替比夫定对乙型肝炎病毒高载量孕妇母婴传播的阻断效果及其安全性

替比夫定对乙型肝炎病毒高载量孕妇母婴传播的阻断效果及其安全性 韩国荣 江红秀 王根菊 岳欣 王翠敏 阚乃颖 吴岷岷 【摘要】 目的 评价妊娠中晚期应用替比夫定阻断 HBeAg 阳性且高病毒载量孕妇母婴传播的安全 性及有效性。 方法 选择孕 2032 周，HBeAg 阳性、HBV DNA 1.0107 拷贝/ml 孕妇，按患者 意愿分替比夫定组和对照组，替比夫定组予替比夫定 600 mg/d 口服抗病毒治疗直至产后 4 周或产后 继续服用，对照组患者不用抗病毒药物，肝功能异常者使用复方甘草酸苷。两组婴儿产后均接受主、 被动联合免疫，出生后 12 h 内、15 d 注射乙型肝炎免疫球蛋白 200 IU 及 0、1、6 个月注射乙型肝 炎疫苗 20g。婴儿 7 月龄时 HBsAg 及 HBV DNA 阳性者为 HBV 宫内感染。 结果 共纳入 220 例 孕妇，其中替比夫定组 120 例，对照组 100 例。替比夫定治疗者均在美国抗逆转录酶药物妊娠登记 处注册。分娩前替比夫定组孕妇 HBV DNA、HBeAg、ALT 水平下降明显。替比夫定组 HBV DNA 定量于治疗 2 周迅速下降，之后缓慢下降直至分娩。至分娩前替比夫定抗病毒孕妇有 37 例 HBV DNA 定量转阴，转阴率达 31%（37/120），而对照组无一例转阴。随访至 7 月龄，替比夫定组婴儿 HBV 宫内感染率为 0，显著低于对照组 8%（P = 0.002）。替比夫定组无一例母儿因不良反应或先天 性畸形失访。80 例替比夫定治疗者于产后 4 周停药，随访至产后 28 周无一例发生严重肝功能损害。 两组孕妇产后出血、不良妊娠、剖宫产率及新生儿胎龄、身长、体质量、Apgar 评分，差异无统计学 意义。 结论 HBeAg 阳性、HBV DNA 高滴度孕妇妊娠中晚期应用替比夫定抗病毒治疗能明显降低 母亲外周血 HBV DNA 定量，阻断 HBV 母婴传播，且耐受性和安全性良好。 【关键词】 肝炎病毒，乙型； 妊娠; 疾病传播，垂直； 预防和控制； 替比夫定 Efficacy and safety of telbivudine in pregnant women to prevent perinatal transmission of hepatitis B virus HAN Guo-rong, JIANG Hong-xiu, WANG Gen-ju, YUE Xin, WANG Cui-min, KAN Nai-ying, WU Min- min. Department of Gynecology and Obstetrics, the Second Affiliated Hospital of the Southeast University, Nanjing 210003, China Email: 【Abstract】 Objective To evaluate the efficacy and safety of telbivudine use during the second and third trimester of pregnancy for reducing hepatitis B virus (HBV) transmission from highly viremic hepatitis B e antigen-positive (HBeAg+) mothers to their fetuses. Methods Pregnant women, between weeks 2032 of gestation, who were HBeAg+ and had HBV DNA 1.0107 copies/mL were enrolled in our study. The women were offered inclusion into one of two treatment arms, based upon their personal preference: telbivudine or no telbivudine. The patients in the telbivudine treatment arm were adminstered 600 mg/d tebivudine at least until postpartum week 4. All delivered infants in both treatment arms were administered hepatitis B immune globulin (HBIG; 200 IU) within 12 hours of delivery and recombinant HBV vaccine (20 g) at 0, 1 and 6 months. The HBV perinatal transmission rate was determined by measuring HBsAg and HBV DNA in infants at postpartum week 28. Results A total of 220 pregnant women were enrolled in our study, 120 chose the telbivudine arm and 100 chose the control arm. All telbivudine treated subjects were registered in the Antiretroviral Pregancy Registry. Telbivudine treatment