Web Annex ASystematic review of the efficacy and safety of antiviral therapy during pregnancy

Acronyms and Abbreviations

3TC

lamivudine

ADV

adefovir dipivoxil

ALT

alanine aminotransferase

ANC

antenatal care

APASL

Asian Pacific Association for the Study of the Liver

CI

confidence interval

CK

creatine kinase

ETV

entecavir

FTC

emtricitabine

GHSS

Global Health Sector Strategy (on viral hepatitis)

GRADE

Grading of Recommendations Assessment, Development and Evaluation

HBeAg

hepatitis B e antigen

HBIG

hepatitis B immunoglobulin

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HDV

hepatitis D virus

HIV

human immunodeficiency virus

ITT

intention to treat

LdT

telbivudine

MTCT

mother-to-child transmission

OR

odds ratio

PICO

Population, Intervention, Comparison, Outcome

PMTCT

prevention of mother-to-child transmission

PPA

per protocol analysis

RCT

randomized controlled trial

TAF

tenofovir alafenamide fumarate

TDF

tenofovir disoproxil fumarate

ULN

upper limit of normal

WHO

World Health Organization

Background

Currently, the World Health Organization (WHO) estimates that chronic hepatitis B virus (HBV) infection affects close to 260 million persons and causes an estimated 900 000 deaths annually through manifestations of chronic liver disease, such as cirrhosis and hepatocellular carcinoma (HCC). The regions with the highest prevalence of chronic HBV infection are the Western Pacific and African regions (WHO, 2017a). In 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis, which calls for the elimination of HBV worldwide as a public health threat by 2030, to be accomplished through reducing the incidence of chronic HBV infection by 90%, and its mortality by 65% (WHO, 2016).

Chronic infection is more likely to develop when HBV is acquired early in life, and therefore, perinatal mother-to-child transmission (MTCT) is a major contributor to the incidence of chronic HBV infection (Edmunds et al., 1993). Moreover, the risk of developing chronic liver disease, including HCC, may be higher in those with established chronic HBV infection through MTCT compared to those who ended up with chronic HBV infection through horizontal transmission later in life (Chang 2008; Shimakawa et al., 2013). To decrease the incidence of chronic HBV infection and eventual chronic liver disease, WHO recommends that all infants be vaccinated against the virus, with the first dose being administered within 24 hours of birth (i.e. timely birth dose vaccination) (WHO, 2017b). Since this recommendation made by WHO in 2009, there has been a significant uptake of the HBV birth dose vaccination globally; however, there are many countries, specifically in highly endemic areas in Africa, where coverage of timely administration is very low (Miyahara et al., 2016; WHO, 2009; WHO, 2017a).

The birth dose vaccination is meant not only to prevent perinatal MTCT that usually happens at the time of birth, but also to prevent horizontal transmission during early childhood. However, the birth dose vaccination alone may be inadequate to prevent MTCT in infants born to mothers with high replication of HBV. In some countries, therefore, hepatitis B immunoglobulin (HBIG) is additionally administered to babies born to HBV-infected mothers. However, this combined active and passive immunoprophylaxis does not completely prevent all MTCT (Chen et al., 2012). The risk of immunoprophylaxis failure is closely correlated with hepatitis B e-antigen (HBeAg) positivity as well as an elevated viral load in pregnant women (Keane et al., 2016; Machaira et al., 2015; Wen et al., 2013). Consequently, MTCT remains a significant contributor to HBV incidence in all regions, and supplementary interventions to further decrease this transmission are urgently needed.

AIM

Rationale

To date, the major international guidelines for the management of chronic HBV infection all recommend the administration of antiviral therapy to pregnant women with high HBV DNA levels to prevent MTCT (AASLD 2018; EASL 2017; APASL 2016); all guidelines recommend tenofovir disoproxil fumarate (TDF), and the Asian Pacific Association for the Study of the Liver (APASL) also recommends telbivudine (LdT). The Food and Drug Administration (FDA) of the United States has classified TDF, LdT, and emtricitabine (FTC) as being category B (i.e. no current evidence of a risk to the fetus during pregnancy; however, robust controlled studies are lacking) (see Table 1).

Table 1

International recommendations for prevention of mother-to-child transmission (PMTCT) using antiviral therapy.

Although the WHO HBV treatment guidelines in 2015 contained a systematic review and meta-analysis on the efficacy, safety and cost–effectiveness of antiviral therapy administered during pregnancy for the prevention of MTCT (PMTCT), this review had some limitations, which dissuaded WHO from making a formal recommendation for its use at that time. In addition, only one observational study that examined the efficacy of tenofovir for PMTCT was available for inclusion; tenofovir is considered a key first-line antiviral therapy for chronic HBV infection given its high potency, higher barrier to drug resistance and evidence of safety in pregnancy (WHO, 2015).

An updated systematic review and meta-analysis on this topic is now pertinent for various reasons. First, there have been important new findings with regard to maternal and infant safety of HBV antiviral medications administered during pregnancy; some recent studies have further evaluated the risk of postpartum hepatic flare in the mother after cessation of treatment as well as changes in bone mineral density in the infant (Pan et al., 2016; Kourtis et al., 2018; Jourdain et al., 2018). Second, recent epidemiological and modelling studies have demonstrated the likely inadequacy of the birth dose vaccination with or without HBIG administration, alone, to reduce the incidence of HBV enough in order to achieve the 2030 elimination goals (Nayagam et al., 2016; Hutin et al., 2018). Third, in countries that have achieved a very high uptake of birth dose vaccination, recommendations are now needed for a further reduction in MTCT.

Methods

PICO question

Population

Pregnant women with chronic HBV infection

• Chronic HBV infection was defined as HBsAg seropositivity on two occasions at least 6 months apart. However, because new HBV infection in adults is uncommon in highly endemic areas where the vast majority of HBsAg-positive people acquired the infection perinatally or during childhood, HBsAg positivity on only one occasion (at antenatal care [ANC]) in women living in highly prevalent countries was assumed to reflect chronic HBV infection (Evans et al., 1998).

Intervention

Maternal treatment with antiviral therapy during pregnancy with or without infant birth dose vaccination and/or HBIG.

• The following antiviral therapies were considered for inclusion:

  • adefovir dipivoxil (ADV)
  • emtricitabine (FTC)
  • entecavir (ETV)
  • lamivudine (3TC/LAM)
  • telbivudine (LdT)
  • tenofovir alafenamide fumarate (TAF)
  • TDF.

Comparison

Table 2

Comparison groups considered in PICO1.

Outcomes

The primary outcome of interest will be MTCT of HBV, as indicated by infant HBsAg positivity at 6–12 months of life.

Further infant outcomes of interest, specified in the study protocol, included:

• infant HBV DNA positivity at 6–12 months of life
• any infant adverse event, such as

  -

  neonatal death (within 28 days of life [WHO, 2006])

  -

  preterm birth (<37 weeks of gestational age [WHO, 2018])

  -

  congenital abnormality

  -

  Apgar score at 1 minute of life

  -

  measurement of bone density of infants.

Maternal outcomes of interest, specified in the study protocol, included:

• any maternal adverse event, including:

  -

  miscarriage (<28 weeks gestational age, [WHO, https://www​.who.int/maternal​_child_adolescent​/epidemiology/stillbirth/en/])

  -

  stillbirth (>=28 weeks gestational age, [WHO, https://www​.who.int/maternal​_child_adolescent​/epidemiology/stillbirth/en/.])

  -

  HBV flare after discontinuation of treatment (e.g. elevated HBV DNA and/or elevated ALT)

  -

  postpartum haemorrhage

• antiviral resistance.

Other inclusion and exclusion criteria: study design, languages, dates of publication

Randomized controlled trials (RCTs) and non-randomized comparative studies were considered for this analysis. Case series without a comparison group were excluded. Studies published in any language were considered. Non-RCTs with a high risk of bias (i.e. a score on the Newcastle-Ottawa scale of <=5 were excluded from analysis. Studies published till 28 March 2019 were included. Studies reported as conference abstracts only were not considered.

