Research ArticleEfficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus
Introduction
Worldwide 350 million patients are chronically infected with hepatitis B virus (HBV), with perinatal transmission remaining the predominant mode of infection despite active and passive immunization reducing rates to 3–7% [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. In addition to HBeAg positivity, we have shown that maternal HBV DNA level of >108 copies/ml (∼7 log IU/ml) is associated with increased transmission, approaching a rate of 9% despite immunoprophylaxis [11], [12], [13]. Antepartum antiviral therapy (AVT) is suggested and supported by cost-effectiveness modeling, although safety and efficacy data is limited [14], [15], [16], [17], [18], [19], [20], [21], [22].
Use of antepartum lamivudine and telbivudine has been investigated, however, both agents have limitations of potency and low threshold to resistance. Lamivudine still failed to prevent transmission from highly viraemic mothers in 6% (3/49) in a randomized, double-blind, placebo controlled study [21]. Whilst telbivudine, a more potent agent, has been shown to completely abrogate perinatal transmission, the potential for resistance is concerning [23], [24], [25], [26], [27], [28], [29]. Telbivudine use to prevent perinatal transmission resulted in selection of mutants in two of 38 cases tested [24]. Furthermore, using next generation sequencing, even short duration lamivudine in pregnancy has been shown to significantly increase viral quasi-species diversity [30]. Use of lamivudine or telbivudine in future pregnancies might amplify resistant variants and archiving could impact subsequent effectiveness of AVT [28], [31].
In contrast tenofovir disoproxil fumarate (TDF) has both a higher potency and barrier to resistance, however, there remains reluctance to use antepartum TDF perhaps related to infant growth concerns. TDF has not been associated with an increased risk of major birth defects or adverse fetal outcomes above expected population rates in analysis of the antiretroviral pregnancy registry [32]. Whilst antepartum administration of high dose TDF in Rhesus monkeys was associated with impaired fetal growth, this was not replicated when doses comparable to therapeutic human doses were used [33]. With respect to human infant growth, a small difference was reported in growth percentiles at one year of age between TDF exposed and unexposed infants in the human immunodeficiency virus (HIV) setting, however, such differences were not seen in birth or two year data, nor in a similar study which had follow up to five years of age [34], [35]. A retrospective cohort of eleven mothers and their babies provides the only published information to date of TDF use to prevent perinatal transmission of HBV [36].
We report a prospective opt-in real life observational study of AVT to prevent HBV transmission from highly viraemic mothers, and examine the efficacy and tolerability, as well as the maternal and fetal safety profile. We report on the TDF cohort for which there is little information in the HBV literature and provide comparisons to our earlier lamivudine treated and untreated cohorts.
Section snippets
Patients and methods
Pregnant women with chronic HBV and high viral load (VL) (>7 log ± 0.5 IU/ml) in the second trimester were prospectively recruited. From 2007 to 2010, lamivudine 100 mg daily was suggested, commencing at 32 weeks gestation. From late 2010 due to concerns about lamivudine potency and resistance and the availability of TDF for HBV infection in Australia, TDF 300 mg daily was offered. Consenting women who chose not to take AVT were included as controls. Maternal compliance, tolerability, biochemical and
Results
One hundred and twenty highly viraemic women participated during 130 pregnancies, with ten women presenting in more than one pregnancy. In 62 pregnancies TDF was used, in 48 lamivudine and in 20, no AVT was commenced. Four TDF treated women were switched to lamivudine after less than one week of therapy because of intolerance. Therefore cohorts comprised 58 TDF and 52 lamivudine treated and 20 untreated pregnancies from which data was prospectively collected (Fig. 1).
Discussion
TDF may be the optimal agent for prevention of perinatal transmission of HBV, yet there is limited information regarding safety and efficacy. This study provides the largest detailed prospective observational series using TDF from 32 weeks gestation in 58 highly viraemic HBV pregnancies and comparative data from our lamivudine treated and untreated mothers. TDF has superior virological potency compared to lamivudine and both significantly reduced HBV perinatal transmission.
TDF had close to a one
Financial support
There was financial support of $35,000 (AUS) received from Gilead Sciences, Australia and New Zealand for a portion of the work conducted in 2013. Additional financial support at the Westmead Hospital site from a Sydney West Translational Cancer Research Center grant and the Robert W. Storr Bequest to the University of Sydney. The remainder was investigator funded.
Conflict of interest
Gilead Sciences, Australia and New Zealand provided support for a portion of the work conducted in 2013.
Acknowledgements
Financial disclosure of $35,000 (AUS) from Gilead Sciences for a portion of work conducted in 2013 and additional financial support at the Westmead Hospital site from a Sydney West Translational Cancer Research Center grant and the Robert W. Storr Bequest to the University of Sydney; remainder investigator funded.
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