PREVENTION OF THE HBsAg CARRIER STATE IN NEWBORN INFANTS OF MOTHERS WHO ARE CHRONIC CARRIERS OF HBsAg AND HBeAg BY ADMINISTRATION OF HEPATITIS-B VACCINE AND HEPATITIS-B IMMUNOGLOBULIN: Double-blind Randomised Placebo-controlled study

doi:10.1016/S0140-6736(84)92388-2

The Lancet

Volume 323, Issue 8383, 28 April 1984, Pages 921-926

https://doi.org/10.1016/S0140-6736(84)92388-2 Get rights and content

Abstract

Newborn infants of Chinese HBeAg-carrier mothers in Hong Kong were randomly assigned to one of four study groups. Group I was treated with 3 μg heat-inactivated hepatitis B (HB) vaccine at birth and at 1, 2, and 6 months thereafter, in conjunction with seven monthly HBIg injections; group II was treated according to the same vaccine schedule but received only one HBIg injection at birth; group III received only the vaccine, at months 0, 1, 2, and 6; and group IV received placebos for both vaccine and HBIg. The first set of injections was given within 1 h after birth. Comparisons were made in the 140 children who were at least six months old at the close of the trial (495 days). In all three treatment groups development of the persistent carrier state was significantly (p0·0001) less frequent than in controls (2·9%, 6·8%, and 21·0% versus 73·2%). Although vaccination alone was significantly less protective than vaccination plus multiple HBIg injections (p=0·03), the degree of protection was still remarkable. 12 months after the first set of injections 96-100% of the infants in the three treatment groups were anti-HBs positive; the geometric mean titres of anti-HBs in the three groups did not differ significantly. This indicates that even high doses of HBIg do not interfere with the anti-HBs response to the vaccine. Probable intra-uterine HB infections were observed in 3 infants. No serious side-effects were observed from the interventions, even in the babies with intra-uterine infections who had received HBIg and HB-vaccine at birth. To prevent development of the persistent HBsAg carrier state, and thereby the consequent chronic liver disease and/or primary carcinoma of the liver, HB vaccine and HBIg should be administered as soon as possible after birth to all newborn infants at risk of perinatal hepatitis B infection.