Results

Summary of included studies

The search strategy identified 7419 papers across English and Chinese databases. An additional 44 articles were manually included. After excluding 2894 articles that were duplicates, 4569 articles were screened and 595 papers were assessed in full text. Finally, 136 original studies were potentially eligible; however, seven of these were deemed at a very high risk of bias and were excluded from the quantitative analysis in this review (see Fig. 1). Although the objectives of this meta-analysis as well as its search strategy included seven different treatments of interest, only studies including TDF 300 mg, LAM 100–150 mg, LdT 100 mg and 600 mg, and ADV 10 mg and 500 mg were found eligible. No studies that investigated any regimens with FTC, ETV, TAF were included (Table 3).

Table 3

Excluded and included studies by treatment, with summary of analyses types presented.

Very few of the RCTs included presented adequate details of loss to follow up (7/33) (Bai HL, 2013; Feng Y, 2018; Jourdain G, 2018; Lin Y, 2018; Pan CQ, 2016; Xu WM, 2009; Zhang LJ, 2009), which limited our ability to perform ITT meta-analysis systematically; therefore, per protocol analysis (PPA) was considered throughout (Table 4).

Table 4

Summary of quantitative/qualitative results presented by the type of treatment.

Fig. 1PRISMA diagram

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097 For more information, visit www.prisma-statement.org. [PMC free article: PMC2707599] [PubMed: 19621072] [CrossRef]

Tenofovir disoproxil fumarate (TDF) 300 mg versus no treatment or placebo

Summary of included studies

There were 20 original studies, including 26 unique treatment arms, eligible for this meta-analysis that used TDF 300 mg. Following risk of bias assessment, one study (with one treatment arm) was excluded (Kochaksaraei et al., 2016). Therefore, 19 original studies with 25 unique treatment arms were included in the analysis. Of the included studies, five were RCTs and 14 were non-randomized trials/observational studies (six prospective and eight retrospective studies).

Risk of bias assessment 

• Randomized controlled trials

Of the five RCTs included that investigated TDF, only one study by Jourdain et al., (2018) achieved a “low risk of bias” rating on the main criteria in the Cochrane Collaboration’s Risk of Bias Assessment Tool; only one domain – attrition bias for maternal safety outcomes – was identified as possibly at high risk of bias. Another study, by Pan and colleagues (2016) was deemed at low risk of bias on five of the eight evaluated criteria; however, no allocation concealment was described and blinding was not performed, leading to this study being at a high risk for some selection bias, as well as for performance and detection bias. The other three RCTs were all deemed low risk on the majority of criteria evaluated; the main issues revolved around apparent limited use of blinding and lack of reporting on loss to follow up (Lin Y et al., 2018; Liu MH et al., 2017; Yu CY et al., 2018). The detailed risk of bias assessment for the RCTs investigating TDF can be found in Appendix E.

• Non-randomized controlled trials

The majority of studies (73.3%) were ranked at a score of 6 (high) to 7 (low) on the Newcastle Risk of Bias scale, and only three studies achieved scores of 8–9 on the scale (signifying very low risk of bias). The main weakness of included studies was in reference to loss to follow up – this information was missing in 11 of 15 articles, and was less than adequate (i.e. <80% follow up) in two further studies. The detailed risk of bias assessment for the non-RCTs investigating TDF can be found in Appendix F (Table 5).

Table 5

Risk of bias scores for non-RCTs (prior to exclusion of very high-risk studies).

Publication bias/small study effects assessment

It was possible to examine publication bias for the following outcomes: MTCT indicated by HBsAg positivity at 6–12 months in non-RCTs, neonatal deaths in non-RCTs, and miscarriages and stillbirths in non-RCTs. Of these, there was possible evidence of publication bias only in the first study set (MTCT indicated by HBsAg positivity at 6–12 months in non-RCTs). Funnel plots for TDF 300 mg study sets, as well as results of the Egger test for asymmetry (if examining OR only) can be found in Appendix G.

Characteristics of included studies

Across all included studies (n=19), recruitment took place as early as 2007 and up until 2018. Almost all studies took place in the WHO Western Pacific Region; including China (n=15), Japan (n=1) and Australia (n=1). Additionally, one study took place in the WHO South-East Asia Region (Thailand), and one study in the WHO European Region (Turkey).

HBV genotyping for the entire study population was performed only in three instances. A study from China estimated that the treatment group was 70% genotype B and 30% genotype C, while the control group was 71% B and 29% C (Chen HL et al., 2015). One Chinese study estimated the treatment group as 7% B2 and 93% C2, with the control group being 6% B2 and 94% C2 (Lin Y et al., 2018). In a small study in Japan (n=8), 50% of participants were genotype C and the other 50% had undetermined genotype (Wakano Y et al., 2018).

Most included study arms (i.e. 14/25) started maternal antiviral therapy between 24 and 30 weeks of gestation. The most common HBV DNA level designated for inclusion was >6.0 or >6.3 log10 IU/mL (11 of 25 treatment arms) (table 6).

Table 6

Characteristics of included studies investigating TDF (n=19).

Primary efficacy analysis, narrative descriptions and forest plots

1.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels at inclusion, stratified by study design (RCT and non-RCT).

• Overall pooled OR=0.16 (95% CI: 0.10–0.26), P<0.001, I²=0%

  • RCTs only: pooled OR=0.10 (95% CI: 0.03–0.35), P<0.001, I²=0%
  • Non-RCTs only: pooled OR=0.17 (95% CI: 0.10–0.29), P<0.001, I²=0%
  • When looking at heterogeneity between RCTs and non-RCTs we arrive at a P value of 0.47, indicating no difference between the estimates.

2.

PMTCT, as indicated by detection of HBV DNA at 6–12 months of age, all treatment start times, all HBV DNA levels at inclusion, stratified by study design (RCT and non-RCT).

• Overall pooled OR=0.08 (95% CI: 0.03–0.19), P<0.001, I²=0%

  • RCTs only: pooled OR=0.11 (95% CI: 0.03–0.43), P=0.001, I²=0%
  • Non-RCTs only: pooled OR=0.06 (95% CI: 0.02–0.19), P<0.001, I²=0%
  • When looking at heterogeneity between RCTs and non-RCTs we arrive at a P value of 0.52, indicating no difference between the estimates.

Subgroup analysis

In the protocol, it was specified that subgroup analysis would be performed by the following variables: type of antiviral therapy administered, stage of pregnancy at time of treatment start, maternal HBV viral load and HBeAg status, coinfections (e.g. HDV, HIV), other preventive measures provided (i.e. infant immunoprophylaxis), and WHO region where the study was conducted. Finally, all analyses have been presented by treatment type (no “all treatment” analysis was performed), and within that, it was possible to do subgroup analysis by stage of pregnancy, maternal HBV viral load and HBeAg status, and types of other preventive measures provided. It was not possible to do a subgroup analysis by coinfection status, as there were eventually no eligible studies that included coinfected populations. Furthermore, it was not possible to do subgroup analysis by WHO region, as almost all studies came from just one region (i.e. Western Pacific). For TDF, one additional subgroup analysis was presented, which is by timing of treatment end postpartum.

1.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all HBV DNA levels at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by trimester of treatment start

• 1st trimester: not enough studies for meta-analysis (i.e. n<3)
• 2nd trimester: pooled OR=0.14 (95% CI: 0.04–0.48), P=0.002, I²=0.0%
• 3rd trimester: pooled OR=0.21 (95% CI: 0.12–0.36), P<0.001, I²=0.0%
• The P value for heterogeneity between 2nd and 3rd trimester was 0.57.

2.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all HBV DNA levels at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by median weeks’ gestation at the time of treatment start (<28 weeks, 28 weeks, >28 weeks)

• <28 weeks: pooled OR=0.11 (95% CI: 0.05–0.26), P<0.001, I²=0.0%
• 28 weeks: pooled OR=0.24 (95% CI: 0.13–0.44), P<0.001, I²=0.0%
• >28 weeks: pooled OR=0.11 (95% CI: 0.03–0.35), P<0.001, I²=0.0%
• When looking at heterogeneity across the three subgroups, the P value was 0.26. If comparing <28 weeks median with 28 weeks median, there was no heterogeneity (P=0.15). If comparing <28 weeks median with >28 weeks median, there was no heterogeneity (P=0.98). If comparing 28 weeks median with >28 weeks median, there was no heterogeneity (P=0.24).

