Prospective Study Open Access
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 27, 2024; 16(7): 1039-1050
Published online Jul 27, 2024. doi: 10.4254/wjh.v16.i7.1039
Immunoprophylaxis failure and vaccine response in infants born to mothers with chronic hepatitis B infection in Djibouti
Sahal Darar Dirir, Laboratoire Medical de la Caisse National de Sécurité Social de Djibouti, Caisse National de Sécurité Social de Djibouti, Djibouti BP 696, Senegal
Ambroise D Ahouidi, Parasitology, Institut de Recherche en santé de Surveillance épidémiologique et de Formation, Dakar 7325, Senegal
Aboubacry Drame, Ecole Doctoral, Université Alioune Diop de Bambey, Dakar 7325, Senegal
Warsama Osman Abdi, Department of Des Soins, Caisse National de Securite Social, Djibouti 696, Senegal
Guelleh Youssouf Kayad, Centre de Soin, Caisse National de Securite Social, Djibouti 696, Senegal
Mohamed Houmed Aboubakar, Laboratoire Medical Mer Rouge, Djibouti 99399, Senegal
Makhtar Camara, Centre Hospitalier Universitaire Aristide le Dantec, Laboratoire Bactériologie-Virologie-Hôpital Aristide le Dantec, Dakar 7325, Senegal
Coumba Toure Kane, Department of Virology, Institut de Recherche en Santé de Surveillance épidémiologique et de Formation, Dakar 7325, Senegal
Halimatou Diop Ndiaye, Bacteriology and Virology Laboratory, Le Dantec University Teaching Hospital, Dakar BP 7325, Senegal
ORCID number: Sahal Darar Dirir (0009-0006-5310-4251); Ambroise D Ahouidi (0000-0002-7009-8408); Halimatou Diop Ndiaye (0000-0001-5885-5448).
Author contributions: Darar Dirir S, Ahouidi AD, Houmed Aboubakar M, Camara M, Toure Kane C, and Diop-Ndiaye H conceived the research study; Darar Dirir S, Drame A, and Diop-Ndiaye H analyzed the data and wrote the manuscript; Osman Abdi W and Youssouf Kayad G provided reagents and analytical tools; All authors read and approved the final version of the manuscript.
Supported by the Attestation de Financement de These de Doctorat, Dakar le 28/10/2019.
Institutional review board statement: The study was approved by the Scientific Committee of the Ministry of Health of the Republic of Djibouti under N0 149/DG/INSPD/2023.
Clinical trial registration statement: Not applicable, as the study did not involve randomized clinical trials.
Informed consent statement: All study participants provided informed written consent before study enrolment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data source will be shared upon request.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Halimatou Diop Ndiaye, BPharm, Professor, Professor Emerita, Bacteriology and Virology Laboratory, Le Dantec University Teaching Hospital, 30 Ave Pasteur, Dakar BP 7325, Senegal. halimatoudiop@yahoo.fr
Received: December 30, 2023
Revised: May 3, 2024
Accepted: June 4, 2024
Published online: July 27, 2024
Processing time: 209 Days and 0.4 Hours

Abstract
BACKGROUND

In endemic areas, vertical transmission of hepatitis B virus (HBV) remains a major source of the global reservoir of infected people. Eliminating mother-to-child transmission (MTCT) of HBV is at the heart of World Health Organization’s goal of reducing the incidence of HBV in children to less than 0.1% by 2030. Universal screening for hepatitis B during pregnancy and neonatal vaccination are the main preventive measures.

AIM

To evaluate the efficacy of HBV vaccination combined with one dose of immunoglobulin in children born to hepatitis B surface antigen (HBsAg)-positive mothers in Djibouti city.

