Download Review Antiviral therapy for hepatitis B infection during pregnancy

Antiviral Therapy 2011; 16:621–628 (doi: 10.3851/IMP1813)
Review
Antiviral therapy for hepatitis B infection during
pregnancy and breastfeeding
Michelle Giles1,2,3,4,5*, Kumar Visvanathan2,4, Joe Sasadeusz1,5
Infectious Diseases Unit, Alfred Hospital, Melbourne, Australia
Department of Infectious Diseases, Monash Medical Centre, Melbourne, Australia
3
Department of Microbiology and Infectious Diseases, Royal Women’s Hospital, Melbourne, Australia
4
Department of Medicine, Monash University, Melbourne, Australia
5
Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Australia
1
2
*Corresponding author e-mail: [email protected]
It is estimated there are 350–400 million people worldwide chronically infected with HBV. Many of these are
women and of reproductive age. As such, they may
face therapeutic decisions regarding antiviral therapy
and the implication this may have on future or current
pregnancies. This article reviews the data of all antivirals
licensed for use against hepatitis B infection regarding teratogenicity, carcinogenicity, clinical experience
during pregnancy, placental transfer and excretion in
breast milk.
Introduction
It is estimated there are approximately 350–400 million
individuals chronically infected with HBV worldwide
[1]. Exposure to HBV early in life is associated with the
highest rates of chronic infection, with 90% of children
developing chronic infection if infected in the first year
of life with subsequent rates progressively decreasing
with increasing age at the time of exposure [2,3]. Women
from countries endemic for HBV who are infected at a
young age, often remain chronically infected with HBV
during their reproductive years and are an important
source for ongoing perinatal transmission. As a result
it is common for these women to face therapeutic decisions regarding HBV infection during this time.
The number of treatment options available for
HBV has increased in the last decade and now include
interferon-α (both standard and pegylated), lamivudine, entecavir, tenofovir, adefovir and telbivudine.
All large registration trials of these agents have specifically excluded pregnant or breastfeeding women.
Consequently they have not been licensed for use in
this population. Moreover there have been no prospective studies in pregnant women directly comparing the safety and efficacy of specific antiviral agents.
This has resulted in a marked lack of experience of
antiviral agents in this group of patients. Despite this,
women of reproductive age with chronic HBV infection often require treatment of their HBV infection;
©2011 International Medical Press 1359-6535 (print) 2040-2058 (online)
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therefore, this indication needs to be balanced against
their reproductive intent. Furthermore women already
on therapy may become pregnant, raising issues of
safety to the fetus. In addition to maternal indications
for therapy, there is also increasing data which suggests
that antiviral therapy may be of benefit over and above
hepatitis B vaccination and hepatitis B immunoglobulin in preventing mother-to-child transmission [4]. If
these medications are used in this patient population,
the important considerations include: whether the drug
crosses the placenta, whether the drug is teratogenic,
and whether the drug is excreted in breast milk and can
harm the infant.
The safety of drugs in pregnancy is stratified by the
FDA into a classification system on the basis of experience of human exposure and the potential to cause
harm to the fetus from animal studies. The other major
source of information on teratogenicity is derived from
the Antiretroviral Pregnancy Registry, which was initially established in 1989 to evaluate teratogenicity of
HIV agents. Since 2003 this has also included antivirals
with activity against HBV. The registry is voluntary and
collects information on congenital anomalies in exposed
offspring and compares the rate of congenital anomalies with the background rate from sentinel counties in
Atlanta (GA, USA). While this resource deals with the
issue of teratogenicity, it does not address the issue of
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M Giles et al.
toxicity in exposed infants either during the third trimester or post-partum during breastfeeding when teratogenicity is no longer relevant but toxicity may occur.
The purpose of this review is to summarize the data
currently available for antiviral agents licensed for use
in chronic HBV infection with a particular focus on
their known effect on reproduction, pregnancy and
breastfeeding. Each medication is discussed in detail
with a summary provided in Table 1.
Interferon-α
Interferon-α is a class of immune modulating agents
that has been licensed for the treatment of chronic
HBV since 1992. Interferons possess in vitro antiviral,
immunomodulatory and anti-proliferative activity and
work by binding to specific receptors on the cell surface
thereby initiating intracellular signalling and activation
of gene transcription. The products resulting from gene
transcription act to inhibit viral replication within cells
and cell proliferation [5]. Accordingly, they are used in
the treatment of viral infections and malignancies.
