Received: 23 October 2016 | First decision: 27 November 2016 | Accepted: 9 March 2017

DOI: 10.1111/apt.14068

Systematic review with meta-analysis: the efficacy and safety

of tenofovir to prevent mother-to-child transmission of
hepatitis B virus

M. H. Hyun1,* | Y.-S. Lee2,* | J. H. Kim2 | J. H. Je2 | Y. J. Yoo2 | J. E. Yeon2 |

K. S. Byun2

1
Department of Internal Medicine, Korea
University Medical Center, Seoul, Korea Summary
2
Division of Gastroenterology and Background: Preventing mother to child transmission of chronic hepatitis B infec-
Hepatology, Department of Internal
tion in the setting of a high maternal viral load is challenging. The idea has emerged
Medicine, Korea University Medical Center,
Seoul, Korea from antepartum tenofovir treatment with combination immunoprophylaxis.
Aims: To demonstrate the efficacy and safety of tenofovir to prevent mother to
Correspondence
Dr JH Kim, Department of Internal child transmission of hepatitis B virus.
Medicine, Korea University Guro Hospital,
Methods: PubMed, EMBASE, and Cochrane databases were searched through
Korea University Medical Center, Seoul,
Korea. August 16, 2016. Comparative trials of second or third trimester tenofovir adminis-
Email: kjhhepar@naver.com
tration vs. controls for patients with chronic hepatitis B infection and non-compara-
Funding information tive case series assessing mother to child transmission rates and evaluating maternal
This study was funded in full by the
and foetal safety outcomes were included.
National Research Foundation of Korea
(NRF) grant funded by the Korea Results: Ten studies (one randomised controlled trial, four non-randomised con-
government (the Ministry of Education,
trolled trials and five case series) that enrolled 733 women were included. The
Science and Technology)
(2015R1C1A1A01052360). pooled results from comparative trials (599 pregnancies) showed that tenofovir sig-
nificantly reduced the risk of infant hepatitis B surface antigen seropositivity by
77% (odds ratio=0.23, 95% confidence intervals=0.10-0.52, P=.0004) without
heterogeneity (I2=0%). In the case series analysis (134 pregnancies), only two cases
(1.5%) of mother to child transmission with extremely high maternal viral load and
non-compliance to treatment were identified. Maternal and foetal safety parameters
including congenital malformation and foetal death were re-assuring.
Conclusions: For pregnant women with high hepatitis B virus DNA levels, tenofovir
administration in the second or third trimester can prevent mother to child transmis-
sion when combined with hepatitis B immunoglobulin and the hepatitis B vaccine.
Tenofovir is safe and tolerable for both the mother and foetus.

1 | INTRODUCTION
Chronic hepatitis B virus (HBV) infection is a global public health
issue affecting approximately 240 million people, and more than
*These authors contributed equally to this work.
As part of AP&T’s peer-review process, a technical check of this meta-analysis was per-
formed by Dr Y Yuan. The Handling Editor for this article was Professor Geoffrey Dush-
eiko, and it was accepted for publication after full peer-review.
600 000 people die annually because of HBV complications, accord-
ing to World Health Organization (WHO) estimates.1 In highly ende-
mic areas, especially the Asia Pacific region, mother to child
transmission (MTCT) accounts for the majority of infections.2-4 If
untreated, the likelihood of chronicity depends on what age a person
acquired the infection (80%-90% of infants vs. <5% of adults).5,6 The
recent universal newborn vaccination program using a combination
of active and passive immunoprophylaxis led to a significant

Aliment Pharmacol Ther. 2017;45:1493–1505. wileyonlinelibrary.com/journal/apt © 2017 John Wiley & Sons Ltd | 1493
1494 | HYUN
reduction in the MTCT rate, from 90% to 10%.7-9 In spite of this
combination strategy, infants born to mothers with high maternal
viral DNA levels (more than 106 copies/mL) with positive maternal
hepatitis B envelope antigen (HBeAg) showed 10%-30% immunopro-
phylaxis failure compared to less than 3% in those with a low mater-
nal viral load (less than 106 copies/mL).10-16 Therefore, the idea has
emerged from antepartum anti-viral therapy for pregnant women
with high maternal HBV DNA levels to help achieve global eradica-
tion of chronic HBV infection.
Among the oral anti-HBV agents approved by the United States
Food and Drug Administration (FDA), lamivudine (GlaxoSmithKline,
Middlesex, United Kingdom), telbivudine (Norvatis, Basel, Switzer-
land), and tenofovir (Gilead Sciences, Foster City, CA, USA) have
been relatively well-investigated for the prevention of MTCT.17 A
recent meta-analysis, including five randomised controlled trials
(RCT), reported that lamivudine showed a 71% risk reduction com-
pared to the control group.18 In addition, the latest meta-analysis,
including four RCTs, reported similar risk reduction in MTCT (77%)
using telbivudine without serious adverse events.18 Despite of their
efficacy, however, there were still concerns of developing resistant
mutants in spite of the short therapy duration.19,20 Therefore, lami-
vudine and telbivudine are limited by a low threshold to resistance
and multiplying viral quasi-species that might make treatment in
future pregnancies difficult.19-22
23-26
In this regard, majority of worldwide guidelines recommend
tenofovir as the preferred choice for MTCT prevention in terms of
anti-viral potency, available safety data during pregnancy, and con-
cerns for resistance compared to other anti-viral agents. To date, a
small number of case series and relatively well-designed non-rando-
mised controlled trials (NRCT) using tenofovir have been conducted
recently.27-35 Recently, Pan et al.36 published the first multicenter
RCT with a high quality of evidence. The authors found 75% risk
reduction for tenofovir with comparable safety outcomes compared
36
to the control group. However, since there is only one RCT cur-
rently available, there are still concerns whether 1 RCT provides suf-
ficient evidence to disregard all the NRCTs. Because well-designed
observational studies are not necessarily more biased than RCTs,
including observational studies increases the sample size and estab-
lishes more solid evidence if the study design is the single reason for
the possible discrepancy.37,38 Therefore, we conducted a systematic
review and meta-analysis of tenofovir for prevention of perinatal
HBV transmission to better determine the efficacy and safety of
tenofovir.
2 | MATERIALS AND METHODS
2.1 | Search strategy
This meta-analysis was performed according to the PRISMA state-
ment for reporting of systematic reviews and meta-analyses.39
PubMed, EMBASE, and Cochrane databases were searched for Eng-
lish-language articles published from database inception through
August 16, 2016. The detailed search strategy and search terms are
ET AL.
available in Table S1. To supplement electronic searches, the links
of every search result and all references in the pertinent articles
were reviewed to identify additional literature that was not
indexed.
2.2 | Eligibility criteria
Two independent investigators (MHH and JHK) identified compara-
tive, peer-reviewed studies of second or third trimester tenofovir
administration vs. controls for pregnant patients with chronic HBV
infection that included objective evaluations of maternal and/or foe-
tal safety outcomes and non-comparative case series that assessed
the MTCT rate and evaluated maternal and foetal safety outcomes.
If multiple publications reported on the same population, the most
recent or most comprehensive data were chosen. Only data of con-
ference abstracts were excluded. The detailed trial selection process
is summarised in Figure S1. Any disagreement was resolved by con-
sensus or referral to a third investigator (JEY).
2.3 | Data extraction and risk of bias assessment
The same two investigators independently performed data extrac-
tion and risk of bias assessment. Retrieved data from full text
papers included: first author, ethnicity, study design, inclusion crite-
ria, number of participants, age, HBV DNA suppression, alanine
aminotransferase (ALT) normalisation, HBeAg seroconversion, hep-
atitis B surface antigen (HBsAg) positivity within 24 hours after
birth and at 6-12 months of age, infant HBV DNA positivity within
24 hours after birth and at 6-12 months of age, and maternal and
foetal adverse outcomes. The Cochrane Collaboration’s tool was
used to assess the risk of bias in the RCT.40 The risk of bias of
NRCTs and case series were measured on the basis of the
Newcastle-Ottawa scale and Moga scale, respectively.41,42 The
assessment of outcome in Newcastle-Ottawa scale indicated
measurement of infants’ HBV infection status at least 1 month
after the last vaccine injection. Discrepancies were resolved by
consensus.
2.4 | Outcome measurements
The maternal efficacy outcomes included HBV DNA suppression,
ALT normalisation, and HBeAg seroconversion. MTCT rates were
defined as HBsAg or HBV DNA positivity of newborns and of
infants at 6-12 months of age.15 Maternal safety outcomes included
creatinine kinase (CK) elevation, serum creatinine (Cr) elevation, ALT
flare, caesarean section (CS) and post-partum haemorrhage rate.
Foetal safety outcomes included congenital malformation, pre-term
birth rate, low birth weight (<2500 g), and foetal death.
2.5 | Statistical analysis
The pooled log-transformed odds ratio (OR) and the 95% confidence
interval (CI) were provided in a forest plot for dichotomised
HYUN ET AL. | 1495

