重组人Ⅱ型TNF-α受体-抗体融合蛋白对不同HBV感染状态下脊柱关节炎患者肝功能的影响

Liver safety of biosimilar of recombinanttumor necrosis factor-α receptor-antibody fusion protein in Spondyloarthritis patients under different status of HBV infection： a prospective observational study

目的 探讨国产重组Ⅱ型肿瘤坏死因子（TNF）受体-抗体融合蛋白（rh TNFR： Fc）对不同乙型肝炎病毒（HBV）感染状态下脊柱关节炎（SPA）患者肝功能及HBV感染的影响.方法 纳入2012年2月至2014年8月在中山大学孙逸仙纪念医院风湿免疫科就诊的活动期SpA患者,经rhTNFR：Fc单药或联合治疗至少12周,治疗前及治疗第4、12周（主要观察终点）评估SpA病情、肝功能及HBV感染指标.如患者同意,延长rh TNFR：Fc治疗并随访至第24周（次要观察终点）.结果 81例患者完成12周随访,其中HBV携带组21例,既往HBV感染组25例,无HBV感染组35例.第4周时3组各1例丙氨酸转氨酶（ALT）升高但未超过3倍.治疗24周,既往感染组均无再激活,无感染组均无新感染,携带组4例出现再激活,均无伴ALT超过正常上限2倍,其中7例基线HBV-DNA阴性且未预防性抗病毒治疗者,2例患者分别于第10、24周时发生HBV再激活,HBV-DNA自行转阴或抗病毒治疗后转阴;1例rh TNFR：Fc联合沙利度胺12周后改沙利度胺维持,第16周发生HBV-DNA再激活,第24周自行转阴.4例基线HBV轻度复制的携带组患者均未发生再激活,9例基线HBV高复制者1例对预防性抗病毒药物耐药而出现再激活.结论 rh TNFR：Fc为基础的短期治疗可引起HBV再激活,但多不引起肝炎活动.

Objective To investigate the influence of recombinant human tumor necrosis factor α receptor-antibody fusion protein （rhTNFR： Fc） to the Hepatitis B virus （HBV） infection status and liver function of Spondyloarthritis （SpA） patients under different HBV infection status.Methods Active SpApatients with normal liver function were enrolled in Sun Yat-sen Memorial hospital from February 2012 to August 2014.All were treated with rhTNFR ： Fc based therapy （monotherapy or combined therapy） for at least 12 weeks.SpA disease activity, HBV infection status and liver function were evaluated at each interview（baseline, 4th and 12th week, as primary endpoint）.Part of the patients were evaluated at 24th week with or withoutextendedrhTNFR： Fc treatment （as secondary endpoint） based on their choice.Results Eighty-one patientswho completed 12-week follow-up visit were divided into chronic HBV carrier group（n =21）, past HBV exposure group（n =25） and free of HBV infection group（n =35）.Alanine transaminase （ALT） elevated （no more than 3-fold of normal） in 3 patients from 3 groups respectively at 4th week.During 24-week follow-up, none in past HBV exposure group or in free of HBV infection group developed HBV reactivation or HBV infection;and 4 patients in chronic HBV carrier group developed HBV reactivation without more than 2-fold of normalelevation of ALT.Among 7 patients with negative baseline HBV-DNA and without antiviral prophylaxis, 2 patients developed HBV reactivation at 10th, 24th week of rhTNFR： Fc therapy respectively and 1 patient developed reactivation at 16th week （12-week rhTNFR： Fc ＋ thalidomide therapy and following 4-week thalidomide monotherapy）, whose HBV-DNA load returned to normal spontaneously or after antiviral therapy.Four chronic HBV carriers with low-load of baseline HBV-DNA did not develop reactivation.One of 9 chronic HBV carriers with high-load of baseline HBV-DNA developed reactivation due to resistance of antiviral prophylaxis.Conclusions Short-term rhTNFR ： Fc based therapy may induce mild and transient HBV reactivation, usually without hepatitis.