Standard interferons have previously been demonstrated to achieve approximately 30% hepatitis B e
antigen (HBeAg) seroconversion [6]. More recently,
interferon-α has been modified by conjugation with a
polyethylene glycol side chain. This alters its pharmacology to allow weekly administration and is now the
preferred form of interferon for treatment of HBV, and
results in similar rates of HBeAg seroconversion [7,8]
which are largely sustainable [9]. Given that there is a
defined duration of therapy with interferons, they are
particularly suited to the treatment of female patients
of reproductive age in an attempt to avoid long-term
nucleoside/nucleotide analogue therapy. However, the
significance of HBV DNA rebound after ceasing interferon therapy in this group of patients is unknown.
Data on the pharmacokinetics of interferons in
pregnancy are limited. A study of two women given a
single intramuscular dose prior to termination of pregnancy [10] reported that interferon was undetectable
in fetal blood and amniotic fluid. Animal studies have
reported a similar finding with no placental transfer
demonstrated unless the interferon was coadministered
with a chemical inducer [11].
Another study attempted to measure placental transfer as well as excretion of interferon in human breast
milk in two women. The authors measured neonatal
serum levels as a surrogate marker of placental transfer along with a sample of breast milk and correlated
it to maternal serum levels in two women with chronic
myeloid leukaemia treated with interferon-α (8 million units daily and 8 million units three times per
week, respectively) during pregnancy [12]. A blood
sample from the first newborn was tested for the level
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of interferon and was found to be <0.6 U/ml compared with 20.8 U/ml in the maternal serum, whereas
the concentration in breast milk was 1.4 U/ml. In the
second newborn, immediate post-partum levels were
<1 U/ml in the newborn and 58 U/ml in the mother,
and levels in breast milk were 6 U/ml [12]. The conclusion from the authors of this paper was that there
was minimal placental transfer due to the large size
of the molecule. Another case report measured breast
milk interferon concentration on two occasions prior
to a large intravenous dose of interferon for malignant
melanoma, and then on five occasions post-dose over
the next 21 h [13]. The authors found that even after
massive doses of drug (30 million IU), interferon levels
in breast milk were only marginally increased above
control samples. They concluded that even after very
large doses, interferon is not excreted in human breast
milk at levels high enough to be clinically relevant or
to induce side effects in the breastfed infant. This was
thought to be due to the mammary alveolar epithelial
cell barrier, which is impervious to substances with a
molecular weight >1,000 daltons, particularly after
the first 2 weeks post-partum [13].
There are no reported animal studies examining the
potential teratogenicity of interferon in animal models.
Despite the recommendation to avoid interferon during
pregnancy, it has been used by pregnant women for a
variety of medical conditions including chronic myelogenous leukaemia [14], essential thrombocythaemia
[15] and chronic inflammatory demyelinating polyneuropathy (CIDP) [16]. There are also case reports of
fetal exposure following unplanned pregnancy during
its administration for conditions such as hepatitis C
infection [17]. In the case of CIDP, treatment has been
used for the entire duration of a successful pregnancy,
although the fetus was delivered at 33 weeks secondary
to the development of maternal pre-eclampsia. It is difficult to ascertain if the associated intrauterine growth
restriction was related to the antiproliferative effect of
interferon or the pre-eclampsia [16]. A series of 26 pregnancies with interferon exposure reported no abortions
or fetal malformations in 27 cases where interferon
was used alone [18]. A higher incidence of intrauterine
growth restriction among infants exposed compared
with the general population has been documented [19],
although a causal effect has not been established due to
small numbers (6/27, 22%). More recently, there has
been a case report of an infant exposed to pegylated
interferon for 16 weeks in utero with no evidence of
fetal malformation [19].
There have been no clinical studies of interferons in
pregnancy; therefore, the safety in this setting has not
been established, This, together with its very limited
data in animal studies, means that its use is not advised,
especially given its known antiproliferative effects.
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FDA pregnancy Placental passage, categorya
(newborn:mother drug ratio)
Long-term animal carcinogenicity
Animal teratogenicity studies
Reproductive toxicity studies
Pharmacokinetics in pregnancy
Animal studies
demonstrate excretion
in breast milk; no
human data
Unknown in human
or animals
Case reports only
suggesting minimal
excretion due to large
molecular size
Animal studies
demonstrate excretion
in breast milk; no
human data
Animal studies
demonstrate excretion
in breast milk. No
human data
Yes
Breast milk
excretion
a
Regarding US Food and Drug Administration (FDA) category B, animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; or, animal studies have
shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. Regarding FDA category C, animal reproduction studies have shown an adverse effect
on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. AUC, area under the curve.