outcomes. Heterogeneity between studies for each of the outcomes
was tested with both the v test and I statistics.
2 2
zel random-effects meta-analysis was performed in outcomes in con-
sideration of the inter-study heterogeneity.
intervention effect achieved statistical significance if the two-sided
p-value was <.05. All statistical analyses were performed using the
RevMan statistical package (Review Manager Version 5.3, The
Cochrane Collaboration, Copenhagen, Denmark). The study protocol
was approved by the Institutional Review Board of Korea University
Guro Hospital (KUGH-16210).
HBV DNA (more than 29105 IU/mL). Both tenofovir and control
43
A Mantel-Haens- group infants received the hepatitis B vaccine with the hepatitis B
immunoglobulin (HBIG) at birth. The mean maternal age was
44
The overall 29.7 years. Most of enrolled mother were HBeAg positive (>95%)
except for one trial.30 The risk of bias for the RCT was high attributa-
ble to the open label study design.36 One of four NRCT was assigned
as high level of risk of bias owing to the different inclusion criteria
among the groups and insufficient follow-up periods.30 The detailed
risk of bias measurement results are shown in Tables S2 and S3.

3.2 | Maternal efficacy outcomes and MTCT rate

3 | RESULTS
3.1 | Characteristics of the studies
The detailed study selection process is described in Figure S1. In this
study, 10 studies (one RCT, four NRCT, and five case series) with a
total of 733 pregnant women were included. Among them, five com-
parative trials (one RCT, four NRCT) with 599 pregnant women were
pooled for analysis.27–30,36 The characteristics of the included compar-
ative trials are summarised in Table 1. The RCT was a multicentre trial
conducted in five geographic regions in China. 36
The four NRCTs
27-30
were performed in Turkey, Australia, Taiwan, and Canada.
studies, tenofovir was administered in the second or third trimester to
pregnant women who were HBeAg positive and had high maternal
The maternal efficacy outcomes and MTCT rate of the included trials
are described in Table 2. Three studies (one RCT and two NRCT)
reported HBV DNA suppression. The pooled analysis of tenofovir
showed a significantly higher maternal HBV DNA suppression rate
than the control group with a high grade of heterogeneity
(OR=260.41, 95% CI=29.92-2266.17, P<.00001, I2=61%), although
the definition of HBV DNA suppression differed between studies
(<200 000 IU/mL for Pan et al.36; <50 IU/mL for Celen et al.;27 and
<1 000 000 IU/mL for Chen et al.29) (Figure S2A). ALT normalisation
rates (1 NRCT, OR=2.55, 95% CI=0.65-10.01, P=.18, I2=not available
In all [NA]) and HBeAg seroconversion rates (1 RCT, 1 NRCT, OR=1.28,
95% CI=0.07-24.11, P=.87, I2=60%) were similar between tenofovir
and control groups (Figures S2B, C).29,45

T A B L E 1 Characteristics of the clinical trials included in the meta-analysis

Participants Maternal
Country (Mother: Interventions on Age HBeAg
Study (Year) (Ethnicity) Study design Inclusion criteria Infant) Interventions on mother infant (years)a (%) Risk of biasb

RCT

Pan et al. China RCT (Multicentre HBeAg positive + HBV 97:95 Tenofovir (Gestation HBIG+Vaccination 27.43.0 100% High (Open
(2016)36 (Asians) trial of 5 DNA>29105 IU/mL week 30-32 to label study
geographic post-partum week 4) design)
regions in China)
Same as above 100:88 Controlc HBIG+Vaccination 26.83.0 100%

NRCT

Celen et al. Turkey NRCT (Retrospective HBeAg positive+HBV 21:21 Tenofovir (Gestation HBIG+Vaccination 28.24.1 100% Low
(2013)27 (Asians) chart review of six DNA≥29106 IU/mL week 18-27 to
hospitals in Turkey) post-partum week 4)

Same as above 24:23 Controlc HBIG+Vaccination 26.92.9 100%

Greenup et al. Australia NRCT (Multicentre HBV DNA>107IU/mL 58:44 Tenofovir (Gestation HBIG+Vaccination 30.08.5 95% Low
(2014)28 (Asians) prospective cohort week 32 to
study in Australia) post-partum week 12)

Same as above 20:10 Controlc HBIG+Vaccination 28.05.3 100%

Chen et al. Taiwan NRCT (Multicentre HBeAg positive+HBV 62:65 Tenofovir (Gestation HBIG+Vaccination 32.53.2 100% Low
(2015)29 (Asians) prospective cohort DNA≥107.5 IU/mL week 28 to
of 14 collaborative post-partum week 4)
hospitals in Taiwan)
Same as above 56:56 Controlc HBIG+Vaccination 32.43.1 100%
7
Samadi Canada NRCT (Single centre HBV DNA≥10 IU/mL 23:24 Tenofovir (Gestation HBIG+Vaccination 30 (28-34) 70% High
Kochaksaraei (Asians, prospective cohort week 28-32 to
et al. (2015)30 Africans, study in Canada) post-partum week 12)
and
HBV DNA<107IU/mL 138:146 Controlc HBIG+Vaccination 32 (29-36) 9%
others)

HBeAg, hepatitis B envelope antigen; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT, alanine aminotransferase; RCT, randomised controlled
trial; HBIG, hepatitis B immunoglobulin; NRCT, non-randomised controlled trial; NR, not reported.
a
Parentheses indicates interquartile range; otherwise data are expressed as meanSD.
b
Risk of bias measured by Cochrane Collaboration’s tool in the RCT40 and the Newcastle-Ottawa scale in the NRCT41.
c
Immunoprophylaxis only.
1496 | HYUN ET AL.

