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中华实验和临床感染病杂志(电子版) ›› 2022, Vol. 16 ›› Issue (03) : 158 -164. doi: 10.3877/cma.j.issn.1674-1358.2022.03.003

临床论著

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
曹秀贞1, 易为1,†(), 王夫川1, 杨秀梅1   
  1. 1. 1000015　北京，首都医科大学附属北京地坛医院妇产科
  • 收稿日期:2021-08-05 出版日期:2022-06-15
  • 通信作者: 易为
  • 基金资助:
    国家科技重大专项(No. 2017ZX10203202-003，2017ZX10201201-001-006，2017ZX10201201-002-006，2018ZX10715-005-003-005); 首都临床特色专项资助项目(No. Z151100004015122); 北京市医管中心临床专项项目(No. XMLX 201706，XMLX 202127)

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

Xiuzhen Cao1, Wei Yi1,†(), Fuchuan Wang1, Xiumei Yang1   

  1. 1. Department of Obstetrics and Gynecology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
  • Received:2021-08-05 Published:2022-06-15
  • Corresponding author: Wei Yi
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引用本文：

曹秀贞, 易为, 王夫川, 杨秀梅. 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[J]. 中华实验和临床感染病杂志(电子版), 2022, 16(03): 158-164.

Xiuzhen Cao, Wei Yi, Fuchuan Wang, Xiumei Yang. 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[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2022, 16(03): 158-164.

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10 μg及100 IU乙肝免疫球蛋白，出生后1个月、6个月常规给予10 μg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（χ2 = 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（χ2 = 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（χ2 = 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。

关键词: 肝炎病毒，乙型, 替比夫定, 乙肝疫苗, 免疫应答, 母婴阻断
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 (10 μg) 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 chi-square 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%: χ2 = 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 (χ2 = 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 (χ2 = 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.