3.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all study designs merged (i.e. RCT and non-RCT), stratified by the minimum HBV DNA level specified in the study inclusion criteria

• >4–4.99 log10 IU/mL: not enough studies (i.e. <3)
• >5–5.99 log10 IU/mL: pooled OR=0.16 (95% CI: 0.05–0.47), P=0.001, I²=0.0%
• >6–6.99 log10 IU/mL: pooled OR=0.11 (95% CI: 0.05–0.26), P<0.001, I²=0.0%
• >7–7.99 log10 IU/mL: not enough studies (i.e. <3)
• When looking at heterogeneity between studies with inclusion criteria of >5–5.99 log10 IU/mL versus >6–6.99 log10 IU/mL, the P value was 0.64.

4.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels specified at inclusion, all study designs merged (i.e. RCT and non-RCT), only including studies where all women were confirmed HBeAg positive

• Pooled OR=0.09 (95% CI: 0.04–0.21), P<0.001, I²=0.0%

5.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels specified at inclusion, all study designs merged (i.e. RCT and non-RCT), by infant immunoprophylaxis regimen (Table 7).

• As most studies provided all of the infant immunoprophylaxis measures (birth dose vaccine, HBIG at birth and subsequent infant vaccinations), stratification by type or combination of infant immunoprophylaxis was not possible in this meta-analysis.
• Therefore, we stratified by whether or not both birth dose vaccine and HBIG were given within 12 hours of life, versus within 24 hours of life.

  -

  <12 hours: pooled OR=0.30 (95% CI: 0.13–0.69), P=0.004, I²=0.0%

  -

  <24 hours: pooled OR=0.15 (95% CI: 0.06–0.38), P<0.001, I²=0.0%

  -

  When looking at heterogeneity between studies that administered both forms of prophylaxis within 12 hours, versus within 24 hours, the P value was 0.28.

Table 7

Infant immunoprophylaxis regimens seen in studies investigating TDF.

6.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all study designs merged (i.e. RCT and non-RCT), stratified by the timing that treatment was discontinued postpartum

• At delivery: pooled OR=0.11 (95% CI: 0.04–0.28), P<0.001, I²=0.0%
• 4–8 weeks postpartum: pooled OR=0.12 (95% CI: 0.04–0.34), P<0.001, I²=0.0%
• 12 weeks postpartum: not enough studies for subgroup analysis
• 24+ weeks postpartum: no studies within this subgroup
• When looking at heterogeneity across the two subgroups, the P value was 0.96.

Safety analysis, narrative descriptions and selected forest plots

Infant safety outcomes

In the protocol, it was specified that the following safety outcomes for infants would be investigated: neonatal death, prematurity, congenital abnormalities, Apgar score, and bone mineral density. Finally, information on all of these outcomes were collected and results for all of these outcomes, except for the Apgar score, are provided here. The data for Apgar score were not available for the majority of included studies and where it was available the format varied greatly; this led to an inability to combine results in a meaningful way.

1. Neonatal deaths (death within 28 days of life)

Information on this outcome was available for all studies that administered TDF to mothers. Three neonatal deaths were reported across all study populations. Two deaths (non-weighted average 0.2%; one each from two separate studies) occurred across all treatment groups, out of a total of 1079 infants whose mothers were treated with TDF during pregnancy. One death (non-weighted average 0.1%) occurred in one of the control groups in one study, out of total of 858 infants whose mothers were not treated during pregnancy. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.00 (95% CI: −0.01–0.01). The I² statistics for the overall pooled OR, as well for RCTs and non-RCTs separately, were all 0%.

2. Prematurity (typically defined as birth earlier than 37 weeks of gestation)

Information on this outcome was available for nine of the 19 included studies that administered TDF to mothers. Within these studies, 19 of 622 (non-weighted average 3.1%) infants whose mothers were treated with TDF during pregnancy were born prematurely, whereas 22 of 479 (non-weighted average 4.6%) infants whose mothers were not treated during pregnancy were born prematurely. The weighted pooled risk difference for this safety outcome seen following meta-analysis was −0.003 (95% CI: −0.024–0.019). The I² statistics for the overall pooled OR, as well as for RCTs and non-RCTs separately, were all 0%.

3. Congenital abnormalities

Information on this outcome was available for 14 of the 19 included studies that administered TDF to mothers. Within these studies, four of 802 (non-weighted average 0.5%) infants whose mothers were treated with TDF during pregnancy were noted to have some sort of congenital abnormality, including: torticollis (n=1), umbilical hernia (n=1), congenital unilateral deafness (n=1), polydactyly (n=1). Five of 687 (non-weighted average 0.7%) infants whose mothers were not treated during pregnancy were noted to have some sort of congenital abnormality, including: hypospadias (n=1), “gross abnormalities” (n=1), no detail provided (n=3). The weighted pooled risk difference for this safety outcome seen following meta-analysis was −0.002 (95% CI: −0.013–0.009). The I² statistics for the overall pooled OR, as well as for RCTs and non-RCTs separately, were all 0%.

4. Bone mineral density

This outcome was investigated only for one of the 19 included studies, an RCT, that administered TDF to mothers. In this study, infant lumbar spine bone mineral density was measured in 62 infants from the treatment group, and 53 infants from the control group at 1 year of age (i.e. not the entire original study population of 163 treatment-exposed infants and 161 controls), with a mean score of 0.324 (SD +/− 0.036), and 0.330 (SD +/− 0.036), respectively. There was no statistically significant difference detected between the two groups (Jourdain et al., 2018; Salvadori et al., 2019).

Maternal safety outcomes

Information was collected and presented on the following maternal safety outcomes: miscarriage/stillbirth, postpartum haemmorhage, antiviral resistance, HBV flare.

1. Fetal demise (miscarriage [<28 weeks], stillbirth [>=28 weeks])

Information on this outcome was available for all studies that administered TDF to mothers. Four cases of fetal demise were reported across all study populations. Three cases (non-weighted average 0.4%; one each from three separate studies) occurred across all treatment groups, out of a total of 942 mothers/fetuses who were treated with TDF during pregnancy. One case (non-weighted average 0.1%) occurred in one of the control groups in one study, out of a total of 882 mothers/fetuses who were not treated during pregnancy. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.003 (95% CI: −0.006–0.012). The I² statistics for the overall pooled risk difference estimate, and RCTs and non-RCTs separately, were all 0%.

2. Postpartum haemorrhage

Information on this outcome was available for six of the 19 included studies that administered TDF to mothers. Within these studies, nine of 365 (non-weighted average 2.5%) mothers who were treated with TDF during pregnancy experienced postpartum haemorrhage, whereas seven of 256 (2.7%) mothers who were not treated during pregnancy experienced postpartum haemorrhage. The weighted pooled risk difference for this safety outcome seen following meta-analysis was −0.001 (95% CI: −0.024–0.022). The I² statistics for the overall pooled risk difference estimates, as well as for RCTs and non-RCTs separately, were all 0%.

3. Antiviral resistance

Only one of the 19 studies where mothers were treated with TDF during pregnancy performed antiviral resistance testing for the entire study population. This study, with 120 participants, found no HBV mutations related to antiviral therapy; it was not clearly stated at which time-point this testing was performed (Lin Y et al., 2018). Two further studies reported investigations into antiviral resistance for women defaulting from treatment or where infants were found positive for HBV at 6–12 months, both of these studies reported that no resistance mutations were found (Chen HL et al., 2015; Pan CQ et al., 2016).

4. HBV flare after treatment discontinuation

Information on this outcome was available for six of the 19 included studies that administered TDF to mothers. Various definitions were used, including: “postpartum flare”, “severe flare”, “ALT >5 ULN”, and others. Within these studies, 34 of 418 (non-weighted average 8.1%) mothers who were treated with TDF during pregnancy experienced a type of HBV flare at the time of treatment discontinuation, whereas 20 of 382 (non-weighted average 5.2%) mothers who were not treated during pregnancy experienced the same type of HBV flare at a matched time-point. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.007 (95% CI: −0.027–0.041). There was no heterogeneity in the RCTs (i.e. I²=0%), however, in non-RCTs and in the overall pooled risk difference estimate, there was an I² of 13.2% and 17.1%, respectively.

