Article

Mother to Child Transmission of Hepatitis B: Examining Viral Cut Offs, Maternal HBsAg Serology and Infant Testing

Authors:
Article

Mother to Child Transmission of Hepatitis B: Examining Viral Cut Offs, Maternal HBsAg Serology and Infant Testing

If you want to read the PDF, try requesting it from the authors.

Abstract

Background/aims: Anti-partum antiviral therapy in the setting of high viral load is recommended to prevent mother-to-child transmission of hepatitis B although recommended viral load cut-offs vary. Quantitative HBsAg has been proposed as an alternative screening strategy to identify high viral load in this setting. Guidelines suggest testing all infants for vaccine response and infection. We set out to re-examine viral load cut-offs; the predictive value of quantitative HBsAg and the need for follow-up infant testing in our cohort. Methods: A retrospective cohort study of 469 HBsAg positive mother-baby pairs from two tertiary hospitals in Sydney was performed. Antiviral therapy (lamivudine or tenofovir disoproxil fumarate) was offered to women with viral load ≥6 log10IU/mL (high) from 32 weeks gestation. Transmission and vaccine response was analysed according to viral load. The utility of quantitative HBsAg in identifying high viral load was examined. Results: Mother-to-child transmission only occurred in setting of high viral load, in 0.85% (1/117) of those who received antiviral therapy and in 8.66% (2/23) of those who chose not to. Quantitative HBsAg did not accurately identify high risk mothers ≥6 log10IU/mL. Infant vaccine response was 98.7% overall, and 99.4% when viral load was <6 log10IU/mL. Conclusion: Antiviral therapy initiated at 32 weeks when maternal viral load is ≥6 log10IU/mL almost completely abrogates transmission. Quantitative HBsAg does not reliably predict high viral load. When maternal viral load is <6 log10IU/mL, high vaccine efficacy and zero transmission suggests testing infants is of little value. This article is protected by copyright. All rights reserved.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... L'administration à la naissance d'une dose d'HBIG dans les pays en développement n'est plus actuellement recommandée par l'OMS et n'est probablement pas réalisable dans un avenir proche en raison des limites telles que le coût, la disponibilité, et l'obligation du respect de la chaîne de froid qui demeurent très problématiques. Au Burkina 35 Faso, le coût des HIBG pour la sérovaccination à la naissance est à la charge de la mère, il est ...
... For the first study question, assessment of the viral load threshold for immunoprophylaxis failure, we examined 4198 mother-child pairs from 13 studies. [25][26][27][28][29][30][31][32][33][34][35][36][37] All infants received both the hepatitis B vaccine birth dose and HBIG. The risk of immunoprophylaxis failure was negligible when maternal viral load was lower than 5·30 log 10 IU/mL (<200 000 IU/mL; one [0·04%; 95% CI 0·00-0·25] of 2592 infants evaluable for this threshold; figures 2, 3). ...
... Consequently, for the second study question, assessment of the accuracy of HBeAg testing during pregnancy to diagnose this viral load threshold, we examined 41 studies of HBeAg testing for identifying women with a HBV viral load above a threshold of 5·30-6·29 log 10 IU/mL: 5·30 IU/mL (n=26), 38-63 5·85 log 10 IU/mL (n=1), 24 and 6·00 log 10 IU/mL (n=14). 35,[64][65][66][67][68][69][70][71][72][73][74][75][76] All included studies allowed for estimation of both sensitivity and specificity. Heterogeneity did not appear to be high, as all studies except for two 40,47 reported sensitivities or specificities higher than 80% (figure 4, appendix 3 p 27). ...
Thesis
La stratégie mondiale de l’OMS pour lutter contre l’hépatite, approuvée par tous les États Membres de l’OMS, vise à réduire les nouvelles infections par le virus de l’hépatite de 90% et les décès de 65% entre 2016 et 2030. La réalisation de cet objectif passe en particulier par le dépistage de personnes exposées au VHB et par l’élimination de la transmission de l’hépatite B ‎de la mère à l’enfant. L’OMS recommande ainsi de séro-vacciner les nouveau-nés dans les 24 premières heures de vie et de traiter les femmes enceintes à risque de transmission de la mère à l’enfant (TME) (charge virale > 200 000 UI/ml) par du ténofovir disoproxyl fumarate pour éviter la transmission périnatale du VHB. Le but de ce travail était: i) d’évaluer la prévention de la transmission du virus de l’hépatite B de la mère à l’enfant (PTME) telle qu’elle est aujourd’hui pratiquée à Ouagadougou; ii) de proposer des pistes d’amélioration en tenant compte des possibilités médico-économiques et des réalités socio culturelles, iii) d’évaluer une stratégie de dépistage familial du VHB à partir de l’identification des femmes enceintes infectées par le VHB. Ce travail de thèse s’est déroulé en trois phases.La première étude consistait en une analyse de la cascade de soins de l’hépatite B à partir du dépistage lors de la consultation prénatale dans les formations sanitaires périphériques à Ouagadougou jusqu’au traitement des femmes à risque de TME et la vaccination à la naissance des nouveau-nés. Après mise en place de l’intervention, sur 5200 femmes enceintes consultant pour la visite prénatale, 2261 (43,5%) se sont vues proposer un counseling pré-test et un dépistage de l’Ag HBs et 2220 (98,2%) ont accepté le dépistage. Parmi les 1580 (71,2%) femmes qui sont revenues pour le counseling post-test, 75 étaient positives pour l’Ag HBs (4,8%). Soixante-treize (97,3% des femmes ayant fourni le résultat de l'Ag HBs) ont consenti à une consultation médicale avec des hépato-gastro-entérologues et 53 (72,6%) ont effectué le test ADN du VHB. Quarante-sept sur 60 (78,3 % ; 65,8-87,9) enfants ont été vaccinés contre le VHB dans les 24 heures suivant la naissance. La rétention dans les soins était notamment associée au niveau d'éducation du père de l'enfant.La deuxième étude évaluait une stratégie de dépistage familial du virus de l'hépatite B dans les foyers où une femme avait été identifiée comme porteuse de l’AgHBs durant la consultation prénatale. Ce travail nous a permis d’évaluer les freins et leviers à la réalisation du dépistage familial à partir d’un cas index.Résultats: au total, 1000 femmes enceintes, porteuses de l'AgHBs, ont accepté de participer à cette étude. Sur 2 281 conjoints et enfants éligibles au dépistage familial, 651 (28,5%) ont été testés pour l'AgHBs, dont 436/1000 (43,6%) conjoints et 215 /1281 (16,8%) enfants. L'Ag HBs a été détecté chez 55 (12,6 %) conjoints (âge médian [IQR] : 33 ans [29-38]) et 24 enfants (11,2 %) (âge médian [IQR] : 7 ans [4 -12]). Le portage de l'AgHBs était plus élevé chez les enfants nés avant l'introduction de la vaccination universelle contre l'hépatite B au Burkina Faso en 2006 (4,4 [1,47-13,15] ; p=0,008), chez les enfants dont les mères étaient porteuses de l'antigène HBe (AgHBe) (11,47 [4,41-29,81] ; p = 0,0001) ou avaient un taux d'ADN du VHB ≥ 200 000 UI/mL (14,04 [4,89-40,28] ; p = 0,001). La PTME constitue une stratégie majeure et indispensable à l’atteinte de l’objectif de l’OMS qui est d’éliminer les hépatites virales comme menace de santé publique d’ici 2030. Plusieurs méthodes complémentaires de PTME existent et il faut les choisir en fonction des réalités socio-économiques de notre pays.
... Other risk factors for MTCT of HBV: Recently, it has been proposed that quantification of HBsAg may predict MTCT of HBV [237,238]; however, this is controversial [239]. ...
... Recently, it has been proposed that quantification of HBsAg may predict MTCT of HBV [237,238]; however, others reported different results [239]. HBsAg level > 4.0 log 10 IU/mL has been suggested as a cut-off to start antiviral prophylaxis to prevent MTCT of HBV [237], as high maternal HBsAg level has been associated with higher risk of HBV immunoprophylaxis failure in some studies [238]. ...
... HBsAg level > 4.0 log 10 IU/mL has been suggested as a cut-off to start antiviral prophylaxis to prevent MTCT of HBV [237], as high maternal HBsAg level has been associated with higher risk of HBV immunoprophylaxis failure in some studies [238]. However, the correlation of HBsAg level with maternal HBV DNA level was not found in many studies [239]. Further prospective studies are needed before introduction of HBsAg quantification as a reliable test in pregnant females for eligibility of maternal NAs prophylaxis to prevent MTCT of HBV [215]. ...
Article
Full-text available
Hepatitis B virus (HBV) infection still remains a major public health issue in the Asia-Pacific region. Most of the burden of HBV-related disease results from infections acquired in infancy through perinatal or early childhood exposure to HBV in Asia-Pacific. Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These APASL guidelines provide a comprehensive review and recommendations based on available evidence in the literature, for the management of females with HBV infection through every stage of pregnancy and postpartum. These also address the concerns, management challenges, and required follow-up of children born to hepatitis B-positive mothers.
... Analyses of HBeAg-positive NA-naïve patients has shown high correlation between HBsAg and HBV DNA levels 85 . These have supported similar high correlation to HBV DNA titres and HBsAg levels in pregnant mothers from Taiwan 86 , Mainland China 87 and Australia 88 . Given these studies took place NA treatment-naïve individuals, HBV DNA titres likely closely reflect cccDNA levels. ...
... In HBeAg-negative patients however, the correlation between HBsAg and HBV DNA disappears and they become decoupled 86,88 . This is likely due to the marked reduction of cccDNA in HBeAg-negative phases 44 , reduction in cccDNA transcriptional activity 89 , and the extensive clonal expansion of hepatocytes containing integrated HBV DNA 20,21 (that can encode a transcriptionally-active HBs ORF 63,[90][91][92][93]. ...