Lamivudine C
Yes (human; 1.0)
Negative (no tumours in Negative
Increased early embryolethality Not significantly
a lifetime rodent study)
in rabbits at exposure levels
altered
similar to humans; this effect
was not seen in rats at exposure levels up to 35× those in humans
Interferon
C
Minimal due to large Not tested for its Interferon-α2b at 90–360× Effect on fertility has not been Unknown
molecular size
carcinogenic potential
human dose had an abortifacient studied
effect in rhesus monkeys
Entecavir
C
Unknown
Positive (lung tumors in
Skeletal malformations in Testicular seminiferous tubule Unknown
mice, pancreatic tumours
rabbits at drug exposures >883×
degeneration or germinal
and fibromas in rats)
human levels and in rats at
epithelial maturation arrest
exposures >3,100× human levels
in dogs and rodents
Tenofovir
B
Yes (human; 0.95–0.99)
Positive (hepatic Negative; osteomalacia when No evidence in rats or rabbits Limited studies in adenomas in female mice
given to juvenile animals at
of fetal harm or impaired
human pregnancy. at high doses)
high doses and a reduction in fertility at exposures up to Data indicate AUC
weight and crown-rump length 19× human exposure
lower in third compared with age-matched
trimester than controls (rhesus macaques)
postpartum but
trough levels were
similar. Phase I study
in late pregnancy
in progress
Adefovir
C
Unknown
Negative in mice and rats
Increased fetal malformations Negative in rats and rabbits
Unknown
in rats exposed to doses at least 38× higher than
human exposure
Telbivudine B
Yes, rats and rabbits
Negative in mice and rats No adverse effects in developing No impaired fertility in male Unknown
at exposures up to 14× embryos and fetuses in preclinical or female rats at exposures human therapeutic dose
studies at doses up to 14× human exposure doses
1,000 mg/kg/day (exposure levels 6–37× higher than the
therapeutic dose in humans)
Drug
Table 1. HBV drugs and pregnancy or breastfeeding
Antiviral therapy during pregnancy and breastfeeding
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Lamivudine
Lamivudine is a member of the nucleoside reverse
transcriptase inhibitor class of antiretroviral drugs. It
is a dideoxynucleoside analogue of cytidine and is a
potent inhibitor of HIV-1 and HIV-2, as well as HBV
[20]. Lamivudine was the first oral agent to show
efficacy against and to be licensed for the treatment
of HBV. Studies in non-pregnant chronic HBV infection have demonstrated that lamivudine therapy for
52 weeks leads to improved hepatic necroinflammatory scores and reduces progression of fibrosis. In
addition, HBeAg seroconversion, suppression of HBV
DNA replication and normalization of alanine aminotransferase (ALT) levels was observed in 16%, 98%
and 72% of individuals, respectively [21]. A further
placebo-controlled, randomized, double-blind clinical trial of lamivudine in chronic HBV infection and
advanced liver disease also demonstrated its efficacy in
decreasing liver disease progression, and reduced the
rates of hepatocellular carcinoma and hepatic decompensation [22]. Unfortunately this drug has been associated with high levels of HBV resistance when used
long term [23], and with the advent of newer agents
with higher barriers to resistance, its routine use in
clinical practice has become more limited.
In pregnant women, lamivudine crosses the placenta
readily by simple diffusion [24]. In a study of 57 HIVinfected pregnant women receiving lamivudine as part
of their antiretroviral therapy, maternal blood, cord
blood and amniotic fluid samples correlated with fetal
concentrations [25]. Indeed, the median concentration
in the amniotic fluid was 5× higher than that in maternal
plasma [25]. Animal teratogenicity studies have been
performed in rats and rabbits with exposures up to 40
and 36× higher than human doses, respectively, with
no observed teratogenicity [26]. There was, however, a
reduction in litter size of rabbits observed at exposures
less than that observed at human clinical dosage [26].
Lamivudine has been used extensively by pregnant
women (predominantly for HIV infection), and to
date there has been no increase in fetal malformations
compared with the background rate as reported to
the Antiretroviral Pregnancy Registry for 3,754 first
trimester exposures and 6,080 second/third trimester
exposures [27].