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Administration of HepB with HBIG resulted in reduced responses to HepB following the first 2 doses, regardless of site, compared to mice that received HepB only. Lower levels of antibody to HBV surface antigen (anti-HBs) were observed at the end of the 3-dose series (p < 0.0001) in all groups of newborn mice that received HepB and HBIG. In adult mice, this difference was only seen when HepB and HBIG were delivered at the same site. However, following a HepB booster at 26 weeks, HBsAg-specific B-cell expansion and memory phenotype were not impacted by initial HBIG administration
Administration of HBIG with HepB can delay and reduce responses to HepB in mice. Our findings suggest that the initial circulating levels of HBIG could prevent infection despite an impaired response to vaccine and support the current recommendation of assessing seroprotection after series completion for infants born to HBV carrier mothers, including in cases where vaccine and HBIG are administered incorrectly at the same site.
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Immunoglobulin-free strategy to prevent HBV mother-to-child transmission in Cambodia (TA-PROHM): a single-arm, multicentre, phase 4 trial
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Prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is based on administration of vaccine and immunoglobulins (HBIg) to newborns at birth and maternal antiviral prophylaxis for those with an HBV-DNA viral load of at 5·3 log₁₀ IU/mL or more. Many low-income and middle-income countries face difficulty in accessing HBIg and HBV-DNA quantification. The aim of this study was to evaluate the effectiveness of an HBIg-free strategy to prevent MTCT of HBV.
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From Oct 4, 2017, to Nov 27, 2020, 21 251 pregnant women were screened for HBsAg, of whom 1194 (6%) were enrolled in the study: 338 (28%) were eligible to receive tenofovir disoproxil fumarate. For the tenofovir disoproxil fumarate eligible group, four (1% [95% CI 0·34–3·20]) of 317 infants had HBV infection at 6 months; in the subgroup of 271 children who did not receive HBIg, four (1% [0·40–3·74]) had HBV infection at 6 months. In absence of HBIg, MTCT HBV transmission occurred in none (0% [0–1·61]) of 227 women who received tenofovir disoproxil fumarate for more than 4 weeks before giving birth and three (8% [1·75–22·47]) of 36 women who received tenofovir disoproxil fumarate for less than 4 weeks. In the tenofovir disoproxil fumarate ineligible group, seven (1% [0·40–2·02]) of 712 infants had HBV infection at 6 months; in the subgroup of 567 children who did not receive HBIg, six (1% [0·39–2·30]) had HBV infection at 6 months.
An immunoglobulin-free strategy using an HBeAg rapid diagnosis test and alanine aminotransferase-based algorithm to assess eligibility for tenofovir, is effective at preventing MTCT of HBV when tenofovir was initiated at least 4 weeks before birth.
French Agency for Research on AIDS and Viral Hepatitis and Emerging Infectious diseases.
For the French translation of the abstract see Supplementary Materials section.
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Citation Excerpt :
Treatment ranking by SUCRA values suggested that m.TDF/i.HBIG+i.Vaccine was likely to be the best treatment in lowering vertical transmission of HBV, followed by m.LDT/i.HBIG+i.Vaccine and m.HBIG/i.HBIG+i.Vaccine, with probabilities of 92.9%, 87.7%, and 66.5%, respectively (Supplemental Figure S4). AEs in infants were reported in 7 studies.18,19,31,33,44,47,49 Most studies reported no AEs or minor AEs, such as cough or slight and transient elevation of alanine aminotransferase (ALT).18,31,44,47
This study investigated the efficacy and safety of pharmacologic interventions to prevent vertical transmission of the hepatitis B virus.
Medline, Cochrane, and Scopus databases were searched up to October 28, 2020.
All randomized controlled trials reporting vertical hepatitis B virus transmission with pharmacologic intervention were included.
Risk of bias was assessed using the Cochrane Risk-of-Bias tool, version 2. Treatment efficacy was estimated using stratified network meta-analysis on the basis of maternal hepatitis B envelope antigen status.
Nineteen studies were included for mothers positive for hepatitis B surface and envelope antigens. Pooling indicated that a combination of hepatitis B vaccination and hepatitis B immunoglobulin in infants significantly reduced transmission risk compared with vaccination alone, with a risk ratio of 0.52 (95% confidence interval; 0.30–0.91). Only the addition of maternal tenofovir disoproxil fumarate, but not telbivudine, lamivudine, or maternal hepatitis B immunoglobulin further reduced transmission risk compared with a combination of hepatitis B vaccination and hepatitis B immunoglobulin in infants, with a pooled risk ratio of 0.10 (0.03–0.35). Twelve studies conducted in mothers with hepatitis B surface antigen positivity and mixed, unknown, or negative hepatitis B envelope antigen status provided limited evidence to suggest that maternal hepatitis B immunoglobulin combined with hepatitis B vaccination and immunoglobulin in infants was the likely best treatment, but this failed to reach statistical significance compared with a combination of hepatitis B vaccination and immunoglobulin in infants. Similarly, infant hepatitis B immunoglobulin, added to vaccination, likely provides additional benefit but failed to reach statistical significance.
A combination of hepatitis B vaccination and immunoglobulin in infants is the cornerstone for prevention of vertical transmission for mothers positive for both hepatitis B surface and envelope antigens. The addition of maternal tenofovir to this infant combination regimen was considered the likely most effective treatment. For infants of mothers with hepatitis B surface antigen positivity and mixed, unknown, or negative hepatitis B envelop antigen status, no additional agents provided further benefit beyond hepatitis B vaccination alone.

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PREVENTION OF THE HBsAg CARRIER STATE IN NEWBORN INFANTS OF MOTHERS WHO ARE CHRONIC CARRIERS OF HBsAg AND HBeAg BY ADMINISTRATION OF HEPATITIS-B VACCINE AND HEPATITIS-B IMMUNOGLOBULIN: Double-blind Randomised Placebo-controlled study

Abstract

Lancet

Lancet

Lancet

Lancet

Viral hepatitis in pregnancy: the obstetrician's role

Clin Obstet Gynaecol

Transmission of hepatitis B antigens from symptom free carrier mothers to the fetus and the infant

Br J Obstet Gynaecol

Epidemiology of hepatitis B infection in Liberian infants

Infect Immun

Vertical transmission of HBV and interruption with globulin

Hepatitis B immunoglobulin (HBIg) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state

Lancet

Efficacy of hepatitis B immunoglobulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo controlled trial

Hepatology

Postnatal infectivity of hepatitis B surface antigen-carrier mothers

J Infect Dis

Preparation of hepatitis B vaccine by heat-inactivation