HBV DNA高载量孕妇孕中晚期应用富马酸替诺福韦二吡呋酯抗病毒治疗停药时间对母婴的影响

Effects of tenofovir disoproxil fumarate antiviral withdrawal timepoints on maternal and child in pregnant women with high HBV DNA load in the middle and late pregnancy

目的探讨妊娠中晚期乙型肝炎病毒(hepatitis B virus,HBV)DNA高载量孕妇使用富马酸替诺福韦二吡呋酯(tenofovir disoproxil fumarate,TDF)抗病毒治疗停药时间对母婴健康的影响及停药后丙氨酸氨基转移酶(alanine aminotransferase,ALT)升高的影响因素。方法选取2016年1月至2018年1月邯郸市传染病医院收治的350例妊娠中晚期高HBV DNA载量孕妇为研究对象,所有孕妇均于妊娠24~28周开始口服TDF。根据患者意愿分为A组(160例)和B组(190例),其中A组分娩当天即停药,B组分娩后4~12周停药。新生儿出生后均予注射100 IU乙肝免疫球蛋白和10μg重组酵母乙肝疫苗(出生时、出生1个月和出生6个月)。比较两组孕妇治疗前、停药时、停药后4周、8周及12周时HBV DNA载量及ALT水平;比较两组新生儿产后2个月和7个月HBV阻断成功率。根据停药8周时ALT水平,将孕妇分为ALT升高组(>45 U/L,60例)和ALT正常组(≤45 U/L,290例),采用Logistic多因素回归分析探讨孕妇停药8周后ALT升高的危险因素。结果治疗前,A组和B组孕妇血清HBV DNA载量[(7.45±1.38)lg IU/ml vs(7.51±1.42)lg IU/ml]差异无统计学意义(t=0.399,P=0.690);停药时,A组血清HBV DNA载量显著高于B组[(4.37±0.65)lg IU/ml vs(2.81±0.42)lg IU/ml],差异有统计学意义(t=27.052,P<0.001);但停药后4周[(5.32±0.78)lg IU/ml vs(5.25±0.71)lg IU/ml]、8周[(6.25±0.96)lg IU/ml vs(6.21±0.92)lg IU/ml]和12周[(7.33±1.27)lg IU/ml vs(7.29±1.23)lg IU/ml],两组孕妇血清HBV DNA差异无统计学意义(P均>0.05)。A组和B组孕妇治疗前[(28.29±5.71)U/L vs(28.72±6.04)U/L]、停药时[(28.05±6.13)U/L vs(28.78±5.78)U/L]、停药4周[(105.92±28.34)U/L vs(103.35±27.58)U/L]、8周[(63.36±18.82)U/L vs(64.11±18.35)U/L]和12周[(30.31±5.38)U/L vs(29.99±5.93)U/L]血清ALT水平差异均无统计学意义(P均>0.05)。A组和B组新生儿出生后2个月HBV阻断成功率分别为96.88%(155/160)和97.37%(185/190),差异无统计学意义(χ^2=2.698,P=0.100);两组新生儿出生后7个月HBV阻断成功率分别为98.75%(158/160)和99.47%(189/190),差异无统计学意义(P=0.464)。多因素Logistic回归分析表明,乙型肝炎病程、基线和停药时HBV DNA载量是孕妇停药8周后ALT升高的独立危险因素(OR=1.235,95%CI:1.074~1.896,P=0.018;OR=1.724,95%CI:1.358~2.265,P=0.008;OR=1.892,95%CI:1.432~2.492,P=0.004)。结论HBV DNA高载量孕妇妊娠中晚期使用TDF联合主被动免疫可有效阻断HBV母婴传播,停药时间对母婴健康影响不大,停药后产妇ALT升高是主要异常表现,其危险因素包括乙型肝炎病程、基线和停药时HBV DNA载量。

