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- 2009-10-5
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- 2022-12-28
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Results
Participants
A total of 2688 pregnant women or women contemplating pregnancy with chronic HBV infection were assessed for eligibility, and 103 and 104 pregnant women with active CHB were enrolled for treatment with TAF and TDF, respectively (Figure 1). Notably, participants in each group were further divided into two subgroups at TAF initiation (Table 1), i.e., the treatment-naïve subgroup and the treatment-experiencing subgroup (switched to or continued TAF or TDF monotherapy). The mean time points of treatment initiation were 1.3 (± 14.6) and 1.0 (± 12.3) weeks referring to the first day of pregnancy (LMP), and 53 (51.5%) and 50 (48.1%) of these patients in the TAF and TDF groups started treatment before pregnancy, respectively. At treatment baseline, 74 (71.8%) and 71 (68.3%) pregnant women had detectable HBV DNA levels, 82 (79.6%) and 88 (84.6%) pregnant women were HBeAg-positive, and 72 (69.9%) and 67 (64.4%) pregnant women had elevated ALT levels in the TAF and TDF groups, respectively (Table 1). In total, 102 and 103 live newborns were born to women in the TAF and TDF groups, respectively (Table 2). Based on the pregnant women’s personal preferences, 71 (69.6%) and 74 (71.2%) infants received breast milk in the TAF and TDF groups, respectively.
Safety of Pregnant Women
The mean TAF treatment durations were 96.1 (± 24.4) and 98.7 (± 21.9) weeks in the TAF and TDF groups. TAF and TDF were both well tolerated in the pregnant women, and no pregnant woman discontinued therapy because of adverse events (Table 3). The most common adverse events and complications were nausea (29.1% [TAF] vs. 31.7% [TDF]) and premature rupture of membranes (12.6% [TAF] vs. 13.5% [TDF]) in both groups, and no significant differences were observed in the occurrences of adverse events and complications between the two groups. Notably, 1 (1.0%) pregnant woman exposed to agricultural chemicals during early pregnancy who initiated TAF from 12 weeks plus 2 days of gestation underwent induced abortion at 23 weeks plus 4 days of pregnancy due to the diagnosis of cleft lip and palate for the fetus at 22 weeks of gestation.
In terms of laboratory abnormalities (Table 4), the most common was anemia in both groups, ranging from 10.7% to 52.9% of pregnant women during pregnancy, and 1.9% to 20.2% of them were diagnosed with moderate anemia, which was defined as a hemoglobin concentration ranging from 70 to 99 g/L.12 However, the hemoglobin levels recovered to normal in almost all pregnant women after delivery. Additionally, the levels of platelets, total bilirubin, creatinine, β2-microglobulin, and eGFR were consistently normal, and no significant fluctuations were observed between the two groups (Table 4 and Supplementary Tables 1 and 2).
Safety of Infants or Fetuses
The prenatal TAF exposure duration for the fetuses was 32.1 (± 9.4) and 33.8 (± 8.3) weeks in the TAF and TDF groups, respectively (Table 2). No infant had an Apgar score of less than 8 at 1 minute of birth. No congenital defects or malformations were observed at birth, with the exception of the one fetus described above that underwent induced abortion due to cleft lip and palate (Supplementary Table 3). The most common abnormal condition was prolonged (neonatal) jaundice, which was defined as neonatal jaundice lasting more than 2 weeks in term infants and more than 3 weeks in preterm infants,13 and it occurred in 13 (12.7%) and 14 (13.4%) infants in the TAF and TDF groups, respectively. Prolonged jaundice either spontaneously resolved or was cured by phototherapy alone in these infants before 2 months of age.
