AIM: To evaluate the effects of tenofovir disoproxil fumarate (TDF) use during late pregnancy to reduce hepatitis B virus (HBV) transmission in highly viremic mothers.

METHODS: This retrospective study included 45 pregnant patients with hepatitis B e antigen (+) chronic hepatitis B and HBV DNA levels > 10⁷ copies/mL who received TDF 300 mg/d from week 18 to 27 of gestation (n = 21). Untreated pregnant patients served as controls (n = 24). All infants received 200 IU of hepatitis B immune globulin (HBIG) within 24 h postpartum and 20 μg of recombinant HBV vaccine at 4, 8, and 24 wk. Perinatal transmission rate was determined by hepatitis B surface antigen and HBV DNA results in infants at week 28.

RESULTS: At week 28, none of the infants of TDF-treated mothers had immunoprophylaxis failure, whereas 2 (8.3 %) of the infants of control mothers had immunoprophylaxis failure (P = 0.022). There were no differences between the groups in terms of adverse events in mothers or congenital deformities, gestational age, height, or weight in infants. At postpartum week 28, significantly more TDF-treated mothers had levels of HBV DNA < 250 copies/mL and normalized alanine aminotransferase compared with controls (62% vs none, P < 0.001; 82% vs 61%, P = 0.012, respectively).

CONCLUSION: TDF therapy during the second or third trimester reduced perinatal transmission rates of HBV and no adverse events were observed in mothers or infants.

Hepatitis B virus (HBV) infection is a important medical problem affecting approximately 2 billion people globally[1]. The vertical transmission of HBV from hepatitis B surface antigen (HBsAg)-positive mothers to their infants at birth or in early infancy has a significant role in the endemicity of HBV infection and causes an increased risk of chronic hepatitis B (CHB)[2]. The prevention of perinatal or vertical transmission is crucial in the control of hepatitis B endemicity. Without immunoprophylaxis > 90% of infants, born to mothers with hepatitis B e antigen (HBeAg), become chronically infected with HBV. In recent years, active and passive immunoprophylaxis of newborns and universal vaccination programs have reduced the transmission rates of HBV[1-4]. It was reported that passive or active immunization within 12 h of birth may lead to the prevention of perinatal transmission of HBV[5]. However, some studies showed that HBV immunoprophylaxis fails in 10%-15% of infants[6,7], mainly as a result of vertical infection[8-11]. A high level of maternal viremia is a significant factor in prophylaxis failure. A positive correlation between high maternal serum HBV DNA levels and an increased risk for vaccination breakthrough was found in these studies[8-11]. These data have introduced the idea of antiviral therapy in pregnant women with a high level of maternal viremia and high maternal serum HBV DNA levels.

Among the oral anti-HBV agents approved by United States Food and Drug Administration (FDA), Tenofovir disoproxil fumarate (TDF) is an effective agent due to its potency and resistance profile[13-15]. TDF is a nucleotide analog which inhibits reverse transcriptase and blocks HBV replication in liver cells[2,16]. In over 600 human immunodeficiency virus (HIV) mono-infected and HIV/HBV co-infected mothers, it was reported that TDF had a favorable efficacy and safety profile[16-18]. However, to our knowledge, there are limited data available in the literature on the safety and efficacy of TDF therapy during pregnancy in highly viremic mothers with chronic hepatitis B and its impact on the perinatal transmission of HBV.

In the current study, we evaluated the efficacy and safety of TDF use during late pregnancy to reduce HBV transmission in highly viremic HBeAg positive mothers.

In this retrospective study, we report the efficacy and safety of TDF in the prevention of vertical transmission (VT) in pregnant women with high viremia HBV infection[15]. Immunoprophylaxis with immediate HBIG and HBV vaccine after delivery effectively prevented VT in these cases. Failure of immunoprophylaxis is generally caused by high maternal viral load[9,11,15]. It has been clearly demonstrated that there is a correlation between intrauterine serum HBV DNA levels and perinatal transmission of HBV in pregnant women[15]. HBV DNA level was found to be an independent risk factor for failure of immunoprophylaxis in HBeAg-positive mothers with high HBV DNA levels (≥ 6 log10 copies/mL)[19]. For these reasons we included mothers with high levels of DNA in the present study.