T A B L E 2 Maternal efficacy outcomes and mother to child transmission rates of the clinical trials included in the meta-analysis
MTCT rate

Maternal efficacy outcomes Newborn within 24 hours Infants within 6-12 months

Study (Year) Interventions HBV DNA ALT HBeAg HBsAg HBV DNA HBV DNA
(Number of M:I) suppressiond normalization seroconversion positive positive HBsAg positive positive
Pan et al. (2016)36a
Tenofovir (97:95) 68.0% (66/97) NR 1% (1/97) 6.2% (6/97) 3.1% (3/97) 5.2% (5/97) NR
c
Control (100:88) 2.0% (2/100) NR 3% (3/100) 4.0% (4/100) 15.0% (15/100) 18.0% (18/100) NR
Celen et al. (2013)27
Tenofovir (21:21) 61.9% (13/21) 80.9% (17/21) NR NR NR 0% (0/21) NR
Controlc (24:23) 0% (0/24) 62.5% (15/24) NR NR NR 8.3% (2/24) NR
Greenup et al. (2014)28
Tenofovir (58:44) NR NR NR NR NR 2.3% (1/44) NR
c
Control (20:10) NR NR NR NR NR 20.0% (2/10) NR
Chen et al. (2015)29
Tenofovir (62:65) 98.4% (61/62) NR 4.8% (3/62) 10.8% (7/65) 6.2% (4/65) 1.5% (1/65)e NR
c e
Control (56:56) 1.8% (1/56) NR 0% (0/56) 17.8% (10/56) 31.5% (17/56) 10.7% (6/56) NR
Samadi Kochaksaraei et al. (2015)30b
Tenofovir (23:24) NR NR NR NR NR 0% (0/12) NR
Controlc (138:146) NR NR NR NR NR 1.3% (1/73) NR

MTCT, mother to child transmission; M, mother; I, infant; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT, alanine aminotransferase; HBeAg,
hepatitis B envelope antigen; HBsAg, hepatitis B surface antigen; NR, not reported.
a
Using intention-to-treat analysis data.
b
Half of the infants had not reached the appropriate age to complete the 3-dose HBV vaccine series and undergo testing.
c
Immunoprophylaxis only.
d
Defined as less than 200 000 IU/mL for Pan et al.36, less than 50 IU/mL for Celen et al.27, and less than 1 000 000 IU/mL for Chen et al.29.
e
Data indicates MTCT rate in infants within 6 months; no different MTCT rates were shown in infants within 12 months between two groups (tenofovir
vs control, 3.0% (2/65) vs 10.7% (6/56), respectively; P=.1423).

Two studies (1 RCT and 1 NRCT) reported newborn HBsAg
29,36
seropositivity and HBV-DNA levels within 24 hours after birth.
The newborn HBsAg positive rates were 8.0% (13/162) in the teno-
fovir group and 9.0% (14/156) in the control group. The pooled analy-
sis demonstrated that newborn HBsAg seropositivity was similar
between the tenofovir and control groups with a low grade of hetero-
geneity (OR=0.87, 95% CI=0.31-2.40, P=.79, I =34%) (Figure 1A). On
2
the other hand, use of tenofovir resulted in 4.3% (7/162) of newborns
testing positive for HBV DNA compared to 20.5% (32/156) in the con-
trol group. The pooled analysis showed that tenofovir reduced the risk
of newborn HBV DNA positivity by 84% without heterogeneity
(OR=0.16, 95% CI=0.07-0.39, P<.0001, I2=0%) (Figure 1B). All five
studies (1 RCT and 4 NRCT) demonstrated HBsAg seropositivity of
infants within 6-12 months.27–30,36 HBsAg seropositivity in infants at
6-12 months of age was 2.9% (7/239) in the tenofovir group and
11.0% (29/263) in the control group. The pooled result showed that
tenofovir significantly reduced the risk of infant HBsAg seropositivity
by 77% (OR=0.23, 95% CI=0.10-0.52, P=.0004, I2=0%) without
heterogeneity (Figure 1C). The study of Samadi Kochaksaraei et al.
had several critical limitations that can give biased result; including dif-
ferent inclusion criteria between tenofovir group (HBV DNA≥107
IU/mL) and the control group (HBV DNA<107 IU/mL), and half the
infants had not completed the 3-dose HBV vaccine series and under-
gone testing. Therefore, sensitivity analysis excluding Samadi Kochak-
saraei et al. was performed. Tenofovir significantly reduced the risk of
infant HBsAg seropositivity and showed similar intensity with the
result of analysis including this study. (OR=0.20, 95% CI=0.09-0.46,
P=.0002, I2=0%) (Figure 1D). None of the studies showed HBV DNA
levels of infants within 6-12 months.
3.3 | Maternal and foetal safety outcomes
The forest plots of odds ratio (OR) for maternal safety outcomes are
shown in Figure 2. The tenofovir group showed a similar CK eleva-
tion rate (1 RCT, 1 NRCT, OR=8.49, 95% CI=0.98-73.28, P=.05,
I2=0%), Cr elevation rate (1 NRCT, OR=0.34, 95% CI=0.01-8.45,
P=.51, I2=not available [NA]), ALT flare (1 RCT, 3 NRCT, OR=1.00,
95% CI=0.31-3.24, P=.99, I2=49%), CS rate (1 RCT, 3 NRCT,
OR=1.27, 95% CI=0.85-1.87, P=.24, I2=0%), and post-partum haem-
orrhage rate (1 RCT, 1 NRCT, OR=0.76, 95% CI=0.27-2.16, P=.61,
30
I2=0%) compared to the control group.
Figure 3 shows forest plots of foetal safety outcomes. When
comparing tenofovir vs. control for foetal harm, no significant differ-
ence was found, including congenital malformation (1 RCT, 4 NRCT,
HYUN ET AL. | 1497

(A) HBsAg positivity in newborns within 24 hours

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
RCT
Pan et al 2016 6 97 4 100 42.9% 1.58 [0.43, 5.79]
Subtotal (95% CI) 97 100 42.9% 1.58 [0.43, 5.79]
Total events 6 4
Heterogeneity: Not applicable
Test for overall effect: Z = 0.69 (P = 0.49)