METHODS

We conducted a study in a prospective cohort of HBsAg-positive pregnant women and their infants. The study ran from January 2021 to May 2022, and infants were followed up to 7 mo of age. HBV serological markers and viral load in pregnant women were measured using aVidas microparticle enzyme-linked immunosorbent assay (Biomérieux, Paris, France) and the automated Amplix platform (Biosynex, Strasbourg, France). All infants received hepatitis B immunoglobulin and were vaccinated against HBV at birth. These infants were closely monitored to assess their seroprotective response and for failure of immunoprophylaxis. Simple logistic regression was also used to identify risk factors associated with immunoprophylaxis failure and poor vaccine response. All statistical analyses were performed with version 4.0.1 of the R software.

RESULTS

Of the 50 pregnant women recruited, the median age was 31 years, ranging from 18 years to 41 years. The MTCT rate in this cohort was 4% (2/50) in HBsAg-positive women and 67% (2/3) in hepatitis B e antigen-positive women with a viral load > 200000 IU/mL. Of the 48 infants who did not fail immunoprophylaxis, 8 (16%) became poor responders (anti-HB < 100 mIU/mL) after HBV vaccination and hepatitis B immunoglobulin, while 40 (84%) infants achieved a good level of seroprotection (anti-HB > 100 mIU/mL). Factors associated with this failure of immunoprophylaxis were maternal HBV DNA levels (> 200000 IU/mL) and hepatitis B e antigen-positive status (odds ratio = 158, 95% confidence interval: 5.05-4958, P < 0.01). Birth weight < 2500 g was associated with a poor immune response to vaccination (odds ratio = 34, 95% confidence interval: 3.01-383.86, P < 0.01).

CONCLUSION

Despite a failure rate of immunoprophylaxis higher than the World Health Organization target, this study showed that the combination of immunoglobulin and HBV vaccine was effective in preventing MTCT of HBV. Therefore, further studies are needed to better understand the challenges associated with immunoprophylaxis failure in infants in Djibouti city.

Key Words: Hepatitis B surface antigen; Infants; Hepatitis B immunoglobulin; Hepatitis vaccine; Djibouti

Core Tip: This study evaluated the effectiveness of hepatitis B virus (HBV) vaccination and immunoglobulin administration in infants born to hepatitis B surface antigen-positive mothers. The mother-to-child transmission rate was 4%, increasing to 67% in hepatitis B e antigen (HBeAg)-positive women with a viral load > 200000 IU/mL. A seroprotective response was achieved in 84% of infants, and immunoprophylaxis failure was associated with maternal HBV DNA levels and positive HBeAg status. This combination has been shown to be effective in preventing HBV mother-to-child transmission in HBeAg-negative women and demonstrated the value of peripartum prophylaxis for women at risk.



INTRODUCTION

Hepatitis B virus (HBV) is a major public health problem affecting approximately 2 billion people worldwide, with 296 million chronically infected, including 6 million children under 5-years-old[1,2]. Mother-to-child transmission (MTCT) is the major mode of HBV transmission in endemic areas. Without preventive measures, 70%-90% of HBV-infected mothers will transmit HBV to their infants, and 90% of these infants will be at high risk of developing chronic hepatitis B, which can lead to cirrhosis and hepatocellular cancer in adulthood[3,4]. In highly endemic areas such as sub-Saharan Africa (SSA), MTCT accounts for approximately 50% of new infections, compared to 30% in low endemic areas[5]. Therefore, the cornerstone of the global strategy to eliminate viral hepatitis by 2030 is the prevention of MTCT[6].

The most important prevention measures are antenatal screening for HBV, postpartum prophylaxis for mothers at high risk, and the universal introduction of the hepatitis B vaccine[7]. In 2009, the World Health Organization (WHO) recommended that all countries in the world vaccinate infants using three or four doses of the HBV vaccine, with the first dose administered within 24 h of birth[8,9]. African countries have progressively introduced the hepatitis B vaccine into their Expanded Programme on Immunization (EPI) since the 1990s. To date, all countries have introduced a two or three doses series (Hep B3) using a pentavalent or hexavalent vaccine programmed at 6 wk, 10 wk, and 14 wk[10]. However, only 14/47 countries offered the WHO-recommended monovalent Hepatitis B Birth Dose (Hep B-BD) vaccine administered within the first 24 h[11]. This strategy should be complemented by the administration of hepatitis B immunoglobulin (HBIG) at birth. However, this is not currently feasible in SSA due to concerns about the cost and availability of HBIG[11].