Lamivudine is the only HBV antiviral to date that
has been used in a randomized controlled trial of pregnant women, where it was studied to determine if it
could prevent perinatal HBV transmission [4]. This
followed several small observational cohort studies
involving women with high viral loads [28–30], where
it was suggested that it could prevent perinatal transmission when compared rates with historical controls.
The more recent study of 114 women was conducted
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in China and the Philippines [4]. While the intention to
treat analysis of the study suggested a significant reduction in HBV transmission to infants whose mothers
received lamivudine (10/56 [18%] lamivudine versus
23/59 [39%] placebo; P=0.014), there was a very high
loss to follow-up rate in the placebo arm, leading to
potentially significant bias. Attempts to adjust for this
by sensitivity analyses resulted in a loss of statistical
significance [4].
Lamivudine is found in higher concentrations in
human breast milk than serum [31]. The actual concentration, coupled with the average feed volume ingested
by an infant suggests the amount of drug the infant
would be exposed to via this route is negligible compared with standard oral dosing [32]. In a recent study
the median breast milk concentration of lamivudine in
67 HIV-infected women treated with a combination
of lamivudine, zidovudine and nevirapine was 1,214
ng/ml compared with 508 ng/ml in maternal plasma
(breast milk to plasma ratio 2.56) [33].
The other issue that has been investigated is that of
potential long-term carcinogencity in children exposed
to nucleoside analogues in utero or post-partum.
A nationwide prospective cohort reported cancer
incidence in 8,853 children (median age 5.4 years)
exposed to ≥1 antiretroviral drug (5,908 received lamivudine) during pregnancy or post-partum [34]. The
incidence did not differ significantly from the general
population, with 10 tumours detected. Prematurity
and exposure to the combination of didanosine/lamivudine remained independently associated with cancer
on multivariate analysis [34], but the authors advise
that longer surveillance is warranted.
Of all the antivirals with activity against HBV, lamivudine has the most safety data in pregnancy and its
use in women of reproductive age who are pregnant
or considering pregnancy can therefore be recommended if indicated after careful assessment of risk
and benefits.
Adefovir dipivoxil
Adefovir dipivoxil is a prodrug of adefovir which,
following absorption, is phosphorylated to the active
metabolite, adefovir diphosphate, by cellular kinases.
Adefovir diphosphate competes with the natural substrate deoxyadenosine triphosphate and is incorporated
into viral DNA leading to chain termination. Randomized controlled trials of adefovir in both HBeAgpositive and HBeAg-negative patients have shown it to
be superior to placebo at 48 weeks in terms of histological response, HBV DNA level, and HBeAg loss and
seroconversion [35,36]. In addition, in patients with
lamivudine-resistant HBV, adefovir in combination
with lamivudine is associated with greater reduction in
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serum HBV DNA and normalization of ALT compared
with lamivudine alone [37]. There are no studies of adefovir in pregnant women and no data regarding effect
on mother-to-child transmission of HBV. There is no
data on placental transfer.
No increase in tumour incidence was reported in
carcinogenicity studies in mice and rats at 10 and 4×
human doses, respectively [38]. At levels ≥38× higher
than human exposure doses, adefovir given intravenously to pregnant rats was associated with increased
fetal malformations (anasarca, depressed eye bulge,
umbilical hernia and kinked tail) [38]. There have been
39 reports to the Antiretroviral Pregnancy Registry [27]
of first trimester adefovir exposure with no reported
congenital malformations.
It is not known whether adefovir is excreted in human
or animal milk. There have been no clinical studies in
pregnancy and given the limited information available
its safety in this setting has not been established and its
use is not advised.
Entecavir
Entecavir monohydrate is a guanosine nucleoside
analogue with activity against HBV polymerase. It
is phosphorylated to the active triphosphate form by
cellular kinases and then competes with the natural
substrate deoxyguanosine-TP and inhibits all three
functional activities of HBV polymerase.
Randomized clinical trials using entecavir have demonstrated its superiority to lamivudine in HBV DNA
reduction and histological improvement at 48 weeks
in both HBeAg-positive and -negative antiviral-naive
patients [39,40]. Sustained virological suppression has
been reported after 5 years of therapy with minimal
resistance [41].
There are no clinical studies of entecavir use in
pregnant women and no data regarding effect on
mother-to-child transmission of HBV.