NRCT
Chen et al 2015 7 65 10 56 57.1% 0.56 [0.20, 1.57]
Subtotal (95% CI) 65 56 57.1% 0.56 [0.20, 1.57]
Total events 7 10
Heterogeneity: Not applicable
Test for overall effect: Z = 1.11 (P = 0.27)

Total (95% CI) 162 156 100.0% 0.87 [0.31, 2.40]

Total events 13 14
Heterogeneity: Tau2 = 0.19; Chi2 = 1.52, df = 1 (P = 0.22); I 2 = 34% 0.01 0.1 1 10 100
Test for overall effect: Z = 0.27 (P = 0.79)
Favours tenofovir group Favours control group

(B) HBV DNA positivity in newborns within 24 hours

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
RCT
Pan et al 2016 3 97 15 100 45.4% 0.18 [0.05, 0.65]
Subtotal (95% CI) 97 100 45.4% 0.18 [0.05, 0.65]
Total events 3 15
Heterogeneity: Not applicable
Test for overall effect: Z = 2.63 (P = 0.009)

NRCT
Chen et al 2015 4 65 17 56 54.6% 0.15 [0.05, 0.48]
Subtotal (95% CI) 65 56 54.6% 0.15 [0.05, 0.48]
Total events 4 17
Heterogeneity: Not applicable
Test for overall effect: Z = 3.20 (P = 0.001)

Total (95% CI) 162 156 100.0% 0.16 [0.07, 0.39]

Total events 7 32
Heterogeneity: Tau2 = 0.00; Chi2 = 0.04, df = 1 (P = 0.83); I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 4.14 (P < 0.0001)
Favours tenofovir group Favours control group

F I G U R E 1 Effects of tenofovir treatment vs. controls on vertical transmission as indicated by HBV DNA in newborns within 24 hours, and
hepatitis B surface antigen positivity in newborns within 24 hours and in infants within 6-12 months. The size of the squares indicates point
estimates and the weight of each study. The horizontal lines show 95% confidence intervals. CI, confidence interval; HBsAg, hepatitis B
surface antigen; HBV DNA, hepatitis B virus deoxyribonucleic acid; RCT, randomised controlled trial; NRCT, non-randomised controlled trial

OR=1.60, 95% CI=0.30-8.47, P=.58, I2=0%), pre-term birth rate (1 maternal HBV DNA levels from 9.38 log10 copies/mL to 3.55 log10
RCT, 3 NRCT, OR=2.39, 95% CI=0.84-6.81, P=.10, I2=0%), low birth copies/mL.32,34,35 Two cases (2/134 [1.5%]) of MTCT were reported.
weight<2500 g (1 NRCT, OR=1.10, 95% CI=0.06-18.77, P=.95, The first case had an extremely high serum maternal HBV DNA level
I2=NA), and foetal death (1 RCT, 4 NRCT, OR=1.28, 95% CI=0.20- (152 000 000 copies/mL) and began tenofovir at gestational week
8.25, P=.80, I =0%). The overall maternal and foetal safety outcomes
2
28.32 In the other case, the mother was treated with tenofovir for
are summarised in Table 3. only 17 days due to non-compliance with pre-natal care.34 Regarding
safety, a total of four cases (3.0% [4/134]) of serious adverse events
were described in the case series: one case of hypospadias,32 one
3.4 | Case series analysis
case of post-partum haemorrhage,33 one case of patent foramen
The summary of the case series analyses is displayed in Table 4. Five ovale33 and one case of congenital dislocation of the right knee.33
case series analyses with a total of 134 pregnant women were However, there were no known foetal deaths after tenofovir treat-
included. The administration of tenofovir showed decreased ment. The risk of bias of the case series is shown in Table S4.
1498 | HYUN ET AL.

(C) HBsAg positivity in infants within 6-12 months

Odds Ratio
Tenofovir group Control group M-H, Random, Odds Ratio
Study or Subgroup Events Total Events Total Weight 95% CI Year M-H, Random, 95% CI
RCT
Pan et al 2016 5 97 18 100 62.0% 0.25 [0.09, 0.70] 2016
Subtotal (95% CI) 97 100 62.0% 0.25 [0.09, 0.70]
Total events 5 18
Heterogeneity: Not applicable
Test for overall effect: Z = 2.64 (P = 0.008)
NRCT
Celen et al 2013 0 21 2 24 6.9% 0.21 [0.01, 4.62] 2013
Greenup et al 2014 1 44 2 10 10.5% 0.09 [0.01, 1,15] 2014
Kochaksaraei et al 2015 0 12 1 73 6.3% 1.93 [0.07, 50.18] 2015
Chen et al 2015 1 65 6 56 14.4% 0.13 [0.02, 1.12] 2016
Subtotal (95% CI) 142 163 38.0% 0.20 [0.05, 0.76]
Total events 2 11
Heterogeneity: Tau2 = 0.00; Chi2 = 2.37, df = 3 (P = 0.50); I 2 = 0%
Test for overall effect: Z = 2.38 (P = 0.02)

Total (95% CI) 239 263 100.0% 0.23 [0.10, 0.52]

Total events 7 29
Heterogeneity: Tau2 = 0.00; Chi2 = 2.43, df = 4 (P = 0.66); I 2 = 0%
Test for overall effect: Z = 3.55 (P = 0.0004) 0.01 0.1 1 10 100
Favours tenofovir group Favours control group

(D) HBsAg positivity in infants within 6-12 months, excluding Samadi Kochaksaraei et al
Odds Ratio
Tenofovir group Control group Odds Ratio
M-H, Random,
Study or Subgroup Events Total Events Total Weight 95% CI Year M-H, Random, 95% CI
RCT
Pan et al 2016 5 97 18 100 66.1% 0.25 [0.09, 0.70] 2016
Subtotal (95% CI) 97 100 66.1% 0.25 [0.09, 0.70]
Total events 5 18
Heterogeneity: Not applicable
Test for overall effect: Z = 2.64 (P = 0.008)
NRCT
Celen et al 2013 0 21 2 24 7.4% 0.21 [0.01, 4.62] 2013
Greenup et al 2014 1 44 2 10 11.2% 0.09 [0.01, 1.15] 2014
Chen et al 2015 1 65 6 56 15.3% 0.13 [0.02, 1.12] 2015
Subtotal (95% CI) 130 90 33.9% 0.13 [0.03, 0.55]
Total events 2 10
Heterogeneity: Tau2 = 0.00; Chi2 = 0.16, df = 2 (P = 0.92); I 2 = 0%
Test for overall effect: Z = 2.78 (P = 0.006)
Total (95% CI) 227 190 100.0% 0.20 [0.09, 0.46]
Total events 7 28
Heterogeneity: Tau2 = 0.00; Chi2 = 0.67, df = 3 (P = 0.88); I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 3.77 (P = 0.0002)
Favours tenofovir group Favours control group

