HBeAg阳性慢性乙型肝炎患者HBV前C/BCP突变/准种与HBeAg和HBV DNA的关系

目的探讨HBeAg阳性慢性乙型肝炎（eP-CHB）HBV前C/BCP突变/准种及其与HBeAg、HBV DNA水平的关系。 方法采用断面研究对2016年1月至2018年12月就诊于首都医科大学附属北京佑安医院的220例eP-CHB患者进行前C/BCP突变检测,其中24例患者进行前C/BCP区扩增、克隆,同步检测血清HBeAg和HBV DNA水平,分析前C/BCP突变/准种的发生情况及其与HBeAg和HBV DNA水平的关系。 结果220例eP-CHB患者中,HBV前C/BCP总突变率为70.0%（154/220）,前C/BCP共同突变率为18.2%（40/220）,前C突变率为30.9%（68/220）,BCP突变率为57.3%（126/220）。HBV DNA≥ 5 lgIU/ml患者上述4种突变检出率均高于HBV DNA< 5 lgIU/ml者,其中前C/BCP总突变和BCP突变患者差异有统计学意义（χ² = 5.809、P = 0.016,χ² = 5.081、P = 0.024）。HBeAg水平越低（< 500 COI、500～1 000 COI和> 1 000 COI共3组患者比较）,以上4种突变检出率越高,差异有统计学意义（χ² = 31.738、17.291、16.263、22.164,P均< 0.001）。HBV DNA≥ 5 lgIU/ml患者中,HBeAg水平越低,以上4种突变检出率越高,差异亦均有统计学意义（χ² = 40.503、19.654、16.727、29.119,P < 0.001）。准种检测中,前C区高突变组患者HBeAg水平低于低突变组,差异有统计学意义（t = 2.230、P = 0.017）,前C、BCP高突变组与低突变组间HBV DNA水平差异无统计学意义（t = 0.624、P = 0.462,t = 0.893、P = 0.317）。 结论eP-CHB患者中仍存在广泛的前C/BCP突变。高HBV DNA、低HBeAg表达者,前C和BCP突变的发生率较高;前C区突变株在准种中比率高者更影响HBeAg的表达。推测前C/BCP突变可能是eP-CHB出现低HBeAg、高HBV DNA,并导致抗病毒治疗停药后易复发的原因。

Relationship between HBV pre-C/BCP mutation/quasispecies and HBeAg and HBV DNA in HBeAg positive patients with chronic hepatitis B

ObjectiveTo investigate the pre-C/BCP mutation and quasispecies in patients with hepatitis B virus e antigen (HBeAg) positive (eP-CHB) and the relationship with the levels of HBeAg and HBV DNA. MethodsThe pre-C/BCP mutation was detected in 220 patients with eP-CHB from January 2016 to December 2018 admitted in Beijing You’an Hospital, Capital Medical University by cross-sectional study. Among whom, the pre-C/BCP region in 24 patients was amplified and cloned. Serum HBeAg and HBV DNA levels were detected simultaneously. The pre-C/BCP mutation and quasispecies and the relationship with HBeAg and HBV DNA levels were analyzed, respectively. ResultsAmong the 220 patients with eP-CHB, total mutation rate of pre-C/BCP was 70.0% (154/220), co-mutation rate of pre-C/BCP was 18.2% (40/220) and mutation rate of pre-C and BCP were 30.9% (68/220) and 57.3% (126/220), respectively. The detection rates of the above four mutations in patients with HBV DNA ≥ 5 lgIU/ml were all higher than those of patients with HBV DNA < 5 lgIU/ml, the rates of BCP mutation and pre-C/BCP total mutation were significantly different (χ² = 5.809, P = 0.016; χ² = 5.081, P = 0.024). The lower HBeAg level was (< 500 COI, 500-1 000 COI and > 1 000 COI), the higher detection rates of the above four mutations were, all with significant difference (χ² = 31.738, 17.291, 16.263, 22.164; all P < 0.001). Similarly, among the cases with HBV DNA ≥ 5 lgIU/ml, the detection rates of the above four mutations were higher among the cases with lower HBeAg level, with significant differences (χ² = 40.503, 19.654, 16.727, 29.119; all P < 0.001). In quasispecies detection, HBeAg level of cases with high mutation of the pre-C region was lower than that with low mutation, with significant difference (t = 2.230, P = 0.017). There was no significant difference between HBV DNA levels of cases with high mutation and low mutation of the pre-C region (t = 0.624, P = 0.462) and BCP (t = 0.893, P = 0.317). ConclusionsThere were still extensive pre-C/BCP mutations in eP-CHB. The mutation rates of pre-C and BCP were higher in patients with high HBV DNA and low HBeAg level. The high proportion of pre-C mutants in quasispecies had more influence on HBeAg expression. Combined with the previous studies, it was speculated that the pre-C/BCP mutation may be the cause of low HBeAg and high HBV DNA in eP-CHB and lead to the recurrence after withdrawal of antiviral therapy.