Background
Chronic hepatitis B virus (HBV) infection is a serious threat to public health and is associated with cirrhosis and liver cancer [
1,
2]. Although the universal infant immunization reduces 80–90% of chronic HBV infection, the active/passive immunoprophylaxis has not eradicated mother-to-infant HBV transmission [
3‐
5]. The vertical transmission of HBV from mothers to their infants at birth or in early infancy has a significant role in the endemicity of HBV infection [
6]. Moreover, after immunoprophylaxis, children with HBV infection have a higher risk of developing hepatocellular carcinoma [
7,
8].
HBV immunoprophylaxis failure is influenced by maternal hepatitis B e antigen (HBeAg) positivity and viral load [
9,
10]. Several studies have demonstrated a positive correlation between high maternal serum HBV DNA levels and an increased risk for vaccination breakthrough [
11,
12]. Thus, these data have introduced the idea of antiviral therapy in pregnant women with high HBV DNA levels to help achieve the goal of global eradication of HBV infection.
Three oral anti-HBV agents have been approved by United States Food and Drug Administration for the preventing of mother-to-infant transmission. These agents included lamivudine, telbivudine, and tenofovir. Lamivudine has been reported to reduce 72–78% risk of vertical transmission compared with passive/active immunization alone [
13,
14]. However, it could lead to the emergence of lamivudine-resistant mutants because of its lower genetic barrier to resistance [
15]. Telbivudine has been proven to prevent immunoprophylaxis failure in all cases treated; however, the increased risk of resistance limited its prolonged therapy [
6,
16].
Tenofovir is one of the most potent anti-HBV agents with a high genetic barrier to resistance [
17]. A small but growing body of evidence has suggested that tenofovir may reduce the risk of mother-to-child transmission, however, their results remain inconsistent [
6,
13,
16,
18‐
20]. To increase power and precision, we conducted this meta-analysis based on relevant studies to assess the efficacy of tenofovir in reducing perinatal HBV transmission, as well as monitoring safety for mothers and infants.
Discussion
This study is a meta-analysis with the objective of assessing the efficacy of tenofovir in reducing mother-to-infant HBV transmission, as well as monitoring safety for mothers and infants. Our study suggested that tenofovir was associated with significant reductions in maternal HBV DNA levels, infant HBsAg/HBeAg positivity, infant HBV DNA positivity, and immunoprophylaxis failure. Moreover, tenofovir induced a similar incidence of ALT, CK, and Cr elevation with other treatments. This study indicated that tenofovir was effective and safe for both mother and infant in the prevention of vertical transmission of HBV.
In this meta-analysis, we found that tenofovir significantly reduced the maternal HBV DNA levels. This finding was in consistent with the results of other studies available about the efficacy of tenofovir in preventing vertical transmission [
20,
36,
40,
41]. In a prospective, multicenter trial conducted in China [
36], the authors enrolled 118 pregnant patients who had chronic HBV and HBV DNA levels ≥7.5 log
10 IU/ mL. These patients received tenofovir 300 mg daily (
N = 62, HBV DNA 8.18 ± 0.47 log
10 IU/mL), or no medication (
N = 56, HBV DNA 8.22 ± 0.39 log
10 IU/mL) [
36]. At the time of delivery, the mean reduction of HBV DNA in the two groups were 3.89 ± 0.87 and 0.11 ± 0.51 log
10 IU/mL, respectively [
36], which indicated that tenofovir had a greater reduction in maternal HBV DNA than no medication. Similarly, in another multi-center, prospective opt-in observational study from Austria [
20], the authors also reported greater decrease of HBV DNA in the tenofovir group. In that study, pregnant women with high viral load (>7 log IU/mL) were treated with tenofovir (
N = 58), lamivudine (
N = 52), or no therapy (
N = 20). The mean reduction of HBV DNA in tenofovir group was 3.64 ± 0.9 log IU/mL, compared with 2.81 ± 1.33 in the lamivudine group [
20]. This result indicated that tenofovir had a significant greater reduction of HBV DNA levels than lamivudine.