GRADE summary of findings

Table 8

GRADE evidence profile – TDF 300 mg during pregnancy to prevent HBV mother-to-child transmission (MTCT).

Lamivudine (LAM) 100–150 mg versus no treatment or placebo

Summary of included studies

There were 42 original studies, including 46 unique treatment arms, eligible for this meta-analysis that used LAM 100–150 mg. Following risk of bias assessment, two studies (each with one treatment arm investigating LAM) were excluded (van Zonneveld et al., 2003, Liu CP et al., 2015). Therefore, 40 original studies with 44 unique treatment arms were included in analysis. Of the included studies, eight were RCTs and 32 were non-randomized trials/observational studies (17 prospective and 15 were retrospective studies).

Risk of bias assessment

• Randomized controlled trials

Of the eight RCTs included that investigated LAM, none achieved a “low risk of bias” rating on the majority of the main criteria in the Cochrane Collaboration’s Risk of Bias Assessment Tool. One study, by Xu WM et al. (2009), the only study published in English, had a low risk in selection bias (specifically, allocation concealment), as well as in performance bias and detection bias, but had a high or unclear risk in all other domains. The remaining seven of the eight included RCTs only fulfilled one or two criteria as “low risk of bias”. In these studies, there was always a low risk of selection bias (specifically random sequence generation) and sometimes a low risk of selective reporting; however, no study described loss to follow up and no study described all important adverse outcomes in mothers and infants. The detailed risk of bias assessment for the RCTs investigating LAM can be found in Appendix E.

• Non-randomized controlled trials

Of the original 34 non-RCTs, the majority of studies (67.6%) had low risk of bias scores (i.e. scores of 7, 8, 9) on the Newcastle Risk of Bias scale. The main weakness of included studies was in reference to loss to follow up – this information was missing in 28 of 34 studies, and was less than adequate (i.e. <80% follow up) in three further studies. The detailed risk of bias assessment for the non-RCTs investigating LAM can be found in Appendix F (Table 9).

Table 9

Risk of bias scores for non-RCTs (prior to exclusion of very high-risk studies).

Publication bias/assessment of small study effects

It was possible to examine publication bias for the following outcomes: MTCT indicated by HBsAg positivity at 6–12 months in non-RCTs, MTCT indicated by HBV DNA positivity at 6–12 months in non-RCTs, neonatal deaths in non-RCTs, congenital abnormalities in non-RCTs, and miscarriages and stillbirths in non-RCTs. Of these, there was only possible evidence of publication bias/small study effects in the first study set (MTCT indicated by HBsAg positivity at 6–12 months in non-RCTs. Funnel plots for LAM 100–150 mg study sets, as well as results of the Egger test for asymmetry (if examining OR only) can be found in Appendix G.

Characteristics of included studies

Across all included studies (n=40), recruitment took place as early as 2001 and up to 2016. Almost all studies took place in the WHO Western Pacific Region; including China (n=35), China and the Philippines (n=1), Japan (n=1), and Australia (n=1). Additionally, one study took place in the WHO Eastern Mediterranean Region (i.e. Egypt), and one study took place in the WHO European Region (i.e. Ireland).

HBV genotyping for the entire study population was performed only in three instances. A study from Ireland estimated that the treatment group was 39% genotype B, 33% genotype C, 11% genotype D, 3% genotype E and 14% non-determined (Jackson et al., 2015). One Chinese study estimated the treatment group as 37% genotype B, 63% genotype C, whereas in the control group there were 29% genotype B and 71% genotype C (Shen et al., 2016). In a small study in Japan, all three mothers treated with LAM were genotype C, and in the control group one mother was genotype C and the two other mothers had indeterminable genotype (Wakano et al., 2018).

Most included study arms (i.e. 30/44) started maternal antiviral therapy between 24 and 30 weeks of gestation. The most common HBV DNA level designated for inclusion was >5.3 log10 IU/mL (14 of 44 treatment arms) (Table 10).

Table 10

Characteristics of included studies investigating LAM 100–150 mg.

Primary efficacy analysis, narrative descriptions and forest plots

1.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels at inclusion, stratified by study design (RCT and non-RCT)

• Overall pooled OR=0.17 (95% CI: 0.13–0.22), P<0.001, I²=0%

  • RCTs only: pooled OR=0.16 (95% CI: 0.10–0.26), P<0.001, I²=0%
  • Non-RCTs only: pooled OR=0.17 (95% CI: 0.12–0.24), P<0.001, I²=0%
  • When looking at heterogeneity between RCTs and non-RCTs, we arrive at a P value of 0.80, indicating no difference between the estimates.

2.

PMTCT, as indicated by detection of HBV DNA at 6–12 months of age, all treatment start times, all HBV DNA levels at inclusion, stratified by study design (RCT and non-RCT).

• Overall pooled OR=0.16 (95% CI: 0.11–0.23), P<0.001, I²=0.0%

  • RCTs only: pooled OR=0.22 (95% CI: 0.10–0.47), P<0.001, I²=39.8%
  • Non-RCTs only: pooled OR=0.14 (95% CI: 0.09–0.23), P<0.001, I²=0%
  • When looking at heterogeneity between RCTs and non-RCTs, we arrive at a P value of 0.47.

Subgroup analysis

Of the potential sources of heterogeneity prespecified in the protocol, it was not possible to do a subgroup analysis by coinfection status, as there were eventually no eligible populations who were coinfected. Furthermore, it was not possible to do subgroup analysis by WHO region, as almost all studies came from just one region (i.e. Western Pacific). For LAM, one ad hoc subgroup analysis is presented; timing of treatment being end postpartum.

1.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all HBV DNA levels at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by trimester of treatment start.

• 1st trimester: not enough studies for meta-analysis (i.e. n<3)
• 2nd trimester: pooled OR=0.09 (95% CI: 0.02–0.37), P=0.001, I²=0.0%
• 3rd trimester: pooled OR=0.19 (95% CI: 0.14–0.25), P<0.001, I²=0.0%
• When looking at heterogeneity between studies where treatment was started in the 2nd versus the 3rd trimester, we arrive at a P value of 0.29, indicating no difference between the estimates.

2.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all HBV DNA levels at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by median weeks of gestation at the time of start of treatment (<28 weeks, 28 weeks, >28 weeks).

• <28 weeks: pooled OR=0.10 (95% CI: 0.04–0.26), P<0.001, I²=0.0%
• 28 weeks: pooled OR=0.16 (95% CI: 0.11–0.23), P<0.001, I²=0.0%
• >28 weeks: pooled OR=0.31 (95% CI: 0.16–0.57), P<0.001, I²=7.7%
• When looking at heterogeneity across the three subgroups, the P value was 0.06. If comparing <28 weeks median with 28 weeks median, there was no heterogeneity (P=0.38). If comparing <28 weeks median with >28 weeks median, or if comparing 28 weeks median with >28 weeks median, there was evidence of heterogeneity (both with P=0.04); however, because of the mild heterogeneity within the subgroup starting at >28 weeks median, this test may not be valid.

3.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all study designs merged (i.e. RCT and non-RCT), stratified by the minimum HBV DNA level specified in the inclusion criteria of the study.

• >4–4.99 log10 IU/mL: pooled OR=0.11 (95% CI: 0.05–0.25), P<0.001, I²=0.0%
• >5–5.99 log10 IU/mL: pooled OR=0.15 (95% CI: 0.10–0.22), P<0.001, I²=0.0%
• >6–6.99 log10 IU/mL: pooled OR=0.51 (95% CI: 0.12–2.12), P=0.357, I²=36.4%
• >7–7.99 log10 IU/mL: not enough studies (i.e. <3)
• When looking at heterogeneity between studies with inclusion criteria of 4–4.99 log10 IU/mL versus 5–5.99 log10 IU/mL, the P value was 0.48. No comparison was done with 6–6.99 log10 IU/mL, as this OR was both heterogeneous and non-significant.