FIGURE 1 Continued

4 | DISCUSSION 10%-30%).10-16 Therefore, a growing number of reports have been

There are clinical challenges in preventing MTCT in women with
chronic HBV infection. A substantial portion of pregnant women are
in an immune-tolerant stage of the disease, which indicates HBeAg
positivity and high maternal HBV DNA levels.46 The risk of MTCT in
maternal HBeAg positive individuals is higher than that of HBeAg
negative individuals without immunoprophylaxis (range: 70%-90% vs.
45
10%-40%). In addition, the high level of maternal HBV DNA with
HBeAg positivity correlated with immunoprophylaxis failure despite
of adequate combination HBIG and HBV vaccination, and the MTCT
rate increased dramatically around 106-108 copies/mL of HBV DNA
level (less than 10 copies/mL vs. more than 10 copies/mL; <3% vs.
6 8
published about the use of antepartum anti-viral therapy to reduce
MTCT in this population.
Among the current FDA approved drugs, tenofovir disoproxil
fumarate is the only preferred first-line agent for the treatment of
chronic HBV infection.23,24,47 The first use of tenofovir to prevent
MTCT was reported in 2012.31 Pan et al. included 11 pregnant HBeAg
positive women (HBV DNA>106 copies/mL) who were treated with
tenofovir in the third trimester and showed no MTCT or serious
adverse events. Subsequently, four more case series were published
from 2012 to 2016, including 123 women who were HBeAg positive
(except Koruk et al.34) and had a high maternal HBV DNA level from
USA, China, and Turkey, mostly Asian populations.32–35 Overall, the
HYUN ET AL. | 1499

(A) CK elevation
Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Celen et al 2013 1 21 0 24 43.9% 3.59 [0.14, 92.83]
Pan et al 2016 7 97 0 100 56.1% 16.66 [0.94, 295.78]

Total (95% CI) 118 124 100.0% 8.49 [0.98, 73.28]

Total events 8 0
Heterogeneity: Tau2 = 0.00; Chi2 = 0.51, df = 1 (P = 0.48); I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 1.95 (P = 0.05)
Favours tenofovir group Favours control group

(B) Cr elevation
Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Pan et al 2016 0 97 1 100 100.0% 0.34 [0.01, 8.45]

Total (95% CI) 97 100 100.0% 0.34 [0.01, 8.45]

Total events 0 1
Heterogeneity: Not applicable
0.01 0.1 1 10 100
Test for overall effect: Z = 0.66 (P = 0.51)
Favours tenofovir group Favours control group

(C) ALT flare

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Celen et al 2013 1 21 0 24 10.4% 3.59 [0.14, 92.83]
Chen et al 2015 2 62 7 56 26.4% 0.23 [0.05, 1.17]
Kochaksaraei et al 2015 3 24 7 146 29.6% 2.84 [0.68, 11.83]
Pan et al 2016 5 97 6 100 33.6% 0.85 [0.25, 2.89]

Total (95% CI) 204 326 100.0% 1.00 [0.31, 3.24]

Total events 11 20
Heterogeneity: Tau2 = 0.68; Chi2 = 5.91, df = 3 (P = 0.12); I 2 = 49%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.01 (P = 0.99)
Favours tenofovir group Favours control group

(D) CS rate
Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Chen et al 2015 27 62 17 56 26.8% 1.77 [0.83, 3.78]
Greenup et al 2014 10 58 2 20 5.9% 1.88 [0.37, 9.40]
Kochaksaraei et al 2015 8 24 36 146 17.9% 1.53 [0.60, 3.87]
Pan et al 2016 47 97 50 100 49.4% 0.94 [0.54, 1.64]

Total (95% CI) 241 322 100.0% 1.27 [0.85, 1.87]

Total events 92 105
Heterogeneity: Tau2 = 0.00; Chi2 = 2.22, df = 3 (P = 0.53); I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 1.17 (P = 0.24)
Favours tenofovir group Favours control group

(E) Postpartum hemorrhage

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Greenup et al 2014 5 58 3 20 46.0% 0.53 [0.12, 2.47]
Pan et al 2016 4 97 4 100 54.0% 1.03 [0.25, 4.25]

Total (95% CI) 155 120 100.0% 0.76 [0.27, 2.16]

Total events 9 7
Heterogeneity: Tau2 = 0.00; Chi2 = 0.38, df = 1 (P = 0.54); I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.51 (P = 0.61)
Favours tenofovir group Favours control group

F I G U R E 2 Forest plots of odds ratios for maternal safety outcomes. CI, confidence interval; CK, creatinine kinase; Cr, serum creatinine;
ALT, alanine aminotransferase; CS, caesarean section. The size of the squares indicates point estimates and the weight of each study. The
horizontal lines show 95% confidence intervals

rate of MTCT reported in the case series was markedly low (1.5%). In
addition, the birth defect rate was not higher than the Centers for Dis-
ease Control and Prevention’s population surveillance rate (case series
48
analysis vs. CDC’s population surveillance; 3.0% vs. 3.3%).
Along with the case series, there were several well-designed com-
parative NRCTs supporting tenofovir treatment to reduce the risk of
MTCT.27–30 Celen et al. conducted the first NRCT of 42 women (21
tenofovir at gestational age 18-28 weeks vs. 21 women in the control
1500 | HYUN ET AL.

(A) Congenital malformation

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Celen et al 2013 0 21 0 23 Not estimable
Chen et al 2015 1 65 0 56 26.7% 2.63 [0.10, 65.80]
Greenup et al 2014 1 44 0 10 25.9% 0.72 [0.03, 19.07]
Pan et al 2016 2 95 1 88 47.4% 1.87 [0.17, 21.00]
Total (95% CI) 225 177 100.0% 1.60 [0.30, 8.47]
Total events 4 1
Heterogeneity: Tau2 = 0.00; Chi2 = 0.33, df = 2 (P = 0.85); I 2 = 0%
Test for overall effect: Z = 0.56 (P = 0.58) 0.01 0.1 1 10 100
Favours tenofovir group Favours control group

(B) Preterm birth rate

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Chen et al 2015 5 65 2 56 38.8% 2.25 [0.42, 12.08]
Greenup et al 2014 1 44 0 10 10.2% 0.72 [0.03, 19.07]
Kochaksaraei et al 2015 2 24 3 146 32.2% 4.33 [0.69, 27.41]
Pan et al 2016 2 95 1 88 18.7% 1.87 [0.17, 21.00]
Total (95% CI) 228 300 100.0% 2.39 [0.84, 6.81]
Total events 10 6
Heterogeneity: Tau2 = 0.00; Chi2 = 0.97, df = 3 (P = 0.81) I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 1.63 (P = 0.10)
Favours tenofovir group Favours control group

(C) Low birth weight (< 2500 g)

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Celen et al 2013 1 21 1 23 100.0% 1.10 [0.06, 18.77]