Article
Chronic infection with the Hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral transcripts, covalently closed circular (cccDNA). Detecting changes in cccDNA transcriptional activity is key to understanding fundamental virology, determining the efficacy of new therapies, and deciding the optimal clinical management of HBV patients. In this review, we summarize surrogate circulating biomarkers that have been used to infer cccDNA levels and activity in people with chronic hepatitis B. Moreover, we outline the current shortcomings of the current biomarkers and highlight the clinical importance in improving them and expanding their use.
... Previous studies have reported that antiviral therapy with tenofovir can substantially reduce perinatal transmission of HBV in mothers with high viral load (Greenup et al., 2014;Hyun et al., 2017;Jourdain et al., 2016Jourdain et al., , 2018Thilakanathan et al., 2018;) and is a cost-effective treatment . Jourdain et al. reported that MTCT is rare when passive/active immunization is done timely (Jourdain et al., 2018). ...
... Moreover, in our study, maternal liver function was stable and viral control was good during pregnancy, there were no preterm delivery or abortion occurred in our study, and the Apgar scores of the newborns were also normal after birth. Therefore, we concluded that the use of telbivudine or tenofovir after 24 weeks of pregnancy was safe and effective, which was similar to the results of previous studies (Greenup et al., 2014;Han et al., 2011;Hyun et al., 2017;Jourdain et al., 2016;Lu et al., 2014;Pan et al., 2012;Thilakanathan et al., 2018;Wu et al., 2015). ...
Article
Full-text available
To investigate whether HBV genotype influences the effect of tenofovir and telbivudine on HBV DNA and RNA levels in HBsAg-positive pregnant women. This was a retrospective study of 74 HBsAg-positive pregnant women in Guizhou of China. All patients were treated with telbivudine or tenofovir from 12 weeks of pregnancy and HBV infection to the date of delivery. Blood samples were collected at 12–24, 28–32, and 36–40 weeks of pregnancy for the measurement of genotype, HBsAg, hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA, and liver function, including alanine transaminase, aspartate transaminase, total bilirubin, total bile acids, cholinesterase, alkaline phosphatase (ALP), and gamma-glutamyl transferase. All women with HBsAg were followed up. The HBV genotype was B in 64.9% and C in 35.1%. There were 37 patients of telbivudine and tenofovir group respectively. The telbivudine and tenofovir groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA). Compared with baseline (12–24 weeks), telbivudine group showed a significant increase in ALP and significant reductions in HBsAg, HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36–40 weeks (p < .05). Tenofovir group exhibited a significant increase in ALP and significant reductions in HBeAg, log10(HBV DNA), and log10(HBV RNA) at 36–40 weeks, compared with baseline (p < .05). HBV genotype (B vs. C) was independently associated with HBV DNA change after therapy (p = .005). In telbivudine group, log10 (HBV DNA) increased from 3.38 (2.00–7.30) to 7.43 (4.68–8.70). In tenofovir group, log10 (HBV DNA) decreased from 7.52 (3.32–8.70) to 2.98 (2.00–5.01). HBV genotype was independently associated with HBV DNA change response to telbivudine or tenofovir in pregnant women with hepatitis B. These findings might be helpful for risk assessment regarding vertical transmission of HBV in HBeAg-positive mothers treated with nucleos(t)ide analogues.
... Direct comparison of result using copies/ml and IU/ml was difficult as the conversion factor maybe different using various DNA platform [57]. The difference in methodology, especially the use of in-house PCR technique in some studies [22,24], may make conversion from copies/ml to IU/ml not feasible or give imprecise estimation [58]. Timing of HBV DNA quantification may also be important as immunomodulated effect of pregnancy could affect the activity of HBV replication throughout the pregnancy, and most previous studies did not specify the timing of assessment of viral activity. ...
... However, most of the maternal HBsAg level and HBV DNA quantification were done after delivery (median time was 2 days after delivery) and 9% infants of HBsAg-mother did not receive HBIG at birth, which may affect the interpretation of the result. In fact, the correlation of HBsAg level with IF was not demonstrated in another retrospective cohort [58]. The suggested cut off (4.1log 10 IU/ml) only gave 70.5% sensitivity and 91% specifically in predicating women with HBV DNA ≥ 6log 10 IU/ml. ...
Article
Hepatitis B virus (HBV) infection is the commonest cause of chronic hepatitis, with an estimated global prevalence of 3.5%, and which leads to significant morbidity and mortality. Mother-to-child transmission (MTCT) during pregnancy is the leading form of transmission in endemic populations, and its interruption is thus crucial as the initial step in the elimination of HBV infection, notwithstanding the availability of potent antiviral medications. The risk of MTCT is dramatically reduced by timely neonatal HBV vaccination and administration of hepatitis B immunoglobulin after birth in high risk infants. Maternal HBV DNA quantification during pregnancy allows the assessment of the risk of newborn immunoprophylaxis failure (IF). Maternal antiviral treatment in highly viraemic women can reduce the risk of IF. However, the optimal HBV DNA cut-off level for initiation of antiviral treatment remains to be determined.
... Initially, an HBV DNA of ≥6 log10 IU/ml was associated with a higher risk of MTCT, suggesting that women in this category were the most important to target for antiviral therapy. [11][12][13] Although a maternal HBV DNA <6 log10 IU/ml is thought to be lower risk for MTCT, the studies reporting this provided the infants with HBIG and vaccination. Although provision of TDF 300 mg daily in the third trimester of pregnancy significantly reduced perinatal transmission (OR 0.10; 95% CI 0.01 to 0.77; p=0.03), 6 14-16 a mean of 8.6±0.5 weeks of TDF prior to delivery resulted in a mean HBV DNA at delivery of 4 log 10 IU/mL with 32% of mothers having HBV DNA >5.3 ...
Article
Full-text available
Introduction: Hepatitis B virus (HBV) remains a public health threat and the main route of transmission is from mother to child (MTCT). Tenofovir disoproxil fumarate (TDF) treatment can reduce MTCT of HBV although the optimal timing to attain undetectable HBV DNA concentrations at delivery is unknown. This protocol describes the procedures following early initiation of maternal TDF prior to 20 weeks gestation to determine efficacy, safety and feasibility of this approach in a limited-resource setting. Methods and analyses: One hundred and seventy pregnant women from the Thailand-Myanmar border between 12 and <20 weeks gestational age will be enrolled into a one-arm, open-label, TDF treatment study with cessation of TDF 1 month after delivery. Sampling occurs monthly prenatal, at birth and at 1, 2, 4 and 6 months post partum. Measurement of tenofovir concentrations in maternal and cord plasma is anticipated in 10-15 women who have detectable HBV DNA at delivery and matched to 20-30 women with no detectable HBV DNA. Infant HBsAg status will be determined at 2 months of age and HBV DNA confirmed in HBsAg positive cases. Adverse events including risk of flare and adherence, based on pill count and questionnaire, will be monitored. Infants will receive HBV vaccinations at birth, 2, 4 and 6 months and hepatitis B immunoglobulin at birth if the mother is hepatitis B e antigen positive. Infant growth and neurodevelopment at 6 months will be compared with established local norms. Ethics and dissemination: This study has ethical approval by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University (FTM ECF-019-06), Johns Hopkins University (IRB no: 00007432), Chiang Mai University (FAM-2559-04227), Oxford Tropical Research Ethics Committee (OxTREC Reference: 49-16) and by the local Tak Community Advisory Board (TCAB-02/REV/2016). The article will be published as an open-access publication. Trial registration number: NCT02995005, Pre-results.
... Among the selected studies, 3 RCTs [7-9] and 12 non-RCTs [10,[16][17][18][19][20][21][22][23][24][25][26] compared treatment started in the third trimester versus control, 7 non-RCTs compared the timing of second trimester versus control [27][28][29][30][31][32][33], 3 non-RCTs compared first trimester versus control [14,34,35], 4 non-RCTs compared second and third trimester versus control respectively [11,[36][37][38], 3 non-RCTs compared first, second trimester versus control respectively [39][40][41]; 2 non-RCTs compared first, third trimester versus control respectively [12,42], 1 non-RCTs compared first, second trimester, third trimester versus control respectively [13]. No randomized controlled trials were conducted for the treatment that was applied during first or second trimester except for several non-RCTs. ...
Article
Full-text available
Background Several antiviral agents licenced for blocking mother-to-child transmission (MTCT) of HBV, but their relative efficacy beginning from different trimesters has scarce been evaluated. We aimed to conduct a network meta-analysis to statistically differ the efficacy and safety of each antiviral agents initiating on different timings in preventing mother-to-infant transmission of HBV.Methods Studies were included from PubMed, EMBASE, Web of Science, and Cochrane databases through July 1, 2019. Eligible studies recruited randomized controlled trials and nonrandomized studies reporting about infant or/and maternal efficacy and safety outcomes and were screened by two investigators independently. Extracted data were analyzed by pair-wised and network meta-analysis, respectively.Results3 Randomized and 32 nonrandomized studies enrolling 6738 pregnant female were included. Using network analysis, any antiviral agent interrupted HBV vertical transmission much more effectively than placebo. No agent showed significant efficacy different from others, but a strong trend toward significance was found in telbivudine and tenofovir, of which had the highest probability of being ranked the first- or second-best treatment for reducing MTCT of HBV. The treatment applied in the first and second trimester had a similar efficacy in preventing MTCT. Compared with the initiation during the third trimester, lower rate of MTCT was revealed when antiviral therapy was administrated before third trimester, (RR = 0.045, 95% CI 0.0053 to 0.20); a similar effect at delivery on suppressing maternal HBV DNA level and converting serum HBeAg were achieved if the timing of antiviral treatment started prior, but an obvious improvement of normalizing ALT flare was calculated out; no statistically differences among maternal and fetal safety outcomes were found if mothers received antiviral agents before pregnant 28 weeks.Conclusion This network meta-analysis recommended the earlier use of telbivudine or tenofovir, tends to be better to prevent MTCT of HBV in pregnancy with no increased adverse maternal or fetal outcomes.