Despite the existence of the vaccine, the failure rate of immunoprophylaxis in infants born to hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg)-positive mothers is 5%-10%[12]. A systematic review in 2023 described a failure rate of 6.5% in SSA. The main confounding factors were maternal HBV DNA viral load and HBeAg positivity, although other studies have identified other non-constant factors such as infant weight, mode of delivery, and vaccination schedule, with some countries starting the first dose at 6 wk of age[13,14].

In Djibouti, data on HBV infection are very limited, with studies conducted among blood donors in 1986 and 2005 reporting a prevalence of 7% and 10%, respectively. A recent study reported a prevalence of 9% in pregnant women in 2023[15-17]. Vaccinating against HBV (Hep-B3) has been included in the EPI since 2008, supported by the Global Alliance for Vaccines. The monovalent Hep B-BD vaccine was introduced in 2012. Djibouti also does not perform post vaccination serological testing (PVST) for infants born to HBsAg-positive mothers, and this lack of surveillance makes it difficult to assess high-risk infants. In the present study, we conducted a prospective study of a cohort of HBsAg-positive mothers and their infants to assess the protective efficacy of an immunoprophylaxis protocol combining HBV vaccine + HBIG and to evaluate vaccine response by PVST.

MATERIALS AND METHODS
Study population recruitment

We conducted a multicenter prospective cohort study in the city of Djibouti (Republic of Djibouti) between January 2021 and May 2022 to assess whether early administration of HBIG and hepatitis B vaccine at birth (within 1 h of birth) in infants born to HBV-infected mothers can further increase the protective efficacy of current immunoprophylaxis. Nine antenatal care centers, geographically located in the southern, central, and northern regions of the city of Djibouti, participated in the study. Pregnant women who tested positive for HBsAg in the antenatal clinics were invited to participate in the study on a voluntary basis after a detailed explanation. The inclusion criteria were: Pregnancy; above 18-years-old; confirmation of HBsAg positivity; and willingness to bring the unborn child for the planned follow-up visits at about 6 mo postpartum. An informed consent form was signed, and a questionnaire completed. The interview with the mother was scheduled at the time of enrolment.

Within the first 24 h of life, neonates received HBIG 200 IU (HEPATITIS B-IG Behring 200 IU CSL Behring AG) and one dose of monovalent hepatitis B vaccine (Hep B-BD). The infants were further vaccinated with a pentavalent vaccine (Hep B3) at 6 wk, 10 wk, and 14 wk of age, in accordance with national recommendations for maternal and child health. Children born to HBsAg-positive mothers were seen at birth and at 7 mo of age. Their clinical course and infection status were assessed.

Data collection

When the mothers visited the polyclinics, the principal investigator was responsible for completing the standardized questionnaires. The questionnaires were administered in person and the following sections were covered: Sociodemographic data; weeks of pregnancy; family history of hepatitis B; antiviral treatment; and whether they were aware of the HBV infection. Mothers were followed up by telephone after delivery, including mode of delivery, infant sex, infant weight, gestational age, and HBV vaccine dose at the time of injection. In addition, infants were followed up three times after birth (24 h, 1 mo, and 6 mo) to obtain information on HBV vaccination, and HBV serological markers were measured at 7 mo of age.

Biological analysis

All pregnant women were screened for hepatitis B markers using a rapid diagnostic test, the ACON® HBsAg Rapid Test (T&C Beheer BV, China). For women who tested positive, a 5-6 mL EDTA-blood sample was taken. The plasma was separated by centrifugation, and aliquots were stored at -30 ºC. Plasma samples were serologically tested for hepatitis B markers, including HBsAg, HBs antibodies, HBeAg, HBe antibodies, and hepatitis B core antibodies, using a microparticle enzyme-linked immunosorbent assay (Vidas; Biomerieux, Paris, France) at the Caisse National de Securite Social laboratory. HBV DNA viral load in infected patients was quantified by real-time PCR using the Amplix automated platform (Biosynex, Strasbourg, France). The detection threshold for this instrument was set at 26 copies/mL.