Total (95% CI) 21 23 100.0% 1.10 [0.06, 18.77]

Total events 1 1
Heterogeneity: Not applicable
Test for overall effect: Z = 0.07 (P = 0.95) 0.01 0.1 1 10 100
Favours tenofovir group Favours control group

(D) Fetal death

Tenofovir group Control group Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
Celen et al 2013 0 21 1 24 32.9% 0.36 [0.01, 9.43]
Chen et al 2015 0 65 0 56 Not estimable
Greenup et al 2014 0 44 0 10 Not estimable
Kochaksaraei et al 2015 0 24 1 146 33.4% 1.98 [0.08, 50.00]
Pan et al 2016 1 95 0 88 33.7% 2.81 [0.11, 69.88]
Total (95% CI) 249 324 100.0% 1.28 [0.20, 8.25]
Total events 1 2
Heterogeneity: Tau2 = 0.00; Chi2 = 0.88, df = 2 (P = 0.65); I 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.26 (P = 0.80)
Favours tenofovir group Favours control group

F I G U R E 3 Forest plots of odds ratios for foetal safety outcomes. The size of the squares indicates point estimates and the weight of each
study. The horizontal lines show 95% confidence intervals. CI, confidence interval

group) with a mean age of 27.73.7 years who were HBeAg positive
with high HBV DNA levels (>29106 IU/mL) in 6 Turkish hospitals.27
The reported MTCT rate was 0% (0/21) in infants born to the women
who received tenofovir therapy compared with 8% (2/24) in infants
born to women in the control group (P=.194). There were no differ-
ences between the groups in terms of adverse events in mothers or
congenital deformities. Later, Greenup et al.,28 Chen et al.,29 and
Samadi Kochaksaraei et al.30 reported similar NRCT comparing teno-
fovir administration in the second or third trimester and control groups
for women with HBeAg positivity and high maternal HBV infection.
Chen et al. enrolled 118 woman (62 tenofovir vs. 56 control) and
showed a significantly lower rate of HBsAg positivity for infants at
6 months of age (tenofovir 1.5% (1/65) vs. control 10.7% (6/56);
P=.048) with comparable safety outcomes.29 One infant in the teno-
fovir group did not avoid MTCT despite maternal HBV viral load
reduction to 4.24 log10 IU/mL at delivery. Greenup et al. showed a
significant MTCT rate (HBsAg positivity for infants at 6-12 months of
age) reduction in the tenofovir group (2.3% [1/44]) compared to the
control group (20.0% [2/10]; P=.046) with 78 enrolled woman (58
tenofovir vs. 20 control).28 MTCT was detected in 1 infant born by
HYUN ET AL. | 1501

T A B L E 3 Maternal and fetal safety outcomes of the clinical trials included in the meta-analysis
Maternal safety outcomes Fetal safety outcomes

Study (Year) Low birth

Interventions Tenofovir Postpartum Congenital Preterm birth weight
(Number of M:I) tolerabilityc CK elevationd Cr elevatione ALT flaref CS rate hemorrhage malformation rate (<2500 g) Fetal death
36a
Pan et al. (2016)

Tenofovir (97:95) 1.0% (1/97) 7.2% (7/97) 0% (0/97) 5.2% (5/97) 48.5% (47/97) 4.1% (4/97) 2.1% (2/95)1 2.1% (2/95) NR 1.1% (1/95)
b
Control (100:88) N/A 0% (0/100) 1.0% (1/100) 6.0% (6/100) 50.0% (50/100) 4.0% (4/100) 1.1% (1/88)2 1.1% (1/88) NR 0% (0/88)

Celen et al. (2013)27

Tenofovir (21:21) 0% (0/21) 4.8% (1/21) NR 4.8% (1/21) NR NR 0% (0/21) NR 4.8% (1/21) 0% (0/21)

Controlb (24:23) N/A 0% (0/24) NR 0.0% (0/24) NR NR 0% (0/23) NR 4.3% (1/23) 4.2% (1/24)

Greenup et al. (2014)28

Tenofovir (58:44) 6.9% (4/58) NR NR NR 17.2% (10/58) 8.6% (5/58) 2.3% (1/44)3 2.3% (1/44) 4.5% (2/44) 0% (0/44)

Controlb (20:10) N/A NR NR NR 10.0% (2/20) 15.0% (3/20) 0% (0/10) 0% (0/10) NR 0% (0/10)
29
Chen et al. (2015)

Tenofovir (62:65) 0% (0/62) NR NR 3.2% (2/62) 43.5% (27/62) NR 1.5% (1/65)4 7.7% (5/65) NR 0% (0/65)
b
Control (56:56) N/A NR NR 12.5% (7/56) 30.4% (17/56) NR 0% (0/56) 3.6% (2/56) NR 0% (0/56)

Samadi Kochaksaraei et al. (2015)30

Tenofovir (23:24) NR NR NR NR 33.3% (8/24) NR 0% (0/24) 8.3% (2/24) 8.3% (2/24) 0% (0/24)

Controlb (138:146) N/A NR NR NR 24.7% (36/146) NR 0.7% (1/146)5 2.1% (3/146) NR 0.7% (1/146)

M, mother; I, infant; CK, creatinine kinase; Cr, creatinine; ALT, alanine aminotransferase; HBV DNA, hepatitis B virus deoxyribonucleic acid; HBeAg, hep-
atitis B envelope antigen; CS, cesarean section; NR, not reported; N/A, not available.
a
Using intention-to-treat analysis data.
b
Immunoprophylaxis only.
c
Defined as treatment discontinuation of tenofovir due to side effects; 1 mother with grade 2 nausea for Pan et al.36 Two mothers with gastrointestinal
side effects and 2 other mothers with dyspnea for Greenup et al.28
d
Defined as elevation of serum creatinine kinase level>39upper limit normal (ULN) for Pan et al.36,>165 mg/dL for Celen et al.27
e
Defined as elevation of serum creatinine level≥.5 mg/dL for Pan et al.36
f
Defined as elevation of ALT level>109ULN for Pan et al.36, Celen et al.27, >59ULN for Chen et al.29
1
Torticollis and umbilical hernia.
2
Hypospadias.
3
Unilateral deafness.
4
Polydactyly of the left thumb.
5
Chromosomal abnormality.

