替比夫定阻断HBV母婴传播的效果和短期安全性
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摘要
目的观察高病毒载量乙型肝炎孕妇在孕晚期服用替比夫定对HBV母婴传播的阻断效果和短期安全性。方法募集2012年7月-2015年6月在吉林大学第一医院接受母婴阻断的HBsAg和HBe Ag均阳性,HBV DNA≥2×10~6IU/ml的孕妇;向孕妇说明目前乙型肝炎母婴传播阻断所采用的方法,根据其意愿分为主被动免疫阻断+替比夫定组(替比夫定组)和主被动免疫阻断组(免疫阻断组)。替比夫定组孕妇从妊娠32周开始,口服替比夫定(600 mg,1次/d)至分娩时停药,免疫阻断组孕妇孕期不接受任何抗病毒治疗;2组婴儿产后均接受20μg乙型肝炎疫苗联合100单位乙型肝炎免疫球蛋白的主被动免疫;7月龄时婴儿检测HBsAg阳性者为母婴传播阻断失败。符合正态分布的计量资料组间比较采用t检验;不符合正态分布的计量资料组间比较采用Wilcoxon秩和检验。计数资料组间比较采用χ~2检验或Fisher精确检验。结果符合纳入标准的孕妇447例,其中替比夫定组81例,免疫阻断组366例。替比夫定组孕妇平均年龄高于免疫阻断组[(28.8±3.3)岁vs(27.6±3.8)岁,t=-2.55,P=0.01);替比夫定组HBV DNA载量>10~8IU/ml的孕妇所占比例高于免疫阻断组(82.7%vs 61.5%,χ~2=13.21,P<0.001);2组孕妇在ALT水平、分娩方式和喂养方式方面的差异均无统计学意义(P值均>0.05)。替比夫定组婴儿81例,在7月龄时无HBsAg阳性者;免疫阻断组婴儿370例,7月龄时HBsAg阳性者21例,2组阳性率比较差异有统计学意义(0 vs 5.7%,P=0.02)。2组孕妇均未出现子痫、胎膜早破、产后出血等现象;2组婴儿在早产率、身长、体质量、Apgar评分方面差异均无统计学意义(P值均>0.05)。结论在新生儿接受主被动免疫的基础上,如在孕晚期对高病毒载量孕妇进行抗病毒干预,可显著提高HBV母婴阻断率,达到HBV母婴零传播,且新生儿的短期安全性良好。
Objective To evaluate the clinical effect and short-term safety of telbivudine administered in late pregnancy for blocking mother-to-child transmission of HBV in pregnant women with high HBV DNA load. Methods Pregnant women with positive HBsAg and HBe Ag and HBV DNA ≥2 × 10~6 IU/ml who underwent blockade of mother-to-child transmission in The First Hospital of Jilin University from July 2012 to June 2015 were enrolled. These patients were informed of current methods for blocking mother-to-child transmission of hepatitis B,and according to their own will,they were divided into active/passive immunization + telbivudine( telbivudine group) and active/passive immunization group( immunization group). The patients in the telbivudine group were given oral telbivudine( 600 mg,once a day) from week 32 of pregnancy to delivery,and those in the immunization group were not given antiviral therapy. The infants in both groups were given 20 μg hepatitis B vaccine combined with 100 IU hepatitis B immunoglobulin after birth. Positive HBsAg in infants at an age of 7months was defined as failed blockade of mother-to-child transmission. The t-test was used for comparison of normally distributed continuous data between groups,and the Wilcoxon rank sun test was used for comparison of non-normally distributed continuous data between groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. Results A total of 447 pregnant women were enrolled,and there were 81 pregnant women in the telbivudine group and 366 women in the immunization group. Compared with the immunization group,the telbivudine group had a significantly higher mean age( 28. 8 ± 3. 3 years vs 27. 6 ± 3. 8 years,t =-2. 55,P = 0. 01) and a significantly higher proportion of pregnant women with HBV DNA load > 10~8 IU/ml( 82. 7% vs 61. 5%,χ~2=13. 21,P < 0. 001). There were no significant differences in alanine aminotransferase level,delivery mode,and feeding pattern between the two groups( all P > 0. 05). No infants in the telbivudine group had positive HBsAg at an age of 7 months,while among the 370 infants in the immunization group,21 had positive HBsAg; there was a significant difference in positive rate between the two groups( 0 vs 5. 7%,P =0. 02). No women experienced eclampsia,premature rupture of membranes,or postpartum bleeding,and there were no significant differences between the two groups of infants in premature birth rate,body length,body weight,and Apgar score( all P > 0. 05). Conclusion In addition to active and passive immunization for neonates,antiviral therapy for pregnant women with a high viral load in late pregnancy can significantly improve the blocking rate of mother-to-child transmission of HBV and achieve no mother-to-child transmission of hepatitis B,and the neonates have good short-term safety.
