Telbivudine can safely reduce mother-to-child transmission in chronic hepatitis B women after 12 weeks of gestation

Although the weighted prevalence of hepatitis B surface antigen (HBsAg) for Chinese population aged 1–59 years were 7.2%, immunization program should be further strengthened to reach those remaining at highest risk [1]. Perinatal or mother-to-child transmission (MTCT) is the most common form of transmission of hepatitis B virus (HBV) in many high-prevalence areas, particularly in Asian countries. The regions of the world where HBV genotype C is found as MTCT is associated with high maternal viral load (HBV DNA > 10⁶ IU/mL), and may occur in up to 90% of mothers who are HBsAg positive and hepatitis B e antigen (HBeAg) positive in the absence of prophylaxis [2‐9]. Application of Hepatitis B vaccine combined with Hepatitis B immune globulin (HBIG) considerably reduced perinatal transmission [10]. However, in a previous study from China, the rate of immunoprophylaxis failure by predelivery HBV DNA levels, was 0% for levels < 10⁶ copies/mL, 3.2% for levels of 6–6.99 log₁₀ copies/mL, 6.7% for levels between 7 and 7.99 log₁₀ copies/mL, and 7.6% for levels > 8 log₁₀ copies/mL, respectively [9]. No perinatal transmission has also been reported in infants born to mothers with viral loads < 6 log₁₀ copies/mL in other studies [6, 11]. The HBV DNA threshold to consider antiviral therapy to prevent perinatal transmission is > 2 × 10⁵ IU/mL [9]. The use of these agents in HBeAg positive women whose HBV DNA are > 10⁶ copies/mL in the third trimester to prevent MTCT is recommended [12]. Thus, antiviral therapy was started at 28–32 weeks of gestation in most of the studies [13]. It’s still have failed immunoprophylaxis in some high viral load mothers, so antiviral therapy start at a earlier time may be considered such as at the second trimesters of pregnancy [14]. Since tenofovir is not approved for the treatment of chronic hepatitis B (CHB) before 2014 in China and very expensive, the use of telbivudine would appear to be a favorable treatment option for CHB mothers [15]. Moreover, some previous studies found that patients in the telbivudine group had significantly lower HBV DNA and HBeAg levels and higher HBV DNA negative conversion rates compared to those in the lamivudine group before delivery [16, 17]. Thus, we performed this study to evaluate the efficacy and safety of using telbivudine treatment started at 12–34 weeks of gestation in HBeAg positive or negative CHB mothers (rare of the studies including HBeAg negative mothers) on MTCT prevention, HBV DNA suppression, and maternal and fetal safety including major birth defect rates.

According to national guidelines 2010 version, application of Hepatitis B vaccine combined with HBIG is as the standard of care for prevent MTCT of HBV in China. By the end of 2015, the use of lamivudine, telbivudine or tenofovir in HBeAg positive women whose HBV DNA are > 10⁶ copies/mL at 28–32 weeks of gestation is added as a new method in Chinese guide 2015 version to prevent MTCT [21, 22]. In our study, antiviral therapy was started at week 12–34 of pregnancy, some of them started antiviral therapy earlier than previous studies, which antiviral therapy was started at week 28–32 of pregnancy according to the American Association for the Study of Liver Disease (AASLD) guideline [13]. In the telbivudine group, only one infant’s HBsAg was positive after 7 months, whose mother started antiviral therapy at 34 weeks of gestation. It maybe too later, so her HBV DNA levels was still above 6 log₁₀ IU/mL at delivery. If the patient who started antiviral therapy at 34 weeks of pregnancy was not included in our study, the rate of immunoprophylaxis failure was zero. That is very encouraging and impressive. About 57.6% patients started antiviral therapy at week 12–27 of gestation, but adverse events reported in telbivudine group was similar to control group.

In our study, we enrolled the patients who started antiviral treatment at ALT above > one fold the upper limit of normal, which is lower than AASLD or Asian Pacific Association for the Study of the Liver (APASL) guideline, but the same as the European Association for the Study of the Liver (EASL) guideline [13, 23, 24]. Thus, more people may achieve benefit from our study.

Treatment was usually administered in the second and third trimesters of gestation, because the most sensitive period of fetal development generally occurs in the first trimester, especially at the first 8 weeks of pregnancy [25]. Telbivudine is an L-reverse transcriptase inhibitor, and has shown no effects on human nucleotides or DNA synthesis [26]. Toxicological research has demonstrated that telbivudine has no carcinogenic, teratogenic, or mutagenic effects, and no mitochondrial toxicity [26, 27]. The duration of antiviral treatment should be considered, because it requires several weeks to suppress serum viral loads effectively. It would be desirable to minimize the adverse events to fetal development while to suppress serum HBV DNA levels of pregnant women as early as possible, so that it can probably enhance the efficacy of the antiviral agent in reducing MTCT of HBV. Therefore, we evaluated the patients received antiviral treatment at 12–34 weeks of gestation more earlier than previous studies, and the limited safety data suggest that it did not increase the risks of adverse events of maternal or fetal. The results of our study was similar to two previous studies, which the initiation of NA treatment time were at week 12–30 and week 8–32, but those studies were only enrolled HBeAg positive women with chronic hepatitis B [16, 28]. Moreover, another previous study shown that treatment with telbivudine during the second and third trimesters of pregnancy safely blocked perinatal transmission of HBV and infants born to telbivudine-treated mothers showed normal growth and development during long-term follow-up of up to 5 years [14].

The most common telbivudine-related adverse events was increased serum CK levels [29]. In our study, CK levels was slightly increased in 7 cases from telbivudine group and spontaneously recovered without drug withdrawal. In telbivudine group, fetal malformation was found in two cases (1 case at antenatal examination after 4 weeks of treatment, and another newborn had a ruptured abdominal aortic aneurysm in the perinatal period), and it’s no statistically significant difference compared with that in control group. These findings indicated that telbivudine treatment is safe in the second and third trimesters. Another study of 489 pregnancies found that treatment with telbivudine presents a favorable safety profile without increasing the rates of live birth defect, spontaneous abortion or elective termination, and neonatal toxicity [30].

There were a few limitations of this study. First, there maybe have a risk of bias in this single center and observational study. Second, all the patients were naïve treatment patients with serum HBV DNA > 6.0 log₁₀ IU/mL, the efficacy of telbivudine in the CHB patients with a history of antiviral therapy on MTCT was still unknown. Third, we didn’t detect genotypes of HBV in this study, which was a important point for antiviral treatment. However, viral genotypes have diverse geographical distribution and the genotypes of HBV are almost genotype B or C in China according to a previous study [31].

The antiviral therapy in HBeAg positive women whose HBV DNA are > 10⁶ IU/mL was started at the third trimester to prevent MTCT is recommended. However, it’s still have failed immunoprophylaxis in some high viral load CHB mothers. Antiviral therapy start at a earlier time may be a solution, but we have insufficient data to prove that it is a safe method. In this study, we found that telbivudine treatment at 12–34 weeks of gestation in HBeAg positive or negative CHB mothers with serum HBV DNA > 6.0 log₁₀ IU/mL is well tolerance and safe in our limited data. Thus, telbivudine can safely reduce mother-to-child transmission in chronic hepatitis B women after 12 weeks of gestation.