4.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels specified at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by whether or not all women were HBeAg- positive.

• All HBeAg-positive: pooled OR=0.17 (95% CI: 0.12–0.23), P<0.001, I²=0.0%
• Mixed HBeAg positivity: pooled OR=0.26 (95% CI: 0.08–0.82), P=0.022, I²=0.0%
• When looking at heterogeneity between studies where all women versus only some women were HBeAg positive, we arrive at a P value of 0.46, indicating no difference between the estimates.

5.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels specified at inclusion, all study designs merged (i.e. RCT and non-RCT), by infant immunoprophylaxis regimen (Table 11).

• As most studies provided all of birth dose vaccine, HBIG at birth, and subsequent infant vaccinations, stratification by type or combination of infant immunoprophylaxis was not done in this meta-analysis.
• Therefore, we stratified by whether or not both birth dose vaccine and HBIG were given within 12 hours of life, versus within 24 hours of life.

  • <12 hours: pooled OR=0.14 (95% CI: 0.05–0.39), P<0.001, I²=0.0%
  • <24 hours: pooled OR=0.26 (95% CI: 0.16–0.43), P<0.001, I²=16.1%
  • The P value for heterogeneity between the two subgroups was 0.31.

Table 11

Infant immunoprophylaxis regimens seen in studies investigating LAM.

6.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all study designs merged (i.e. RCT and non-RCT), stratified by the timing that treatment was discontinued postpartum.

• At delivery: pooled OR=0.15 (95% CI: 0.10–0.23), P<0.001, I²=0.0%
• 4–8 weeks postpartum: pooled OR=0.23 (95% CI: 0.15–0.36), P<0.001, I²=0.0%
• 12 weeks postpartum: pooled OR=0.08 (95% CI: 0.02–0.37), P=0.001, I²=0.0%
• 24+ weeks postpartum: no studies within this subgroup
• When looking at heterogeneity across the four subgroups, the P value was 0.20.

Safety analysis, narrative descriptions and selected forest plots

Infant safety outcomes

Of the infant safety outcomes prespecified in the protocol, the data for Apgar score were not available for the majority of included studies and where it was available the format varied greatly; this led to an inability to combine results in a meaningful way. None of the included studies for LAM investigated bone mineral density in infants.

1. Neonatal deaths (death within 28 days of life)

Information on this outcome was available for all except one study that administered LAM to mothers. One death in 2010 infants (non-weighted average 0.05%) was reported across the treatment groups and one death in 2093 infants (non-weighted average 0.05%) was reported across the control groups. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.000 (95% CI: −0.006–0.006). The I² statistics for the overall pooled risk difference, as well as for RCTs and non-RCTs separately, were all 0.0%.

2. Prematurity (typically defined as birth earlier than 37 weeks of gestation)

Information on this outcome was available for 10 of the 40 included studies that administered LAM to mothers. Within these studies, 14 of 609 (non-weighted average 2.3%) infants whose mothers were treated with LAM during pregnancy were born prematurely, whereas 11 of 399 (non-weighted average 2.8%) infants whose mothers were not treated during pregnancy were born prematurely. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.000 (95% CI: −0.025–0.025). The I² statistics for the overall pooled risk difference estimated was 43.0%. The I² statistics for non-RCTs was 55.6%. There were too few RCTs (i.e. <3) to consider the pooled risk difference separately in this subgroup.

3. Congenital abnormalities

Information on this outcome was available for 16 of the 40 included studies that administered LAM to mothers. Within these studies, eight of 845 (non-weighted average 0.9%) infants whose mothers were treated with LAM during pregnancy were noted to have some sort of congenital abnormality, including: atrial septal defect with Ebstein anomaly and pneumothorax (n=1), cleft palate (n=1), polydactyly (n=3), auricular defect (n=1), left ear pinna turn malformation (n=1), and absent ear (n=1). Five of 953 (non-weighted average 0.5%) infants whose mothers were not treated during pregnancy were noted to have some sort of congenital abnormality, including: polydactyly (n=1), talipes equinovarus (n=1), ear accessory (n=1), pulmonary stenosis (n=1), hydrocephalus (n=1). The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.003 (95% CI: −0.007–0.014). The I² statistics for the overall pooled risk, as well as for RCTs and non-RCTs separately, were all 0%.

Maternal safety outcomes

1. Fetal demise (miscarriage [<28 weeks], stillbirth [>=28 weeks])

Information on this outcome was available for 39 of the 40 studies that administered LAM to mothers. Ten cases of fetal demise were reported across all study populations. One case (non-weighted average 0.05%) occurred across 2003 mothers/fetuses who were treated with LAM during pregnancy. Nine cases (non-weighted average 0.4%) occurred across 2087 mothers/fetuses who were not treated during pregnancy. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.000 (95% CI: −0.006–0.005). The I² statistics for the overall pooled risk difference estimate as well as for RCTs and non-RCTs separately, were all 0%.

2. Postpartum haemorrhage

Information on this outcome was available for eight of the 40 included studies that administered LAM to mothers. Within these studies, 98 of 611 (non-weighted average 16.0%) mothers who were treated with LAM during pregnancy experienced postpartum haemorrhage, whereas 61 of 752 (8.1%) mothers who were not treated during pregnancy experienced postpartum haemorrhage. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.008 (95% CI: −0.012–0.028). The I² statistics for the overall pooled OR, as well as for non-RCTs separately were 0%. Not enough RCTs evaluated this safety outcome to consider this subgroup separately.

3. Antiviral resistance

Four studies that treated mothers with LAM during pregnancy reported on some results of antiviral resistance testing. One study from Australia reported the selection of primary resistant variants to LAM in 21 treated women (Greenup AJ et al., 2014). One study from China reported no cases of antiviral resistance in both treated and control groups, with no other details provided (Shen ML et al., 2016). Another Chinese study performed resistance testing in five women with viral breakthrough and found no resistance mutants (Zhang H et al., 2014). Finally, a study from Ireland carried out antiviral resistance testing on 28 of the 36 women treated with LAM during pregnancy and reported identification of wild-type strains in all women (Jackson V et al., 2015).

4. HBV flare after treatment discontinuation

Information on this outcome was available for six of the 40 included studies that administered LAM to mothers. Various definitions were used, including: “postpartum ALT elevations”, “postpartum flare”, “grade 3/4 elevation”, as well as no definition in some cases. Within these studies, 53 of 370 (non-weighted average 14.3%) mothers who were treated with LAM during pregnancy experienced a type of HBV flare at the time of treatment discontinuation, whereas 46 of 550 (non-weighted average 8.4%) mothers who were not treated during pregnancy experienced the same type of HBV flare at a matched time-point. The weighted pooled risk difference for this safety outcome seen following meta-analysis was −0.059 (95% CI: −0.207–0.089). Overall, the pooled risk difference had a high level of heterogeneity (I² of 88.3%), as well as within the non-RCTs only, the I² was 87.8%. It was not possible to examine the RCTs alone as a subgroup as there was only one study.

GRADE summary of findings

Table 12

GRADE evidence profile: LAM 100–150 mg during pregnancy to prevent HBV mother-to-child transmission (MTCT).

Telbivudine (LdT) 600 mg versus no treatment or placebo

Summary of included studies

There were 87 original studies, including 101 unique treatment arms, eligible for this meta-analysis that used LdT 600 mg. Following risk of bias assessment, four studies (all non-RCTs and each with one treatment arm investigating LdT) were excluded (Chen YL et al., 2014; Liu CP, 2015; Luo DX et al., 2017; Zhang R et al., 2016). Therefore, 83 original studies with 97 unique treatment arms were included in the analysis. Of the included studies, 21 were RCTs and 62 were non-randomized trials/observational studies (39 prospective and 23 retrospective studies).

Risk of bias assessment 

• Randomized controlled trials

Of the 21 RCTs included that investigated LdT, none achieved a “low risk of bias” rating on the majority of the main criteria in the Cochrane Collaboration’s Risk of Bias Assessment Tool. All studies had only one or two criteria deemed as “low risk of bias”; in almost all studies there was a low risk of selection bias (specifically random sequence generation) and sometimes a low risk of selective reporting. The remaining criteria for all studies had a high or unclear risk, usually due to a lack of detailed reporting. The detailed risk of bias assessment for the RCTs investigating LdT 600 mg can be found in Appendix E.

