P=0.015）、停药时HBsAg水平（RR=2.143,P=0.008）是影响停药后复发的独立危险因素。HBeAg血清学转换在12个月以后的复发率高于发生在12个月以内（80.0%vs 48.9%,P〈0.001）。结论HBV感染家族史、HBeAg血清学转换时间晚、停药时HBsAg高水平是导致NAs治疗达标停药后复发的主要危险因素。HBeAg阳性的CHB患者若能获得免疫控制有利于减少NAs停药后的复发。

Objective To investigate the risk factors for recurrence after drug withdrawal in HBeAg- positive chronic hepatitis B（ CHB）patients completing the treatment with nucleos（ t） ide analogues（ NAs）. Methods A total of 60 HBeAg- positive CHB patients who visited and were treated in The First Hospital Affiliated to Guangxi Medical University from May 2004 to December 2014 were enrolled. The drugs were withdrawn after the patients reached the criteria for drug withdrawal in related guidelines. The univariate and multivariate Cox proportional hazards regression model analyses were performed for 15 factors which might influence recurrence,i. e.,sex,age,a family history of HBV infection,baseline HBV DNA load,baseline total bilirubin（ TBil） level,baseline alanine aminotransferase（ ALT） level,baseline aspartate aminotransferase（ AST） level,duration of virologic response,time to disappearance of HBeAg,time from the start of medication to the development of HBeAg seroconversion,duration of consolidation therapy after HBeAg seroconversion,total course of the treatment,prolonged course of the treatment,HBs Ag level at drug withdrawal,and drug type. The Kaplan- Meier method was used for calculating the cumulative recurrence rate. Results The mean course of the treatment was 37. 36 ± 12. 67 months,the prolonged course of the treatment was 7. 0（ 2. 0 - 13. 0） months,and 56. 7% of all patients experienced recurrence. Sex,age,baseline HBV DNA load,baseline TBil level,baseline ALT level,baseline AST level,duration of virologic response,duration of consolidation therapy,total course of the treatment,prolonged course of the treatment,and drug type were not significantly associated with recurrence after drug withdrawal in patients who met the criteria for drug withdrawal（ all P〉0. 05）. A family history of HBV infection（ RR = 1. 583,P = 0. 047）,time to HBeAg seroconversion（ RR = 1. 205,P = 0. 015）,and HBs Ag level at drug withdrawal were independent risk factors for recurrence after drug withdrawal. The patients with time to HBeAg seroconversion 〉12 months had a significantly higher recurrence rate than those with time to HBeAg seroconversion 12 months（ 80. 0% vs 48. 9%,P〈0. 001）. Conclusion A family history of HBV infection,delayed HBeAg seroconversion,and high HBs Ag level at drug withdrawal are major risk factors for recurrence after drug withdrawal in HBeAg- positive CHB patients who have met the criteria for drug withdrawal in the treatment with NAs. If HBeAg- positive CHB patients can acquire immune control,recurrence after withdrawal of NAs will be reduced.