The Importance of HBV MTCT in the Elimination Agenda
Whilst commending the global efforts to scale up HBV infant vaccination over the last three decades, it is vital to acknowledge that this alone will not be sufficient to eliminate new incident HBV infections by 2030 as it does not interrupt transmission occurring from mother-to-child at the time of birth. Since the risk of becoming a chronic carrier of HBV if infected through this route is as high as 90% [
17], prevention of HBV transmission from mother to child during this critical period remains vital. In the pre-vaccination era, it was estimated that in Asia, about 40% of HBV transmission occurred from mother-to-child, versus 10% in Africa. However, modelling studies have suggested that due to the successes of infant vaccination, the epidemiology of transmission has changed with a more prominent relative contribution of HBV MTCT in all world regions [
2••]. The contribution of HBV MTCT in maintaining ongoing HBV transmission has often been underappreciated in sub-Saharan Africa. However, it is now time to take action as an estimated 350,000 neonates are being infected with HBV annually at birth, a number which represents twice the number of neonatal HIV infections in the region [
18••]. Furthermore, data is accumulating to support the hypothesis that those who acquired their infection through MTCT have more severe fibrosis and HCC risk than those acquired horizontally [
19‐
21].
Availability of Safe and Effective HBV PMTCT Interventions
Three safe and effective interventions are available to combat HBV MTCT: birth dose vaccination (BDV), hepatitis B immunoglobulin (HBIG) and antiviral prophylaxis for HBV-infected mothers with high viral load in the last trimester of pregnancy [
22••,
23]. However, worryingly from a global perspective, the coverage of these interventions falls well below the 90% coverage levels recommended to reach the WHO hepatitis elimination targets. Data from the Polaris Observatory estimates that only 46% of infants received timely BDV, 13% of infants born to HBsAg-positive mothers received HBIG, birth dose and at least two doses of infant vaccination and < 1% of mothers with high viral load received antiviral treatment in 2016 [
1••]. A closer inspection reveals highly heterogenous coverage of HBV PMCT interventions between countries and regions. China, for example, has led the way towards elimination of HBV MTCT by reaching high coverage of infant vaccination, universal timely BDV and HBsAg screening of pregnant women with HBIG to those born to HBsAg positive mothers. This concerted effort has reduced under 5-year-old HBsAg prevalence from 9.67% in 1992 to 0.32% in 2014, which is a significant achievement [
24••]. Whereas, in sharp contrast in the African region, there is 10% coverage of timely BD vaccination and only 12 countries have incorporated BD vaccination into their national policy. Furthermore, most countries in Africa do not offer women systematic HBsAg screening in pregnancy as part of national policy, therefore missing a vital opportunity to offer appropriate interventions. This disparity highlights the need to focus on understanding the key barriers and challenges to intervention scale-up in underperforming regions and focus on how these interventions could be scaled up using an evidence-based strategy which takes into account questions about efficacy, impact and cost-effectiveness.
Universal birth dose vaccination has been a WHO recommendation since 2009 and the advice is that all children receive a dose of HBV vaccine within 24 h of birth. Birth dose vaccination has been shown to be effective at reducing HBV MTCT and reduces transmission in hepatitis B e antigen (HBeAg)-positive mothers from about 90 to 15% and from about 5–30% to < 0.5% in HBeAg-negative mothers [
18••,
25]. Birth dose vaccination is less effective against MTCT when delayed beyond 24 h [
26]. However, the majority of the data on transmission rates are from studies in Asian or western settings, with a paucity of data from the African region, particularly on MTCT stratified by HBeAg status and viral load or efficacy of birth dose vaccination. The existing studies are often limited by small sample size and heterogeneity in study design [
18••]. Caution needs to be taken when extrapolating transmission and disease progression rates from Asian to African populations, particularly given the differences in viral genotype and host factors [
27].
The addition of passive immunisation with HBIG to BDV reduces PMTCT further, particularly in infants born to HBeAg-positive mothers, and is given systematically in high-income settings for all children born to HBsAg-positive mothers. However, its high cost, need for cold chain and associated frequent supply issues makes it an unfeasible option in many LMICs [
28]. Furthermore, new data suggests that HBIG does not provide additional protection to BD alone, in infants born to HBeAg mothers with low viral load if BDV is given within 24 h.
