替诺福韦酯阻断乙型肝炎病毒母婴传播不同停药时间的安全性评价

目的探讨采用替诺福韦酯(TDF)阻断乙型肝炎病毒(HBV)母婴传播的高HBV DNA载量孕妇分娩后不同停药时间对母婴安全性的影响。方法招募2015年1月至2017月12月于深圳市第三人民医院就诊的免疫耐受期HBsAg阳性孕妇109例,均于孕24～28周开始服用TDF治疗,根据简单随机化方法将入组患者分为分娩时停药组(58例)和分娩后4～12周停药组(51例)。定量检测两组孕妇抗病毒治疗后4周、8周、12周、停药时与停药后4周、8周、12周、24周的HBV DNA载量和ALT水平,并定量检测新生儿产后4周HBsAg和HBsAb水平。结果所有孕妇分娩前HBV DNA载量均显著降低,较基线水平差异有统计学意义(分娩时停药组:Z=8.459、P <0.001;分娩后4～12周停药组:Z=7.760、P <0.001)。停药时两组产妇HBV DNA载量差异有统计学意义(Z=2.242、P=0.025)。停药后4周两组产妇HBV DNA载量差异无统计学意义(Z=1.041、P=0.298),且较基线水平差异均无统计学意义(分娩时停药组:Z=0.155、P=0.877;分娩后4～12周停药组:Z=0.376、P=0.707)。随访至停药后24周,两组产妇产后ALT升高的发生率差异无统计学意义(χ~2=1.319、P=0.251),两组产妇ALT升高的中位时间点均在停药后4周,差异无统计学意义(Z=0.196、P=0.844)。孕期ALT升高可能引起分娩停药后ALT升高,但并非独立危险因素。20例新生儿在产后4周行外周血HBsAg、HBsAb定量检测,HBsAg均为阴性,均产生保护性抗体。结论妊娠中晚期使用替诺福韦酯能有效阻断HBV母婴传播;随访24周发现分娩后停药与延后停药对产后安全性的无显著影响,新生儿4周龄即能产生保护性抗体并有效发挥作用,母乳喂养是安全的。

Safety of withdrawal during treatment with tenofovir disoproxil of mothers and infants at various time-points

ObjectiveTo investigate the safety of different withdraw timepoint of tenofovir disoproxil (TDF) for pregnant women with high hepatitis B virus (HBV) DNA load in blocking mother-to-child transmission of HBV. MethodsFrom January 2015 to December 2017, a total of 109 pregnant women with HBsAg positive and immunoresistance were recruited from Shenzhen Third People’s Hospital, all patients were treated with TDF at 24-28 weeks of gestation, who were divided into two groups according to simple randomized grouping method: withdrawal immediately after delivery group (58 cases) and withdrawal 4-12 weeks after delivery group (51 cases). The levels of HBV DNA and ALT were measured quantitatively at 4 weeks, 8 weeks, 12 weeks after antiviral therapy, at withdrawal and 4 weeks, 8 weeks, 12 weeks and 24 weeks after TDF discontinuation in both groups. Quantitative HBsAg and HBsAb levels of newborns at 4 weeks after birth were detected. ResultsHBV DNA levels of all pregnant women before delivery were significantly lower than those of the baseline (withdrawal immediately after delivery group: Z = 8.459, P < 0.001; withdrawal 4-12 weeks after delivery group: Z = 7.760, P < 0.001). HBV DNA levels at the timepoint of withdrawal between the two groups were significantly different (Z = 2.242, P = 0.025). The difference of HBV DNA level 4 weeks after withdrawal between the two groups was not significant (Z = 1.041, P = 0.298), and no significant differences were found compared with the baseline levels (withdrawal immediately after delivery group: Z = 0.155, P = 0.877; withdrawal at 4-12 weeks after delivery group: Z = 0.376, P = 0.707). The difference of postpartum ALT levels between the two groups following up until 24 weeks after withdrawal was not significantly different (χ² = 1.319, P = 0.251). The median timepoint of ALT elevation of both groups was 4 weeks after withdrawal, with no significant difference (Z = 0.196, P = 0.844). The level of ALT increase during pregnancy may cause ALT increase after delivery, but it is not an independent risk factor. Total of 20 newborns were quantitatively detected for peripheral blood HBsAg and HBsAb at 4 weeks postpartum, all of them were HBsAg negative and successfully produced protective antibody. ConclusionsTDF application in middle and late pregnancy could effectively block HBV transmission from mother to child. Following up for 24 weeks showed that there was no difference in postpartum safety between postpartum withdrawal and delayed withdrawal. Newborns produce protective antibody 4 weeks after birth and breast feeding was safe.