贵州地区HBeAg阳性乙型肝炎病毒高载量孕妇母婴阻断的临床研究

Clinical study on blocking mother-to-child transmission of hepatitis B virus with high viral load and HBeAg positivity during pregnancy in Guizhou province

目的观察贵州地区HBeAg阳性高载量乙型肝炎孕妇母婴阻断的有效性、安全性及相关母婴结局。方法回顾性收集2016年5月至2017年07月感染科、产科的门诊及住院病例,分为干预组、非干预组及非乙型肝炎孕妇组,每组75例。干预组为HBsAg及HBeAg均阳性,HBV DNA≥10^6 IU/ml乙型肝炎孕妇并于孕24~28周开始至分娩前进行抗HBV治疗,根据口服药物又分为:替诺福韦(TDF)组或替比夫定(LDT)组;非干预组为HBsAg及HBeAg均阳性,HBV DNA阳性乙型肝炎孕妇,孕期未用抗HBV药物;非乙型肝炎孕妇为正常未感染HBV孕妇。3组产妇所生婴幼儿均接受国家标准规范的乙型肝炎计划免疫接种,观察及统计出生时所孕孕周,出生时Apgar评分、分娩方式、喂养方式、性别及7个月龄时定量检测血清乙型肝炎标志物(HBVM)及HBV DNA。应用时间分辨荧光免疫定量分析法检测HBVM,荧光定量PCR技术检测HBV DNA;统计孕期干预组在用药前(孕12~24周),用药4周(孕28~32周),分娩前(孕36~40周)肝功能指标、HBsAg、HBeAg、HBV DNA变化及药物不良反应,治疗应答情况。计量资料数据组间比较采用t检验,组内比较采用秩和检验进行统计分析。结果干预组治疗用药:TDF组和LDT组在人口统计学和临床特征方面没有差异,包括肝功能检测指标、HBsAg、HBeAg及log10HBV DNA水平。log10HBV DNA与治疗前(TDF组:4.84 ± 2.01;LDT组:5.08±1.99)相比,TDF与LDT在孕期治疗结束时(TDF组:3.06±0.66;LDT组:3.51±1.20)均显著降低(P<0.05),治疗应答率100%。干预组服药均未出现严重不良反应。3组孕妇所分娩的婴幼儿HBV母婴传播感染结局:非干预组婴儿7个月龄时检测HBsAg阳性率为20.0%(15/75),HBeAg阳性率为17.3%(13/75)及HBV DNA阳性率为17.3%(13/75),其HBV母婴传播感染率为20%(15/75)。进一步分析非干预组婴幼儿HBV感染与母亲HBV DNA载量的关系,发现母婴传播感染者其母亲HBV DNA均≥10^6 IU/ml。干预组婴儿7个月龄时检测HBsAg、HBeAg及HBV DNA均阴性,HBV母婴传播感染率为0,HBV母婴阻断率为100%,而且其婴幼儿均有不同程度的乙型肝炎保护性抗体出现(抗-HBs,均值为144.33 mIU/ml),其抗体滴度高于非干预组及非乙型肝炎孕妇,与非干预组(抗-HBs,均值为65.91 mIU/ml)及非乙型肝炎孕妇(抗-HBs,均值为58.43 mIU/ml)比较,差异有统计学意义(P<0.05),与抗病毒药及分娩方式及喂养方式之间无明显相关性。结论非干预组发生了HBV母婴传播,母婴传播感染者其母亲分娩前HBV DNA均≥106 IU/ml.提示HBeAg阳性,高载量HBV DNA复制是发生乙型肝炎母婴传播的独立危险因素。因此,针对乙型肝炎高危孕妇,需产前药物干预及产后标准联合免疫阻断,才能从真正临床上实现乙型肝炎母婴零传播。

ObjectiveTo observe the efficacy and safety related measures by blocking mother-to-child transmission of hepatitis B virus with high viral load and HBeAg positivity during pregnancy in Guizhou province.MethodsOutpatient and inpatient cases of the Department of Infectious Diseases and Obstetrics of Guizhou Medical University Affiliated Hospitals from May 2016 to July 2017 were retrospectively divided into intervention group, non-intervention group and nonhepatitis B pregnant women group; with 75 cases in each group. HBsAg and HBeAg were positive in the intervention group. Pregnant women with HBV DNA ≥10^6 IU/ml were treated with anti-HBV therapy for 24 to 28 weeks of gestation until delivery. According to oral drugs, they were divided into tenofovir (TDF) group or telbivudine (LDT) group, non-intervention group (HBsAg and HBeAg positive), HBV DNA positive pregnant women, pregnant women with no anti-HBV drugs, non-hepatitis B pregnant women (normal pregnant women without HBV infection). Infants and young children born to the three groups of women were immunized with the national viral hepatitis B action plan. The gestational weeks and Apgar scores at birth, delivery mode, feeding mode, sex and 7-months-old age were observed and counted. Serum hepatitis B markers (HBVM) and HBV DNA were quantitatively detected. HBVM was detected by time-resolved fluorescence immunoassay (TRFIA), and HBV DNA was detected by real-time PCR (FQ-PCR). The changes of liver parameters, HBsAg, HBeAg, HBV DNA, adverse drug reactions and treatment response of pregnant intervention group before medication (12-24 weeks of gestation), 4 weeks of medication (28-32 weeks of gestation), 36-40 weeks of gestation (36-40 weeks of gestation) were statistically calculated. A t-test was used to compare the data between the measurements. Data measurements within the groups were analyzed using rank -sum test.ResultsIn the intervention group, therapeutic medications showed no differences in demographic and clinical characteristics between TDF group and LDT group, including liver parameters, HBsAg, HBeAg and log10HBV DNA level. Compared with pre-treatment (TDF group: 4.84±2.01; LDT group: 5.08±1.99), TDF and LDT were significantly lower at the end of pregnancy (TDF group: 3.06±0.66; LDT group: 3.51±1.20). P<0.05); and the treatment response rate was 100%. There were no serious adverse events in the intervention group. Infants and young children (7-months-old) in the intervention group had negative HBsAg, HBeAg and HBV DNA. The mother-to-child transmission rate of HBV was zero, with blocking rate of 100%. In addition, both infants and young children had different degrees of hepatitis B protective antibodies (anti-HBs, M: 144.33), and their antibody titers were higher than that of non-intervention group (anti-HBs, M: 65.91) and non-hepatitis B pregnant women (anti-HBs, M: 58.43). The difference was statistically significant (P<0.05), and there was no significant correlation between the use of antiviral and the way of delivery and feeding. Outcomes of mother-to-child transmission of HBV infection in infants and young children (7-months-old) delivered by three groups of pregnant women in the non-intervention groups had 20.0% (15/75)/ 17.3% (13/75) HBsAg/HBeAg positivity rate, and 17.3% (13/75) HBV DNA positivity rate. Overall, mother-to-child transmission rate of HBV infection was 20% (15/75). Furthermore, the relationship between mother's HBV DNA load and infant HBV infection in the non-intervention group showed mother's HBV DNA≥10^6 IU/ml.ConclusionIn the non-intervention group, mother-to-child transmission of HBV occurred, and infected mothers HBV DNA was ≥10^6 IU/ml before delivery. This suggests that HBeAg positive and high load HBV DNA replication were independent risk factors for mother-to-child transmission of hepatitis B. Therefore, prenatal drug intervention and postpartum standard immune blockade are necessary for high-risk pregnant women with hepatitis B to achieve zero mother-to-child transmission of hepatitis B in realclinical practice.