There is no data regarding placental transfer of entecavir. Entecavir was not genotoxic in in vitro studies,
but was carcinogenic in both mice and rats. An increase
in the incidence of lung tumours were observed in mice
at exposures >3 and 40× that in humans. A number
of other tumours were observed at exposures >20× the
exposure in humans at 1 mg/day. These tumours tended
to appear late after long-term exposure [42]. In rat and
rabbit animal models embryofetal development was
not affected at exposures up to 28× and 212× human
exposure, respectively [42]. At a maternotoxic dose
(>2,500× human levels) embryofetal development in
the rat was severely retarded. In addition, skeletal malformations in rabbits was observed at drug exposures
>883× human levels in the absence of maternal toxicity,
and in rats at exposures >3,100× human levels [42].
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Overall 22 prospective cases of entecavir exposure
during pregnancy, including follow-up data, have been
reported to the Antiretroviral Pregnancy Registry [27]
as of 31 July 2010. Further cases of entecavir exposure
are required before there would be sufficient numbers
to detect an increase in fetal malformations compared
with the background rate in the population.
Entecavir monohydrate and/or its conjugate metabolites are excreted in the milk of rats, but it is not known
whether human breast milk excretion occurs.
Entecavir has not been studied in pregnant women
and, due to its significant carcinogenic potential in
animal studies, its use in this population can not be
recommended at this time.
Tenofovir
Tenofovir disoproxil fumarate is an acyclic nucleoside
phosphonate diester analogue of adenosine monophosphate. It is the prodrug of tenofovir, a nucleotide analogue and obligate chain terminator with activity against
HIV reverse transcriptase and HBV polymerase [43].
In a non-pregnant population, tenofovir was demonstrated to be superior to adefovir through to 48 weeks
in a double blind Phase III study, where it demonstrated
superior HBV DNA reductions [44]. Tenofovir also has
been demonstrated to have a very high barrier to resistance with no reported signature resistance mutations to
date. As such, together with entecavir, it has become the
preferred oral agent for HBV therapy.
Studies of placental transfer of tenofovir have been
performed in HIV-infected women rather than HBVmonoinfected women, and therefore usually in association with other antiretroviral drugs. These studies
have reported a median ratio of maternal to umbilical
cord concentration of 1.00 [45,46]. While studies have
reported a reduced area under the curve during pregnancy compared with post-partum, no dosage modification during pregnancy is currently recommended
[46]. Reproductive toxicity studies in rats and rabbits
did not reveal harmful effects to the fetus at concentrations of 4–13 and 66× higher than human exposure
levels, respectively. In addition, fertility and embryonic development were not affected in rats by tenofovir exposure at 5× the human therapeutic dose [43] In
gravid rhesus monkeys (n=4) administered tenofovir
subcutaneously once daily from 20 to 150 days of gestation, there was normal fetal development, although
overall body weights and crown-rump lengths were
less than those for age-matched controls along with a
small reduction in fetal bone porosity [47]. Tenofovir
has been taken by pregnant women (predominantly
for HIV infection) and to date there has been no
increase in congenital malformations compared with
the background rate as reported to the Antiretroviral
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Pregnancy Registry for 981 first trimester exposures
and 584 second/third trimester exposures [27].
Secretion in breast milk has been demonstrated when
tenofovir has been administered to rats and rhesus
macaques [48]. Excretion in human breast milk has not
been studied.
In terms of long-term follow up of infants, two
retrospective case series examining the safety profile
in HIV-infected pregnant women and their offspring
reported no observed tenofovir-related toxicity in the
children [49,50]. More recently, preliminary data on
perinatal tenofovir exposure did not find any evidence
of renal impairment, abnormal bone metabolism or
impaired growth in children exposed to tenofovir
in utero [51–53]. However, studies in children taking tenofovir as treatment for HIV infection have
reported decreased bone density, mostly reversible
upon cessation [54,55].
Due to its growing safety data in pregnant women
(albeit in HIV-infected rather than HBV-monoinfected
pregnant women) and its potency and high barrier to
resistance regarding HBV, it should be considered as
a therapeutic option in women of reproductive age
planning pregnancy or in pregnant women considering
interventions to reduce perinatal HBV transmission.
Telbivudine
Telbivudine is an HBV-specific l-nucleoside analogue
of thymidine. When activated by phosphorylation, it
competes with naturally occurring thymidine triphosphate and is incorporated into the viral DNA leading to
chain termination. Unlike other nucleoside analogues,
such as lamivudine, telbivudine preferentially inhibits
anti-complement or second-strand DNA [56] and has
no activity towards other human viruses [57].