vaginal delivery to a breastfeeding mother treated with tenofovir,
despite compliance and good virological response (maternal HBV DNA
at birth 4.42 log IU/mL). One case of unilateral deafness was identified
(2.3%, 1/44) in the tenofovir group, but no congenital anomaly was
found in the control group without statistical difference. On the other
hand, Samadi Kochaksaraei et al. showed a similar MTCT (HBsAg posi-
tive infants at 6-12 months of age) rate for the tenofovir and control
groups (tenofovir vs. control: 0% [0/12] vs. 1.3% [1/73], respectively;
P=.685).30 All NRCT including Samadi Kochaksaraei et al. assessed
HBsAg positive rate in infants 6-12 months of age at least 1 month
after the last vaccination. However, as mentioned at result, this study
had significant methodological problems including different inclusion
criteria between the tenofovir and control groups and inadequate fol-
low-up periods. Therefore, we analysed the efficacy of tenofovir
through NRCTs including and excluding this study30 and confirmed
the benefit of tenofovir for MTCT in both analyses.
The first RCT of tenofovir was published in June 2016, demonstrat-
ing that the MTCT rate (defined as HBsAg positivity of infants at 6-
12 months of age) of tenofovir was significantly lower than that of the
placebo group (intention-to-treat analysis: 18% vs. 5%; P=.007) without
identified safety issues (birth defect rate, 2% vs. 1%; P=1.000).36
Although robust data are available from this study, more evidence is
needed to consider tenofovir as the first-line anti-viral therapy to pre-
vent MTCT. However, there is only one previous meta-analysis analys-
ing three NRCT for tenofovir that mainly focused on other anti-viral
therapies including lamivudine and telbivudine.18 To the best of our
knowledge, this is the first systematic review and meta-analysis to eval-
uate the efficacy and safety of tenofovir for reducing the risk of MTCT.
In this meta-analysis, we demonstrated that tenofovir treatment
in HBV infected mothers, as compared with controls (immunopro-
phylaxis only), reduced the MTCT rate by 77%, as indicated by
serum HBsAg levels of infants at 6-12 months of age with a low
degree of heterogeneity (I2=0%). The only identified side effect was
maternal CK level elevation in the tenofovir group compared to con-
trols, but the statistical significance was borderline (P=.50). More-
over, there was no identified muscle dysfunction or muscular pain,
and most cases of CK elevation were asymptomatic. Other major
foetal safety parameters including congenital malformation and foe-
tal death were comparable in this analysis.
Previous meta-analyses have shown the efficacy and safety of
other anti-viral agents (Table 5). Lamivudine showed 67%-78% risk
reduction in MTCT.18,49-51 Telbivudine have shown 77%-94% risk
1502 | HYUN ET AL.

T A B L E 4 Case series of tenofovir for the prevention of vertical transmission of the hepatitis B virus in the systematic review
Maternal HBV DNA level

Study Number Country Interventions Mean age HBeAg Before Serious adverse
(Year) of case (Ethnicity) Inclusion criteria on mother (years)a (%) intervention Before delivery MTCT caseb events

Pan et al. 11 USA (Asians) HBeAg positive+ Tenofovir 29 (23-45) 100% 8.870.45log10 5.251.79log10 None None
(2012)31 HBV DNA>106 (Gestation copies/mL copies/mL
copies/mL week 28-32)+
HBIG+
Vaccination

Tsai et al. 22 USA (Pacific HBV DNA>106 Tenofovir (Median 287.5 100% 8.991.98log10 5.441.06 log10 1 case; the 1 case of
(2014)32 island copies/mL gestation week copies/mL copies/mL mother was hypospadias
ancestry/ at 31) +HBIG + treated with
Asians) Vaccination tenofovir for
only 17 days
due to non-
compliance
with prenatal
care

Hu et al. 17 China Previous Tenofovir 30.6 (23-45) 94.1% 5.9 (4.2-7.2) log10 NR (82.4% of None 1 case of
(2015)33 (Asians) lamivudine (Gestation copies/mL participants postpartum
or telbivudine week 28)+ had HBV DNA hemorrhage,
resistance, HBIG+ levels <500 1 case of
HBV DNA>104 Vaccination copies/mL) patent
copies/mL foramen ovale,
1 case of
congenital
dislocation of
the right knee

Koruk 36 Turkey HBV DNA>107 Tenofovir NR NR NR NR 1 case, HBV None

et al. (Turkish) copies/mL (Median DNA 152 000
(2015)34 (or women who gestation 000 copies/mL,
accepted antiviral week at 22)+ Began Tenofovir
treatment with HBIG+ at gestational
HBV DNA < 107 Vaccination week 28
copies/mL)

Wang 48 China Previous lamivudine Tenofovir 29.33.8 93.8% 7.530.81 2.301.96 log10 None None
et al. (Asians) resistance+HBV (Gestation log10IU/mL IU/mL
(2015)35 DNA>106IU/mL week 24-28)+
HBIG+
Vaccination

HBIG, hepatitis B immunoglobulin; HBV DNA, hepatitis B virus deoxyribonucleic acid; HBeAg, hepatitis B envelope antigen; MTCT, mother to child
transmission; NR, not reported; TDF, tenofovir disoproxil fumarate.
a
Parentheses indicate interquartile range; data is otherwise expressed as meanSD.
b
HBsAg positive infants within 6-12 months.

reduction in MTCT, which is a more cost-effective agent than other
agents in China.18,50,52-55 Despite similar efficiency, tenofovir has a
higher resistance barrier with no resistance identified after 6 years fol-
low-up when comparing two agents.23,47,56,57 Regarding foetal safety,
the FDA has removed previous pregnancy letter categories—A, B, C,
D and X (Lamivudine, Telbivudine and Tenofovir; category C, category
B, category B; respectively) in the updated Pregnancy and Lactation
Labeling Rule (PLLR or final rule), and recommended each specific risk
summary and clinical consideration, published in December, 2014.
According to the Antiretroviral Pregnancy Registry (APR) for evaluat-
ing the effect of anti-viral agents against human immunodeficiency
virus (HIV) infection, the prevalence of birth defects in foetus were
2.8% (208/7311) for lamivudine, 0% (0/9) for telbivudine and 2.0%
(28/1412) for tenofovir.58 Even some studies have reported that teno-
fovir-exposed foetuses showed declined foetal and infantile growth
retardation due to bone density and mineral contents changes,59,60
the adverse event data according to both the APR and cumulative clin-
ical experience for HIV patients’ data demonstrated that tenofovir can
be safely used to treat pregnant women.58,61 The details of risk sum-
mary and clinical consideration which labelled in FDA are summarised
in Table 5. To establish the relative efficacy and safety of tenofovir,
high-quality, direct, head-to-head trials of different anti-viral regimens
together with HBIG to reduce MTCT HBV transmission are needed.
Nonetheless, especially for women who are HBeAg positive with an
HBV DNA level greater than 29105 IU/mL, tenofovir therapy in the
second or third trimester seems necessary.
However, as shown in this meta-analysis, the 0%-5.2% MTCT
rates still remained despite of tenofovir treatment. Suboptimal mater-
nal HBV-DNA suppression by tenofovir may be attributable to MTCT
prevention failure. Pan et al. reported that mothers with higher base-
line HBV DNA level showed more suboptimal HBV DNA suppression
rates after tenofovir treatment compared to mothers with lower base-
line HBV DNA level (>8log10 IU/mL vs. ≤8log10 IU/mL, 39% vs.
25%, P=.19), although, this finding did not reach statistical signifi-
cance.36 Moreover, according to the current RCT36 and NRCTs,27,29
HBV DNA suppression rates were 61.9%-98.4%. It might be due to
HYUN ET AL. | 1503

