核苷类药物治疗HBV相关慢加急性肝衰竭患者24个月的生存分析

Nucleoside analogues for acute-on-chronic liver failure associated with hepatitis B virus infection： a 24-month survival analysis

目的 探讨不同核苷类似物对HBV相关慢加急性肝衰竭患者的远期生存率的影响.方法 采用前瞻性队列研究,选择HBV相关慢加急性肝衰竭180例患者作为研究对象,按自主选择原则,分为基础治疗组及抗病毒治疗组（包括拉米夫定治疗组、替比夫定治疗组、恩替卡韦治疗组）,随访24个月,应用Kaplan-Meier法进行生存分析. 结果 180例患者均完成随访,4组患者基线临床特征差异无统计学意义.治疗1个月时各组生存率比较,差异无统计学意义（Breslow=4.475,P=0.215）,但2、3、6、12和18个月时基础治疗组生存率均低于拉米夫定组、替比夫定组及恩替卡韦组,差异有统计学意义（P＜ 0.05）;但3组抗病毒组生存率组间比较,差异均无统计学意义（P＞0.05）.24个月时,基础治疗组生存率仍低于拉米夫定组、替比夫定组及恩替卡韦组（Breslow 值分别为5.604、5.621、14.701,P值均＜0.05）,差异均有统计学意义.24个月时,拉米夫定组与替比夫定组的生存率比较,P＞ 0.05,差异无统计学意义;但这两组生存率均低于恩替卡韦组,Breslow值分别为4.010、4.307,P值均＜0.05,差异均有统计学意义.分层分析发现基线30％＜凝血酶原活动度（PTA）≤40％或MELD评分≤29或HBV DNA≥51og10 IU/ml的患者治疗1个月时,基础治疗组与抗病毒治疗组累积生存率比较,差异无统计学意义（P＞ 0.05）;而2、3、6、12、18、24个月时基础治疗组累积生存率则低于抗病毒治疗组（P＜0.05）;20％＜PTA≤30％患者随访1个月至24个月基础治疗组累积生存率均低于抗病毒治疗组,P＜ 0.05,差异有统计学意义;而PTA≤20％或MELD≥30％两组患者随访1个月至24个月累积生存率差异均无统计学意义.基线HBV DNA＜5 log10 IU/ml的患者,治疗1、2、3、6、12、18个月时基础治疗组生存率与抗病毒治疗组比较,差异无统计学意义;而24个月生存率低于抗病毒治疗组,差异有统计学意义（B reslow=4.055,P=0.044）. 结论 核苷类似物能够提高HBV相关慢加急性肝衰竭患者的长期生存率,恩替卡韦更适合患者的长期治疗.早期、中期及HBV DNA阳性的患者均应尽早进行抗病毒治疗.

Objective To investigate the effect of different nucleoside analogues on the long-term survival rate of patients with acute-on-chronic liver failure （ACLF） associated with hepatitis B virus （HBV） infection.Methods One hundred and eighty patients with HBV-related ACLF were enrolled in this prospective cohort study and divided into a basic trcatmcnt group （n =30） and an antiviral treatment group,the latter of which was further subdivided into the lamivudine treatment group （n =66）,telbivudine treatment group （n =38） and entecavir treatment group （n =46） according to voluntary choice by the patient.All study participants were followed-up for 24 months.The Kaplan-Meier method was applied for survival analysis.Results The patients in the four antiviral treatment groups had statistically similar baseline clinical characteristics and 1-month survival rates （Breslow =4.475,P =0.215）.However,the basic treatment group had a significantly lower survival rate than the antiviral treatment groups that received lamivudine,telbivudine,or entecavir （all P ＜ 0.05） at the treatment periods of 2,3,6,12 and 18-months; however,these three treatment groups showed no significant differences in survival rates.At the time point of 24 months of treatment,the basic treatment group retained its lower rate of survival than the three antiviral treated groups （lamivudine：Breslow =5.604,P =0.018; telbivudine：Breslow =5.621,P =0.018; entecavir：Breslow =14.701,P ＜ 0.001）; while the survival rates were similar for the lamivudine treatment group and the telbivudine treatment group at this time point,their survival rates were significantly lower than that of the entecavir treatment group （Breslow =4.010,P =0.045; Breslow =4.307,P =0.038）.Stratification analysis showed that when the baseline was 30 ＜ PTA ≤ 40 or MELD ≤ 29 or HBV DNA ≥ 5 log10 IU/mL,the cumulative survival rates of the basic treatment group and antiviral treatment group were statistically similar even though the patients had completed 1 month of treatment After being treated for 2,3,6,12,18 and 24 months,the cumulative survival rates of the basic treatment group were consistently below those of the overall antiviral treatment group （P ＜ 0.05）.The cumulative survival rate of the basic treatment group followed-up for 1 to 24 months,with PTA values between 20 and 30,was lower than that of the overall antiviral treatment group （P ＜ 0.05）; two groups of patients with PTA ≤ 20 or MELD ≥ 30 were followed-up for 1 months to 24 months,and their cumulative survival rates showed no significant difference （P ＞ 0.05）.Among the patients whose baseline was HBV DNA ＜ 5 log10 IU/mL,the comparison of survival rates between the basic treatment group and the overall antiviral treatment group showed no significant differences after treatment for 1,2,3,6,12 or 18 months,and the survival rate was lower than that of the overall antiviral treatment group （Breslow =4.055,P =0.044） after 24 months.Conclusion Nucleoside analogues can improve the long-term survival rate of HBV-related ACLF patients.Entecavir is preferred for the long-term treatment of these patients.Patients in the early and middle stages of this disease and HBV DNA-positive patients should adopt antiviral treatment as early as possible.