静注乙型肝炎人免疫球蛋白(pH 4)预防肝移植术后乙型肝炎病毒感染的Ⅲ期临床观察

Phase Ⅲ Clinical Trial of Prevention of Hepatitis B Virus Reinfection after Liver Transplantation by Human Hepatitis B Immunoglobulin(pH 4) for Intravenous Injection

目的在常规使用拉米夫定的基础上,观察联合使用静注乙型肝炎人免疫球蛋白(pH 4)(Human hepatitis B im-munoglobulin for intravenous injection,HBIVIG)对乙型肝炎相关性肝病肝移植术后乙型肝炎病毒(HBV)再感染的预防效果及安全性。方法采用多中心、开放、以单用拉米夫定的历史文献和资料作为对照,与在每天口服100 mg拉米夫定常规用药的基础上,联合应用HBIVIG的肝移植术后患者HBV再感染的结果进行比较;以术后第7、30、90、180天时血清中HBsAg阴转率作为主要疗效指标,术后180 d为主要疗效评价时间点,其余为次要评价时间点;以术后第7、30、90、180天时血清HBV DNA定性检查结果为次要疗效指标;以不良反应、严重不良反应的种类、发生频率及抗-HCV检测结果为安全性评价指标。结果本研究138例患者进入安全性分析,125例患者进入疗效分析。联合用药180 d患者血清HBsAg阴转率为95.96%,7 d阴转率为99.08%,30 d阴转率为99.07%,90 d阴转率为99.01%;单用拉米夫定的历史文献数据分析共收集到肝移植患者153例,血清HBsAg在180 d阴转率为89.54%;4家中心收集到的43例单用拉米夫定历史病例180 d血清HBsAg的阴转率为74.42%;共发生不良反应48例,发生率为34.78%,其中,43例(89.58%)与研究药物无关,相关性不良反应为5例,其中与研究药物的关系为"很可能"的为1例(皮疹),与研究药物的关系原始描述为"可疑"的为4例。结论在常规使用拉米夫定的基础上,联合使用静注乙型肝炎人免疫球蛋白(pH 4)对预防乙肝相关性肝病肝移植术后HBV再感染是安全有效的,其疗效优于历史资料单用拉米夫定。

Objective To observe the effect and safety of human hepatitis B（HB） immunoglobulin for intravenous injection（HBIVIG）（pH 4） in prevention of HB virus（HBV） reinfection after liver transplantation due to HBV infection-associated diseases on the basis of routine administration of lamivudine.Methods A multi-center open trial was performed using the historical documents and data of administration of lamivudine as control.The preventive effect of HBV reinfection in patients receiving liver transplantation by HBIVIG combined with lamivudine（100 mg daily by oral route） was compared with that by lamivudine alone.The effect was evaluated using the serum HBsAg negative conversion rates on days 7,30,90 and 180 after transplantation as main indexes,and the qualitative determination results of serum HBV DNA at the time points as secondary indexes.Day 180 after transplantation was served as a main time point,while the others as secondary time points.Safety was evaluated using the kind and frequency of adverse and severe adverse reactions as well as determination result of anti-HCV as indexes.Results Safety was performed on 138 patients,and preventive effect on 125 ones.The serum HBsAg negative conversion rates of patients treated by HBIVIG combined with lamivudine were 95.96% on day 180,and 99.08%,99.07% and 99.01% on days 7,30 and 90 after transplantation respectively.Historical documents on 153 patients treated with lamivudine alone showed that the HBsAg negative conversion rate on day 180 was 89.54%.However,the historical data on 43 patients treated with lamivudine alone,collected from four centers,showed that the negative conversion rate was 74.42%.A total of 48 cases（34.78%） of adverse reactions were observed,of which 43 cases（89.58%） were unassociated with drugs.Of the other 5 cases,the relationships to the drugs used were described as ＂probable＂ in one case and ＂suspicious＂ in 4 cases.Conclusion HBIVIG combined with lamivudine was safe and effective in prevention of HBV reinfection after liver transplantation due to HBV infection-associated diseases,of which the effect was superior to that of lamivudine alone in historical data.