PVST for hepatitis B was performed in children at 7 mo of age. HBsAg-positive infants were considered to have failed immunoprophylaxis and to have HBV infection. The vaccine response was assessed by the level of HBs antibodies at the end of the vaccination regimen with: (1) No response if HBs antibody level was < 10 mUI/mL; (2) Poor response if HBs antibody level was between 10 and 100 mIU/mL; and (3) Good response when HBs antibody level was ≥ 100 mIU/mL. The study design is presented in Figure 1.

Figure 1
Figure 1 Diagram of study design for hepatitis B surface antigen-positive pregnant women and their infants. AcHBs: Hepatitis B surface antibody; HBIG: Hepatitis B immunoglobulin; HBsAg: Hepatitis B surface antigen; Hep B-BD: Hepatitis B Birth Dose.
Statistical analysis

Data from the questionnaire were entered into the Care Center Entry database. Variables of interest included infant status and vaccine response. Secondary variables included the mother’s sociodemographic, clinical, and biological factors associated with infant infection. Descriptive analysis was performed to examine the distribution of frequencies and variabilities.

χ2 or Fisher exact tests were used for categorical variables. Simple logistic regression was also used to identify risk factors associated with immunoprophylaxis failure and poor vaccine response. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to estimate risks, and a P value of less than 0.05 was considered significant. All statistical analyses were performed with R software version 4.0.1.

Ethical considerations

The study was approved by the Scientific Committee of the Ministry of Health of the Republic of Djibouti under N0 149/DG/INSPD/2023. Participants were informed of the purpose of the study and their right to confidentiality. Informed consent was obtained from each participant.

RESULTS
Characteristics of pregnant women

From January 2021 to May 2022, 882 pregnant women were screened, and 82 tested positive for HBsAg. Only 50 were recruited for this study, and the 32 pregnant women who were lost to follow-up had the following reasons for dropping out: Distance from the hospital; moving to a neighboring country; and fear of family stigma. The characteristics of the pregnant women and their infants are summarized in Table 1. Out of the 50 pregnant women recruited, the median age was 31 years, with a minimum of 18 years and a maximum of 41 years. Forty-two women (84%) were aged between 20 years and 40 years, and 38% (n = 19) and 44% (n = 22) were unemployed and illiterate, respectively.

Table 1 Sociodemographic characteristics of the hepatitis B surface antigen-positive pregnant women, n = 50.
Variables
Frequency
%
Age of mother in yr, n = 46
    18-2012
    20-302146
    30-402146
    > 4036
Mother occupation
    Employed3162
    Unemployed1938
Mother education level
    Illiterate2244
    Primary510
    Secondary1836
    University510
Parity
    Nulli or primiparous 0-1714
    Multiparous 1-33162
    Large multiparous1224
First antenatal care
    1 trimester1632
    2 trimester1632
    3 trimester1836
History of blood transfusion
    Yes1428
    No3672
History of abortion
    Yes1530
    No3570
Family history of HBV
    Yes1734
    No3366
Vaccination against HBV
    Yes00
    No50100
Marital status of mother
    Married50100
    Not married00
Monitoring by a health care worker
    Yes50100
    No00
HBeAg status of mother
    Negative4794
    Positive34
Viral load HBV DNA
    < 2000004794
    > 20000036

All the pregnant women were monitored by a health worker, and 62% (n = 31) were multiparous. They were all married, and 68% (n = 34) of pregnant women were examined after the first trimester. About one-third of the pregnant women had received a blood transfusion (28%, n = 14), had a family history of HBV (34%, n = 17), or had a history of abortion (30%, n = 15). Biological analyses of HBV-DNA viral load and serological markers of HBV virus were available for all patients. Three (6%) mothers had a viral load superior to 200000 IU/mL and were positive for HBeAg.