However, the advantage effect of tenofovir over other treatments in reducing HBV DNA levels was not observed in a prospective cohort study conducted in China [
40]. In that study, 153 chronic HBV infectious mothers were assigned into the tenofovir group (
N = 30) and telbivudine group (
N = 79) [
40]. At the time of delivery, the reductions of HBV DNA levels in these groups were 4.64 ± 0.5 and 3.54 ± 0.8 log IU/mL, respectively. Although tenofovir seemed to have a greater reduction in HBV DNA levels than telbivudine, the difference was not significant. Owning to the limited available data, we did not perform subgroup analysis to explore whether tenofovir had superior effect than telbivudine in reducing the HBV DNA levels.
In this meta-analysis, our results suggested that tenofovir significantly reduced the mother-to-infant transmission compared with other treatments. The use of tenofovir significantly reduced the risk of infant HBsAg positivity by 75% (RR = 0.25, 95% CI: 0.16, 0.38), the infant HBeAg positivity by 74% (RR = 0.26, 95% CI: 0.14, 0.48), and the infant HBV DNA positivity by 85% (RR = 0.15, 95% CI: 0.07, 0.31). Our results were in consistent with the study conducted by Chen WJ, et al. [
40]. In that study, 3.3 and 10.0% of infants in tenofovir group had HBsAg and HBeAg positivity, as compared with 40.9 and 43.2% of infants in the control group, respectively. Similarly, other studies also reported the reduced rates of HBsAg/HBeAg positivity by tenofovir. In one prospective trial in China, the rates of HBsAg and HBV DNA positivity in tenofovir group were 1.5 and 6.15%, as compared with 10.7 and 31.48% in the control group, respectively [
36]. In another multicenter, open-label, randomized, parallel-group trial in China [
37], a striking decline in HBsAg positivity rate was seen from the tenofovir treatment. According to that study, 5.2% (5/97) of infants in the tenofovir group had HBsAg positivity, as compared with 18% (18/100) of infants in the control group (
P = 0.007). These results indicated that tenofovir was effective in reducing the risk of HBV transmission from their mothers.
Regarding the immunoprophylaxis failure, our study showed that infant in the tenofovir group had a lower immunoprophylaxis failure rate than that in the control group. This result was also observed among the included studies. In a multicenter, open-label RCT, the rate of immunoprophylaxis failure in tenofovir group was 5.2%, as compared with 18% in the control group, which indicated that tenofovir therapy could reduce the immunoprophylaxis failure rate [
37]. In another two cohort studies [
20,
39] that evaluated the efficacy and safety of tenofovir use in pregnant HBV women, none of the infants of the tenofovir-treated mothers had immunoprophylaxis failure; whereas, 2 of 23 (8.7%) and 1 of 73 (1.4%) of infants in the control group had immunoprophylaxis failure [
20,
39].
When the potential benefit of tenofovir is evaluated, the adverse effects of that also should be taken into consideration. These adverse effects include maternal ALT, CK, and Cr flares, and infant congenital malformation. Our results suggested that these adverse events were comparable between the tenofovir and control groups. There were several studies [
18,
44] reporting data on ALT flares during and after the antiviral treatment in pregnant women; however, their results remained inconsistent. In the study that used telbivudine or lamivudine for the treatment of late pregnancy women [
18], it was reported that 17.1% of the mothers in the treated group had severe hepatitis flare (ALT> 10 times the ULN) compared with 6.3% in the untreated mothers [
18]. In another study that used lamivudine or tenofovir, the incidences of postpartum ALT flare (> 95 U/L) in the treatment and no-treatment groups were 40–50 and 29%, respectively [
44]. The highly variable and conflicting results could be explained by the different criteria for the definition of ALT flares, different follow-up protocols, different antiviral agents, and lack of controls [
44].
This meta-analysis has several potential limitations that should be considered. First, substantial heterogeneity was identified among the included studies. However, it should not be surprising given the differences in maternal age at delivery, gestational age, gravidity, HBV DNA levels, and baseline ALT. These factors may account for the heterogeneity and have an impact on the treatment effect. Second, some of the included studies have a relatively small sample size (N < 50). Compared with larger trials, studies with small sample size are more likely to overestimate the treatment effect. Third, among the nine included studies, only one was RCT, and the remaining seven were cohort studies. Despite the cohort studies can reflect the “real-world” and further support the conclusion, the cohort data may be inclined to bias because of the patient selection. Fourth, most of the included studies were conducted in China. Thus, these findings were not representative of experts’ prescribing practices all around world. Therefore, physicians should interpret our results with caution when applying them into the clinical practice.