核苷（酸）类似物加干扰素延长疗程对HBeAg阳性患者HBsAg转换的初探

A study of seroconversion of HBsAg in chronic hepatitis B patients with HBeAg positive by combination treatment with interferon and nucleoside analogue

目的探讨使用IFN和核苷（酸）类似物联合治疗HBeAg阳性慢性乙型肝炎获得HBsAg血清转换患者的临床特点和作用机制。方法收集2001年1月至2007年5月使用IFN和拉米夫定或阿德福韦酯联合治疗后出现HBsAg转换的慢性乙型肝炎患者共32例，转阴后定期随访并分析其临床特点。结果HBVDNA于治疗后3～6个月转阴，初治和复治（包括拉米夫定耐药）患者治疗2年均未见病毒学反弹或新的临床耐药出现。HBsAg转换后平均随访13．2个月，2例出现HBsAg复阳，其中1例抗病毒治疗重新获得HBsAg转换，另1例未再治疗，维持在HBeAg转换状态。余30例患者均维持在HBsAg转换状态。7例治疗后（其中3例治疗前、后两次）行肝穿刺病理和免疫组织化学检查。6例肝内HBsAg及HBcAg均阴性，1例HBsAg免疫组织化学阳性者复发；3例治疗前、后对比肝组织炎性反应和纤维化程度均减轻，其中1例由G2S4变为G1S2～3，该例停用IFN后AI。T仍异常，余4例有轻度炎性反应和纤维化。转阴模式有三种，转阴顺序为HBVDNA—HBeAg—HBsAg，占59％（19／32例）；HBeAg和HBsAg同步转阴，占31％（10／32例）；HBsAg先于HBeAg转阴，占9％（3／32例）。治疗1年时血清HBsAg滴度71．4％（15／21例）〈100COI；63．6％（7／11例）〈250IU／L。联合治疗的不良反应基本上同IFN单药治疗。结论联合治疗和延长疗程是获得HBsAg血清转换的关键。肝组织内HBsAg阳性和血清抗-HBs低水平者易复发。疗程1年时血清HBsAg滴度〈100COI或〈250IU／L,可能是HBsAg易转阴的预测指标。

Objective To study clinical features and mechanism in patients suffered from chronic hepatitis B achieving seroconversion of HBsAg by combination treatment with interferon （IFN） and nucleoside analogue （NA）. Methods Thirty-two cases with chronic HBV hepatitis were enrolled into this retrospective study. All of them received combination treatment with IFN and Lamivudine/ Adefovir, as well as achieved seroconversion of HBsAg from June, 2001 to May, 2007. All the cases in this study were followed up. Results Generally, serum HBV DNA fell below the detection limit 3 to 6 months after starting combination treatment. Virological breakthrough/relapse or new clinical resistant had not been found in all enrolments after combination treatment, including patients with previous resistant to Lamivudine, although the average length of treatment was over 2 years. The average period of following up after seroconversion of HBsAg was 13.2 months. Two cases transfered back to HBsAg positive, one of them achieved seroconversion of HBsAg again by the anti-virus treatment, and the other one gave up treatment and remained anti-HBe positive and HBeAg negative. The other 30 cases kept at the stage of seroconversion of HBsAg. Seven patients underwent liver biopsy after seroconversion of HBsAg, and 3 of them had taken liver biopsy before combination therapy too. Biopsy specimens were scored for fibrosis and necroinflammation according to the Knodell histological activity index. Six cases showed HBsAg and HBcAg negative by immunohistochemistry, and only 1 case with HBsAg positive in liver tissue experienced relapse. Inflammation and fibrosis grade of the 3 cases who had taken liver biopsy twice were lowered after HBsAg seroconversion, although the ALT level of 1 case who had turned from G2S4 to G1S2-3 remained abnormal after HBsAg seroconversion. According to the sequence and character of HBsAg seroeonversion, there were three models of HBsAg conversion. The sequence of transition was HBV DNA→HBeAg→HBsAg, which was dominant one, accounting for 59% （19/32 cases）. HBV DNA negative, and the titer of HBeAg wandering at a low level, after then HBeAg and HBsAg change to negative in the same time, 31% （10/32 cases）. The titer of HBsAg decreased rapidly after the HBV DNA clearance, and the HBsAg clearance was earlier than HBeAg, 9% （3/32 cases）. After 1 year of combination therapy, there were 15 of 21 cases （71.4%） whose titer HBsAg showed less than 100 COI by agent from Roche, and 7 of 11 cases （63.6%） whose titer HBsAg showed less than 250 IU/L by agent from Abbott. The frequency of adverse reaction was similar with that induced by IFN monotherapy, and no new adverse reaction was found. Conclusions Combination therapy and long course treatment might be the key to achieve the HBsAg seroconversion. Those with HBsAg in liver tissue and （or） low serum antbHBs are more likely to relapse. The titer of HBsAg（100 COI （Roche, Germany ） or,（ 250 IU/L （Abbott, USA） after one year treatment may be regarded as a predict index of HBsAg seroconversion.