Clinical studies comparing telbivudine with lamivudine demonstrated telbivudine to be superior to
lamivudine in therapeutic response in HBeAg-positive
patients [58,59]. In HBeAg-positive patients telbivudine treatment was associated with higher rates of
undetectable HBV DNA at 2 years, a higher proportion of patients had normalization of ALT at 2 years
but there was no difference in HBeAg seroconversion
compared with the group treated with lamivudine
[58]. In HBeAg-negative patients, telbivudine was also
associated with a higher rate of therapeutic response
compared with lamivudine at 2 years [58]. Participants in this large trial were predominantly male with
only approximately 25% of participants being female.
In a recently reported study from China, 52 viraemic
women were given telbivudine during the second or
third trimesters of pregnancy, which resulted in a
reduction of HBV DNA and HBeAg levels at delivery [60]. One-third of the telbivudine-treated mothers
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achieved an undetectable viral load prior to delivery.
Infant follow-up at 7 months post-partum demonstrated a statistically significant difference in intrauterine transmission rate between the telbivudine and
the control group (0% versus 18%; P<0.05) [60]. No
serious adverse effects were noted in the telbivudinetreated mothers or their infants.
In pre-clinical animal studies telbivudine crossed
the placenta in rats, but did not demonstrate any teratogenicity in rats or rabbits at doses 6× (rats) to 37×
(rabbits) higher than therapeutic human doses [61].
An increase in premature delivery and abortion was
observed in rabbits at plasma levels 37× higher than
those in humans at therapeutic dose. Studies in male
and female rats confirmed telbivudine had no effect on
pregnancy rate or fertility and has shown no carcinogenic potential [61]. Data on human placental passage
and breast milk excretion is not yet available.
Telbivudine has been taken by a small number of
pregnant women and to date no congenital malformations have been reported to the Antiretroviral Pregnancy Registry for six first trimester exposures and
eight second and third trimester exposure [27].
Although the safety data of telbivudine looks
promising and there is a small amount of experience
in pregnant women infected with HBV, more clinical
experience is required before its widespread use can
be recommended.
Conclusions
Many women with chronic HBV who are being considered for treatment are of reproductive age; therefore,
balancing their reproductive intent with their need for
treatment to reduce progressive liver fibrosis is an important aspect of clinical management. Factors to consider
include maternal age, extent of existing liver fibrosis,
and safety and efficacy data of available licensed antiHBV medications. Although none of these drugs are
recommended in pregnancy, there is increasing safety
and efficacy data (predominantly from the HIV-infected
pregnant population) emerging particularly for lamivudine and tenofovir.
In addition, women who are on antivirals and become
pregnant have one of three options. These include continuing therapy (particularly if this agent is lamivudine
or tenofovir), ceasing therapy or switching to a drug
with more safety data in pregnancy. The safety of ceasing therapy needs to be carefully considered as there is
no data in the pregnancy setting detailing the clinical
implications for the mother and/or the fetus of a hepatitis flare, particularly in the first trimester. In light of this,
and in the scenario of women with significant liver fibrosis, switching to an agent such as lamivudine or tenofovir
for the duration of the pregnancy may be warranted.
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The third therapeutic scenario emerging is the role of
antivirals for prevention of mother-to-child transmission of HBV. Only lamivudine has been demonstrated
in a clinical trial to potentially confer benefit, although
both tenofovir (due to its potency and safety data)
along with telbivudine (due to its recent reported use
in a small study of pregnant women) should also be
considered, but warrant further study.
The implications of this include the following: for
some women, treatment should not be delayed if it is
clinically warranted, even if the woman is trying to conceive; and, there is a need to further investigate the additional benefit (if any) of anti-HBV medications other
than lamivudine on preventing perinatal HBV transmission over and above the standard care of hepatitis B
immunoglobulin and hepatitis B vaccination at birth.
With such a high burden of disease amongst women
of reproductive age, and ongoing perinatal transmission
occurring despite widespread use of hepatitis B immunoglobulin and hepatitis B vaccination at birth, further
research of this population is warranted. There is an
urgent need for more data in the pregnancy setting to
guide our therapeutic choices. Moreover, while most of
that focus has been on teratogenicity, there also needs
to be a greater emphasis on efficacy of the various treatments in pregnancy and the evaluation of potential longterm effects of using these drugs in the third trimester of
pregnancy and in the post-partum period.
Disclosure statement
The authors declare no competing interests.
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Accepted 3 December 2010; published online 2 June 2011
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