was associated with a marked reduction in the mothers serum HBV DNA, HBeAg and ALT levels before delivery. A striking decline of HBV DNA levels in treated mothers was observed at week 2 of treatment, which was followed by a gradual and steady decrease that continued until delivery. Thirty-seven (31%) of the telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction- undetectable viremia at delivery. At week 28, 0% of the infants delivered from telbivudine-treated mothers were HBsAg+ or HBV DNA+, as compared to 8% HBsAg+ or HBV DNA+ in the untreated control arm (P = 0.002). No telbivudine discontinuations occurred from adverse events, and no congenital deformities were observed in the infants delivered to telbivudine-treated mothers. Eighty mothers discontinued telbivudine at week 4 postpartum, and there were no cases of severe hepatitis. There were no significant differences between the two treatment arms for postpartum hemorrhage, adverse events during pregnancy, cesarean section, gestational age, or infants height/weight or Apgar scores. Conclusions Telbivudine use during the second and third trimester of pregnancy in HBeAg+ highly viremic mothers can safely reduce perinatal HBV transmission rates. Telbivudine was well-tolerated by our patient group. Furthermore, no safety concerns were observed in either the telbivudine-treated mothers or their delivered infants in short term follow-up. 【Keywords】 Hepatitis B virus; Pregnancy; Disease transmission, vertical; Prevention Telbivudine 虽经新生儿主被动联合免疫使 HBV 母婴传播率大大降低，但仍有约 10%的婴儿免疫失败而成为 HBV 携带者1-2。有学者在妊娠 32 周对高病毒载量的孕妇予拉米夫定抗病毒治疗，明显降低了新 生儿 HBV 感染，但仍有一定的失败率3-4。本研究于妊娠中晚期行替比夫定抗病毒治疗，评价替比 夫定对 HBV 母婴阻断的疗效及安全性，探讨孕期替比夫定抗病毒治疗的适应证、治疗时机及疗程， 为进一步降低 HBV 母婴传播的方法提供依据。 资料与方法 一、研究对象 经东南大学附属第二医院伦理委员会批准，选择 2009 年 1 月至 2010 年 3 月在东南大学附属第二医 院妇产科就诊、分娩的孕妇及其婴儿 220 例，根据患者意愿将其分为替比夫定组（120 例）和对照组 （100 例），服用替比夫定者签署书面知情同意书，并在美国抗逆转录酶药物妊娠登记处（APR）登 记注册。替比夫定组孕妇于妊娠 2032 周始服替比夫定（600 mg/d）至分娩后。HBV 携带者于分娩 后 1 个月停药，慢性乙型肝炎患者产后继续服用替比夫定。患者不用抗病毒药物，肝功能异常者使 用复方甘草酸苷。新生儿出生 12 h 内及 15 d 分别于臀大肌注射人乙型肝炎免疫球蛋白（hepatitis B immunoglobulin，HBIG）200 IU，新生儿 0、1、6 月龄于三角肌注射基因乙型肝炎疫苗 20g。两 组新生儿均行人工喂养。孕妇纳入标准：年龄 2040 岁；孕周 2032 周；HBsAg、HBeAg 阳性，且持续时间大于 6 个月；血清 HBV DNA 1107 拷贝/ml； ALT 5 log10 拷贝/ml，抗病毒治 疗有效率达 100%。 替比夫定组中 80 例产妇于分娩后 1 个月停药，停药后 1 个月，HBV DNA 反弹至（6.00 1.36） log10 拷贝/ml，停药后 6 个月 HBV DNA 定量为（ 7.92 0.52）log10 拷贝/ml。38 例继续服用替比 夫定者中无一例患者发生病毒学突破。 3. 