Other abnormal conditions that occurred in one or more infants included fever (13/102 [12.7%] vs. 13/104 [12.5%]), cough (10/102 [9.8%] vs. 9/104 [8.7%]), vomiting (9/102 [8.8%] vs. 9/104 [8.7%]), skin rash (6/102 [5.9%] vs. 5/104 [4.8%]), diarrhea (4/102 [3.9%] vs. 5/104[4.8%]), hearing impairment (1/102 [1.0%]) vs. 0/104 [0%], and cutaneous hemangioma (1/102 [1.0%] vs. 0/104 [0%]; on the left arm, size: 15 × 25 mm) in TAF and TDF groups, respectively. The infant diagnosed with hearing impairment at 1 week was then identified as having a conductive hearing impairment due to secretory otitis media at 3 months, but the condition eventually recovered spontaneously at 6 months; additionally, the other infant who was reported with cutaneous hemangioma at 4 weeks of age had been cured at 1 year (Supplementary Table 3). Notably, the infants’ physical development at birth, 7 months, 12 months, and 18 months were comparable to the China national and WHO standards for children's growth (Table 5); at some time points, the growth parameters may be even better due
to the possibly better nutrition for the infants currently. However, no significant differences in infants’ growth parameters were observed between the TAF and TDF groups (Table 5).
On-time Rate of Immunoprophylaxis
Among the 206 newborns, the on-time conditions and the first doses of immunoprophylaxis are presented in Table 2. Regarding the administration of the second and third doses of HBV vaccine, 86 (84.3%) and 89 (85.6%) infants were injected on time, and the remaining 16 (15.7%) and 15 (14.4%) infants were delayed within 1-3 weeks because of prolonged neonatal jaundice, pregnant women’s personal preferences, vaccination station reasons, or traffic influenced by coronavirus disease 2019 described in our previous studies.7,14
Effectiveness in Pregnant Women
The mean serum HBV DNA levels gradually decreased to 1.2 (± 1.7) and 0.9 (± 1.4) log10 IU/ml at delivery and 0.2 (± 0.2) and 0 (± 0.2) log10 IU/ml at postpartum month 6 in the TAF and TDF groups, respectively (Table 4 and Supplementary Tables 1 and 2). The percentages of women with undetectable HBV DNA, ALT normalization, and HBeAg seroconversion gradually increased with the continuation of treatment (Supplementary Figures 1, 2, and 3); however, no significant differences were observed between the TAF and TDF groups (all P > 0.05). Additionally, no pregnant woman in either group exhibited HBsAg loss during treatment. Notably, virological breakthrough occurred in 2 (2.0%) TAF-treated pregnant women after approximately 6 months of switchover from previous entecavir or entecavir/TDF regimens to TAF therapy, and Supplementary Table 4 presents the details.
Effectiveness in Infants
At the 7-month visit for infants, no infant was positive for HBsAg, i.e., the MTCT rate was 0%. Additionally, 101 (99.0%) and 104 (100%) infants were positive for anti-HBs, with mean levels of 404.9 (± 285.3) and 411.0 (± 253.8) mIU/ml in the TAF and TDF
groups, respectively. Notably, the abovementioned anti-HBs levels may be underestimated because 7 and 6 infants’ anti-HBs levels were reported as “> 1000 mIU/ml” in the TAF and TDF groups, respectively, and were calculated as 1000 mIU/ml.
DISCUSSION
Although infants born to pregnant women with chronic HBV infection share the same immunization prophylaxis procedures, pregnant women who had active CHB require longer or even indefinite durations of antiviral treatment, and pregnant women with inactive chronic HBV infection only need definite short-term antiviral prophylaxis. Therefore, safety is the priority for pregnant women with active CHB who require long-term therapy. As shown in the present study, a mean of two years of TAF treatment is well tolerated with no major safety concerns and presents favorable effectiveness for pregnant women with active CHB who initiated TAF before or beginning in the early
phase of pregnancy. Additionally, no congenital defects or malformations were observed in live infants at birth after approximately full gestational TAF exposure. Unsurprisingly, the MTCT rate was 0% in combination with standard HBV immunoprophylaxis for infants.
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发表于 2021-12-14 20:41