T A B L E 5 Summary of the current evidence of antiviral treatment to prevent vertical transmission of the hepatitis B virus
Lamivudine (GlaxoSmithKline,
Clinical issues Middlesex, United Kingdom)
FDA approved indication17 Chronic hepatitis B in patients 12 years
of age or older
Mutant to resistance rate Resistant mutations occur in 20% after
a year, 70% after 5 years56,64
Preventive efficacy 67%-78%18,49–51
against MTCTa
Major congenital anomaly Not significant compared to control
or fetal death group18,49–51
Risk summary and 2.8% (208/7311) birth defects in fetus,
clinical considerationb Lactic acidosis and severe
hepatomegaly with steatosis,
Exacerbation of hepatitis B after
discontinuation of treatment, Risk of
emergence of resistant HIV-1
infection, Risk of emergence of
resistant HBV infection
Previous FDA pregnancy C B
categoryc
Previous meta-analysis Shi et al. 201049, Han et al. 201151,
Wang et al. 201655§, Njei et al.
201650, Brown et al. 201618
Telbivudine (Norvatis, Basel,
Switzerland)
Chronic hepatitis B in adult patients
with evidence of viral replication and
either evidence of persistent elevation
of serum ALT or histologically active
disease
Resistant mutations occur in 5% after a
year, 22% after 2 years56,65,66
77%-94%18,50,52–54
Not significant compared to control
group18,50,52–54
0% (0/9) birth defects in fetus, Lactic
acidosis and severe hepatomegaly
with steatosis, Severe acute
exacerbations of hepatitis after
discontinuation of treatment,
Myopathy, Peripheral neuropathy
Deng et al. 201254, Liu et al. 201353,
Lu et al. 201452, Wang et al. 201655d,
Njei et al. 201650, Brown et al.
201618
Tenofovir (Gilead Sciences, Foster
City, CA, USA)
Chronic hepatitis B in adults
0% after 6 years23,47,56,57
77% (current study)
Not significant compared to
control group (current study)
2.0% (28/1412) birth defects in
fetus, Lactic acidosis and severe
hepatomegaly with steatosis,
Severe acute exacerbation of
hepatitis, New onset or
worsening renal impairment,
Bone effects, Immune
reconstitution syndrome
B
Wang et al. 201655d, Brown et al.
201618

FDA, Food and Drug Administration; ALT, alanine aminotransferase; MTCT, mother to child transmission; HIV, human immunodeficiency virus; HBV,
hepatitis B virus.
a
Defined as interruption of hepatitis B surface antigen (HBsAg) positivity rate in infants 6-12 months of age.
b
According to Antiviral Pregnancy Registry against Human Immunodeficiency Virus (HIV) infection and United States Food and Drug Administration
(FDA).17,58
c
The United States FDA has removed previous pregnancy letter categories—A, B, C, D and X in the updated Pregnancy and Lactation Labeling Rule
(PLLR or final rule), published in December, 2016.17
d
Cost-effective analysis.

the limited duration of tenofovir treatment (up to 27 weeks from 2nd
trimester). In a pivotal study of tenofovir in HBeAg positive patients,
the HBV DNA suppression rate (<400 copies/mL) after 48 weeks of
tenofovir treatment was 76%.47 Therefore, baseline HBV DNA level
along with compliance to tenofovir and treatment duration of teno-
fovir is one of major the obstacles to successful HBV DNA suppres-
sion and MTCT prevention. In pregnancy, tenofovir treatment
administered earlier than the second trimester has not yet been con-
sidered in practice. Therefore, clinicians should carefully observe and
monitor pregnant mother with high baseline HBV DNA levels in con-
sideration of MTCT prevention failure despite tenofovir treatment.
The major limitations of this systematic review and meta-analysis
are as follows: Although tenofovir showed efficacy for intrauterine
infection—defined as detectable HBsAg or HBV DNA in the first
30 days following delivery—in terms of HBV DNA positivity rates,
HBsAg positivity in newborns within 24 hours did not show statisti-
cal difference. Hence, future studies of tenofovir in MTCT protection
for both neonates HBsAg and HBV DNA are needed to clarify this
issue.62 Secondly, due to the limited number of RCT, we performed
a meta-analysis using RCT and NRCT data. Recently, the preliminary
result of phase III, double-blind, clinical trial randomised a total of
331 pregnant woman (294 for primary analysis) with HBV infection
regardless of maternal viral load to tenofovir or matching placebo
was reported in Thailand.63 Although the trial showed that tenofovir
resulted in a small non-significant reduction in perinatal HBV trans-
mission (tenofovir vs. control, 0% [0/147] vs. 2.0% [3/147], respec-
tively; P=.12), the pooled analysis including the trial demonstrated
that tenofovir reduced the risk of MTCT rate (OR=0.22, 95%
CI=0.10-0.49, P=.0002, I2=0%) (Figure S3) with comparable safety
outcomes (ALT flare, congenital malformation, pre-term birth rate
and foetal death) (Figure S4) which supports the conclusion of our
study. Nonetheless, more RCTs and their combined results are
needed. Thirdly, most of the study participants were Asian. More
clinical studies of tenofovir in different ethnicities are required to
generalise the results. Lastly, the safety issues including tenofovir
adverse effect have not been fully evaluated. Future studies should
be conducted to continuously monitor the maternal and foetal safety
of tenofovir.
1504 | HYUN
5 | CONCLUSIONS
In conclusion, tenofovir therapy in HBV infected mothers in the sec-
ond or third trimester efficiently interrupts MTCT, as indicated by
infant serum HBsAg positivity. Tenofovir treatment is safe and toler-
able for both the mother and foetus. Clinicians who manage preg-
nant patients with high hepatitis B viral loads should consider
tenofovir therapy to prevent MTCT in addition to immunoprophy-
laxis combination therapy.
AUTHORSHIP
Guarantor of the article: Ji Hoon Kim.
Author contribution: MHH, YSL and JHK: conception, design;
MHH, YSL, JHK and JEY: acquisition, analysis and interpretation of
data; MHH, and YSL: statistical analysis; MHH, YSL and JHK: draft-
ing of the manuscript; JHJ, YJY and KSB: critical revision of the
manuscript for important intellectual content; MHH, YSL, JHK, JHJ,
YJY, JEY and KSB: final approval of the manuscript.
ACKNOWLEDGEMENTS
Declaration of personal interests: None.
LINKED CONTENT
This article is linked to Zhang et al and Lee and Hyun papers. To
view these articles visit https://doi.org/10.1111/apt.14189 and
https://doi.org/10.1111/apt.14211.
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How to cite this article: Hyun MH, Lee Y-S, Kim JH, et al.
Systematic review with meta-analysis: the efficacy and safety
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