... Our prior studies have documented HBV immune (i.e., cytokine) and ALT flares in pregnancy, and HBV DNA correlation with qHBsAg levels, especially in HBeAg positive mothers with HBV DNA levels (i.e., > 2 × 10 6 IU/mL) [16]. Other studies have also noted that qHBsAg may be useful in predicting MTCT risk, hence EASL recommends to test both HBsAg and HBV DNA pregnancy; yet this data has recently been questioned [17,18]. As such, increased understanding of HBV replication and associated risk of host immune mediated or virological flares during pregnancy and post-partum will help guide clinical management in pregnancy. ...
Article
Introduction: Mother-to-child transmission (MTCT) of the hepatitis B virus (HBV) is a serious public health challenge. Estimating HBV MTCT incidence by region under different prophylaxis regimens is critical to understanding the regional disease burden and prioritizing interventions. This study aimed to calculate HBV MTCT incidence under different prophylaxis regimens globally and regionally and identify the HBV DNA threshold for maternal peripartum antiviral prophylaxis. Material and methods: This review was registered in advance in PROSPERO (CRD 42019120567). We searched PubMed, Embase, China National Knowledge Infrastructure, ClinicalTrials.gov, and Cochrane Library databases for studies on MTCT in pregnant women with chronic HBV infection from their inception until June 13, 2022. MTCT was defined as hepatitis B surface antigen (HBsAg) or HBV DNA seropositivity in infants aged 6-12 months. We calculated the pooled HBV MTCT incidence using the DerSimonian-Laird random-effects model. Results: Among 300 studies, 3402 of 63 293 infants had HBV due to MTCT. Without prophylaxis regimens, the pooled HBV MTCT incidence was 31.3%, ranging from 0.0% (95% confidence interval [CI] 0.0%-6.0%; European Region) to 46.1% (95% CI 29.7%-63.0%; Western Pacific Region). Following the introduction of the hepatitis B vaccine, the HBV MTCT incidence decreased from 82.9% to 15.9% in HBeAg-positive women and from 10.3% to 2.3% in HBeAg-negative women. Maternal peripartum antiviral treatment alongside infant immunoprophylaxis further decreased MTCT incidence to 0.3% (95% CI 0.1%-0.5%). Despite infant immunoprophylaxis, the incidences of MTCT at maternal HBV DNA levels of <2.30, 2.00-3.29, 3.00-4.29, 4.00-5.29, 5.00-6.29, 6.00-7.29 and ≥7.00 log10 IU/ml were 0.0% (95% CI 0.0%-0.0%), 0.0% (95% CI 0.0%-0.0%), 0.0% (95% CI 0.0%-0.5%), 0.6% (95% CI 0.0%-2.6%), 1.0% (95% CI 0.0%-3.1%), 4.3% (95% CI 1.8%-7.5%), and 9.6% (95% CI 7.0%-12.5%), respectively. Conclusions: HBV MTCT incidence varies across regions. The Western Pacific Region bears the heaviest burden. Peripartum antiviral prophylaxis plus infant immunoprophylaxis is promising for interrupting HBV MTCT. Regarding the HBV DNA threshold for peripartum antiviral prophylaxis, maternal HBV DNA of 4.00 log10 IU/ml or greater seems justified.
Article
Hepatitis B virus (HBV) is a global health problem. Vertical transmission of HBV from HBV surface antigen (HBsAg)‐positive mothers to their infants is the most common cause of HBV infection worldwide. The use of passive–active immunoprophylaxis is >90% effective in reducing the risk of vertical transmission, but immunoprophylaxis failure can occur in infants born to mothers with high viremia. Thus, it is recommended that pregnant women with HBV‐DNA level >200,000 IU/mL receive nucleos(t)ide analogue (NA) treatment [i.e., tenofovir disoproxil fumarate (TDF), lamivudine (LAM), or telbivudine (LdT)] during third trimester to prevent infant immunoprophylaxis failure. TDF is recommended as first‐line therapy based on available data on efficacy, safety and resistance profile. However, maternal immunologic reconstitution following parturition can increase immune‐mediated flares to viral antigens, that is potentially exacerbated following TDF withdrawal. In this article, we review available data on the efficacy and safety of TDF administration to prevent HBV mother‐to‐child transmission. We also discuss changes in maternal viral markers [i.e., HBV‐DNA, HBV e antigen (HBeAg) and HBsAg] and alanine aminotransferase (ALT) during follow‐up postpartum in mothers received NA to prevent HBV vertical transmission.
Article
Aim: This study aimed to explore the benefits of different antiviral regimens in pregnant women with hepatitis B virus (HBV) infection in an attempt to provide scientific reference for clinically relevant interventions. Methods: The study cohort comprised 64 pregnant women with HBV infection who presented to our hospital from May 2018 to July 2020. The women were grouped according to the treatment administered: a control group consisting of 32 pregnant women who received routine intervention and an observation group consisting of 32 pregnant women who received routine intervention plus tenofovir disoproxil fumarate (TDF) tablets. The two groups were compared in terms of liver function; HBV load (HBV DNA); neonatal characteristics (hepatitis B surface antigen and HBV DNA positivity); levels of interleukin (IL)-2, IL-4, and IL-6; neonatal growth and development; Apgar scores; incidence of adverse events; and incidence of maternal adverse effects during treatment. Results: The observation group had lower levels of alanine aminotransferase, glutamic acid aminotransferase, IL-4, IL-6, and HBV DNA and higher levels of IL-2 than the control group after 1 month of treatment (p < 0.05). There was no significant difference in the incidence of adverse events between the two groups (p > 0.05). Conclusion: The administration of TDF tablets significantly reduced the HBV DNA levels and did not increase the physiological burden or adverse effects in pregnant women with HBV infection.
Article
The management of viral hepatitis in the setting of pregnancy requires special consideration. There are five liver-specific viruses (hepatitis A, B, C, D, E), each with unique epidemiology, tendency to chronicity, risk of liver complications and response to antiviral therapies. In the setting of pregnancy, the liver health of the mother, the influence of pregnancy on the clinical course of the viral infection and the effect of the virus or liver disease on the developing infant must be considered. Although all hepatitis viruses can harm the mother and the child, the greatest risk to maternal health and subsequently the fetus is seen with acute hepatitis A virus or hepatitis E virus infection during pregnancy. By contrast, the primary risks for hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus are related to the severity of the underlying liver disease in the mother and the risk of mother-to-child transmission (MTCT) for HBV and HCV. The prevention of MTCT is key to reducing the global burden of chronic viral hepatitis, and prevention strategies must take into consideration local health-care and socioeconomic challenges. This Review presents the epidemiology of acute and chronic viral hepatitis infection in pregnancy, the effect of pregnancy on the course of viral infection and, conversely, the influence of the viral infection on maternal and infant outcomes, including MTCT.
Article
Background To eliminate mother-to-child transmission (MTCT) of hepatitis B virus (HBV), peripartum antiviral prophylaxis might be required for pregnant women infected with HBV who have a high risk of MTCT despite infant immunoprophylaxis. We aimed to determine the efficacy and safety of peripartum antiviral prophylaxis to inform the 2020 WHO guidelines. Methods In this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, CENTRAL, CNKI, and Wanfang for randomised controlled trials and non-randomised studies of peripartum antiviral prophylaxis versus placebo or no prophylaxis, with no language restriction, published from database inception until March 28, 2019. We used search terms covering HBV, antiviral therapy, and pregnancy. We included studies that enrolled pregnant women with chronic infection with HBV who received antiviral prophylaxis anytime during pregnancy; that included any of the following antivirals: adefovir, emtricitabine, entecavir, lamivudine, telbivudine, tenofovir alafenamide fumarate, and tenofovir disoproxil fumarate; and that reported the following outcomes: MTCT, indicated by infant HBsAg positivity or HBV DNA positivity, or both, at age 6–12 months, and any infant or maternal adverse events. Two reviewers independently extracted data. Our primary endpoint was MTCT based on infant HBsAg positivity. We assessed pooled odds ratios (ORs) of the efficacy of peripartum antiviral prophylaxis to reduce the risk of MTCT. We assessed safety of prophylaxis by pooling risk differences. The protocol for the systematic review was pre-registered in PROSPERO, CRD42019134614. Findings Of 7463 articles identified, 595 articles were eligible for full-text review and 129 studies (in 157 articles) were included. The following antivirals were assessed in the meta-analysis: tenofovir disoproxil fumarate 300 mg (19 studies, with 1092 mothers and 1072 infants), lamivudine 100–150 mg (40 studies, with 2080 mothers and 2007 infants), and telbivudine 600 mg (83 studies, with 6036 mothers and 5971 infants). The pooled ORs for randomised controlled trials were similar, at 0·10 (95% CI 0·03–0·35) for tenofovir disoproxil fumarate, 0·16 (0·10–0·26) for lamivudine, and 0·14 (0·09–0·21) for telbivudine. The pooled ORs in non-randomised studies were 0·17 (0·10–0·29) for tenofovir disoproxil fumarate, 0·17 (0·12–0·24) for lamivudine, and 0·09 (0·06–0·12) for telbivudine. We found no increased risk of any infant or maternal safety outcomes after peripartum antiviral prophylaxis. Interpretation Peripartum antiviral prophylaxis is highly effective at reducing the risk of HBV MTCT. Our findings support the 2020 WHO recommendation of administering antivirals during pregnancy, specifically tenofovir disoproxil fumarate, for the prevention of HBV MTCT. Funding World Health Organization.
