慢性乙型肝炎患者核苷（酸）类似物停药后病情变化的临床观察

Clinical observation of condition changes following medication withdraw of nucleoside/nucleotide analogues in patients with chronic hepatitis B

目的 观察慢性乙型肝炎患者（CHB）服用核苷（酸）类似物（NAs）进行抗病毒治疗停药后的病情变化,分析停药复发的因素,探讨安全停药的时机.方法 选取南京市第二医院2002年1月至2017年12月门诊及住院的服用NAs进行抗病毒治疗的停药CHB患者85例,按照是否达到停药标准而停药分为按标准停药组（n＝22）和未按标准停药组（n＝63）.回顾性分析两组患者停药2年后出现肝功能异常、HBV DNA阳转率及肝衰竭的情况与服药的疗程、停药时HBeAg血清学转换、HBsAg水平、服药时是否肝硬化的关系.结果 按标准停药的患者中,服药时间均＞3年,仅1例发生HBV DNA阳转,同时出现丙氨酸转氨酶（ALT）、总胆红素（TBil）异常和发生肝衰竭情况.未按标准停药患者中,50例（79.4%）出现HBV DNA阳转,36例（57.1%）出现ALT异常,25例（39.7%）出现TBil异常,14例（22.2%）出现肝衰竭情况.按标准停药患者停药时HBsAg＞1 000 IU/mL 19例, HBsAg≤1 000 IU/mL 3例,其中仅HBsAg＞1 000 IU/mL患者1例（5.3%）出现HBV DNA阳转,ALT、TBil异常和肝衰竭情况.未按标准停药患者停药时HBsAg＞1 000 IU/mL 52例,其中45例（86.5%）出现HBV DNA阳转,31例（59.6%）出现ALT异常,25例（48.1%）出现TBil异常,13例（25.0%）出现肝衰竭情况;HBsAg≤1 000 IU/mL 11例患者中,6例（54.5%）出现HBV DNA阳转,5例（45.4%）出现ALT异常,未出现TBil异常及肝衰竭情况.按标准停药患者停药时肝硬化患者5例,仅1例发生HBV DNA阳转、ALT、TBil异常且发生肝衰竭;非肝硬化患者17例中,均未出现异常情况.未按标准停药的患者,停药时肝硬化患者29例,均出现HBV DNA阳转,28例（96.6%）出现ALT异常,22例（75.8%）出现TBil异常,11例（37.9%）出现肝衰竭情况;非肝硬化患者34例中,21例（61.8%）出现HBV DNA阳转,8例（23.5%）出现ALT异常,3例（8.8%）出现TBil异常,2例（5.9%）出现肝衰竭情况.按标准停药患者中,12例患者HBeAg血清学转换后,2例（16.7%）出现HBV DNA阳转,未出现ALT异常、TBil异常和肝衰竭情况;未按标准停药患者中,17例仅HBeAg消失未出现血清学转换,10例（58.8%）出现HBV DNA阳转,5例（29.4%）出现ALT异常,2例（11.8%）出现TBil异常,未出现肝衰竭情况.结论 服用NAs的CHB患者应按照停药标准进行停药,勿盲目停药.停药时机可参考患者服药的疗程、停药时的免疫指标、服药时是否有肝硬化等情况.

Objective To observe the condition changes in patients with chronic hepatitis B （CHB） following medication withdraw of nucleoside/nucleotide analogues （NAs） treatment and to analyze the factors related to disease relapse.Methods Eighty-five CHB patients who discontinued medication of nucleoside/nucleotide analogues for antiviral therapy in Nanjing Second Municipal Hospital from January 2002 to December 2017 were enrolled in the study, among whom 22 cases met the withdrawal criteria （standard withdrawal group ） and 63 cases did not meet the withdraw criteria （ non-standard withdrawal group）.The correlation of condition changes （abnormal liver function, positive rate of HBV DNA, hepatic failure with the drug withdrawal , the course of medication, serological transformation of HBeAg during drug withdrawal, HBsAg level, and liver cirrhosis during drug administration was analyzed.Results In standard withdraw group, the medication lasted for 〉3 years, only 1 case had HBV DNA positive conversion , abnormal ALT and TBil, and liver failure.In non-standard withdraw group, 50 cases （79.4%） had HBV DNA positive conversion, 36 （57.1%） had abnormal ALT, 25 （ 39.7%） had abnormal TBil and 14 （22.2%） had liver failure.There were 19 cases with HBsAg 〉1 000 IU/mL and 3 cases with HBsAg ≤1 000 IU/mL, and 1 case with HBsAg〉1 000 IU/mL （5.3%） had HBV DNA positive conversion , ALT, TBil abnormality and liver failure.In non-standard withdraw group, there were 52 cases with HBsAg 〉1000 IU/mL, among whom 45 cases （86.5%） had positive HBV DNA conversion , 31 （59.6%） had ALT abnormalities, 25 （48.1%） had TBil abnormalities, and 13 （25.0%） had liver failure; there were 11 patients with HBsAg ≤1 000 IU/mL, among whom 6 cases （54.5%） had HBV DNA positive conversion , 5 （45.4%） had ALT abnormalities, and no TBil abnormalities or liver failure occurred.There were 5 cases of liver cirrhosis in the standard withdraw group , only 1 case had HBV DNA positive conversion , ALT, TBil abnormality and liver failure.None of the 17 patients with non-cirrhosis had HBV DNA positive conversion , ALT, TBil abnormality and liver failure.There were 29 patients with liver cirrhosis in non-standard withdraw group showed positive HBV DNA conversion , 28 （96.6%） had ALT abnormalities, 22 （75.8%） had TBil abnormalities, and 11 （37.9%） had liver failure; among 34 non-cirrhosis patients, 21 （61.8%） had positive HBV DNA conversion, 8 （23.5%） had ALT abnormalities, 3 （8.8%） had TBil abnormalities, and 2 （5.9%） had liver failure.According to the standard discontinuation , 12 patients （16.7%） had positive HBV DNA transformation after HBeAg serological conversion , and no ALT abnormality, TBil abnormality and liver failure occurred.In non-standard withdraw group, only 17 cases without HBeAg serological conversion , 10 cases （58.8%） had positive HBV DNA conversion , 5 cases （29.4%） had ALT abnormalities, 2 cases （11.8%） had TBil abnormalities and liver failure did not occur.Conclusion CHB patients with medication of NAs should be discontinued according to the withdrawal criteria .and the course of medication, the immune index and the liver cirrhosis should be taken into account.