Evaluation On The Safety Of Different Time-point Of Withdrawal During The Tenofovir Disoproxil Fumarate(TDF) Treatment To Prevent The Mother To Child Transmission(MTCT) Of Hepatitis B Virus

BackgroundChronic hepatitis B(CHB)is still a global health issue.About 240 million people worldwide are chronic hepatitis B virus(HBV)carriers.There are currently more than 93 million chronic HBV infections in China,and the infection rate among women of childbearing age is 6% to 8%.Mother-to-child transmission(MTCT)is one of the main routes of transmission of HBV.Newborns with HBsAg positive mothers,hepatitis B immunoglobulin(HBIG)and hepatitis B vaccine co-immunization can block more than 90% of mother-to-child transmission in time after birth.However,5% to 10% of newborns still have unsuccessful interruptions and vertical infections.In recent years,the major guidelines suggest that pregnant women with high hepatitis B virus load taking antiviral drugs during pregnancy can further reduce the mother-to-child transmission rate.Tenofovir Disoproxil Fumarate(TDF)has the advantages of strong antiviral effect,low drug resistance,low side effects,and better maternal and child safety.It has become a first-line drug for chronic hepatitis B antiviral therapy and is considered as the preferred drug for pregnant women with HBV.In 2017,the European Association for the Struy of the Liver(EASL)chronic hepatitis B management guidelines only recommended TDF for high viral load pregnant women,and recommended that it be started in 24 to 28 weeks of gestation.At present,the recommendations of the major guidelines for withdrawal time are not uniform,and the choice of different withdrawal times also directly affects whether HBV mothers choose breastfeeding after delivery.At present,the effectiveness and safety of antiviral treatment during pregnancy have been recognized internationally and written in major guidelines.However,there is much controversy about the understanding of the postpartum safety of pregnant women with antiviral therapy during pregnancy.there is no consensus in the world that the incidence of liver function abnormalities,the time range of occurrence,the degree of occurrence,and the development trend of antiviral drugs blocking the mother-to-child transmission of HBV after childbirth and stopping are currently not reached.And no risk factors can be used to assess the safety and follow-up of antiviral therapy during pregnancy.ObjectiveTo explore the maternal and infant safety of different withdrawal time during the TDF treatment to prevent MTCT of HBV in pregnant women with hepatitis B virus surface antigen(HBsAg)positive and HBV DNA > 2×106 IU/ml and analyze the possible risk factors associated with the elevation of ALT after withdrawal of TDF.MethodsPregnant women with HBsAg,HBeAg positive and HBV DNA > 2×106 IU/m L were included,started taking tenofovir during 24 to 28 weeks of gestation and were randomly divided into two groups.Group A took the drug until the time of delivery,and group B took the drug until 4 to 12 weeks after delivery.HBV DNA quantitative and ALT levels were measured at 4 weeks,8 weeks and 12 weeks after antiviral treatment in two groups of pregnant women,4 weeks,8 weeks,12 weeks,and 24 weeks after drug withdrawal,and detect the levels of HBsAg and HBs Ab at 4 weeks postpartum.ResultsA total of 109 eligible pregnant women were recruited in the study,18 of whom were excluded due to multiple elevations in ALT,loss of follow-up,or insufficient follow-up time.91 women were included in the final statistics,of whom 50 and 41 in group A and B respectively.(1)There was no statistical difference between the two groups of pregnant women in terms of age,family history of hepatitis B,history of delivery,mode of delivery,baseline HBsAg,HBeAg,HBV DNA,ALT levels,and incidence of ALT elevation during pregnancy.(2)The HBV DNA levels before delivery in both groups were significantly lower than their baseline levels respectively,with statistical significance(P < 0.05).There was no statistical difference between the two groups.HBV DNA levels in the two groups of pregnant women were different with a statistical difference(P < 0.05)after discontinuation,The HBV DNA level in group A(4.20 Log10 IU/ml)was significantly higher than that in group B(3.53 Log10 IU/ml).There was no significant difference in maternal HBV DNA levels between the two groups at 4 weeks after discontinuation,and there was no statistically significant difference from baseline levels.(3)There was also no significant difference in the incidence of postpartum ALT elevation between the two groups(44% in group A,56.1% in group B,P>0.05),and there was a similar median time-point for ALT elevation,both at 4 weeks after discontinuation(P > 0.05).ALT in most pregnant women can return to normal without intervention.(4)We divided the study population into two groups according to whether or not ALT elevation occurred after discontinuation.46 women with normal ALT after withdrawal and 45 women with elevated ALT.The incidence of ALT elevation during pregnancy was significantly different between the two groups,0/46(0%)and 12/45(26.7%)respectively,P < 0.05,which was statistically significant.However,elevation of ALT during pregnancy is not an independent risk factor for elevation of ALT after maternal withdrawal.(5)A total of 91 newborns were born and completed the injection of immunoglobulin and the first dose of hepatitis B vaccine within 12 hours after birth.Among them,12 newborns in group A and 8 infants in group B completed quantification of HBsAg and HBs Ab at 4 weeks postpartum and before receiving the second dose of hepatitis B vaccine.the levels of HBsAg in both groups were lower than 0.05 IU/ml;the mean,minimum,and maximum of HBs Ab titer in group A were 106.69m IU/ml,59.76 m IU/ml,and 153.12 m IU/ml,respectively.The average,minimum,and maximum HBs Ab titer in group B were 96.14 m IU/ml,56.01 m IU/ml,and 160.14 m IU/ml,respectively.The other 71 neonates completed the HBsAg and HBs Ab tests after the second or third dose of the vaccine.Both HBsAg were negative,and the HBs Abs were positive.Conclusions(1)There was no difference in maternal safety between withdrawal immediately after delivery and 4 to 12 weeks after delivery during the TDF treatment to prevent MTCT of HBV in pregnant women.(2)In addition,elevation of ALT postpartum is a common feature,mostly in early stage after withdrawal of TDF with mild elevation,which can return to normal without any interventions.(3)Increased ALT during pregnancy may affect ALT elevation after discontinuation of delivery but is not an independent risk factor.(4)when the newborn was 4 weeks old,it can produce protective antibodies which can effectively play a role and the breastfeeding is safe to the infant.