Elsevier

Journal of Hepatology

Volume 61, Issue 3, September 2014, Pages 502-507
Journal of Hepatology

Research Article
Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus

https://doi.org/10.1016/j.jhep.2014.04.038Get rights and content

Background & Aims

Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice.

Methods

We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7 log IU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared.

Results

120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, with baseline viral load mean 7.8 log IU/ml (±0.72) and ALT median 25 U/L (18.75–33). Duration of antiviral theraphy before birth was mean 58 days (±19) TDF and 53 (±14) lamivudine. Viral load declined by 3.64 log IU/ml (±0.9) TDF and 2.81 log IU/ml (±1.33) lamivudine. Virologic failure (birth viral load >7 IU/ml) occurred in 3% and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to 2% and 0% in TDF and lamivudine cohorts, compared with 20% in untreated.

Conclusions

TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts.

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.

References (53)

  • H. Blencowe et al.

    National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications

    Lancet

    (2012)
  • G. Carroli et al.

    Epidemiology of postpartum haemorrhage: a systematic review

    Best Pract Res Clin Obstet Gynaecol

    (2008)
  • K.Y. Tse et al.

    The impact of maternal HBsAg carrier status on pregnancy outcomes: a case-control study

    J Hepatol

    (2005)
  • S. Blanche et al.

    Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues

    Lancet

    (1999)
  • WHO. Hepatitis B. World Health Organisation Fact Sheet; 2012,...
  • A.S. Lok

    Chronic hepatitis B

    N Engl J Med

    (2002)
  • P. Coursaget et al.

    Age- and sex-related study of hepatitis B virus chronic carrier state in infants from an endemic area (Senegal)

    J Med Virol

    (1987)
  • R.P. Beasley et al.

    Incidence of hepatitis B virus infections in preschool children in Taiwan

    J Infect Dis

    (1982)
  • B.J. McMahon et al.

    Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state

    J Infect Dis

    (1985)
  • M.H. Chang

    Natural history of hepatitis B virus infection in children

    J Gastroenterol Hepatol

    (2000)
  • C. Lee et al.

    Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis

    BMJ

    (2006)
  • T.W. Wu et al.

    Chronic hepatitis B infection in adolescents who received primary infantile vaccination

    Hepatology

    (2013)
  • H. Zou et al.

    Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers

    J Viral Hepat

    (2012)
  • E. Wiseman et al.

    Perinatal transmission of hepatitis B virus: an Australian experience

    Med J Aust

    (2009)
  • M. van Zonneveld et al.

    Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection

    J Viral Hepat

    (2003)
  • N.H. Bzowej

    Optimal management of the hepatitis B patient who desires pregnancy or is pregnant

    Curr Hepat Rep

    (2012)
  • Cited by (0)

    View full text