Objective To evaluate the clinical effect and short-term safety of telbivudine administered in late pregnancy for blocking mother-to-child transmission of HBV in pregnant women with high HBV DNA load. Methods Pregnant women with positive HBsAg and HBe Ag and HBV DNA ≥2 × 10~6 IU/ml who underwent blockade of mother-to-child transmission in The First Hospital of Jilin University from July 2012 to June 2015 were enrolled. These patients were informed of current methods for blocking mother-to-child transmission of hepatitis B,and according to their own will,they were divided into active/passive immunization + telbivudine( telbivudine group) and active/passive immunization group( immunization group). The patients in the telbivudine group were given oral telbivudine( 600 mg,once a day) from week 32 of pregnancy to delivery,and those in the immunization group were not given antiviral therapy. The infants in both groups were given 20 μg hepatitis B vaccine combined with 100 IU hepatitis B immunoglobulin after birth. Positive HBsAg in infants at an age of 7months was defined as failed blockade of mother-to-child transmission. The t-test was used for comparison of normally distributed continuous data between groups,and the Wilcoxon rank sun test was used for comparison of non-normally distributed continuous data between groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. Results A total of 447 pregnant women were enrolled,and there were 81 pregnant women in the telbivudine group and 366 women in the immunization group. Compared with the immunization group,the telbivudine group had a significantly higher mean age( 28. 8 ± 3. 3 years vs 27. 6 ± 3. 8 years,t =-2. 55,P = 0. 01) and a significantly higher proportion of pregnant women with HBV DNA load > 10~8 IU/ml( 82. 7% vs 61. 5%,χ~2=13. 21,P < 0. 001). There were no significant differences in alanine aminotransferase level,delivery mode,and feeding pattern between the two groups( all P > 0. 05). No infants in the telbivudine group had positive HBsAg at an age of 7 months,while among the 370 infants in the immunization group,21 had positive HBsAg; there was a significant difference in positive rate between the two groups( 0 vs 5. 7%,P =0. 02). No women experienced eclampsia,premature rupture of membranes,or postpartum bleeding,and there were no significant differences between the two groups of infants in premature birth rate,body length,body weight,and Apgar score( all P > 0. 05). Conclusion In addition to active and passive immunization for neonates,antiviral therapy for pregnant women with a high viral load in late pregnancy can significantly improve the blocking rate of mother-to-child transmission of HBV and achieve no mother-to-child transmission of hepatitis B,and the neonates have good short-term safety.
引文
[1]BEASLEY RP,HWANG LY,LIN CC,et al.Hepatocellular carcinoma and hepatitis B virus.A prospective study of 22 707 men in Taiwan[J].Lancet,1981,2(8256):1129.
[2]MA L,ALLA NR,LI X,et al.Mother-to-child transmission of HBV:review of current clinical management and prevention strategies[J].Rev Med Virol,2014,24(6):396-406.
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[6]CHEN J,JIA JD.Guided reading of 2008 Asian-Pacific consensus statement on the management of chronic hepatitis B[J].Infect Dis Inform,2008,21(4):193-195.(in Chinese)陈杰,贾继东.亚太地区肝病学会2008年《慢性乙型肝炎治疗共识》导读[J].传染病信息,2008,21(4):193-195.
[7]CHEN HL,LIN LH,HU FC,et al.Effects of maternal screening and universal immunizationto prevent mother-to-infant transmission of HBV[J].Gastroenterology,2012,142(142):773-781.
[8]YANG M,LIU YX.New progress of the influencefactors of mother-tochild transmission of chronic hepatitis B[J/CD].Chin J Liver Dis:Electronic Edition,2016,10(3):265-268.(in Chinese)杨敏,刘映霞.慢性乙型肝炎母婴传播的影响因素新进展[J/CD].中华实验和临床感染病杂志:电子版,2016,10(3):265-268.
[9]LIANG X,BI S,YANG W,et al.Epidemiological serosurvey of hepatitis B in China---declining HBV prevalence due to hepatitis B vaccination[J].Vaccine,2009,27(47):6550-6557.
[10]LIANG X,BI S,YANG W,et al.Evaluation of the impact of hepatitis B vaccination amon children born during 1992-2005 in China[J].J Infect Dis,2009,200(1):39-47.