Article
Background Prevention of mother-to-child transmission (MTCT) of hepatitis B virus (HBV) involves neonatal immunoprophylaxis, with a birth dose of hepatitis B vaccine and immune globulin, and provision of peripartum antiviral prophylaxis in highly viraemic women. However, access to assays to quantify HBV DNA levels remains inadequate in resource-poor settings. This study was commissioned by WHO and aimed to identify the HBV DNA threshold for MTCT, to assess the sensitivity and specificity of hepatitis B e antigen (HBeAg) testing to identify pregnant women with HBV DNA levels above this threshold, and to predict MTCT of HBV infection on the basis of HBeAg testing. Methods For this systematic review and meta-analysis, we searched the PubMed, EMBASE, Scopus, CENTRAL, CNKI, and Wanfang databases for studies of pregnant women with chronic HBV infection without concurrent antiviral therapy, published between Jan 1, 2000, and April 3, 2019. Studies were eligible for inclusion if MTCT in mother–child pairs could be stratified by different levels of maternal HBV DNA during pregnancy, if maternal HBeAg status could be stratified by HBV DNA level, and if the MTCT status of infants could be stratified by maternal HBeAg status during pregnancy. Studies that selected pregnant women on the basis of HBeAg serostatus or HBV DNA levels were excluded. Aggregate data were extracted from eligible studies by use of a pre-piloted form; study authors were contacted to clarify any uncertainties about potential duplication or if crucial information was missing. To pool sensitivities and specificities of maternal HBeAg to identify highly viraemic women and to predict MTCT events, we used the DerSimonian-Laird bivariate random effects model. This study is registered with PROSPERO, CRD42019138227. Findings Of 9007 articles identified, 67 articles (comprising 66 studies) met the inclusion criteria. The risk of MTCT despite infant immunoprophylaxis was negligible (0·04%, 95% CI 0·00–0·25) below a maternal HBV DNA level of 5·30 log10 IU/mL (200 000 IU/mL) and increased above this threshold. The pooled sensitivity of HBeAg testing to identify HBV DNA levels of 5·30 log10 IU/mL or greater in pregnant women was 88·2% (83·9–91·5) and pooled specificity was 92·6% (90·0–94·5). The pooled sensitivity of HBeAg testing in predicting MTCT of HBV infection despite infant immunoprophylaxis was 99·5% (95% CI 91·7–100) and pooled specificity was 62·2% (55·2–68·7). Interpretation Maternal HBV DNA of 5·30 log10 IU/mL or greater appears to be the optimal threshold for MTCT of HBV infection despite infant immunoprophylaxis. HBeAg is accurate to identify women with HBV DNA levels above this threshold and has high sensitivity to predict cases of immunoprophylaxis failure. In areas where HBV DNA assays are unavailable, HBeAg can be used as an alternative to assess eligibility for antiviral prophylaxis. Funding World Health Organization.
Article
We appreciate the comments from Vyas et al. (1) Although our study demonstrated that prediction of infants' immunoprophylaxis failure (IF) is possible in early pregnancy, whether women with extremely high viral load require earlier antiviral treatment for prevention of IF remains unknown.(2) Two randomized controlled trials showed no cases of IF (0/239) after the use of tenofovir disoproxil fumarate (TDF) in women with baseline HBV DNA >5.3log10IU/ml in the third trimester.
Article
Full-text available
Background. Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. Methods. We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. Results. Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (−0.41 vs −0.18) or weight (−0.71 vs −0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, −9.5, −1.2; P = .013) in the tenofovir-exposed infants. Conclusions. Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. Clinical Trials Registration. ClinicalTrials.gov NCT01310023.
Article
Full-text available
Chronic hepatitis B virus (HBV) infection due to mother-to-child transmission (MTCT) during perinatal period remains an important global health problem. Despite standard passive-active immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine in neonates, up to 9% of newborns still acquire HBV infection, especially these from hepatitis B e antigen (HBeAg) positive mothers. Management of HBV infection in pregnancy still need to draw careful attention because of some controversial aspects, including the failure of passive-active immunoprophylaxis in a fraction of newborns, the effect and necessity of periodical hepatitis B immunoglobulin (HBIG) injection to the mothers, the safety of antiviral prophylaxis with nucleoside/nucleotide analogs, the benefit of different delivery ways, and the safety of breastfeeding. In this review, we highlight these unsettled issues of preventive strategies in perinatal period, and we further aim to provide an optimal approach to the management of preventing MTCT of HBV infection.
Article
Full-text available
Despite immunoprophylaxis, hepatitis B virus (HBV) transmission in highly viremic mothers remains a global health issue. Using quantitative maternal surface antigen (HBsAg) to predict HBV infection in infants has not been investigated. We enrolled 526 mother-infant pairs with positive maternal HBsAg under current immunoprophylaxis. Maternal viral load and quantitative HBsAg were measured in the peripartum period. Infant HBsAg seropositivity for more than 6 months was defined as chronic infection. Rates of chronic infection in infants at various maternal HBsAg levels were estimated using a multivariate logistic regression model. Results showed that maternal HBsAg was positively correlated with maternal viral load (r = 0.69; P < 0.001) and accurately predicted maternal viral load above 6, 7, and 8 log10 IU/mL with an area under the receiver operating characteristic curve (AUC) of 0.97, 0.98, and 0.95. Nineteen infants were chronically infected. After adjustment for the other risk factor, maternal HBsAg level was significantly associated with risk of infection (adjusted odds ratio for each log10 IU/mL increase, 15.02; 95% confidence interval [CI], 3.89-57.94; P < 0.001). The AUC for predicting infection by quantitative maternal HBsAg was comparable to that by maternal viral load (0.89 vs. 0.87; P = 0.459). Estimated rates of infection at maternal HBsAg levels of 4, 4.5, and 5 log10 IU/mL were 2.4% (95% CI, 0.1-4.6; P = 0.04), 8.6% (95% CI, 4.5-12.7; P < 0.001), and 26.4% (95% CI, 12.6-40.2; P < 0.001). Conclusion: Quantitative maternal HBsAg predicts infection in infants as well as maternal viral load does. Antiviral therapy may be considered in pregnant women with an HBsAg level above 4-4.5 log10 IU/mL to interrupt mother-to-infant transmission. (Hepatology 2016;64:1451-1461).
Article
Full-text available
Background: New cases of hepatitis B virus (HBV) infection continue to occur worldwide. Most of these are due to mother-to-child transmission (MTCT), with maternal viraemia as the most important contributing factor. The hepatitis B surface antigen (HBsAg) level, which correlates positively with viral load, has been used for treatment monitoring in chronic hepatitis B. This study evaluated the usefulness of quantitative HBsAg for viral load prediction in HBsAg-positive pregnant women. Methods: A total of 943 pregnant women in Makassar, Indonesia, were screened for HBsAg. Sixty-four women were HBsAg-positive and investigated. HBsAg level and hepatitis B e antigen (HBeAg)/hepatitis B e antibody (anti-HBe) status were determined serologically. Viral load was measured by real-time PCR. HBV DNA was sequenced and analysed for identification of genotype and basal core promoter (BCP)/precore (PC) mutations. Results: Of 64 subjects, 12 (18.8%) were HBeAg-positive and 52 (81.3%) were HBeAg-negative. HBsAg and HBV DNA levels were significantly higher in the HBeAg-positive group (p
Article
Full-text available
Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
Article
Full-text available
What recommendations are being reviewed? Postvaccination serologic testing (PVST) is recommended for infants born to hepatitis B surface antigen (HBsAg)-positive mothers at age 9–18 months. PVST consists of testing for HBsAg and antibody to HBsAg (anti-HBs). Why are the recommendations being reviewed now? With the discontinuation of Hib/HepB vaccine (Comvax), the hepatitis B vaccine series for infants born to HBsAg-positive mothers will usually be completed at age 6 months, allowing PVST at age 9–12 months. New data from the Enhanced Perinatal Hepatitis B Prevention Program are available that show that lower detectable levels of anti-HBs were associated with increased intervals between receipt of the last vaccine dose and PVST. What is the new recommendation? Considering the lower levels of anti-HBs with increasing time since completing vaccination and the extent of unnecessary revaccination, PVST, consisting of testing for HBsAg and anti-HBs, should be ordered at age 9–12 months (or 1–2 months after the final dose of the vaccine series, if delayed) for infants born to HBsAg-positive mothers. © 2015, Department of Health and Human Services. All rights reserved.
Article
Full-text available
Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide.
Article
Full-text available
Background Viral load measurement is necessary to estimate mother-to-child transmission risk for women with chronic hepatitis B (CHB), however, it is expensive. The present study aimed to investigate the relationship between HBsAg and hepatitis B virus (HBV) DNA levels, and to determine potential applications of HBsAg level monitoring for estimating viral load. Methods 85 patients with CHB (31 pregnant women, 26 non-pregnant women, 28 men) were included in the study. HBV DNA level was measured by real-time PCR, and HBsAg level by chemiluminescent immunoassay method. Dependency between viral load and HBsAg level was determined by Spearman correlation coefficient ρ. Results The correlation between HBsAg and HBV DNA levels was significant for all patients [ρ=0.3762 (P<0.0005; n=85)]. In the group of pregnant women, a low (unmeasurable) HBV DNA level led to a decrease in the Spearman coefficient ρ. In almost all cases a low level of the HBsAg corresponded to a low HBV DNA level. Only 2 patients had a low level of HBsAg and a relatively high viral load. By contrast, a high HBsAg level was observed in patients both with high and low viral load. Conclusions Correlation between HBsAg and HBV DNA levels is significant. In most cases, a low level of HBsAg indicates a low HBV DNA level, whereas a high HBsAg level does not always correspond to a high viral load. The measurement of HBV DNA level is necessary for pregnant women with a high HBsAg level.
Article
Full-text available
Objective: To describe the antiviral treatment patterns for chronic hepatitis B (CHB) among pregnant and nonpregnant women. Methods: Using 2011 MarketScan claims, we calculated the rates of antiviral treatment among women (aged 10-50 years) with CHB. We described the pattern of antiviral treatment during pregnancy and ≥1 month after delivery. Results: We identified 6274 women with CHB during 2011. Among these, 64 of 507 (12.6%) pregnant women and 1151 of 5767 (20.0%) nonpregnant women received antiviral treatment (P < 0.01). Pregnant women were most commonly prescribed tenofovir (73.4%) and lamivudine (21.9%); nonpregnant women were most commonly prescribed tenofovir (50.2%) and entecavir (41.3%) (P < 0.01). Among 48 treated pregnant women with an identifiable delivery date, 16 (33.3%) were prescribed an antiviral before pregnancy and continued treatment for at least one month after delivery; 14 (29.2%) started treatment during the third trimester and continued at least one month after delivery. Conclusion: Among this insured population, pregnant women with CHB received an antiviral significantly less often than nonpregnant women. The most common antiviral prescribed for pregnant women was tenofovir. These data provide a baseline for assessing changes in treatment patterns with anticipated increased use of antivirals to prevent breakthrough perinatal hepatitis B virus infection.
