乙型肝炎病毒感染孕妇替比夫定母婴阻断及其对婴儿乙肝疫苗免疫应答的影响

Mother-to-child blockade with telbivudine of pregnant women infected with hepatitis B virus and the influence on the immune response to hepatitis B vaccine of infants

目的探讨高病毒载量乙型肝炎病毒(HBV)感染的孕妇应用替比夫定行母婴阻断疗效,及其对乙肝疫苗免疫应答的影响。方法回顾性收集2017年10月1日至2019年12月30日于首都医科大学附属北京地坛医院产检并分娩的慢性HBV感染202例孕妇及其分娩婴儿,选取孕中期HBV DNA>2.0×105 IU/ml的孕妇,其中132例孕中晚期给予替比夫定行抗病毒治疗者为研究组,未服用抗病毒药物的70例孕妇中剔除3例母婴阻断失败者为对照组(67例)。两组孕妇所产新生儿出生后2 h内均给予乙肝疫苗10μg及100 IU乙肝免疫球蛋白,出生后1个月、6个月常规给予10μg乙肝疫苗免疫接种。采用微粒化学发光法检测1岁婴儿乙型肝炎病毒表面抗体(HBsAb)水平,采用非参数秩和检验比较两组婴儿对乙肝疫苗的免疫应答。两组孕妇及其新生儿呈正态分布的计量资料采用独立样本t检验,非正态分布的计量资料采用非参数检验;计数资料采用Pearson卡方检验或连续校正卡方检验进行分析。结果入组202例孕妇中,服用替比夫定者与未服用者母婴阻断失败率[0(0/130)vs.4.29%(3/70)]差异有统计学意义(χ^(2)=5.74、P=0.017)。研究组和对照组孕妇年龄(t=-1.62、P=0.110)、孕次(t=0.27、P=0.787)、产次(t=1.325、P=0.187)、体重(t=0.55、P=0.580)、孕中期丙氨酸氨基转移酶(ALT)(Z=-0.19、P=0.85)及HBV DNA载量(t=0.49、P=0.620)、剖宫产率(χ^(2)=0.71、P=0.400)及孕产期并发症等差异均无统计学意义。研究组和对照组孕妇分娩前HBV DNA载量[(3.74±0.78)lgIU/ml vs.(7.29±0.71)lgIU/ml]差异有显著统计学意义(t=31.88、P<0.001)。两组孕妇所产新生儿出生孕周(t=1.72、P=0.090)、身长(t=0.39、P=0.696)、出生体重(t=-0.13、P=0.90)、性别(χ^(2)=0.25、P=0.620)、Apgar评分(t=0.213、P=0.832)、1岁时体重(t=-0.20、P=0.840)、ALT(Z=-0.40、P=0.690)及HBsAb水平(Z=0.76、P=0.450)差异均无统计学意义。研究组孕妇所产婴儿1岁时对乙肝疫苗免疫无应答率、弱应答率和强应答率分别3.79%(5/132)、22.73%(30/132)和73.48%(97/132);对照组分别为0(0/67)、14.93%(10/67)和85.07%(57/67),差异无统计学意义(Z=-1.93、P=0.054)。结论替比夫定可显著降低HBV感染孕妇的HBV DNA载量,提高母婴阻断成功率;孕期应用替比夫定抗病毒治疗不影响婴儿对乙肝疫苗的免疫应答。

Objective To investigate the effect of telbivudine on mother-to-child blockade of pregnant women infected with hepatitis B virus(HBV)and the influence on the immune response to hepatitis B vaccine of infants.Methods The pregnant women with HBV DNA>2.0×105 IU/ml during the middle of the pregnancy and their infants were recruited from Beijing Ditan Hospital,Capital Medical University from October 1st,2017 to December 30th,2019,among them,132 patients who were given telbivudine during middle and late pregnancy were collected as study group,and 70 pregnant women who did not take antiviral drugs excluding 3 cases with mother-to-child block failure were collected as control group(67 cases).All the neonates of pregnant women were injected with recombinant hepatitis B vaccine(10μg)and hepatitis B immunoglobulin(100 IU)within 2 hours after birth,and followed by routine injection of the recombinant hepatitis B vaccine 1 month and 6 months after birth.Microticle chemiluminescence method was used to detect HBV surface antibody(HBsAb)titer in 1-year-old children,and the immune responses of children to hepatitis B vaccine were compared between the two groups by non-parametric rank sum test.The measurement data with normal distribution of the pregnant women and their newborns were analyzed by independent sample t-test and the measurement data without normal distribution were analyzed by non-parametric test;count data were analyzed by Pearson chi-square test or continuously corrected chisquare test.Results Among the 202 pregnant women,the mother-to-child blockade failure rates between pregnant women treated with telbivudine or not were significantly different(0 vs.4.29%:χ^(2)=5.74,P=0.017).There were no statistical differences in age(t=-1.62,P=0.110),number of pregnancies(t=0.27,P=0.787),number of births(t=1.325,P=0.187),body weight(t=0.55,P=0.580),alanine transaminase(ALT)(Z=-0.19,P=0.850),and HBV DNA load(t=0.49,P=0.620),cesarean section rate(χ^(2)=0.71,P=0.400)and complications during pregnancy and perinatal period between cases in study group and control group.The difference of HBV DNA load before delivery between the two groups was statistically significant(t=31.88,P<0.001).There were no statistical differences in gestational weeks of birth(t=1.72,P=0.09),body length(t=0.39,P=0.696),birth weight(t=-0.13,P=0.900),sex ratio(χ^(2)=0.25,P=0.620),Apgar score(t=0.213,P=0.832)between the two groups of neonates,and no statistical difference in weight(t=-0.20,P=0.840),ALT(Z=-0.40,P=0.690)and HBsAb(Z=0.76,P=0.450)between the two groups of infants at 1-year-old.No response rate,low response rate and stong response rate to hepatitis B vaccine were 3.79%(5/132),22.73%(30/132)and 73.48%(97/132)of 1-year-old children in study group,respectively,which were 0(0/67),14.93%(10/67)and 85.07%(57/67)in control group,wihout statistical difference(Z=-1.93,P=0.054).Conclusions Telbivudine treatment during pregnancy could significantly improved the successful rate of mother-to-child blockade by reducing maternal HBV DNA load and did not affect the immune response to hepatitis B vaccine of infants.