Objective To investigate the effects of tenofovir disoproxil fumarate(TDF)antiviral withdrawal timepoints on maternal and child health and factors affecting the increase of alanine aminotransferase(ALT)after withdrawal 8 weeks in pregnant women with high hepatitis B virus(HBV)DNA load in the middle and late pregnancy.Methods A total of 350 pregnant women with high HBV DNA load in the middle and late pregnancy who were admitted to Handan Infectious Disease Hospital from January 2016 to January 2018 were selected.At the 24th^28th week of gestation,TDF was administered orally to all pregnant women.The subjects were divided into group A(160 cases)and group B(190 cases)according to the individual wishes,pregnant women in group A stopped taking drugs on the day of delivery and those in group B stopped taking drugs 4~12 weeks after delivery.All the newborns were given 100 IU hepatitis B immunoglobulin and 10μg recombinant yeast hepatitis B vaccine(at birth,1 month and 6 months after birth).HBV DNA load and ALT level were compared between the two groups before treatment,at withdrawal time,at 4 weeks,8 weeks and 12 weeks after withdrawal.The successful rate of HBV blocking in newborns of the two groups at 2 months and 7 months were compared.According to the levels of ALT at 8 weeks after withdrawal,the pregnant women were divided into ALT elevated group(>45 U/L,60 cases)and ALT normal group(≤45 U/L,290 cases),multivariate Logistic regression analysis was used to analyze the risk factors of increased ALT in pregnant women at 8 weeks after withdrawal.Results Before treatment,there was no significant difference in serum HBV DNA load between patients in group A and group B[(7.45±1.38)lg IU/ml vs(7.51±1.42)lg IU/ml;t=0.399,P=0.690].At the time of withdrawal,the serum HBV DNA load of pregnant women in group A was higher than that in group B[(4.37±0.65)lg IU/ml vs(2.81±0.42)lg IU/ml],the difference was statistically significant(t=27.052,P<0.001).However,there was no significant differences in serum HBV DNA load between patients in group A and group B at 4 weeks[(5.32±0.78)lg IU/ml vs(5.25±0.71)lg IU/ml],8 weeks[(6.25±0.96)lg IU/ml vs(6.21±0.92)lg IU/ml]and 12 weeks[(7.33±1.27)lg IU/ml vs(7.29±1.23)lg IU/ml]after withdrawal(all P>0.05).There were no significant differences in serum ALT levels between patients in group A and group B before treatment[(28.29±5.71)U/L vs(28.72±6.04)U/L],at the time of withdrawal[(28.05±6.13)U/L vs(28.78±5.78)U/L],at 4 weeks[(105.92±28.34)U/L vs(103.35±27.58)U/L],8 weeks[(63.36±18.82)U/L vs(64.11±18.35)U/L]and 12 weeks[(30.31±5.38)U/L vs(29.99±5.93)U/L]after withdrawal(all P>0.05).At the second month after delivery,the successful rates of HBV blocking in group A and group B were 96.88%(155/160)and 97.37%(185/190),respectively,there was no statistically significant difference(χ^2=2.698,P=0.100).An the seventh month after delivery,the successful rates of HBV blocking in group A and B were 98.75%(158/160)and 99.47%(189/190),respectively,there was no statistically significant difference(P=0.464).Multivariate Logistic regression analysis showed that the duration of hepatitis B,HBV DNA load on baseline and at withdrawal were the independent risk factors for ALT elevation at 8 weeks after withdrawal(OR=1.235,95%CI:1.074~1.896,P=0.018;OR=1.724,95%CI:1.358~2.265,P=0.008;OR=1.892,95%CI:1.432~2.492,P=0.004).Conclusions TDF combined with active and passive immunotherapy can effectively block mother-to-child transmission of HBV in pregnant women with high HBV DNA load in middle and late stage of pregnancy.The time of withdrawal has little effects on the heath of maternal and infant.The main abnormal symptoms are elevated ALT after withdrawal.The risk factors include the period of hepatitis B,HBV DNA load on baseline and at withdrawal.