Article
Full-text available
Objective To investigate the age-specific prevalence of hepatitis B virus (HBV) infection in young pregnant women in Hong Kong Special Administrative Region (SAR), China, and to determine whether an increase in prevalence occurs during adolescence. Methods HBV prevalence was quantified using data from routine antenatal screening for hepatitis B surface antigen (HBsAg) in 10 808 women aged 25 years or younger born in Hong Kong SAR and managed at a single hospital between 1998 and 2011. The effect on prevalence of maternal age, parity and birth before or after HBV vaccine availability in 1984 was assessed, using Spearman’s correlation and multiple logistic regression analysis. Findings Overall, 7.5% of women were HBsAg-positive. The prevalence ranged from 2.3% to 8.4% in those aged ≤ 16 and 23 years, respectively. Women born in or after 1984 and those younger than 18 years of age were less likely to be HBsAg-positive (odds ratio, OR: 0.679; 95% confidence interval, CI: 0.578–0.797) and (OR: 0.311; 95% CI: 0.160–0.604), respectively. For women born before 1984, there was no association between HBsAg carriage and being younger than 18 years of age (OR: 0.60; 95% CI: 0.262–1.370) Logistic regression analysis showed that the prevalence of HBsAg carriage was influenced more by the woman being 18 years old or older (adjusted OR, aOR: 2.80; 95% CI: 1.46–5.47) than being born before 1984 (aOR: 1.42; 95% CI: 1.21–1.67). Conclusion Immunity to HBV in young pregnant women who had been vaccinated as neonates decreased in late adolescence.
Article
Full-text available
Background: Newborns who have received hepatitis B immunization in 1980s are now young adults joining healthcare disciplines. The need for booster, pre- and post-booster checks becomes a practical question. Aims: The aim of this study is to refine the HBV vaccination policy for newly admitted students in the future. Methods: A prospective study on medical and nursing school entrants to evaluate hepatitis B serostatus and the response to booster doses among young adults. Findings: Among 212 students, 17-23-year-old, born after adoption of neonatal immunization, 2 (0.9%) were HBsAg positive, 40 (18.9%) were anti-HBs positive. At 1 month after a single-dose booster for anti-HBs-negative students, 14.5% had anti-HBs <10 mIU/mL, 29.0% and 56.5% were 10-100 and >100 mIU/mL, respectively. The anti-HBs levels were significantly higher for females than males (mean [SD]: 431 [418] vs. 246 [339] mIU/mL, P = 0.047). At 2-4 month after the third booster dose, 97.1% had anti-HBs >100 mIU/mL and 2.9% had 10-100 mIU/mL. Conclusions: Pre-booster check is still worthwhile to identify carriers among newly recruited healthcare workers born after adoption of neonatal immunization. A 3-dose booster, rather than a single dose, is required for the majority to achieve an anti-HBs level >100 mIU/mL, as memory immunity has declined in a substantial proportion of individuals. Cost-effectiveness of post-booster check for anti-HBs is low and should be further evaluated based on contextual specific utilization of results.
Article
Full-text available
Unlabelled: Little observational data exist describing telbivudine (LdT) or lamivudine (LAM) use in late pregnancy for preventing hepatitis B mother-to-child transmission (MTCT) in real-world settings. During the period of January 2009 to March 2011, we enrolled hepatitis B e antigen-positive mothers with HBV DNA >6 log10 copies/mL in China. At gestation week 28, the mothers received LdT or LAM until postpartum week 4 or no treatment (NTx). The study endpoints were the safety of LdT/LAM use and MTCT rates. Of the 700 mothers enrolled, 648 (LdT/LAM/NTx=252/51/345) completed the 52-week study with 661 infants (LdT/LAM/NTx=257/52/352). On treatment, viral rebound occurred in 1.6% of mothers, all resulting from medication noncompliance. There was no genotypic mutation detected. At delivery, significantly lower HBV DNA levels were noted in mothers who received LdT or LAM versus NTx. Alanine aminotransferase flares were observed in 17.1% of treated mothers versus 6.3% of untreated mothers (P < 0.001). At birth, hepatitis B surface antigen (HBsAg) was detected in 20% and 24% of newborns in the treated and NTx groups, respectively. At week 52, an intention-to-treat analysis indicated 2.2% (95% confidence [CI]: 0.6-3.8) of HBsAg+ infants from the treated group versus 7.6% (95% CI: 4.9-10.3) in the NTx group (P50.001) and no difference of HBsAg+ rate between infants in the LdT and LAM groups(1.9% vs. 3.7%; P=0.758). On-treatment analysis indicated 0% of HBsAg+ infants in the treated group versus 2.84% in the NTx group (P=0.002). There were no differences for gestational age or infants' height, weight, Apgar scores, or birth defect rates between infants from the treated and untreated groups. Conclusions: LdT and LAM use in late pregnancy for highly viremic mothers was equally effective in reducing MTCT. The treatment was well tolerated with no safety concerns identified.
Article
Full-text available
We sought to determine the prevalence of hepatitis B virus (HBV) lamivudine (LAM)-resistant minority variants in subjects who once received LAM but had discontinued it prior to virus sampling. We performed direct PCR Sanger sequencing and ultra-deep pyrosequencing (UDPS) of HBV RT of plasma viruses from 45 LAM-naïve subjects and 46 LAM-experienced subjects who had discontinued LAM a median of 24 months earlier. UDPS was performed to a depth of ∼3,000 reads per nucleotide. Minority variants were defined as differences from the Sanger sequence present in ≥0.5% of UDPS reads in a sample. Sanger sequencing identified ≥1 LAM-resistance mutations (rtL80I/V, rtM204I, rtA181T) in samples from five (11%) of 46 LAM-experienced and none of 45 LAM-naïve subjects (0%; p=0.06). UDPS detected ≥1 LAM-resistance mutations (rtL80I/V, rtV173L, rtL180M, rtA181T, rtM204I/V) in 10 (22%) of the 46 LAM-experienced subjects - including five in whom LAM-resistance mutations were not identified by Sanger sequencing. Overall, LAM-resistance mutations were more likely to be present in LAM-experienced (10/46, 22%) than LAM-naïve subjects (0/45, 0%; p=0.001). The median time since LAM discontinuation was 12.8 months in the 10 subjects with a LAM-resistance mutation compared with 30.5 months in the 36 LAM-experienced subjects without a LAM-resistance mutation (p<0.001). The likelihood of detecting a LAM-resistance mutation was significantly increased using UDPS compared with Sanger sequencing and was inversely associated with the time since LAM discontinuation.
Article
Full-text available
To determine the therapeutic effect of lamivudine in late pregnancy for the interruption of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). Studies were identified by searching available databases up to January 2011. Inclusive criteria were HBV-carrier mothers who had been involved in randomized controlled clinical trials (RCTs) with lamivudine treatment in late pregnancy, and newborns or infants whose serum hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) or HBV DNA had been documented. The relative risks (RRs) for interruption of MTCT as indicated by HBsAg, HBV DNA or HBeAg of newborns or infants were calculated with 95% confidence interval (CI) to estimate the efficacy of lamivudine treatment. Fifteen RCTs including 1693 HBV-carrier mothers were included in this meta-analysis. The overall RR was 0.43 (95% CI, 0.25-0.76; 8 RCTs; P(heterogeneity) = 0.04) and 0.33 (95% CI, 0.23-0.47; 6 RCTs; P(heterogeneity) = 0.93) indicated by newborn HBsAg or HBV DNA. The RR was 0.33 (95% CI, 0.21-0.50; 6 RCTs; P(heterogeneity) = 0.46) and 0.32 (95% CI, 0.20-0.50; 4 RCTs; P(heterogeneity) = 0.33) indicated by serum HBsAg or HBV DNA of infants 6-12 mo after birth. The RR (lamivudine vs hepatitis B immunoglobulin) was 0.27 (95% CI, 0.16-0.46; 5 RCTs; P(heterogeneity) = 0.94) and 0.24 (95% CI, 0.07-0.79; 3 RCTs; P(heterogeneity) = 0.60) indicated by newborn HBsAg or HBV DNA, respectively. In the mothers with viral load < 10⁶ copies/mL after lamivudine treatment, the efficacy (RR, 95% CI) was 0.33, 0.21-0.53 (5 RCTs; P(heterogeneity) = 0.82) for the interruption of MTCT, however, this value was not significant if maternal viral load was > 10⁶ copies/mL after lamivudine treatment (P = 0.45, 2 RCTs), as indicated by newborn serum HBsAg. The RR (lamivudine initiated from 28 wk of gestation vs control) was 0.34 (95% CI, 0.22-0.52; 7 RCTs; P(heterogeneity) = 0.92) and 0.33 (95% CI, 0.22-0.50; 5 RCTs; P(heterogeneity) = 0.86) indicated by newborn HBsAg or HBV DNA. The incidence of adverse effects of lamivudine was not higher in the mothers than in controls (P = 0.97). Only one study reported side effects of lamivudine in newborns. Lamivudine treatment in HBV carrier-mothers from 28 wk of gestation may interrupt MTCT of HBV efficiently. Lamivudine is safe and more efficient than hepatitis B immunoglobulin in interrupting MTCT. HBV MTCT might be interrupted efficiently if maternal viral load is reduced to < 10⁶ copies/mL by lamivudine treatment.
Article
Full-text available
After several decades of vaccination against hepatitis B virus in newborns, infants, adolescents, and adults, the question remains whether a booster dose is ever needed. Long-term protection is most commonly measured through 4 methods: the anamnestic response after administration of a booster dose, infection rate in vaccinated populations, in vitro B and T cell activity testing, and seroepidemiological studies. Long-term protection is present despite a decrease in anti-hepatitis B surface antibodies over time. The exact mechanism of long-term protection, however, is not yet fully understood. There is no need for boosters in immunologically potent persons as long as a full course was adequately administered that respected the recommended timelines, as evidenced by studies conducted up to 20 years after the original immunization course. However, a booster dose should be planned for immunocompromised patients, based on serological monitoring.