Characteristics of infants

The majority of infants were born via cesarean (78%, n = 39) and weighed between 2500-3500 g (72%, n = 36). Thirty-two (64%) of the neonates were males giving a sex-ratio (male/female) of 1.8. Two infants (2/50) were positive for HBsAg, yielding an MTCT rate of 4% in this cohort. The two infants who failed immunoprophylaxis were born from mothers with a viral load > 200000 IU/mL (2/3) and positive for HBeAg (2/3).

Of the 48 infants who did not fail immunoprophylaxis, 8 (16%) became poor responders (anti-HBs < 100 mIU/mL) after HBV vaccination and HBIG injection, while 40 (84%) infants achieved a good level of seroprotection (anti-HBs ≥ 100 mIU/mL), indicating that they were good responders. Table 2 summarizes the biological status and response to immunization of the infants.

Table 2 Biological status of the infants and response to immunization.
Variables
Frequency
%
Infants birth weight
    < 2500 g918
    2500-3500 g3672
    > 3500 g510
Delivery mode
    Vaginal3978
    Cesarean1112
Sex of infants
    Male3264
    Female1836
HBIG + Hep B-BD vaccine
    Yes50100
    No00
Vaccination Hep B3 (penta 1, 2, 3)
    Yes50100
    No00
Response to vaccine
    < 1003384
    ≥ 100516
    Negative2NA
Immunoprophylaxis failure
    Yes24
    No4896
Characteristics of HBV-infected infants and their mothers

The characteristics of the two infected infants and their mothers are summarized in Table 3. The two mothers were 32-years-old and 34-years-old, illiterate, and a family history of HBV and were diagnosed during the third trimester of pregnancy. Biological results showed a viral load > 200000 IU/mL and the presence of HBeAg. The two infants who failed immunoprophylaxis were born vaginally, were males, and weighed 2.5 kg and 3.5 kg.

Table 3 Characteristics of two hepatitis B virus-infected children born to hepatitis B surface antigen-positive mother.
Characteristics
Infant 1
Infant 2
Mother data
    Age of mother3432
    Education level IlliterateIlliterate
    Family history of HBVYesYes
    Blood transfusionNoNo
    Parity of motherMultiparousLarge multiparous
    First antenatal care3 trimester3 trimester
    History of abortionNoNo
    HBV DNA> 200000 UI/mL> 200000 UI/mL
    HBeAg status PositivePositive
Infant data
    Birth weight 3.5 kg2.5-3.5 kg
    Delivery mode VaginalVaginal
    Birth rank23
    Sex MaleMale
    HBIG + Hep B-BDYesYes
    Hep B3 (penta 1,2, and 3)YesYes
Factors associated with HBV infection in infants

A bivariate analysis was performed to identify the factors associated with this immunoprophylaxis failure (Table 4). Maternal HBV DNA levels (> 200000 IU/mL) and HBeAg-positive status (χ2 = 32.64; OR = 158; 95%CI: 5.05-4958; P < 0.01) were independently associated with an increased risk of immunoprophylaxis failure. Other factors, in particular mode of delivery, were not associated with HBV infection.

