拉米夫定停药后慢性乙型肝炎复发的临床特点及相关因素

目的研究拉米夫定停药后慢性乙型肝炎复发病例的临床特点和相关因素.方法随访调查拉米夫定停药后复发的慢性乙型肝炎患者,记录用药前病程、诊断,拉米夫定用量、疗程、疗效、停药原因,用药前、停药时和复发后的生化指标、免疫学指标、病毒学指标及YMDD变异、前C区变异情况及预后.结果46例纳入研究,其中32.6%疗程不足52周;停药时93.6%乙型肝炎病毒(HBV)DNA转阴者复发时均阳转,6.4%未转阴者复发时HBV DNA上升超过2个对数级;71.7%(33/46)患者自行停药;医生指导停药的患者中61.5%(8/13)未随访.71.7%(33/46)复发时病情较用药前加重,其YMDD变异率为78.8%(x2=23.23,P＜0.01)和前C区变异率为84.8%(x2=21.04,P＜0.01),均高于未加重者;复发的时间中位数为12周,与停药时丙氨酸氨基转移酶(ALT)(r=0.32,P＜0.05)相关;复发时的病情与年龄(r=0.40,P＜0.01)及YMDD变异(r=0.31,P＜0.05)相关.预后与年龄(r=0.49,P＜0.01),服药前诊断(r=0.39,P＜0.01)、总胆红素(TBiI)(r=0.46,P＜0.05)、ALT(r=0.32,P＜0.05),停药时乙型肝炎病毒e抗原(HBeAg)阴转(r=0.31,P＜0.05),复发时TBil(r=0.55,P＜0.01)及凝血酶原活动度(r=0.57,P＜0.01)相关.结论大部分患者没有按照我国拉米夫定临床应用专家组指导意见用药和停药,复发可能主要是由于HBV DNA再度活跃复制引起肝脏炎症活动所致;YMDD和(或)前C区变异可能是复发时肝损害加重的因素之一.患者年龄、服药前的诊断、服药前T Bil与A L T水平、停药时HB eAg是否阴转、复发时TBil及凝血酶原活动度水平影响预后.

Clinical characteristics of and the related factors to the relapse of chronic hepatitis B after lamivudine withdrawal

OBJECTIVES: To investigate the cases of chronic hepatitis B relapse after lamivudine withdrawal, and to find clinical characteristics and related factors to them. METHODS: 46 cases of chronic hepatitis B relapse after lamivudine withdrawal were investigated and followed up. The diagnosis and the course of the diseases before therapy with lamivudine, the dosage, effects, period of treatment, the reasons for lamivudine withdrawal, the biochemistry, immunological and virulogical data in each period, YMDD mutation, pre-C mutation and prognosis after relapse were recorded. RESULTS: The periods of treatment of 32.6% of patients in this group were shorter than 52 weeks. The HBV DNA of 93.6% of patients turned negative at the time of lamivudine withdrawal and returned to positive in all of those patients when relapsed; of the 6.4% of patients who did not turn negative at the time of lamivudine withdrawal, their HBV DNA was elevated more than 2 log when relapsed. A majority of patients (71.7%) did not ask their physicians when they decided to withdraw from lamivudine. There were 61.5% of the other patients who withdrew from lamivudine on the advice of physicians but they were not followed up. The state of their illness in 71.7% (33/46) patients was more severe than before their lamivudine therapy. In these cases, the YMDD mutation was detected in 78.8% of patients (chi2 = 23.23, P<0.01), and pre-C mutation was detected in 84.8% of patients (chi2 = 21.04, P<0.01), higher than that in the cases with aggrevation of their illnesses before the lamivudine therapy. The median time between lamivudine withdrawal and relapse was 12 weeks; it was negatively correlated with ALT (r = 0.32, P<0.05) detected at the time of lamivudine withdrawal. The severity of the illness at the time of relapse was related with age (r = 0.40, P<0.01) and YMDD mutation (r = 0.31, P<0.05). The prognosis was related with the age of the patient (r = 0.49, P<0.01), the diagnosis (r = 0.39, P<0.01), TBil (r = 0.46, P<0.05) and ALT (r = 0.32, P<0.05) detected before lamivudine therapy, HBeAg became negative when lamivudine was withdrawn (r = 0.31, P<0.05), TBil (r = 0.55, P<0.01) and PTA (r = 0.57, P<0.01) detected when relapsed. CONCLUSION: A majority of patients did not follow the lamivudine treatment recommendation of the experts group on lamivudine clinical practice in China. The major reason for relapse perhaps was revived HBV DNA multiplication, which induces damage of hepatocytes after lamivudine withdrawal. The YMDD mutation and/or pre-C mutation may be one of the factors that aggravate the damage of hepatocytes during the relapse. The factors including age of the patient, diagnosis before the treatment, TBil and ALT detected before lamivudine therapy, HBeAg turning to negative when lamivudine is withdrawn, and TBil and PTA detected during relapse may all impact the prognosis.