Article
Full-text available
To determine the rate of perinatal hepatitis B virus (HBV) transmission in an Australian setting and to identify maternal virological factors associated with highest risk of transmission. A prospective, observational study of perinatal transmission of HBV. Participants were pregnant women attending Sydney South West Area Health Service antenatal clinics who tested positive for hepatitis B surface antigen (HBsAg), and their babies. All babies were routinely offered hepatitis B immunoglobulin (HBIG) and HBV vaccination. Babies positive for HBsAg at 9-month follow-up underwent further virological testing, including HBV DNA sequencing. The study was conducted between August 2002 and May 2008. HBV DNA levels and demographic characteristics of HBsAg-positive pregnant women; proportion of their infants with active HBV infection at 9-month follow-up; maternal characteristics affecting transmission rate; HBV DNA sequencing of infected infants and their mothers. Of 313 HBsAg-positive pregnant women, 213 (68%) were HBV DNA-positive and 92 (29%) were positive for hepatitis B "e" antigen (HBeAg); 138 babies born to HBV DNA-positive mothers were tested for HBV infection (HBsAg positivity) at about 9 months of age. Four cases of transmission were identified. All four mothers had very high HBV DNA levels (> 10(8) copies/mL) and were HBeAg-positive. Three of the four infants were infected with wild-type HBV strains, with identical maternal/infant isolates. The fourth mother-infant pair had an S gene variant, HBV D144E, which has been previously reported in association with vaccine/HBIG escape. (Unfortunately, HBIG was inadvertently omitted from the immunisation schedule of this infant.) Transmission rates were 4/138 (3%) from HBV DNA-positive mothers overall, 4/61 (7%) from HBeAg-positive mothers, and 4/47 (9%) from mothers with very high HBV DNA levels. No transmission was seen in 91 babies of mothers with HBV DNA levels < 10(8) copies/mL. In this cohort, HBV perinatal transmission was restricted to HBeAg-positive mothers with very high viral loads.
Article
Full-text available
Carriage of hepatitis B virus (HBV) is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Infant vaccination has been effective in preventing horizontal transmission during early childhood. It is unknown whether protection is maintained into early adulthood. In 1984, early childhood vaccination was introduced in 2 rural Gambian villages. In 2003, serological assessment of 81.5% of 1,350 eligible participants 1-24 years old was done, to determine vaccine efficacy against infection and carriage. Overall vaccine efficacy against infection and carriage was 83.4% (95% confidence interval [CI], 79.8%-86.6%) and 96.5% (85% CI, 93.9%-98.9%), respectively. Vaccine efficacy against infection was similar when restricted to primary responders (85.3%), but a significant effect of peak antibody concentration was found. Both vaccine efficacy and levels of hepatitis B surface antibody (anti-HBs) decreased with age, resulting in a vaccine efficacy against infection and carriage among 20-24-year-old participants of 70.9% (95% CI, 60.4%-80.5%) and 91.1% (95% CI, 75.8%-100%), respectively. Fifteen years after vaccination, fewer than half of the vaccinees had detectable anti-HBs. The prevalence of carriage in the unvaccinated population was similar to the prevalence 20 years earlier. HBV vaccination early during life can provide long-lasting protection against carriage, despite decreasing antibody levels. The role played by subclinical boosting and the necessity of a booster need to be evaluated.
Article
Objective: To determine the rate of perinatal hepatitis B virus (HBV) transmission in an Australian setting and to identify maternal virological factors associated with highest risk of transmission. Design, participants and setting: A prospective, observational study of perinatal transmission of HBV. Participants were pregnant women attending Sydney South West Area Health Service antenatal clinics who tested positive for hepatitis B surface antigen (HBsAg), and their babies. All babies were routinely offered hepatitis B immunoglobulin (HBIG) and HBV vaccination. Babies positive for HBsAg at 9‐month follow‐up underwent further virological testing, including HBV DNA sequencing. The study was conducted between August 2002 and May 2008. Main outcome measures: HBV DNA levels and demographic characteristics of HBsAg‐positive pregnant women; proportion of their infants with active HBV infection at 9‐month follow‐up; maternal characteristics affecting transmission rate; HBV DNA sequencing of infected infants and their mothers. Results: Of 313 HBsAg‐positive pregnant women, 213 (68%) were HBV DNA‐positive and 92 (29%) were positive for hepatitis B “e” antigen (HBeAg); 138 babies born to HBV DNA‐positive mothers were tested for HBV infection (HBsAg positivity) at about 9 months of age. Four cases of transmission were identified. All four mothers had very high HBV DNA levels (> 10⁸ copies/mL) and were HBeAg‐positive. Three of the four infants were infected with wild‐type HBV strains, with identical maternal/infant isolates. The fourth mother–infant pair had an S gene variant, HBV D144E, which has been previously reported in association with vaccine/HBIG escape. (Unfortunately, HBIG was inadvertently omitted from the immunisation schedule of this infant.) Transmission rates were 4/138 (3%) from HBV DNA‐positive mothers overall, 4/61 (7%) from HBeAg‐positive mothers, and 4/47 (9%) from mothers with very high HBV DNA levels. No transmission was seen in 91 babies of mothers with HBV DNA levels < 10⁸ copies/mL. Conclusion: In this cohort, HBV perinatal transmission was restricted to HBeAg‐positive mothers with very high viral loads.
Article
Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This CPG presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2000 IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother-to-child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e. entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa can be also considered in mild to moderate chronic hepatitis B. Combination therapies are not generally recommended. All treated and untreated patients should be monitored for treatment response and adherence, and the risk of progression and development of complications. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve “cure” of disease and new biomarkers are discussed.
Article
Background Few data are available regarding the use of tenofovir disoproxil fumarate (TDF) during pregnancy for the prevention of mother-to-child transmission of hepatitis B virus (HBV). Methods In this trial, we included 200 mothers who were positive for hepatitis B e antigen (HBeAg) and who had an HBV DNA level higher than 200,000 IU per milliliter. Participants were randomly assigned, in a 1:1 ratio, to receive usual care without antiviral therapy or to receive TDF (at an oral dose of 300 mg per day) from 30 to 32 weeks of gestation until postpartum week 4; the participants were followed until postpartum week 28. All the infants received immunoprophylaxis. The primary outcomes were the rates of mother-to-child transmission and birth defects. The secondary outcomes were the safety of TDF, the percentage of mothers with an HBV DNA level of less than 200,000 IU per milliliter at delivery, and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28. Results At delivery, 68% of the mothers in the TDF group (66 of 97 women), as compared with 2% in the control group (2 of 100), had an HBV DNA level of less than 200,000 IU per milliliter (P<0.001). At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (with transmission of virus to 5% of the infants [5 of 97] vs. 18% [18 of 100], P=0.007) and the per-protocol analysis (with transmission of virus to 0 vs. 7% [6 of 88], P=0.01). The maternal and infant safety profiles were similar in the TDF group and the control group, including birth-defect rates (2% [2 of 95 infants] and 1% [1 of 88], respectively; P=1.00), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45% [44 of 97 women] vs. 30% [30 of 100], P=0.03). The maternal HBV serologic outcomes did not differ significantly between the groups. Conclusions In a cohort of HBeAg-positive mothers with an HBV DNA level of more than 200,000 IU per milliliter during the third trimester, the rate of mother-to-child transmission was lower among those who received TDF therapy than among those who received usual care without antiviral therapy. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.)
Article
Background. Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. Methods. We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. Results. Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease in-hibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (−0.41 vs −0.18) or weight (−0.71 vs −0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, −9.5, −1.2; P = .013) in the tenofovir-exposed infants.
Article
Objective: This study aimed to assess risk factors for mother-to-child transmission (MTCT) of hepatitis B virus (HBV) after immunoprophylaxis. Methods: Risk factors for MTCT were assessed using a multivariate logistic regression model. Patients: We enrolled 256 mother-child pairs with positive maternal hepatitis B surface antigens (HBsAg) between January 2010 and June 2013. All children received passive-active immunization after birth. The children were tested for HBsAg at birth and 6-12 months and/or 1-3 years of age. Results: Among 256 children, 10 (3.9%) developed HBV infection, all of whom were born to hepatitis B e antigen (HBeAg)-positive mothers with a high HBV DNA level (median, 7.36; range, 6.75-8.00 log10 IU/mL). A total of 20 mothers received antiviral treatment during pregnancy. The maternal viral load decreased from an average of 7.16 to 3.08 log10 IU/mL (p<0.0001) at delivery. The multivariate logistic regression analysis showed that a high maternal HBV DNA level [odds ratio (OR) for each log10 IU/mL increase, 2.44; 95% confidence interval (CI), 1.13-5.29, p=0.023] and vaginal delivery (OR=6.96, 95% CI, 1.80-26.93, p=0.005) were risk factors for HBV immunoprophylaxis failure. Conclusion: Additional treatment strategies should be considered in HBeAg-positive mothers with an HBV DNA level above 6-7 log10 IU/mL. In addition, our study supports the use of Cesarean section for infants born to HBsAg-positive mothers.
Article
Perinatal transmission of Hepatitis B Virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice. We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7 log IU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared. 120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, baseline viral load mean 7.8 log IU/mL (+/- 0.72) and ALT median 25 U/L (18.75-33). Duration of AVT before birth was mean 58 days (+/- 19) TDF and 53 (+/- 14) lamivudine. Viral load declined by 3.64 log IU/mL (+/- 0.9) TDF and 2.81 log IU/mL (+/- 1.33) lamivudine. Virologic failure (birth viral load >7 IU/ml) occurred in 3 and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to two and zero% in TDF and lamivudine cohorts, compared with 20% in untreated. TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts.