Table 4 Analysis of risk factors for failure of immunoprophylaxis.
Variables
No failure, n = 48
Failure, n = 2
χ2
P value
OR (95%CI)
P value
HBV DNA of mother32.64< 0.001
    > 200000 IU/mL1 (2.1)2 (100)Reference
    < 200000 IU/mL47 (97.9)0 (0)-158.00 (5.05-49.80)0.004
Mother HBeAg status32.64< 0.001
    Negative47 (97.9)0 (0)Reference
    Positive1 (2.1)2 (100)-158.00 (5.05-49.80)0.004
Family history of HBV1.070.300
    No31 (65.0)2 (100)Reference
    Yes17 (35.0)0 (0)-0.36 (0.20-198.00)0.517
History of abortion0.890.340
    No33 (69.0)2 (100)Reference
    Yes15 (31.0)0 (0)-0.43 (0.02-9.55)0.595
Delivery mode in infants0.590.440
    Vaginal37 (77.0)2 (100)Reference
    Cesarean11 (23.0)0 (0)-1.50 (0.06-34.00)0.780
Parity of mother0.930.630
    Null parous7 (15.0)0 (0)Reference
    Multiparous30 (62.0)1 (50.0)-0.73 (0.27-19.00)0.181
    Large multiparous11 (23.0)1 (50.0)-1.95 (0.07-54.00)0.693
Infant birth weight 1.530.460
    2.5-3.5 kg35 (73.0)1 (50.0)Reference
    < 2.5 kg8 (17.0)1 (50.0)-4.37 (0.25-77.65)0.315
    > 3.5 kg5 (10.0)0 (0)-2.15 (0.08-59.70)0.651
Infant sex1.170.280
    Male30 (62.0)2 (100)Reference
    Female18 (38.0)0 (0)-0.54 (0.12-2.49)0.428
Blood transfusion0.500.490
    No35 (73.0)1 (50.0)Reference
    Yes13 (27.0)1 (50.0)-2.69 (0.16-46.00)0.495
First antenatal care of mother3.700.157
    1 trimester16 (33.0)0 (0)Reference
    2 trimester16 (33.0)0 (0)-0.02-53.401.000
    3 trimester16 (33.0)2 (100)-5 (0.22-112.00)0.310
Factors associated with a low level of HBs antibody

Factors associated with a poor response to immunoprophylaxis were assessed using bivariate analysis. Only infant birth weight < 2500 g was associated with a low immune response to vaccination (χ2 = 17.97, OR = 34; 95%CI: 3.01-383.86, P < 0.01) (Table 5).

Table 5 Risk factor analysis for low immune responses.
Variable
AcHBs Vt ≥ 100 mUI/mL
AcHBs Vt < 100 mUI/mL1
χ2
P value
OR (95%CI)
P value
HBV DNA0.200.650
    > 200000 IU/mL1 (2.5)0 (0)Reference0.794
    < 200000 IU/mL39 (97.5)8 (100)-1.54 (0.05-41.38)
HBeAg status0.200.650
    Negative39 (97.5)8 (100)Reference
    Positive1 (2.5)0 (0)-1.54 (0.05-41.38)0.794
Antecedent HBV0.460.500
    No25 (62.0)6 (75.0)Reference
    Yes15 (38.0)2 (25.0)-0.56 (0.10-3.11)0.504
History of abortion4.360.370
    No25 (62.0)8 (100)Reference
    Yes15 (38.0)0 (0)-0.09 (0.01-1.79)0.117
Mode of delivery0.590.440
    Cesarean10 (25.0)1 (12.0)Reference
    Vaginal30 (75.0)7 (88.0)-2.33 (0.25-21.36)0.453
Birth weight in kg17.97< 0.001
    2.5-3.534 (85.0)1 (12.0)Reference
    < 2.54 (10.0)4 (50.0)-34 (3.01-383.86)0.004
    > 3.52 (5.0)3 (38.0)-51 (3.51-740.17)0.004
Infant sex1.170.420
    Male26 (65.0)4 (50.0)Reference
    Female14 (35.0)4 (50.0)-0.54 (0.12-2.49)0.428
DISCUSSION

Our prospective analysis was designed to assess the rate of perinatal HBV transmission as well as the vaccine response of infants. From January 2021 to May 2022, a cohort of 50 HBsAg-positive pregnant women and their infants were followed. A total of 50 mother-infant pairs were monitored at the Care Center 1 in Djibouti city. Indeed, of the 82 patients who tested positive, 32 were lost to follow-up. The main reasons were stigmatization within their households and the lack of proximity between the specialized centers and their homes.

Patients were lost between the medical laboratory, the gastroenterologist, and the prenatal care service. This suggests the need to adopt a public health approach using simplified service delivery, screening, and treatment. Treatment should be decentralized to peripheral health facilities, while cases of advanced hepatopathy requiring advanced clinical support should be referred to specialized centers. Other patients refused to continue the study because of fear of social stigma and self-stigma, negative beliefs about HBV transmission, or lack of knowledge about transmission routes (some thought HBV could be transmitted by sharing food).