• Non-randomized controlled trials

Of the original 66 non-RCTs, the majority of studies (70.0%) had low risk of bias scores (i.e. scores of 7, 8, 9) on the Newcastle Risk of Bias scale. The main weakness of included studies was in reference to loss to follow up – this information was missing in 58 of 66 studies, and was less than adequate (i.e. <80% follow up) in one further study. The detailed risk of bias assessment for the non-RCTs investigating LdT 600 mg can be found in Appendix F (Table 13).

Table 13

Risk of bias scores for non-RCTs (prior to exclusion of very high-risk studies).

Publication bias/assessment of small study effects

It was possible to examine publication bias for most of the outcomes examined. Of these, there was possible evidence of publication bias/small study effects in the three study sets: MTCT indicated by HBsAg positivity at 6–12 months in non-RCTs, MTCT indicated by HBV DNA positivity at 6–12 months in non-RCTs, postpartum haemorrhage in non-RCTs. Funnel plots for LdT 600 mg study sets, as well as results of the Egger test for asymmetry (if examining OR only) can be found in Appendix G.

Characteristics of included studies

Across all included studies, recruitment took place as early as 2000 and up until 2017. All studies took place in the WHO Western Pacific Region, specifically, all studies took place in China (n=83).

HBV genotyping for the entire study population was performed in four instances. One estimated that the treatment group was 44% genotype B, 56% genotype C, whereas the control group was 37% genotype B, 63% genotype C (Hu Y et al., 2018). One study estimated the treatment group as 72% genotype B, 28% genotype C, and the control group was similar with 74% genotype B and 26% genotype C (Liu Y et al., 2016). Another study estimated 40% genotype B, 60% genotype C in the treatment group, compared to 29% genotype B and 71% genotype C in the control group (Shen ML et al., 2016). Finally, one study found 73% genotype B, 26% genotype C, and 1% mixed genotype B/C in the treatment group, compared to 75% genotype B and 25% genotype C in the control group (Wu Q et al., 2015)

Most included study arms (i.e. 59/97) started maternal antiviral therapy between 24 and 30 weeks of gestation. The most common HBV DNA levels designated for inclusion were >5.3 log10 IU/mL (25 of 97 treatment arms) or >6.3 log10 IU/mL (24/97 treatment arms).

Table 14

Characteristics of included studies investigating LdT 600 mg.

Primary efficacy analysis, narrative descriptions and forest plots

1.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels at inclusion, stratified by study design (RCT and non-RCT).

• Overall pooled OR=0.10 (95% CI: 0.08–0.13), P<0.001, I²=0%

  • RCTs only: pooled OR=0.14 (95% CI: 0.10–0.26), P<0.001, I²=0%
  • Non-RCTs only: pooled OR=0.09 (95% CI: 0.07–0.12), P<0.001, I²=0%
  • The P value for heterogeneity between RCTs and non-RCTs was 0.08.

2.

PMTCT, as indicated by detection of HBV DNA at 6–12 months of age, all treatment start times, all HBV DNA levels at inclusion, stratified by study design (RCT and non-RCT).

• Overall pooled OR=0.08 (95% CI: 0.06–0.11), P<0.001, I²=0.0%

  • RCTs only: pooled OR=0.12 (95% CI: 0.05–0.26), P<0.001, I²=0%
  • Non-RCTs only: pooled OR=0.07 (95% CI: 0.05–0.10), P<0.001, I²=0%
  • The P value for heterogeneity between RCTs and non-RCTs was 0.29.

Subgroup analysis

Of the potential sources of heterogeneity predefined in the protocol, it was not possible to do a subgroup analysis by coinfection status, as there were eventually no eligible populations that included those coinfected. Furthermore, it was not possible to do subgroup analysis by WHO region, as almost all studies came from just one region (i.e. Western Pacific). For LdT, one ad hoc subgroup analysis is presented; timing of treatment end postpartum.

1.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all HBV DNA levels at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by trimester of treatment start.

• 1st trimester: pooled OR=0.09 (95% CI: 0.04–0.22), P=0.001, I²=0.0%
• 2nd trimester: pooled OR=0.09 (95% CI: 0.05–0.20), P=0.001, I²=24.3%
• 3rd trimester: pooled OR=0.13 (95% CI: 0.10–0.17), P<0.001, I²=0.0%
• There was no detected heterogeneity between any of the subgroups (i.e. 1st versus 2nd, 2nd versus 3rd, 1st versus 3rd), with P values between 0.49 and 0.80. However, because of the mild heterogeneity seen in the 2nd trimester treatment start subgroup, heterogeneity comparisons with this subgroup may not be valid.

2.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all HBV DNA levels at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by median weeks of gestation at the time of treatment start (<28 weeks, 28 weeks, >28 weeks).

• <28 weeks: pooled OR=0.09 (95% CI: 0.06–0.13), P<0.001, I²=0.0%
• 28 weeks: pooled OR=0.13 (95% CI: 0.10–0.18), P<0.001, I²=0.0%
• >28 weeks: pooled OR=0.10 (95% CI: 0.05–0.21), P<0.001, I²=0.0%
• When looking at heterogeneity across the three subgroups, the P value was 0.28. If comparing <28 weeks median with 28 weeks median, there was no heterogeneity (p=0.12). If comparing <28 weeks median with >28 weeks median for treatment start, there was no evidence of heterogeneity (P=0.72). If comparing 28 weeks median with >28 weeks median, there was no evidence of heterogeneity (P=0.52).

3.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all study designs merged (i.e. RCT and non-RCT), stratified by the minimum HBV DNA level specified in the study inclusion criteria.

• >4–4.99 log10 IU/mL: pooled OR=0.07 (95% CI: 0.03–0.15), P<0.001, I²=0.0%
• >5–5.99 log10 IU/mL: pooled OR=0.12 (95% CI: 0.08–0.17), P<0.001, I²=0.0%
• >6–6.99 log10 IU/mL: pooled OR=0.10 (95% CI: 0.07–0.15), P<0.001, I²=0.0%
• >7–7.99 log10 IU/mL: no studies included
• When looking at heterogeneity across the three HBV DNA level subgroups, the P value was 0.46. If comparing >4–4.99 log10 IU/mL with >5–5.99 log10 IU/mL, there was no heterogeneity (P=0.22). If comparing >5–5.99 log10 IU/mL with >6–6.99 log10 IU/mL, there was no evidence of heterogeneity (P=0.58). If comparing >4–4.99 log10 IU/mL with >6–6.99 log10 IU/mL, there was no evidence of heterogeneity (P=0.36).

4.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels specified at inclusion, all study designs merged (i.e. RCT and non-RCT), stratified by whether or not all women were HBeAg- positive.

• All HBeAg-positive: pooled OR=0.11 (95% CI: 0.08–0.14), P<0.001, I²=0.0%
• Mixed HBeAg-positive: pooled OR=0.10 (95% CI: 0.05–0.23), P<0.001, I²=0.0%
• There was no heterogeneity (P=0.94) between the two subgroups.

5.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all HBV DNA levels specified at inclusion, all study designs merged (i.e. RCT and non-RCT), by infant immunoprophylaxis regimen (Table 15).

• As most studies provided all of birth dose vaccines, HBIG at birth, and subsequent infant vaccinations, stratification by type or combination of infant immunoprophylaxis was not done in this meta-analysis.
• Therefore, we stratified by whether or not both birth dose vaccine and HBIG were given within 12 hours of life, versus within 24 hours of life.

  • <12 hours: pooled OR=0.09 (95% CI: 0.06–0.15), P<0.001, I²=0.0%
  • <24 hours: pooled OR=0.11 (95% CI: 0.06–0.19), P<0.001, I²=0.0%
  • The P value for heterogeneity between the two subgroups was 0.67.

Table 15

Infant immunoprophylaxis regimens seen in studies investigating LdT.

6.