Article
This study sought to assess the antiviral efficacy of lamivudine (LMV) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance. A prospective observational analysis was performed on 26 mothers with high viral load (>10(7) IU/mL). Twenty-one women received LMV (treated group) for an average of 53 days (range 22-88 days), and the remaining five formed the untreated control group. Serum samples from two time points were used to measure HBV DNA levels and antiviral drug resistance. The LMV-treated women achieved a median HBV DNA reduction of 2.6-log10 IU/mL. Although end-of-treatment (EOT) HBV DNA in four (18%) LMV-treated women remained at >10(7) IU/mL (±0.5 log IU/mL), no mother-to-baby transmission was observed. In contrast, a baby from the untreated mother was HBsAg positive at 9 months postpartum. Four technologies were used for drug resistance testing. Only ultra-deep pyrosequencing (UDPS) was sufficiently sensitive to detect minor viral variants down to <1%. UDPS showed that LMV therapy resulted in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA181T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63-5.92%) at EOT, but one LMV-treated mother had an rtA181T variant that increased from 2.2% pretherapy to 25.59% at EOT. This mother was also infected with the vaccine escape variant (sG145R), which was inhibited by LMV treatment. LMV therapy during late pregnancy only reduced maternal viraemia moderately, and drug-resistant viral variants emerged.
Article
To explore the factors influencing failure of an immunization to interrupt perinatal (mother-to-child) transmission of hepatitis B virus (HBV). Between June 2006 and March 2010, a total of 1355 pregnant women testing positive for the hepatitis B surface antigen (HBsAg), at gestational weeks 20 to 42, and without use of antiviral or immunomodulatory drugs during the pregnancy were prospectively recruited to the study. The mothers were given a choice of receiving hepatitis B immunoglobulin (HBIG; three 200 IU intramuscular injections give at four-week intervals starting from gestation week 28) or not. All neonates (1360, including five sets of twins) received hepatitis B vaccine (10 mug) plus HBIG (200 IU) combined immunization within 24 h of birth, as early as possible. Peripheral venous blood samples were collected from the neonates within 24 h of birth and at 7 and 12 months of age for detection of HBV markers, including hepatitis B e antigen (HBeAg) and HBV DNA. The infants were classified according to HBV perinatal transmission status (infection group and non-infection group) and various factors (maternal-related: age, gravidity, parity; pregnancy/birth-related: threatened premature labor, complications; neonate-related: sex, birth weight, apgar score) were compared between the two groups by using non-conditional logistic regression analysis to determine their potential influence on failure of immunization to inhibit transmission. After 12 months of follow-up, 1.54% (21/1360) of the neonates had presented with HBV infection. Analysis of the HBV-infected neonates revealed differences in infection rates between neonates born to mothers with HBIG injection (2.22% vs. without HBIG injection: 1.11%, P less than 0.05) and caesarean section (1.35% vs. vaginal delivery: 1.73%) but neither reached statistical significance (P less than 0.05); only the practice of breastfeeding showed a significant difference for infection rate, with neonates fed artificial formula having higher infection rate (3.13%) than the breastfed neonates (0.27%, P less than 0.05). The neonate HBV infection rate was also significantly higher for neonates born to HBeAg-positive mothers (4.44% vs. HBeAg-negative mothers: 0%, P less than 0.05) and HBV DNA-positive mothers (3.13% vs. HBV DNA-negative mothers: 0%, P less than 0.05). When the mothers were stratified by serum level of HBV DNA, there was a significant difference in HBV-infected neonates born to mothers with more than or equal to 1*10(7) IU/ml(6.01% vs. 10(3)-10(6) IU/ml: 0.56% and less than 1*10(3) IU/ml: 0%, both P less than 0.05). Logistic regression analysis indicated that the independent risk factors for HBV perinatal transmission despite immunization were maternal serum HBeAg-positive status (relative risk (RR)=31.74, 95% confidence interval (CI): 3.88-259.38) and maternal HBV DNA of more than or equal to107 copies/mL (RR=22.58, 95% CI: 4.75-107.40). Failure of vaccine plus HBIG to interrupt mother-to-child transmission of HBV is influenced by maternal serum HBeAg-positive status and maternal HBV DNA of more than or equal to107 copies/mL.
Article
Little is known about the risk factors associated with hepatitis B virus (HBV) intrauterine transmission among HBsAg-positive mothers. We conducted a study in Taiyuan, China, including 1133 HBsAg-positive mothers and their babies. A total of 101 neonates had HBsAg and/or HBV DNA positive with an intrauterine transmission rate of 8.9%. Maternal menstrual irregularity (OR = 4.95, 95% CI: 1.71, 14.33) and severe nausea during the first trimester (OR = 1.86, 95% CI: 1.11, 3.09) were associated with an increased risk of intrauterine transmission, while caesarean delivery (OR = 0.32, 95% CI: 0.20, 0.51) was associated with a decreased risk after adjusting for potential confounders. Maternal HBeAg positive was a strong independent predictor for intrauterine transmission (OR = 2.56, 95% CI: 1.54, 4.27). A positive association between maternal HBV DNA levels and intrauterine transmission was suggested. Maternal HBIG administration during pregnancy, family history of HBV infection and premature rupture of membranes was not associated with the risk of intrauterine transmission. The study confirmed that maternal HBeAg positive was a risk factor and caesarean delivery was a protective factor for intrauterine transmission. The new findings associated with menstrual irregularity and severe nausea during the first trimester warrant further investigation.
Article
Background & aims: Immunoprophylaxis reduces but does not completely eradicate hepatitis B virus (HBV) transmission. This prospective study aims at assessing the rate and risk factors of maternally transmitted HBV infection. Methods: We enrolled 303 mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg) under current immunization program. Maternal viral load was determined by a real-time PCR-based assay. The children were tested for HBsAg at 4-8 months and/or 1-3 years of age. Rates of HBV infection were estimated using a multivariate logistic regression model. Results: HBeAg-positive mothers (81/303, 26.7%) had higher viral loads than HBeAg-negative mothers (7.4 ± 1.9 vs. 2.7 ± 1.4 log10 copies/ml, p<0.0001). Ten children, born to HBeAg-positive mothers with high viral load (median, 8.4; range, 6.5-9.5 log₁₀ copies/ml), were chronically infected. After adjustment for maternal age, birth type, factors related to maternal-fetal hemorrhage, gestational age, infant gender, birth weight, timeliness of vaccination, and feeding practice, maternal viral load was significantly associated with risk of infection (adjusted odds ratio for each log₁₀ copy/ml increase, 3.49; 95% confidence interval (CI), 1.63-7.48; p=0.001). The predictive rates of infection at maternal viral load levels of 7, 8, and 9 log₁₀ copies/ml were 6.6% (95% CI, 0.5-12.6%; p=0.033), 14.6% (95% CI, 5.6-23.6%; p=0.001), and 27.7% (95% CI, 13.1-42.4%; p<0.001), respectively. Conclusions: Additional strategies to further reduce transmission should be considered in mothers with a viral load above 7-8 log₁₀ copies/ml.
Article
Introduction: Hepatitis B vaccination starting at birth provides a safety net for infants exposed to hepatitis B virus (HBV) during delivery or in early life. Hepatitis B vaccine is recommended in the United States for infants prior to birthing facility discharge, and within the first 12h of life for infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We performed a literature review and summarized the response to recombinant hepatitis B vaccine among infants. Methods: Studies published between 1987 and 2011 assessing seroprotection from recombinant hepatitis B vaccine starting within the first 30 days of life were eligible. Seroprotection was defined using an antibody to hepatitis B surface antigen (anti-HBs) threshold of 10mIU/mL at series completion. Infant seroprotection was compared in trial arms varying by maternal hepatitis B antigen status (e antigen [HBeAg], HBsAg), hepatitis B immune globulin (HBIG) administration, birth weight, vaccine dosage, schedule, and age at first dose. Results: Forty-three studies were included. The median seroprotection proportion overall was 98% (range 52%, 100%). The final median seroprotection proportions did not vary appreciably by maternal HBsAg status, HBIG administration, or schedule. Higher compared to lower dosage resulted in earlier increases in anti-HBs but not in final seroprotection proportions. Infants with birth weights <2000g compared to ≥2000g had lower median seroprotection proportions (93% and 98%, respectively). Median seroprotection proportions were also lower when infants with birth weights <2000g were vaccinated at 0-3 days of age compared to 1 month of age or older (68% versus 95%, respectively). Conclusion: High levels of protection from recombinant hepatitis B vaccine are achieved in term infants vaccinated at birth, effectively preventing transmission of HBV and resultant morbidity and mortality. Implications, if any, for long-term protection are unknown for differences in responses among infants vaccinated at birth compared to ages older than 1 month.
Article
The high maternal HBV DNA level is the most important factor contributing to HBV perinatal transmission. This study is to explore whether HBsAg can be used as a surrogate marker of serum HBV DNA for HBsAg-positive pregnant women. A total of 975 HBsAg-positive pregnant women and their infants were enrolled in this study. All infants received three doses of a yeast-derived recombinant Hepatitis B vaccine at 0, 1 and 6 months. They were also given Hepatitis B immunoglobulin (HBIG) at birth. HBsAg and HBeAg were determined using Abbott Architect assays while serum HBV DNA level was detected by the Abbott Real Time HBV DNA assay. Of the 975 subjects, 367 (37.6%) were HBeAg-positive and 608 (62.4%) were HBeAg-negative. Among the HBeAg-positive group, the samples with HBV DNA levels of ≥7.0 logIU/mL were 76.6% (281/367), and it was only 0.7% (4/608) for the HBeAg-negative group. HBV DNA level was positively correlated with HBsAg in HBeAg-positive group (r=0.786, p<0.001) but not in HBeAg-negative group (r=0.022, p=0.593). Among HBeAg-positive group, the area under the receiver-operator curve (ROC) of HBsAg titer for high HBV DNA level (≥7.0 logIU/mL) was 0.961 (95% CI, 0.940-0.983, p<0.001). The optimum cut-off point HBsAg titer above 4.1 logIU/mL had a sensitivity of 85.1%, specificity of 96.5%, and accuracy of 87.5% to predict HBV DNA levels of ≥7.0 logIU/mL. Of 367 infants born to mothers with HBeAg-positive, perinatal transmission was detected in 24 infants (6.5%, 24/367). Their mothers all had serum HBV DNA levels of ≥7.0 logIU/mL, 23 (95.8%) had HBsAg titers of ≥4.1 logIU/mL and the other mother had HBsAg titer of 3.9 logIU/mL. Of 608 infants born to mothers with HBeAg-negative, only one (0.2%, 1/608) became HBsAg-positive at the age of 7 months, and the mother of the infant had serum HBV DNA level of 3.4 logIU/mL and HBsAg titer of 1.8 logIU/mL, respectively. Serum HBsAg titer may be used as a surrogate marker of serum HBV DNA for HBeAg-positive pregnant women.