[11]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:a 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[12]HALLIDAY ML,KANG LY,RANKIN JG,et al.An efficacy trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine in infants born to mothers positive for HBs Ag,in Shanghai,China[J].Int JEpidemiol,1992,21(3):564-573.
[13]STEVENS CE,TOY PT,TAYLOR PE,et al.Prospects for control of hepatitis B virus infection:implications of childhood vaccination and long-term protection[J].Pediatrics,1992,90(12):170-173.
[14]ZOU H,CHEN Y,DUAN Z,et al.Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBs Ag-positive mothers[J].J Viral Hepat,2012,19(2):18-25.
[15]GODBOLE G,IRISH D,BASARAB M,et al.Management of hepatitis B in pregnant women and infants:a multicentre audit from four London hospitals[J].BMC Pregnancy Childbirth,2013,13:222.
[16]WANG C,WANG C,JIA ZF,et al.Protective effect of an improved immunization practice of mother-to-infant transmission of hepatitis Bvirus and risk factors associated with immunoprophylaxis failure[J].Medicine,2016,95(34):e4390.
[17]DENG Y,WU WX,ZHANG DZ,et al.The saty of telbivudine in preventing mother-to-infant transmission of hepatitis B virus in pregnant women after discontinuation[J].Chin J Hepatol,2015,23(8):586-589.(in Chinese)邓勇,吴维新,张大志,等.替比夫定阻断乙型肝炎病毒母婴传播停药后的安全性研究[J].中华肝脏病杂志,2015,23(8):586-589.
[18]ZHANG H,PAN CQ,PANG Q,et al.Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice[J].Hepatology,2014,60(2):468-474.
[19]HAN GR,JIANG HX,YUE X,et al.Efficacy and safety of telbivudine treatment:an open-label,prospective study in pregnant women for the prevention of perinatal transmission of hepatitis B virus infection[J].J Viral Hepat,2015,22(9):754-762.
[20]PAN CQ,HAN GR,JIANG HX,et al.Telbivudine prevents vertical transmission from HBe Ag-positive women with chronic hepatitis B[J].Clin Gastroenterol Hepatol,2012,10(5):520-526.
[21]BRIDGES EG,SELDEN JR,LUO S.Nonclinical safety profile of telbivudine,a novel potent antiviral agent for treatment of hepatitis B[J].Antimicrob Agents Chemother,2008,52(7):2521-2528.
[22]DIENSTAG J,EASLEY C,KIRKPATRICK P.Telbivudine[J].Nat Rev Drug Discov,2007,6(4):267-268.
[23]RUIZ-SANCHO A,SHELDON J,SORIANO V.Telbivudine:a new option for the treatment of chronic hepatitis B[J].Expert Opin Biol Ther,2007,7(5):751-761.
[24]PIRATVISUTH T,GUO RH,POL S,et al.Comprehensive review of telbivudine in pregnant women with chronic hepatitis B[J].World J Hepatol,2016,8(9):452.
[25]ZHOU YJ,ZHENG JL,PAN HJ,et al.Long-term efficacy and safety of telbivudine in the treatment of childbearing patients with chronic hepatitis B[J].Chin J Hepatol,2014,22(8):573-576.(in Chinese)周岳进,郑金莉,潘华将,等.替比夫定治疗妊娠慢性乙型肝炎患者生育子女远期疗效与安全性[J].中华肝脏病杂志,2014,22(8):573-576.
[2]MA L,ALLA NR,LI X,et al.Mother-to-child transmission of HBV:review of current clinical management and prevention strategies[J].Rev Med Virol,2014,24(6):396-406.
[3]ORLANDO R,FOGGIA M,MARAOLO AE.Prevention of hepatitis Bvirus infection:from the past to the future[J].Eur J Clin Microbiol Infect Dis,2015,34(6):1059-1070.
[4]ZHOU YH,HU YL.Achievements and challenges in the prevention of mother-to-child transmission of hepatitis B virus in China[J].Natl Med J China,2015,95(1):15-18.(in Chinese)周乙华,胡娅莉.我国预防乙型肝炎病毒母婴传播的成就和挑战[J].中华医学杂志,2015,95(1):15-18.
[5]DEL CR,GROSHEIDE PM,MAZEL JA,et al.Ten-year neonatal hepatitis B vaccination program,The Netherlands,1982-1992:protective efficacy and long-term immunogenicity[J].Vaccine,1997,15(15):1624-1630.
[6]CHEN J,JIA JD.Guided reading of 2008 Asian-Pacific consensus statement on the management of chronic hepatitis B[J].Infect Dis Inform,2008,21(4):193-195.(in Chinese)陈杰,贾继东.亚太地区肝病学会2008年《慢性乙型肝炎治疗共识》导读[J].传染病信息,2008,21(4):193-195.