There are many studies on the use of TDF to prevent VT in HIV mono-infected and HIV/HBV coinfected mothers in the literature[17,18]. However, there are limited data on the use of TDF in pregnancy and in the prevention of VT in HBV mono-infected mothers. According to previous studies, early post-natal immunoprophylaxis with antiviral therapy in mothers in the third trimester was safe, well-tolerated, and effectively prevented VT of HBV[2,20]. Among five FDA approved oral anti-HBV agents, TDF and entecavir are the most effective agents due to their resistance profile and potency[13,15]. TDF and telbivudine are classified as category B (no evidence of risk to humans: either animal findings indicate risk, but human findings do not; or, if no adequate human studies have been conducted, animal findings are negative) for use in pregnancy, whereas lamivudine, entecavir, and adefovir are category C (risk cannot be ruled out: human studies are lacking, and animal studies are either positive for fetal risk, or are lacking). However, potential benefits may justify the potential risk) in the FDA drug category for pregnancy[15].

In a randomized, double-blind, placebo-controlled study with lamivudine, it was found that lamivudine therapy during late pregnancy can reduce HBV perinatal transmission in highly viremic mothers. This study demonstrated that infants in the lamivudine + vaccine + HBIG group had a significant decrease in the incidence of HBsAg seropositivity (10/56, 18% vs 23/59, 39%, P = 0.014) and in detectable HBV DNA (11/56, 20% vs 27/59, 46%, P = 0.003) compared to infants who received placebo + vaccine + HBIG. The results of this study suggested that lamivudine reduced HBV transmission from highly viremic mothers to their infants following immunization[20]. In another prospective, open-label controlled study evaluating the efficacy and safety of telbivudine use during late pregnancy, a striking decline in HBV DNA levels was seen from treatment onset to week 4, and remained at a low level from week 12. According to this study, 33% of the telbivudine-treated mothers and none of the untreated controls had DNA < 500 copies/mL at delivery and seven months after delivery, and the incidence of perinatal transmission was lower in the infants of telbivudine-treated mothers than in the controls (0% vs 8%; P = 0.002)[2]. In a case series by Pan et al[15], TDF therapy in the third trimester was evaluated in eleven Asian women with HBV. In their uncontrolled study, a significant reduction in serum HBV–DNA was achieved at delivery compared with baseline, and all infants were HBsAg negative 28-36 wk after birth[15]. In our controlled study, at postpartum week 28 significantly more TDF-treated mothers had low levels of HBV DNA and none of the infants of 21 treated mothers had immunoprophylaxis failure. In light of these results, we suggest that TDF use in the third trimester is safe and effectively prevents VT of HBV from high viremic HBeAg-positive mothers.

When the potential benefit of an antiviral-agent is evaluated, adverse effects of that antiviral-agent should also be taken into consideration. These adverse effects include teratogenicity, long-term effects on bone development in the infant, post-treatment ALT flares, and HBV-resistant mutations. Studies have indicated that TDF can cause renal events in HIV patients and patients with preexisting renal disease. However, nephrotoxicity was not observed during a three-year period of TDF use in chronic HBV patients with preserved baseline renal function[21,22]. According to analyzed neonatal safety data from the Antiretroviral Pregnancy Registry (APR), the birth defect prevalence of earliest exposure commencing in the first trimester was 3.1% for lamivudine and 2.4% for TDF; earliest exposure commencing in the second or third trimester was 2.7% for lamivudine and 2.0% for TDF[23]. A meta-analysis of lamivudine in late pregnancy reported that no significant increase in adverse effects or complications in pregnancy was observed[24]. In the large-scale controlled study by Han et al[2], no serious adverse events were noted in the telbivudine-treated mothers or their infants. In a Chinese study conducted in eight pregnant HBV women receiving TDF, HBV flares, an increase in creatinine and birth defects were not observed, and all newborn parameters were appropriate for gestational age[25]. Several clinical studies and the APR have stated that anti-viral agents for hepatitis are safe in pregnancy during the second/third trimester[15,23]. The relationship between TDF and fetal growth, particularly bone development is a matter of concern. Studies of pregnant monkeys showed that the use of TDF can cause reduced fetal growth and a reduction in fetal bone porosity within two months of starting maternal therapy[26]. TDF use in HIV-infected children has been reported to result in decreases in bone mineral density[27,28]. However, long-term safety data in infants perinatally exposed to TDF demonstrated no abnormal bone metabolism or growth impairment in these children[29,30]. In the study by Pan et al[15], serum creatinine levels were stable and within the normal range during TDF treatment in all mothers, and they did not encounter any adverse pregnancy outcomes and/or birth defects. Similarly, in the current study we did not observe any differences in adverse events in mothers or infant congenital deformities, gestational age, height, or weight between the groups.

In conclusion, this controlled study revealed that the use of TDF in highly viremic chronic hepatitis B mothers during the second or third trimester of pregnancy reduced the rate of perinatal transmission. Tenofovir disoproxil fumarate produced no adverse events in infants or mothers by 28 wk and is a safe and effective agent in pregnant women with high viremia.