Seroprevalence of hepatitis B MTCT

In this cohort, infants born to HBsAg-positive mothers received an identical vaccination schedule consisting of Hep B-BD combined with HBIG within the first 24 h, followed by 3 doses of Hep B3 (at 6 wk, 10 wk, and 14 wk of age). However, despite this appropriate post-exposure prophylaxis, some infants became infected, with an immunoprophylaxis failure rate of 4% rate (2/50). None of the infants born to HBeAg-negative mothers became infected with HBV.

Higher MTCT rates for hepatitis B have been reported in several studies in Africa, particularly in Ethiopia (30.9%), Angola (22.0%), and Libya (60.9%)[18-20]. This variation may be due to the different vaccination schedules implemented by each country. For example, Ethiopia has not yet included the hepatitis B vaccine in its EPI, while Djibouti started immunization in 2012 and aimed to reach 85% coverage by 2019[21]. The introduction of the vaccine is not sufficient to warrant a low MTCT rate in a country. In Angola the high rate of MTCT was associated with low birth rates in health facilities and a lack of qualified staff despite the introduction of Hep B-BD.

Our results were close to those observed in Ghana (5.8% out of 454) and Cameroun (5.6% out of 607), and the small observed difference may be due to the size of the study population, the early administration of HBIG and Hep B-BD vaccines to children born to HBsAg-positive mothers in our study[22], or an intrafamilial horizontal transmission. In any case, all these values are well above the WHO target (0.1% for children under 5) and the rates observed in developed countries such as Japan (1.9%), Malaysia (2.6%), Denmark (2.3%), and in a few rare cases in southern countries such as Burkina Faso[23-26]. This difference in the prevalence of MTCT of HBV between northern and southern countries may be due to an overall lower prevalence of HBV in the general population, a well-established systematic vaccination program, improved storage conditions, and better access to health care. However, it is important to note that the situation may vary from country to country. One example is Burkina Faso where the prevalence remains at 1%.

It is also important to note that achieving a 0.1% failure rate in SSA, where HBV prevalence is over 8%, presents significant challenges. Several factors contribute to this situation, including financial and human resource constraints, a high proportion of births in rural areas, poorer quality maternity services, and the prevalence of other major health problems such as HIV/AIDS, malaria, and tuberculosis, which have often taken precedence in health priorities. According to WHO projections, the Afro region will not achieve this goal before 2100[27].

Factors associated with immunoprophylaxis failure

In our study, 2 out of 3 pregnant women with HBeAg-positive and HBV DNA viral load above 200000 IU/mL transmitted HBV to their infants. Analysis of factors associated with immunoprophylaxis failure in infants showed a significant association with HBV DNA levels and the mother’s HBeAg status. These factors have been identified as reliable markers of active HBV replication and were the only factors associated with immunoprophylaxis failure in our study. Several recent meta-analyses have reported a high incidence of MTCT associated with high HBV DNA levels above 200000 IU/mL and HBeAg-positive status despite a vaccination series associated with HBIG[28,29]. These findings highlight potential targets for improving prevention strategies.

In addition, our results confirmed that combined immunoprophylaxis is effective in preventing MTCT in HBeAg-negative pregnant women, but additional measures such as peripartum prophylaxis are definitively needed for high-risk pregnant women (HBeAg positive and high viremia). Indeed, the WHO recommends that pregnant women who test positive for HBV infection (HBsAg positive) and whose HBV DNA viral load is ≥ 200000 IU/mL should receive tenofovir prophylaxis from the 28th week of pregnancy until at least delivery to prevent MTCT of HBV. It is important to note that molecular tests are the first option for stratifying at-risk pregnant women and identifying those who are eligible for treatment. However, their widespread availability is expensive and requires high-quality laboratories, which can be a significant challenge in low-income countries. Therefore, in settings where antenatal HBV DNA testing is not available, HBeAg testing can be used as an alternative to determine eligibility for tenofovir prophylaxis to prevent MTCT of HBV[30]. A meta-analysis showed that HBeAg has a good accuracy in identifying HBV DNA levels of 5.30 Log10 IU/mL or greater in pregnant women with a pooled sensitivity of 88.2% (83.9%-91.5%) and pooled specificity of 92.6% (90.0%-94.5%), and a sensitivity of 99.5% (95%CI: 91.7-100) in predicting MTCT of HBV infection despite infant immunoprophylaxis[31].

