World Hepatitis Day: Focus on the TA-PROHM Project
The Western Pacific and South-East Asia are regions where chronic hepatitis B is highly endemic. One driver of the epidemic is the transmission of the virus from mother to child. The TA-PROHM project studied a strategy to prevent this phenomenon. Olivier Segeral, international technical expert at the ANRS partner site in Cambodia and TA-PROHM principal investigator, presents the advances brought about by this study.
The Western Pacific and South-East Asia regions host 60% of all chronic hepatitis B virus (HBV) infections, affecting 115 and 39 million people, respectively. Mother-to-child transmission (MCT) of the virus is responsible for the majority of chronic hepatitis B cases in these highly endemic countries, and generally occurs at the time of delivery. Therefore, women of childbearing potential with chronic hepatitis B represent the largest reservoir for HBV transmission, especially those with high viral loads. However, in the Western Pacific and South-East Asia, around 30% of young women present a high viral load, probably due to the high proportion of the more aggressive subtype C. For them, the risk of transmission to the child is therefore high: 70-90% in the absence of immunization and 10 to 20% despite immunization.
The key to prevention is the vaccination of all babies at birth, regardless of maternal status, with a first dose injected at the latest during the first week of life and ideally within the first 24 hours, followed by two or three additional doses. This first dose administered at birth is particularly important as it also constitutes post-exposure prophylaxis to prevent HBV transmission to babies exposed during the perinatal period – hence the importance of very early administration. For babies born to mothers infected with HBV, the international guidelines also recommend the administration of immunoglobulins (1) within the first 12 hours of life in addition to the first dose of the vaccine. Finally, at the time the study was conducted in 2016, a clinical trial in China in 200 mothers with a high viral load (> 5.3 Log10 IU/mL) showed that administration of tenofovir, initiated between 30 and 32 weeks of gestation, in addition to the immunoprophylaxis of newborns at birth led to a significant decrease in the MCT of HBV compared to placebo. Subsequently, this prophylactic antiviral treatment was recommended by the WHO in 2020 for women with viral loads exceeding 5.3 Log10 IU/mL.
In Cambodia, where the prevalence of hepatitis B in pregnant women was estimated to be 4.4% in 2017, HBV screening and care during pregnancy follow-up consultations were non-existent and continue to remain so in the vast majority of treatment centers, apart from a few national hospitals in the capital. Vaccination coverage is generally satisfactory, at close to 90% for all three doses and 78% for the first dose at birth (but only 45% for administration within the first 24 hours of life). However, access to quantifying viral load in order to decide whether to initiate prophylactic treatment was restricted to a few locations in the capital, and its cost remained inaccessible for a large majority of the population, as was access to immunoglobulins. Therefore, it was necessary to evaluate a consistent set of interventions that could be used immediately at the end of the study in case of conclusive results.
1. Medicinal product containing anti-HBV antibodies extracted from human blood plasma.
The objective of the project was to design and evaluate a program to reduce the MCT of hepatitis B virus in Cambodia using an alternative strategy based on tools available there. To do this, we formulated two main hypotheses:
- in the absence of methods to quantify HBV load, an algorithm using two rapid diagnostic tests (2) in an antenatal consultation setting could constitute an alternative strategy to identify women eligible for prophylactic antiviral therapy;
- in the absence of available immunoglobulins, prophylactic antiviral therapy started at the beginning of the third trimester for eligible women would be sufficient to limit MCT in combination with a first vaccine dose administered very early on in the delivery room.
The primary objective of TA-PROHM was therefore to evaluate the efficacy of an alternative immunoglobulin-free strategy to prevent MCT of HBV in Cambodia based on:
- the use of rapid diagnostic tests (HBsAg and HBeAg) for the screening and management of peripartum HBV infection;
- treatment with tenofovir from 24 weeks gestation in eligible women including an immediate treatment strategy for those seen after 24 weeks gestation;
- early vaccination for all infants in the delivery room, within the first two hours of life.
For this, we implemented a prospective, single-arm, open-label, multi-center, interventional phase IV trial in five Cambodian hospitals (two in Phnom Penh and three in the provinces). The primary endpoint was the percentage of active HBV infection in children at six months of life among all children born to HBV-positive mothers.
A first step made it possible to show that an algorithm selecting HBeAg-positive women and HBeAg-negative women with an ALT level > 40 U/L was a good alternative for identifying women eligible for tenofovir therapy.
From October 4, 2017 to November 27, 2020, a total of 21 251 pregnant women were screened, 1194 (6%) were included in the study and 338 (28%) were eligible to receive tenofovir.
In the absence of immunoglobulins, our study reports that in women with high viral HBV DNA loads, HBV transmission can be eliminated (0%, 95% CI 0.00 – 1.61) if tenofovir is initiated at least one month before birth. Our study also shows that women treated for less than one month still have a high rate of HBV transmission (8%). The rate of HBV transmission for those ineligible for tenofovir is 1% [95% CI, 0.39 – 2.30]. Of the eligible women, 94% were able to start treatment with tenofovir and the early vaccination of babies in the delivery room within the first two and 24 hours of life was possible for 85% and 95% of them, respectively.
2. Both tests target HBsAg to screen for HBV infection and HBeAg as a predictive marker for high viral replication.
To our knowledge, this is the first major study evaluating an immunoglobulin-free strategy, using antiviral prophylaxis with tenofovir to prevent MCT of hepatitis B.
The results obtained are essential for many countries such as Cambodia which have not yet made the supply and administration of immunoglobulins a public health priority. They make it possible to envisage the implementation of a strategy to prevent MCT of HBV, on a national scale, using tools available in the country, namely rapid tests, tenofovir, and vaccination. Using a decision-making algorithm for the prophylactic therapeutic indication based on HBeAg rapid testing and measurement of ALT levels, this strategy is applicable in decentralized areas, in the provincial and district health structures, which is essential for countries such as Cambodia where access to biological platforms is limited to the capitals or large cities. Thanks to our study, this strategy has been included in the latest national Cambodian recommendations for preventing the MCT of HIV, syphilis, and hepatitis B (6th edition, 2021).
We now want to evaluate its effectiveness in rural areas by developing implementation research projects incorporating an analysis of costs and supply chains for medicines and reagents. Indeed, only a political commitment combining the training of staff and the integration and coverage of the costs of biological tests and medicines at all levels of the health scale will enable the strategy to be rolled out at national level. Given the good results in terms of antenatal screening and care already achieved in the country for HIV and syphilis, nationwide implementation of the TA-PROHM strategy could enable Cambodia to achieve the triple elimination of HIV, syphilis and HBV advocated by the WHO for 2030.
Links to the rest of the kit produced as part of World Hepatitis Day 2022:
- Focus on ICONE, a project to reduce hepatitis C among drug users: https://www.anrs.fr/en/actualites/1123/world-hepatitis-day-focus-icone-project
- Interview with Fabien Zoulim and focus on Julie Lucifora’s research: https://www.anrs.fr/en/actualites/1124/world-hepatitis-day-interview-fabien-zoulim-and-focus-julie-luciforas-research