PMTCT, as indicated by detection of HBsAg at 6–12 months of age, all treatment start times, all study designs merged (i.e. RCT and non-RCT), stratified by the timing that treatment was discontinued postpartum.

• At delivery: pooled OR=0.11 (95% CI: 0.07–0.17), P<0.001, I²=0.0%
• 4–8 weeks postpartum: pooled OR=0.13 (95% CI: 0.09–0.19), P<0.001, I²=0.0%
• 12 weeks postpartum: pooled OR=0.06 (95% CI: 0.3–0.15), P<0.001, I²=0.0%
• 24+ weeks postpartum: pooled OR=0.11 (95% CI: 0.04–0.29), P<0.001, I²=0.0%
• When looking at heterogeneity across the four subgroups, the P value was 0.55.

Safety analysis, narrative descriptions and selected forest plots

Infant safety outcomes

Of the infant safety outcomes predefined in the protocol, the data for Apgar score were not available for the majority of included studies and where it was available the format varied greatly; this led to an inability to combine results in a meaningful way. None of the included studies for LdT investigated bone mineral density in infants.

1. Neonatal deaths (death within 28 days of life)

Information on this outcome was available for all except one study that administered LdT to mothers. Two deaths of 5752 infants (non-weighted average 0.03%) were reported across the treatment groups and no deaths in the 5863 infants (0.0%) were reported across the control groups. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.000 (95% CI: −0.002–0.003). The I² statistics for the overall pooled risk difference, as well as for RCTs and non-RCTs separately, were all 0.0%.

2. Prematurity (typically defined as birth earlier than 37 weeks gestation)

Information on this outcome was available for 24 of the 83 included studies that administered LdT to mothers. Within these studies, 105 of 2427 (non-weighted average 4.3%) infants whose mothers were treated with LdT during pregnancy were born prematurely, whereas 120 of 2191 (non-weighted average 5.5%) infants whose mothers were not treated during pregnancy were born prematurely. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.001 (95% CI: −0.010–0.008). The I² statistics for the overall pooled risk difference estimated was 0.0%. The I² statistics for non-RCTs was 0.0%. There were too few RCTs (i.e. <3) to consider the pooled risk difference separately in this subgroup.

3. Congenital abnormalities

Information on this outcome was available for 40 of the 83 included studies that administered LdT to mothers. Within these studies, 11 of 3585 (non-weighted average 0.3%) infants whose mothers were treated with LdT during pregnancy were noted to have some sort of congenital abnormality, including: anotia (n=1), cerebral palsy (n=1), cinesipathy (n=1), cleft lip and/or palate (n=2), auricular defect (n=1), ear accessory (n=1), no detail provided (n=4). Nine of 2983 (non-weighted average 0.3%) infants whose mothers were not treated during pregnancy were noted to have some sort of congenital abnormality, including: polydactyly (n=1), talipes equinovarus (n=1), ear accessory (n=1), pulmonary stenosis (n=1), hydrocephalus (n=1), congenital ventricular septal defect (n=1), no detail provided (n=3). The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.000 (95% CI: −0.004–0.004). The I² statistics for the overall pooled risk, as well as for RCTs and non-RCTs separately, were all 0%.

Maternal safety outcomes

1. Fetal demise (miscarriage [<28 weeks], stillbirth [>=28 weeks])

Information on this outcome was available for 81 of the 83 studies that administered LdT to mothers. Twenty-three cases of fetal demise were reported across all study populations. Three cases (non-weighted average 0.05%) occurred across 5645 mothers/fetuses who were treated with LdT during pregnancy. Twenty cases (non-weighted average 0.3%) occurred across 5823 mothers/fetuses who were not treated during pregnancy. The weighted pooled risk difference for this safety outcome seen following meta-analysis was −0.001 (95% CI: −0.003–0.002). The I² statistics for the overall pooled risk difference estimate, as well as for RCTs and non-RCTs separately, were all 0%.

2. Postpartum haemorrhage

Information on this outcome was available for 19 of the 83 included studies that administered LdT to mothers. Within these studies, 284 of 1729 (non-weighted average 16.4%) mothers who were treated with LdT during pregnancy experienced postpartum haemorrhage, whereas 116 of 2020 (5.7%) mothers who were not treated during pregnancy experienced postpartum haemorrhage. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.041 (95% CI: −0.089–0.171). The I² statistics for the overall pooled risk difference was 99.4%; that for non-RCTs was 99.5%. Not enough RCTs evaluated this safety outcome to consider this subgroup separately.

3. Antiviral resistance

Seven studies that treated mothers with LdT during pregnancy reported on some results of testing for antiviral resistance. One study reported that in 11 of 257 women in the treated group with previous antiviral therapy (LdT or other) no resistance mutations were detected, and that in the entire study, no participant discontinued due to resistance (Han et al., 2015). One study reported that of 78 treatment women, one participant developed an M204I drug-resistance mutation after receiving LdT for 40 weeks (Liu et al., 2016). Another study evaluated drug resistance in all 103 treated participants (timing not clear) and found no evidence of resistance mutations (Sun et al., 2017). Three studies reported antiviral resistance as a quantitative outcome (few details provided), giving case numbers of two in 31 treated women (Chen et al., 2016), one in 35 treated women (Li et al., 2016), and none in 60 treated women (Shen et al., 2016), respectively. Finally, one study evaluated antiviral resistance in seven women (of 105) whose HBV DNA levels did not reduce during treatment, and found no resistance mutations (Hu et al., 2018).

4. HBV flare

Information on this outcome was available for five of the 83 included studies that administered LdT to mothers. Various definitions were used, including: “ALT >40 U/L”, “ALT >2 times baseline”, “ALT >= 8 times ULN”, “ALT >8 ULN or 5 times baseline”. Within these studies, 38 of 517 (non-weighted average 7.4%) mothers who were treated with LdT during pregnancy experienced a type of HBV flare at the time of treatment discontinuation, whereas 47 of 689 (non-weighted average 6.8%) mothers who were not treated during pregnancy experienced the same type of HBV flare at a matched time-point. The weighted pooled risk difference for this safety outcome seen following meta-analysis was 0.001 (95% CI: −0.061–0.064). Overall, the pooled risk difference (non-RCTs only were included) had a high level of heterogeneity (I² =73.9%).

GRADE summary of findings

Table 16

GRADE evidence profile: LdT 600 mg during pregnancy to prevent HBV mother-to-child transmission (MTCT).

Conclusion

This meta-analysis shows that certain antiviral therapies may be efficacious if used during pregnancy for the PMTCT of HBV, as indicated by the proportion of infants with HBsAg detected at 6–12 months of life. Specifically, meta-analysis of RCTs investigating TDF 300 mg had a protective, pooled OR of 0.10 (95% CI: 0.03–0.35), those investigating LAM 100–150 mg had a protective pooled OR of 0.16 (95% CI: 0.10–0.26), and those investigating LdT 600 mg had a protective pooled OR of 0.14 (95% CI: 0.09–0.21). The GRADE evidence quality for each of these three treatment regimens was “moderate” for RCTs, and “low” for non-RCTs; however, the results for RCTs and non-RCTs were concordant (see Table 17).

Table 17

Meta-analysis odds ratios (OR) for all studies using infant HBsAg as outcome, by study design, by treatment type.

There were almost no differences seen (heterogeneity across pooled OR estimates) for any subgroup analyses for any treatment type included. Only in one subgroup analysis for LAM 100 mg, which examined the difference between treatment starting at a median <28 weeks, 28 weeks or >28 weeks, was heterogeneity observed. In this case, it appeared that starting treatment at median 28 weeks or <28 weeks was significantly more protective than starting treatment at a median >28 weeks.

There was moderate- to low-grade evidence that taking antiviral therapies for PMTCT did not increase the risk of certain infant and maternal safety outcomes, such as neonatal death, congenital abnormalities, fetal demise (miscarriage or stillbirth). However, it is important to note that for some of these outcomes, notably neonatal death and fetal demise, there are important concerns regarding data quality in this review (see Limitations section below). There was always very low evidence with regards to maternal antiviral therapy and the occurrence of HBV flare; few studies presented this information and where it was presented, definitions and time-points varied considerably, limiting our ability to combine these findings in a meaningful way. Across all treatment types, there was very little or no information on antiviral resistance in mothers, and bone mineral density changes in infants; other study designs and evidence should be considered by policy-makers for a better understanding of these risks.

