抗原抗体复合物型治疗性疫苗(乙克)临床研究中患者血清乙型肝炎病毒表面抗原下降的分析与启示

近年来全球慢性乙型肝炎(chronic hepatitis B，CHB)防治指南提出了“功能性治愈”(functional cure)的概念，即患者经过治疗达到血清乙型肝炎病毒表面抗原(hepatitis B virus surface antigen，HBsAg)消失，但现有抗病毒治疗很难实现这一目标。本研究对既往临床试验中经抗原抗体复合物型治疗性疫苗(乙克)治疗后的CHB患者HBsAg下降情况进行了归纳分析，结果显示，经乙克治疗随访后达到乙型肝炎e抗原(hepatitis B e antigen，HBeAg)血清学转换者的HBsAg下降高达0.95log₁₀IU/mL，显著高于未达到HBeAg血清学转换者的0.32log₁₀IU/mL(P<0.01)，而经氢氧化铝佐剂治疗随访后发生HBeAg血清学转换(0.49log₁₀IU/mL)者与未发生HBeAg血清学转换者(0.36log₁₀IU/mL)之间HBsAg下降无统计学差异。乙克组治疗过程中，丙氨酸氨基转移酶(alanine aminotransferase，ALT)骤升(ALT flare)在HBsAg下降>1.0log₁₀IU/mL者中较多见，氢氧化铝组未观察到此现象。回归分析显示，乙克治疗后HBsAg下降的影响因素有患者出现HBeAg血清学转换、感染的HBV为B基因型、治疗过程中ALT出现10倍增高，以及基线血清HBsAg为高水平。结果提示，乙克诱导的特异性免疫对降低CHB患者血清HBsAg水平有一定效果，采用“抗病毒药物治疗＋针对HBsAg的中和性抗体被动免疫＋乙克主动免疫”的“三明治”治疗策略可能会提高“功能性治愈”率。

Impact of antigen-antibody immune complex vaccine on decline of serum hepatitis B virus surface antigen levels in chronic hepatitis B patients

For chronic hepatitis B (CHB) therapy, a new concept named “functional cure” that is defined as loss of the serum hepatitis B virus surface antigen (HBsAg) is proposed and pursued clinically in recent years. However, this goal is hard to be approached by current available antiviral therapy. To understand the performance on reduction of HBsAg in antigen-antibody complex therapeutic hepatitis B vaccine (YIC)-treated CHB patients, a pooled analysis was carried out based on phase Ⅱb and Ⅲb trials. After treatment and withdrawal follow-up, it showed that those who achieved HBV e antigen (HBeAg) seroconversion experienced a decrease of HBsAg level up to 0.95log₁₀IU/mL, which was significantly higher than 0.32log₁₀IU/mL of those who did not achieve HBeAg seroconversion (P<0.01). Conversely, the reduction was 0.49log₁₀IU/mLand 0.36log₁₀IU/mL among HBeAg seroconverted and non-converted patients in control group treated with aluminum hydroxide adjuvant (Alum). During treatment period, alanine aminotransferase (ALT) flare was more frequently detected among those patients who reached a HBsAg reduction of >1.0log₁₀IU/mL in YIC group, rather than in Alum group. Predictors of HBsAg reduction were HBeAg seroconversion, B genotype of HBV infection, ALT flare occurred during treatment, and high serum HBsAg levels at baseline. Since specific adaptive immune response elicited by YIC has been demonstrated in some CHB patients, to further improve the rate of “functional cure”， the “sandwich” strategy (antiviral treatment ＋ HBsAg monoclonal antibody ＋ YIC) might be considerable.