Study design and Patient Selection
We conducted a retrospective cohort study to assess safety and efficacy between TDF and LdT on MTCT in mothers with CHB in Beijing YouAn Hospital, China. The research site is a tertiary infectious disease hospital and devoted to preventing HBV MTCT for the last 20 years. Eligible consecutive women were retrospectively reviewed from January 1, 2012, to September 31, 2018. The study was approved by the Ethics Committee of Beijing You An Hospital, Capital Medical University (approval number: Jing-you-ke-lun-zi 15-hao) in February 2016. The study was conducted according to International Conference Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki.
Pregnant women were reviewed for the following eligibility criteria: age between 20 and 45 years; HBs antigen (HBsAg) and HBeAg positivity; HBV DNA levels ≥2*105 IU/mL; written informed consent before treatment; antiviral therapy started on oral antiviral agents between gestational age of 24 and 32; the infants were administered 200 IU of HBIg intramuscular within 2 hours after birth and two doses of 10ug of recombinant HBV vaccine within 2 hours after birth, 4 and 24 weeks after birth. Key exclusion criteria included ALT ≥2*ULN (ULN=40 U/L); treatment with LAM; co-infection with hepatitis C, D, E, or HIV; evidence of hepatocellular carcinoma or cirrhosis; concurrent treatment with immune modulators, cytotoxic drugs or steroids; evidence of fetal deformity by ultrasound examination.
Women who received TDF treatment (300mg daily) in late pregnancy to prevent hepatitis MTCT were included in TDF- treated group and those who received LdT treatment (600mg daily) in LdT-treated group. Mothers were instructed to discontinue TDF treatment if their hepatitis B remained inactive after delivery, and mothers voluntarily selected their ways of feeding the infants after drug cessation.
Data Collection and Outcome Measurements
Demographic and clinical data were extracted from the electronic clinical records and paper charts from the clinic and inpatient services in YouAn Hospital. Data were assessed at the following time points: 4-week intervals from baseline information to childbirth: 4-8, 12, 24, and 28-52 weeks after birth. The following data from the clinic and inpatient services were collected for analysis: age, initiating administration weeks, treatment duration during pregnancy, childbirth and obstetric complications, pertinent physical findings, and laboratory information which include HBV virological markers, chemistry panel results, and imaging results.
Two primary outcomes are the rates of MTCT and the safety of TDF or LdT use until one year after birth. The rate of MTCT is defined as the proportion of infants who had serum HBV DNA levels of>20 IU per milliliter (i.e. above the lower limit of detection) or who were positive for hepatitis B surface antigen (HBsAg) 7-12months after birth. Rates of ALT elevation were rates of 2 times ULN during treatment or follow-up. AEs were graded according to the Common Terminology Criteria for Adverse Events (version 4.0). Cases of structural defects or other safety reports about newborns or infants were tabulated using data acquired from infants during the prenatal period up to 28 weeks of gestational age or after birth (e.g. ultrasonography examination, reports of birth defects and APGAR scores, measurements from growth charts, and development milestones). Perinatal and peripartum complications (e.g., hypertensive disorders in pregnancy, gestational diabetes mellitus, fetal growth retardation, preterm birth, premature rupture of membranes, and postpartum hemorrhage) were included in the safety analysis.
Secondary outcomes were a decline of HBV-DNA levels at birth and rates of alanine aminotransferase (ALT) elevation >2 upper limits normal (ULN) during the study.
Based on two previous studies, we estimated that 17.1% of mothers had ALT elevations after LdT cessation and 7.7% after TDF cessation. [9,11] The number of women needed to capture the difference of 9.4% adverse events was calculated to be 165 in the TDF-group and 660 in the LdT-group (1:4 matched) with a significance level of 0.05 (one‐tailed). Considering a 10% dropout rate, a sample size of at least 176 in the TDF-group and 726 in the LdT-group was a reasonable estimation for the current study Intention to treat analysis was defined as analysis included all women, also those with protocol deviations. We included all infants to perform ITT analysis of the MTCT rates. Data of mothers and infants who were lost to follow-up were still included in the analysis. Infants who were lost to follow-up were counted as having treatment failure. Baseline characteristics and laboratory results were summarized using descriptive statistics, including percentages, means ±standard deviation (SD) and 95% Confidence Intervals (CI). For quantitative variables, t-test was used to compare group differences. For categorical variables, chi-square test was used for group comparisons. The significance level was set at p< 0.05; all data were analyzed by SPSS 23.0 (SPSS, IBM., New York).