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Appendices

APPENDIX A. Search strategies

Database: PubMed

Date searched: 28 March 2019

Search strategy:

Table

Database: Embase Classic + Embase via OvidSP (1947–2019 March 26th)

Date searched: 28 March 2019

Search strategy:

Table

Database: Scopus

Date searched: 28 March 2019

Search strategy:

Table

Database: CENTRAL Database (The Cochrane Library)

Date searched: 28 March 2019

Search strategy:

Table

Database: CNKI

Date searched: 28 March 2019

Search strategy:

SU=‘乙型肝炎‘+’乙肝‘+’乙型肝炎病毒‘+’乙肝病毒‘+’HBV‘+’乙型肝炎表面抗原‘+’乙肝表面抗原’ AND SU=‘抗病毒‘+’抗病毒药物‘+’核苷‘+’核苷酸‘+’核苷类似物‘+’核苷酸 类似物‘+’NAs‘+’阿德福韦酯‘+’hepsera‘+’preveon‘+’bis-POM PMEA‘+’GS 840‘+’ADV‘+’恩曲他滨‘+’emtriva‘+’FTC‘+’恩替卡韦‘+’baraclude‘+’ETV‘+’拉米夫定 ‘+’epivir‘+’3TC‘+’LAM‘+’替比夫定‘+’sebivo‘+’tyzeka‘+’LdT‘+’替诺福韦酯 ‘+’viread‘+’TDF‘+’替诺福韦艾拉酚胺‘+’vemLidy‘+’TAF’ AND SU=‘妊娠‘+’怀孕‘+’孕 妇‘+’孕期‘+’母胎‘+’母亲‘+’胎儿‘+’子代‘+’子女‘+’垂直传播‘+’产前‘+’产时‘+’产间‘+’围产 ‘+’出生前‘+’围生‘+’宫内‘+’跨胎盘‘+’胎盘‘+’母婴传播‘+’预防母婴传播‘+’阻断母婴传播 ‘+’妊娠并发症‘+’产前诊断‘+’先天’

Database: Wanfang

Date searched: 28 March 2019

Search strategy:

主题: (“乙型肝炎“+”乙肝“+”乙型肝炎病毒“+”乙肝病毒“+”HBV“+”乙型肝炎表面抗 原”+”乙肝表面抗原”) and 主题: (“抗病毒“+”抗病毒药物“+”核苷“+”核苷酸“+”核苷类 似物“+”核苷酸类似物“+”NAs“+”阿德福韦酯“+”hepsera“+”preveon“+”bis-POM PMEA“+”GS 840“+”ADV“+”恩曲他滨“+”emtriva“+”FTC“+”恩替卡韦 “+”baraclude“+”ETV“+”拉米夫定“+”epivir“+”3TC“+”LAM“+”替比夫定 “+”sebivo“+”tyzeka“+”LdT“+”替诺福韦酯“+”viread“+”TDF“+”替诺福韦艾拉酚胺 “+”vemlidy“+”TAF”) and 主题: (“妊娠“+”怀孕“+”孕妇“+”孕期“+”母胎“+”母亲“+”胎儿 “+”子代“+”子女“+”垂直传播“+”产前“+”产时“+”产间“+”围产“+”出生前“+”围生“+”宫内 “+”跨胎盘“+”胎盘“+”母婴传播“+”预防母婴传播“+”阻断母婴传播“+”妊娠并发症“+” 产前诊断“+”先天”)

APPENDIX B. Guidance – Cochrane Collaboration’s risk of bias assessment tool

(table taken directly Higgins JPT et al., 2011)

Table

Notes for filling out the table (adapted/made specific for this systematic review and meta-analysis from the Cochrane handbook 2008 and from Higgins JPT et al., 2011):

-

Within the table, summary descriptions should be provided in order to give an independent reader enough information to see why the specific judgement has been made. For example, if no information on sequence generation can be found in the article or correspondence with the author, you could enter “Comment: no information provided”. If it states that patients were randomly allocated in the article, then you could copy out the phrase directly from the article, e.g. “Quote: “patients were randomly allocated”. In any case, if you have doubts regarding whether or not the study actually did certain things that are mentioned in the article, please include an extra comment describing concern/contradiction in the article.

-

When providing your judgement as a review author, indicate “low risk” of bias, and “high risk” of bias. If insufficient information is provided, then the judgement should be “unclear” risk of bias.

• See table 8.5c on pages 198–202 in the 2008 Cochrane handbook for systematic reviews of intervention (pages 223–227 of the pdf) for specific guidance on how to make your judgement.

Appendix E. Cochrane Collaboration’s Risk of Bias Assessment Tool for Randomized Controlled Trials

TDF 300 mg

A. English language studies

Table

Low risk Quotes: “Enrollment at each center was performed with the use of blocks and randomized for sample balance. Using a randomization table, we randomly assigned 200 mothers, in a 1:1 ratio”

B. Chinese language studies

Table

Low risk/Unclear Quotes: “60 cases of pregnant women with asymptomatic hepatitis B virus were selected and randomly divided into liver protection group and tenofovir group, with 30 cases in each group”

LAM 100–150 mg

A. English language studies

Table

High risk Comment: Mentions that women were randomly assigned but does not give any indication of method for randomization.

B. Chinese language studies

Table

Low risk/Unclear Quotes: “90 cases of pregnant women chronically infected with HBV were selected and randomly divided into lamivudine group, telbivudine group and control group, with 30 cases in each group”

LDT 600 mg

A. Chinese language studies

Table

Low risk/Unclear Quotes: “80 cases of pregnant women with chronic hepatitis B were randomly divided into experimental group and control group, 40 cases in each group”

APPENDIX F. Newcastle–Ottawa Risk of Bias Assessment Tool

TDF 300 mg

A. English language observational studies

Table

B. Chinese language observational studies

Table

LAM 100–150 mg

A. English language observational studies

Table

B. Chinese language observational studies

Table

LDT 600 mg

A. English language observational studies

Table

6 (high) (Arm 1) 8 (low) (Arm 2)

B. Chinese language observational studies

Table

APPENDIX G. Publication bias assessment (>=10 studies)

TDF 300 mg

MTCT indicated by HBsAg positivity at 6–12 months, non-RCTs

• Evidence of possible publication bias/small study effects, Egger test P value=0.002

Neonatal deaths, non-RCTs

• No evidence of publication bias

Miscarriages and stillbirths, non-RCTs

• No evidence of publication bias

LAM 100–150 mg

MTCT indicated by HBsAg positivity at 6–12 months, non-RCTs

• Evidence of possible publication bias/small study effects, Egger test P value=0.002

MTCT indicated by HBV DNA positivity at 6–12 months, non-RCTs

• No evidence of publication bias, Egger test P value=0.055

Neonatal deaths, non-RCTs

• No evidence of publication bias

Congenital abnormalities, non-RCTs

• No evidence of publication bias

Miscarriages and stillbirths, non-RCTs

• No evidence of publication bias

LdT 600 mg

MTCT indicated by HBsAg positivity at 6–12 months, RCTs

• No evidence of publication bias, Egger test P value=0.119

MTCT indicated by HBsAg positivity at 6–12 months, non-RCTs

• Evidence of possible publication bias/small study effects, Egger test P value <0.001

MTCT indicated by HBV DNA positivity at 6–12 months, non-RCTs

• Possible evidence of publication bias/small study effects, Egger test P value=0.038

Neonatal deaths, RCTs

• No evidence of publication bias

Neonatal deaths, non-RCTs

• No evidence of publication bias

Prematurity, non-RCTs

• Unclear/no evidence of publication bias

Congenital abnormalities, non-RCTs

• No evidence of publication bias

Miscarriages and stillbirths, RCTs

• No evidence of publication bias

Miscarriages and stillbirths, non-RCTs

• No evidence of publication bias

Postpartum haemorrhage, non-RCTs

• Possible evidence of publication bias/small study effects