两组孕妇 ALT 的检测结果：替比夫定组治疗前 ALT 异常者 23 例，平均 ALT 水平（81.8 45.2） U/L，分娩前 20 例恢复正常，3 例仍轻度异常（ 41.169.6 U/L ），复常率为 86.9%。对照组 治疗前 ALT 异常者 18 例，平均 ALT 水平（86.5 51.5）U/L，使用常规护肝降酶药物，仍有 8 例 分娩前异常（47.5104.2 U/L），复常率为 55.5%，与替比夫定组复常率比较，t = 5.072，P 400 U/L），两组产妇 ALT 异常率差异无统计学意义。替比夫定组 80 例分娩后 1 个月停药产 妇中，有 17 例（21.2%）于停药后 1 个月 ALT 发生轻度异常，波动于 41.4280.7 U/L 。两组产妇自 分娩后 2 个月 ALT 均逐渐恢复正常，至产后 28 周，替比夫定组仍有 3 例产妇 ALT 轻度异常，3 例 均为产后 1 个月停药者，对照组也有 3 例产妇 ALT 轻度异常者，两组 ALT 异常产妇均于产后 12 个 月恢复正常。 4. 两组孕妇 HBeAg 的检测结果：替比夫定组孕妇治疗前及分娩前的 HBeAg 滴度分别为（1158.57 361.25）S/CO 和（932.58 336.99）S/CO ，替比夫定组孕妇分娩前 HBeAg 较治疗前降低，t = - 6.650，P 106 拷贝/ml，HBV 宫内感染率为 8%，两组比较，t= 9.962，P 400 U/L。说明替比夫定治疗能较好地稳定肝功能，减少妊娠后期及分娩后严重肝功能异常的发生。 有研究报道显示，慢性 HBV 感染与妊娠糖尿病、产前出血、先兆早产、胎儿低 Apgar 评分相关10- 11。替比夫定组 23 例 ALT 异常者中 20 例于分娩前恢复正常，复常率达 87%，较对照组 56%的 ALT 复常率比较，有统计学意义。对于慢性乙型肝炎患者替比夫定抗病毒治疗具有双重目的：降低 产妇分娩前血清 HBV DNA 载量，减少 HBV 母婴传播的发生；改善患者肝功能异常情况，大大增强 患者对妊娠及分娩的耐受能力，降低母婴相关并发症。 本研究选择孕中晚期抗病毒治疗，是因为胎儿发育敏感期一般多发生在妊娠前 3 个月，尤其在妊娠 8 周内敏感性最大。宫内发育至 1516 周时各重要脏器才能基本发育完成，至 20 周生长趋于平稳。 希望在尽量减少药物对胎儿生长发育影响的同时，尽早降低孕妇血中的病毒含量，减少早期 HBV 宫 内感染的发生。 替比夫定为高度特异性抑制 HBV 复制的左旋核苷类似物，FDA 认定为妊娠分类 B 级的抗病毒药物， 目前尚缺乏孕妇在早孕期间服用替比夫定的安全性数据。动物实验表明，雌雄大鼠的全身暴露剂量 约为人治疗剂量的 14 倍时未观察到有损害生育力的证据，对胚胎和胎儿发育无不良作用。毒理学研 究表明替比夫定无致癌性、无致畸性、无致突变性， 亦无线粒体毒性12。本研究中替比夫定组新 生儿无一例发生畸形，随访至 7 月龄其生长发育情况与对照组婴儿无差异。 参 考 文 献 1 Farmer K, Gunn T, Woodfield DG. A combination of hepatitis B vaccine and immunoglobulin does not protect all infants born to hepatitis B e antigen positive mothers. N Z Med J, 1987, 100: 412-414. 2 Grosheide PM, del Canho R, Heijtink RA, et al. Passive-active immunization in infants of hepatitis Be antigen-positive mothers. Comparison of the efficacy of early and delayed active immunization. Am J Dis Child, 1993, 147: 1316-1320. 3 van Zonneveld M, van Nunen AB, Niesters HG, et al. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat, 2003, 10: 294-297. 4 Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat, 2009, 16: 94-103. 5 Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B (2010 version). Chin J Hepatol, 2011, 19: 13-24. (in Chinese) 中华医学会肝病学分会、感染病学分会. 慢性乙型肝炎防治指南(2010 年版). 中华肝脏病杂志, 2011, 19: 13-24. 6 Centers for Disease Control and Prevention (CDC). Progress in hepatitis B prevention through universal infant vaccination-China, 1997-2006. MMWR Morb Mortal Wkly Rep, 2007, 56: 441-445. 7 Osborn MK. Safety and efficacy of telbivudine for the treatment of chronic hepatitis B. Ther Clin Risk Manag, 2009, 12:789-798. 8 Chen W, Hou JL. Pharmacoeconomic evalu