[7]CHEN HL,LIN LH,HU FC,et al.Effects of maternal screening and universal immunizationto prevent mother-to-infant transmission of HBV[J].Gastroenterology,2012,142(142):773-781.
[8]YANG M,LIU YX.New progress of the influencefactors of mother-tochild transmission of chronic hepatitis B[J/CD].Chin J Liver Dis:Electronic Edition,2016,10(3):265-268.(in Chinese)杨敏,刘映霞.慢性乙型肝炎母婴传播的影响因素新进展[J/CD].中华实验和临床感染病杂志:电子版,2016,10(3):265-268.
[9]LIANG X,BI S,YANG W,et al.Epidemiological serosurvey of hepatitis B in China---declining HBV prevalence due to hepatitis B vaccination[J].Vaccine,2009,27(47):6550-6557.
[10]LIANG X,BI S,YANG W,et al.Evaluation of the impact of hepatitis B vaccination amon children born during 1992-2005 in China[J].J Infect Dis,2009,200(1):39-47.
[11]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:a 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[12]HALLIDAY ML,KANG LY,RANKIN JG,et al.An efficacy trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine in infants born to mothers positive for HBs Ag,in Shanghai,China[J].Int JEpidemiol,1992,21(3):564-573.
[13]STEVENS CE,TOY PT,TAYLOR PE,et al.Prospects for control of hepatitis B virus infection:implications of childhood vaccination and long-term protection[J].Pediatrics,1992,90(12):170-173.
[14]ZOU H,CHEN Y,DUAN Z,et al.Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBs Ag-positive mothers[J].J Viral Hepat,2012,19(2):18-25.
[15]GODBOLE G,IRISH D,BASARAB M,et al.Management of hepatitis B in pregnant women and infants:a multicentre audit from four London hospitals[J].BMC Pregnancy Childbirth,2013,13:222.
[16]WANG C,WANG C,JIA ZF,et al.Protective effect of an improved immunization practice of mother-to-infant transmission of hepatitis Bvirus and risk factors associated with immunoprophylaxis failure[J].Medicine,2016,95(34):e4390.
[17]DENG Y,WU WX,ZHANG DZ,et al.The saty of telbivudine in preventing mother-to-infant transmission of hepatitis B virus in pregnant women after discontinuation[J].Chin J Hepatol,2015,23(8):586-589.(in Chinese)邓勇,吴维新,张大志,等.替比夫定阻断乙型肝炎病毒母婴传播停药后的安全性研究[J].中华肝脏病杂志,2015,23(8):586-589.
[18]ZHANG H,PAN CQ,PANG Q,et al.Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice[J].Hepatology,2014,60(2):468-474.
[19]HAN GR,JIANG HX,YUE X,et al.Efficacy and safety of telbivudine treatment:an open-label,prospective study in pregnant women for the prevention of perinatal transmission of hepatitis B virus infection[J].J Viral Hepat,2015,22(9):754-762.
[20]PAN CQ,HAN GR,JIANG HX,et al.Telbivudine prevents vertical transmission from HBe Ag-positive women with chronic hepatitis B[J].Clin Gastroenterol Hepatol,2012,10(5):520-526.
[21]BRIDGES EG,SELDEN JR,LUO S.Nonclinical safety profile of telbivudine,a novel potent antiviral agent for treatment of hepatitis B[J].Antimicrob Agents Chemother,2008,52(7):2521-2528.
[22]DIENSTAG J,EASLEY C,KIRKPATRICK P.Telbivudine[J].Nat Rev Drug Discov,2007,6(4):267-268.
[23]RUIZ-SANCHO A,SHELDON J,SORIANO V.Telbivudine:a new option for the treatment of chronic hepatitis B[J].Expert Opin Biol Ther,2007,7(5):751-761.
[24]PIRATVISUTH T,GUO RH,POL S,et al.Comprehensive review of telbivudine in pregnant women with chronic hepatitis B[J].World J Hepatol,2016,8(9):452.
[25]ZHOU YJ,ZHENG JL,PAN HJ,et al.Long-term efficacy and safety of telbivudine in the treatment of childbearing patients with chronic hepatitis B[J].Chin J Hepatol,2014,22(8):573-576.(in Chinese)周岳进,郑金莉,潘华将,等.替比夫定治疗妊娠慢性乙型肝炎患者生育子女远期疗效与安全性[J].中华肝脏病杂志,2014,22(8):573-576.