Unfortunately, the administration of a timely BDV and HBIG does not completely interrupt MTCT in a subset of HBV-infected mothers and immunoprophylaxis failure is correlated with maternal HBV viral load [
29]. Over the last decade, data has been accumulating about the efficacy and safety of peripartum antiviral therapy as a third intervention in addition to BD and HBIG to reduce MTCT even further in mothers with the highest risk of transmission [
23,
30]. The 2016 open-labelled randomised trial in China comparing HBV MTCT among HBeAg-positive mothers with HBV viral loads over 200,000 IU/ml receiving tenofovir in addition to standard immunisation to those receiving standard immunisation alone provides the strongest evidence to date regarding the effectiveness of this strategy [
31]. The intention to treat analysis showed a 5% HBV MTCT (defined as child positive for HBsAg +/−HBV DNA at 6 months) versus 18% (
p = 0.007) and per protocol analysis of 0 compared to 7% (
p = 0.01). A more recent study in Thailand showed no significant benefit of addition of maternal antiviral treatment to BD and HBIG but was underpowered [
32,
33]. In this study, immunisation was given very early, with a median time of < 1.5 h after birth, raising the possibility of a potential role of earlier vaccination. However, such a strategy is likely to be even more of a challenge in LMICs and whether the low transmission rate without antiviral therapy can be attributed to very early vaccination needs to be confirmed. The addition of antiviral prophylaxis with tenofovir in pregnancy has been found to be cost-effective in China [
34] and, even cost-saving, compared to previous practice of BD and HBIG only in America [
35]. Current HBV treatment guidelines including European Association for the Study of the Liver (EASL) and American Association for the Study of the Liver (AASLD) guidelines recommend antiviral treatment in the last trimester of pregnancy in mothers with HBV viral loads over 200,000 IU/ml [
36••,
37]. However, the first WHO HBV treatment guidelines were released in 2015, prior to the Pan study, and reported that there was not sufficient high-quality data on the safety and efficacy of antiviral treatment in pregnancy in order to make a formal recommendation at that time [
38••]. However, this guideline is currently in the process of being updated. Therefore, from a global perspective, widespread uptake of this strategy is still low and limited to experienced centres where specialist staff and laboratory facilities are available [
1••].
Barriers and Solutions to Increasing Coverage of Timely Birth Dose Vaccination
The delivery of timely birth dose vaccination within 24 h of birth presents a financial and logistical challenge, particularly in sub-Saharan Africa, largely due to the high levels of unassisted births. HBV BDV coverage has been found to correlate with institutional delivery rates and skilled birth attendance rates, both worldwide and in the Africa, South-East Asia and Western Pacific Regions [
39]. However, there are many other contributory obstacles including cost of implementation, perceived need for cold chain, low levels of awareness and a lack of systematic integration of the BDV within maternal child health programmes [
40]. Lack of outreach programmes to reach out-of-hospital births, BDV given at discharge from health facility and absence of weekend vaccination services were also found to be barriers in a recent multi-centre study in five African countries [
41]. Furthermore, in Africa, most countries follow a multi-dose vial vaccination policy and this has been found to be a barrier to BDV as is can lead to vaccinator reluctance to open multi-dose vials when there are only a few births occurring in the health facility to avoid wastage of remaining doses [
42]. Whether switching to a single-dose monovalent vaccine policy would help overcome this barrier or improved education regarding the importance of a timely BD would suffice remains to be established.
Faced with an ever-expanding portfolio of new emerging childhood vaccines, many low-middle-income countries are understandably struggling to keep up with the recommended pace of implementation of multiple vaccines into their immunisation schedules, particularly without external funding support like in the case of HBV BDV. Despite the low cost of a single dose of HBV vaccine (~ US$0.20 per dose), successful implementation of a BDV programme incurs additional associated costs including delivery of intervention, cold chain and infrastructure support. The Global Vaccine Alliance (GAVI) who are the biggest global funders of vaccines in low- and middle-income countries have not historically provided universal funding support for the BDV. However, modelling analyses for GAVI’s recent Vaccine Investment Strategy estimated that supporting birth dose vaccination scale-up in their funded countries (excluding Nigeria) could avert 1.2–1.5 million future HBV cases to 2035 [
43]. GAVI’s prioritisation of support of introduction of hepatitis B BDV in their next 2021–2025 strategy is likely to provide significant momentum for countries to introduce and scale up BDV ahead of the 2030 elimination targets.
Increasing the number of assisted births, although a major challenge, forms a key indicator for achieving the Sustainable Development Goal target to reduce maternal mortality and will have many benefits beyond facilitating the delivery of a BD intervention. China provides a good example of a country where increasing the number of health facility-based births successfully contributed to improved BDV coverage rates [
44].
The need to ensure cold chain for the HBV vaccination has frequently been cited as a barrier to delivery of a timely BDV, particularly in health facilities where maintaining cold chain is difficult and to reach out-of-hospital births. However, data is now accumulating on the thermo-stability of HBV vaccines, therefore raising the possibility of a controlled temperature chain (CTC) strategy, which is one that allows vaccines to be kept outside of the cold chain for a limited time period [
45]. Although some countries adopt an off-label out-of-cold-chain strategy, a formal CTC licenced HBV vaccine strategy would be welcomed in many countries to help scale up BDV as demonstrated through a survey of 25 countries in the African and Western Pacific regions [
42]. Furthermore, the use of a CTC strategy was found to be cost-effective, or even cost-saving in most world regions [
46].
A compact prefilled auto-disposable device (CPAD) is an innovative solution which can facilitate the administration of a timely BDV and has been shown to increase coverage rates in studies in Asia and the Western Pacific Region and has been used in Indonesia to reach out-of-hospital births [
47]. Although it has been shown to be safe, effective and cost-saving when compared to multi-dose vials [
48], its wide-scale uptake is limited by high cost of device and sole manufacturer. The use of the CPAD system by minimally trained health workers has been demonstrated in pilot studies for delivery of other medications and could therefore provide a promising alternative to increase coverage of BD, particularly in rural settings or for out of facility births in the African region—although the feasibility and acceptability of such a strategy needs to be evaluated [
49,
50].