Key words: Hepatitis B virus, Telbivudine, Hepatitis B vaccine, Immune response, Mother-to-child blockade
表1 研究组和对照组孕妇基线资料
基线资料 研究组（132例） 对照组（67例） 统计量 P值
年龄（±s，岁） 28.92 ± 3.19 29.61 ± 2.67 t =-1.62 0.110
孕次（±s，次） 2.13 ± 1.52 2.07 ± 1.07 t = 0.270 0.787
产次（±s，次） 1.50 ± 0.57 1.36 ± 0.53 t = 1.325 0.187
ALT [M（P25，P75），U/L）] 15.7（13.53，22.18） 16.9（11.70，23.50） Z =-0.190 0.850
体重（±s，kg） 73.81 ± 10.71 72.94 ± 10.06 t = 0.550 0.580
剖宫产[例（%）] 49（37.12） 29（43.28） χ2 = 0.710 0.400a
胎膜早破[例（%）] 16（12.12） 9（13.43） χ2 = 0.070 0.792a
糖尿病[例（%）] 42（31.82） 24（35.82） χ2 = 0.321 0.633a
甲状腺功能异常[例（%）] 7（5.30） 5（7.46） χ2 = 0.366 0.543b
HBV DNA（±s，lgIU/ml）        
  治疗前 7.35 ± 0.59 7.30 ± 0.68 t = 0.490 0.620
  分娩前 3.74 ± 0.78 7.29 ± 0.71 t = 31.880 < 0.001
表2 两组孕妇所生新生儿及1岁时基线资料
基线资料 研究组（132例） 对照组（67例） 统计量 P值
出生孕周（±s，周） 39.74 ± 0.93 39.49 ± 0.98 t = 1.720 0.090
男/女（例） 68/64 32/35 χ2 = 0.250 0.620a
身长（±s，cm） 50.11 ± 0.65 50.15 ± 0.68 t = 0.390 0.696
体重（±s，kg）        
  出生时 3.40 ± 0.40 3.41 ± 0.40 t =-0.130 0.900
  1岁时 10.54 ± 1.18 10.58 ± 1.15 t =-0.200 0.840
Apgar评分（±s，分） 9.97 ± 0.23 9.98 ± 0.14 t = 0.213 0.832
1岁时ALT [M（P25，P75），U/L）] 28.85（16.70，23.74） 20.40（16.10，25.0） Z =-0.400 0.690b
表3 两组孕妇所产婴儿1岁时对乙肝疫苗的免疫应答和HBsAb水平
组别 例数 免疫应答[例（%）] HBsAb [M（P25，P75），IU/L）]
无应答 弱应答 强应答
研究组 132 5（3.79） 30（22.73） 97（73.48） 333.79（87.23，948.30）
对照组 67 0（0.00） 10（14.93） 57（85.07） 399.03（164.87，881.86）
统计量     Z =-1.930   Z = 0.760
P值     0.054a   0.450b
[1]
Giles ML, Visvanathan K, Lewin SR, et al. Chronic hepatitis B infection and pregnancy[J]. Obstet Gynecol Surv,2012,67(1):37-44.
[2]
杨汝沛，王津涛，李柯, 等. 成都市2002-2005年出生儿童乙肝疫苗首针及时接种率及影响因素[J]. 中华疾病控制杂志,2009,13(3):267-269.
[3]
张磊，邵中军. HBV宫内传播研究在乙型肝炎防控工作中发挥着重要的作用[J]. 中华流行病学杂志,2019,40(9):9-12.
[4]
Wu JS, Hwang LY, Goodman KJ, et al. Hepatitis B vaccination in high-risk infants: 10-year follow-up[J]. J Infect Dis,1999,179(6):1319-1325.
[5]
Zhang L, Gui X, Teter C, et al. Effect of hepatitis B immunization on prevention of mother-to-infant transmission of hepatitis B virus and on the immune response of infants towards hepatitis B vaccine[J]. Vaccine,2014,32(46):6091-6097.
[6]
Lee KH, Shim KS, Lim IS, et al. Changes in hepatitis B virus antibody titers over time among children: a single center study from 2012 to 2015 in an urban of South Korea[J]. BMC Pediatr,2017,17(1):164.
[7]
李凡，王廷材，刘冰, 等. 甘肃省武威市学龄前儿童乙肝疫苗接种和免疫效果调查[J]. 中华疾病控制杂志,2012,16(6):524-576.
[8]
Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection[J]. J Hepatol,2011,55(6):1215-1221.
[9]
Pan CQ, Duan Z, Dai E, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load[J]. N Engl J Med,2016,374(24):2324-2334.
[10]
Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B[J]. Gastroenterology,2009,136(2):486-495.
[11]
潘禹辰，姜晶. HBsAg和HBeAg双阳性母亲的HBV母婴传播阻断效果影响因素的队列研究及Meta分析[J]. 临床肝胆病杂志,2020,36(11):2514-2514.
[12]
李振华，解宝江，张丽菊, 等. 乙型肝炎病毒表面抗原和e抗原双阳性乙型肝炎病毒稿载量孕妇孕晚期应用替比夫定行母婴阻断的疗效[J/CD]. 中华实验和临床感染病杂志(电子版),2019,13(3):214-220.
[13]
Wu ZG, Yan WM, Guo W, et al. Telbivudine preserves T-helper 1 cytokine production and down regulates programmed death ligand 1 in a mouse model of viral hepatitis[J]. J Viral Hepat,2010,17(1):24-33.
[14]
Zheng YH, Huang ZM, Chen XH, et al. Effects of telbivudinetreannem on tlle circulating CD4+ T-cell subpopulations in chronic hepatitis B patients[J]. Mediat Inflamm,2012,2012:789859.
[15]
Evans A, Riva A, Cooksley H, et al. Programmed death 1 expression during antiviral treatment of chronic hepatitis B: impact of hepatitis B e-antigen seroconversion[J]. Hepatology,2008,48(3):759-769.
[16]
Ma L, Cai YJ, Yu L, et al. Treatment with telbivudine positively regulates antiviral immune profiles in Chinese patients with chronic hepatitis B[J]. Antimicrob Agents Chemother,2013,57(3):1304-1311.
[17]
Wang GQ, Ding YP, Dong YH. Telbivudine treatment is associated with high hepatitis B e antigen seroconversion and immune modulatory effects in chronic hepatitis B patients[J]. J Viral Hepat,2013,20(Suppl 1):S9-S17.
[18]
王根菊，韩国荣，江红秀, 等. 乙肝孕妇服用替比夫定对新生儿阻断效果及外周血T细胞亚群和补体的影响[J]. 南京医科大学学报(自然科学版),2017,37(11):1507-1509.
[19]
Zhuge S, Ge C, Yang Y, 等. 母亲和/或父亲为HBV感染者的儿童在HBV疫苗免疫接种后隐匿性HBV感染的发生率:一项基于医院的研究[J]. 临床肝胆病杂志,2020,36(11):2483-2483.
[20]
周乙华，李彤，庄辉. 对《中国乙型肝炎病毒母婴传播防治指南(2019年版)》的商榷[J]. 临床肝胆病杂志,2020,36(1):59-61.
[21]
中华医学会感染病学分会，中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019)[J/CD]. 中华实验和临床感染病杂志(电子版),2019,13(6):441-466.
[22]
Bruce MG, Bruden D, Hurlburt D, et al. Antibody levels and protection after hepatitis B vaccine: results of a 30-year follow-up study and response to a booster dose[J]. J Infect Dis,2016,214(1):16-22.
[23]
中华医学会妇产科学分会产科学组，中华医学会围产医学分会. 乙型肝炎病毒母婴传播预防临床指南(2020)[J]. 临床肝胆病杂志,2020,36(7): 1474-1481.
[24]
McMahon BJ, Bruden DL, Petersen KM, et al. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up[J]. Ann Int Med,2005,142(5):333-341.
[25]
张艳丽，李明慧，刘风, 等. 乙型肝炎病毒母婴阻断长期效果的随访研究[J]. 中华实验和临床病毒学杂志,2012,26(3):214-217.
[26]
王兰，白淑芬，杨立新, 等. HBsAg阳性孕妇的新生儿注射HBIG剂量与抗-HBs抗体滴度分析[J]. 现代医学,2012,40(1):48-50.
[27]
王斌，许喜喜，温海秀, 等. HBsAg阳性母亲所生婴儿乙型肝炎疫苗无/弱应答的影响因素研究[J]. 中华流行病学杂志,2017,38(7):911-915.
[28]
王彩云. HBsAg阳性母亲其婴幼儿联合阻断后无/低应答状态及加强免疫效果[J]. 中国继续医学教育,2015,7(33):115-116.
[29]
王静，冯玉岭，刘明晖, 等. HBsAg阳性母亲所生婴儿联合免疫后乙型肝炎表面抗体的动态变化[J]. 中华肝脏病杂志,2013,21(8):580-583.
[30]
Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: Recommendations of the advisory committee on immunization practices[J]. MMWR Recomm Rep,2018,67(1):1-31.
[31]
Rubin L, Hefer E, Dubnov Y, et al. An evaluation of the efficacy of the national immunization programme for hepatitis[J]. Public Health,2007,121(7):529-533.
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[12] 覃亚勤, 秦英梅. 8 369例人类免疫缺陷病毒感染/获得性免疫缺陷综合征患者合并乙型肝炎病毒和（或）丙型肝炎病毒感染临床分析[J]. 中华实验和临床感染病杂志(电子版), 2021, 15(05): 295-302.
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