Immune response

Adequate primary vaccination ensures long-term protection, and the anti-HBs titer of infants is an important indicator of whether they have immunity that could protect them from potential exposure to HBV. In this study, all infants received a planned immunoprophylaxis protocol combining HBIG + anti-HBV. The majority of infants (84%) achieved a good level of protection (> 100 mUI/mL), and eight infants showed a weak immune response (< 100 mUI/mL). Our results were closer to those obtained in China, 90% and 80%, but higher than those of Selton et al[32] in France who observed 68% in 60 infants exposed to HBV. Recent studies in Southeast Asia, particularly in Thailand and China, have reported a percentage of infants with 100% satisfactory seroprotection after vaccination[33,34].

In general, it is estimated that 10%-20% of infants vaccinated after birth develop a poor response to the vaccine[35,36]. Our results may depend on the choice of definition of vaccine response. In this study, we considered the achievement of seroprotection (anti-HBs < 100 mIU/mL), considered satisfactory by some authors, to be insufficient and aimed for a rate of excellent protection (anti-HBs > 100 mIU/mL). Vaccine response may also depend on the timing of the HBs antibody test in relation to the last HBV vaccine injection[37]. The eight poorly responding infants are at risk of horizontal contamination. Recommendations for this group vary in the literature, with some advocating the need for a booster dose for infants with an HBs antibody titer less than 10 mIU/mL at 12 mo[38,39].

Factors associated with vaccine response

Nevertheless, few studies focused on the risk factors related to anti-HBs titers under 100 mIU/mL. In our study, only birth weight < 2500 g was an independent predictor of poor response. Indeed, birth weight tended to be lower in poor responders (< 2500 g) than in good responders (2500-3500 g). The difference was statistically significant (P < 0.010), contrary to the data of some authors probably due to insufficient numbers [Linder et al[37] (n = 137) and Losonsky et al[40] (n = 147)]. Low birth weight is not a contraindication to vaccination. However, some low-birth-weight infants with clinical instability may not respond as well to the Hep B-BD vaccine as full-term or normal-weight infants. In this case, Hep B-BD may be delayed until the neonate is 1 mo old[41]. It is essential to pay particular attention to low-birth-weight infants for anti-HBs levels, and booster vaccinations against hepatitis B should also be considered if necessary.

Limitations

This study was not specifically designed to compare the efficacy of the hepatitis B vaccine alone with a combination of HBIG and anti-HBV vaccine. Nevertheless, further studies will be needed to evaluate this observation. It is also difficult to know whether children who tested positive for HBV were infected vertically at birth or horizontally during infancy. Finally, the optimal dose of HBIG in our context or the ideal time to administer the first dose of vaccine at birth was not evaluated.

CONCLUSION

Our study showed that the combination of Hep B-BD and HBIG provided protection against MTCT of HBV, although the results remain above WHO targets. It also highlighted the importance of a national HBV policy that could implement WHO recommendations, such as the introduction of peripartum antiviral prophylaxis for women at risk, which is a strategy more financially feasible than HBIG. This policy should also recommend HBeAg as an alternative to molecular testing for identifying pregnant women eligible for treatment.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country of origin: Senegal

Peer-review report’s classification

Scientific Quality: Grade C

Novelty: Grade C

Creativity or Innovation: Grade C

Scientific Significance: Grade B

P-Reviewer: Kansu A, Türkiye S-Editor: Wang JJ L-Editor: Filipodia P-Editor: Cai YX

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