Article
Telbivudine reduces hepatitis B virus (HBV) DNA and normalizes levels of alanine aminotransferase (ALT) in patients with chronic hepatitis B (CHB). We investigated its use in preventing vertical transmission. We performed an open-label, prospective study of 88 hepatitis B (HB) e antigen (HBeAg)-positive pregnant women with CHB, levels of HBV DNA >6 log(10) copies/mL, and increased levels of ALT. Women were given telbivudine (n = 53) starting in the 2nd or 3rd trimester, or no treatment (controls, n = 35) and followed until postpartum week (PPW) 28. All infants received standard immunoprophylaxis after birth. At 28 weeks, none of the infants whose mothers received telbivudine had immunoprophylaxis failure, whereas 8.6% of the infants of control mothers did (P = .029). There were no differences between groups in mothers' adverse events or infants' congenital deformities, gestational age, height, and weight, or Apgar scores. At postpartum week 28, significantly more telbivudine-treated mothers had levels of HBV DNA <500 copies/mL, normalized levels of ALT, and hepatitis B e antigen seroconversion compared with controls (58% vs none, P < .001; 92% vs 71%; P = .008; and 15% vs none; P < .001, respectively) but none had loss of hepatitis B surface antigen. Telbivudine-treated mothers had no virologic breakthrough (HBV DNA >1 log(10) increase from <500 copies/mL) or discontinuations from adverse events. After delivery, 13/52 patients discontinued telbivudine due to preference. There were no episodes of severe hepatitis (levels of ALT >10 times the upper limit of normal) in either group during 28 weeks of postpartum observation. Women with CHB given telbivudine during the second or third trimester of pregnancy have reduced rates of perinatal transmission. Telbivudine produced no adverse events in mothers or infants by 28 weeks.
Article
In infants born to hepatitis B surface antigen (HBsAg)-positive mothers, failure after passive-active immunization still occurs. The role of maternal hepatitis B DNA level and other risk factors in this setting remains unclear. This study retrospectively evaluated virologic and other risk factors associated with immunoprophylaxis failure in infants born to HBsAg-positive mothers. Between January 2007 and March 2010, we reviewed the clinical and virologic tests in 869 mother-infant pairs. All infants received the identical passive-active immunization schedule after birth. The failure infants (HBsAg positive at 7-12 months of age) were compared to infants who were HBsAg negative when tested during this time period. Among 869 infants, 27 (3.1%) infants were immunoprophylaxis failures and the other 842 (96.9%) infants remained HBsAg negative. When mothers' pre-delivery HBV DNA levels were stratified to <6, 6-6.99, 7-7.99 and ≥ 8 log(10) copies/mL, the corresponding rates of immunoprophylaxis failure were 0%, 3.2% (3/95), 6.7% (19/282) and 7.6% (5/66), respectively (P < 0.001 for the trend). All failure infants were born to hepatitis B e antigen (HBeAg)-positive mothers. Multivariate logistic regression analysis identified maternal HBV DNA levels [odds ratio (OR) = 1.88, 95% confidence interval (CI): 1.07-3.30] and detectable HBV DNA in the cord blood (OR = 39.67, 95% CI: 14.22-110.64) as independent risk factors for immunoprophylaxis failure. All failure infants were born to HBeAg-positive mothers with HBV DNA levels ≥ 6 log(10) copies/mL. The presence of HBV DNA in cord blood predicted failure to passive-active immunization.
Article
Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality worldwide. Chronic hepatitis B (CHB) infection is associated with an increased risk of cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). The likelihood of developing CHB is related to the age at which infection is acquired; the risk being lowest in adults and >90% in neonates whose mothers are hepatitis B e antigen positive. Treatment of CHB infection aims to clear HBV DNA and prevent the development of complications. There are currently seven drugs available for the treatment of CHB: five nucleos(t)ide analogues and two interferon-based therapies. Long-term treatment is often required, and the decision to treat is based on clinical assessment including the phase of CHB infection and the presence and extent of liver damage. A safe and effective HBV vaccine has been available since the early 1980s. Vaccination plays a central role in HBV prevention strategies worldwide, and a decline in the incidence and prevalence of HBV infection following the introduction of universal HBV vaccination programmes has been observed in many countries including the USA and parts of South East Asia and Europe. Post-exposure prophylaxis (PEP) with HBV vaccine +/- hepatitis B immunoglobulin is highly effective in preventing mother to child transmission and in preventing transmission following sharps injuries, sexual contact and other exposures to infected blood and body fluids. Transmission of HBV in the health care setting has become an increasingly rare event in developed nations. However, it remains a significant risk in developing countries reflecting the higher prevalence of CHB, limited access to HBV vaccination and PEP and a lack of adherence to standard infection control precautions.
Article
Despite immunoprophylaxis, mother to child transmission (MTCT) of hepatitis B virus (HBV) still occurs in infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We analyzed methods of risk assessment and interventions for MTCT. We reviewed 63 articles and abstracts published from 1975-2011 that were relevant to MTCT; articles were identified using the PubMed bibliographic database. Administration of HB immunoglobulin and HB vaccine to infants at birth (within 12 hours), followed by 2 additional doses of vaccines within 6-12 months, prevented approximately 95% of HBV transmission from HBsAg-positive mothers to their infants. However, HBV was still transmitted from 8%-30% of mothers with high levels of viremia. It is important to assess the risk for MTCT and identify mothers who are the best candidates for intervention. The most important risk factor is maternal level of HBV DNA >200,000 IU (10(6) copies)/mL; other factors include a positive test result for the HB e antigen, pregnancy complications such as threatened preterm labor or prolonged labor, and failure of immunoprophylaxis in prior children. Antiviral therapy during late stages of pregnancy is the most effective method to reduce transmission from mothers with high levels of viremia, but elective cesarean section might also be effective. Antepartum administration of HB immunoglobulin, giving infants a double dose of HB vaccine, or avoiding breastfeeding had no impact on MTCT. HBsAg-positive mothers should be assessed for risk of MTCT, and infants should receive immunoprophylaxis. Pregnant women with levels of HBV DNA >200,000 IU/mL should be considered for strategies to reduce the risk for MTCT. We propose an algorithm for risk assessment and patient management that is based on a review of the literature and the opinion of a panel of physicians with expertise in preventing MTCT.
Article
The objective of this study was to determine long-term immunity to hepatitis B virus (HBV) in a cohort of adolescents who received plasma-derived HBV vaccine in 1989 and 1990 in a remote Australian Aboriginal community. This was done using a serological survey; primary outcome measures were cut-off titres of HBsAb, and the presence of HBcAb and/or HBsAg. Of 37 adolescents in the cohort, 4 (11%) had evidence of active infection, one with abnormal liver enzymes, 7 (19%) had evidence of past infection, 15 (41%) were HBsAb positive in low titre and 11 (30%) were classed as immune. It was concluded that there was relatively poor long-term serological immunity to HBV vaccination in this group; a finding which is in keeping with similar studies in Indigenous and remote populations elsewhere. This finding raises the concern that a significant proportion of Aboriginal adolescents in other remote communities (vaccinated in 1989 and 1990) were not adequately protected by the vaccine. If so, there will be an unexpected burden of chronic HBV infection in these settings and a substantial group who are non-immune, despite having received complete HBV vaccination courses as infants. The authors recommend followup serosurveys in remote Aboriginal communities to identify people with low HBsAb titres, especially those without an adequate anamnestic response to another dose of HBV vaccine. In addition, community-based active surveillance programs will be required to detect people with chronic HBV infection and provide access to monitoring and appropriate treatment.
Article
Hepatitis B vaccination in children born to hepatitis B surface antigen (HBsAg)-positive mothers considerably decreases the risk of vertical transmission. However, whether this protection against carriage of hepatitis B virus is maintained into early adulthood is as yet unknown. A combined passive-active immunization programme for newborns of HBsAg-positive mothers was initiated in the north-eastern part of the Czech Republic in 1988. The number of immunized newborns had reached 665 newborns by the end of 2006. All mothers of immunized infants were HBsAg-positive during pregnancy, and 34 (5%) were also hepatitis B e antigen (HBeAg)-positive. The immunization programme consists of providing newborns with protection at birth with hepatitis B immunoglobulin, followed by three 10-μg doses of plasma-derived or, since 1990, recombinant vaccine administered at 0, 1 and 6 months of life. Only 29 children of HBeAg-positive mothers received vaccine at 0, 1 and 2 months of life. Blood samples were obtained after immunization, at 2 years of age, and biennially thereafter. Samples were tested for HBsAg and hepatitis B surface and core antibodies (anti-HBs, anti-HBc). The immunization schedules were completed in 640 children. A protective anti-HBs level after immunization was proven in 574 of 620 children (93%). Persistence of protective anti-HBs antibodies was detected in 70, 40 and 25% of children at 5, 10 and 15 years of age. Vertical transmission with chronic HBsAg carrier status was detected in two infants. Anti-HBc seroconversion was proven in ten children from 3 to 15 years of age. Natural boosting with an anti-HBs increase was detected in 38 children (twice in one child). Our results show that combined active-passive immunization of newborns against hepatitis B provides persistent protection up to adolescence despite a frequent waning of anti-HBs antibodies, suggesting there is no need for booster vaccination during adolescence.
Article
To evaluate efficacy of lamivudine in reducing in utero transmission of hepatitis B virus (HBV). A database was constructed from Medline, EMBASE, Cochrane Library, National Science Digital Library, China Biological Medicine Database, and through contact with experts in the field from January 1990 to October 2009. We used the Jadad score and Cochrane Collaboration's tool for assessing risk of bias. We abstracted data regarding HBV intrauterine infection, mother-to-child transmission, maternal HBV DNA level, treatment methods, and adverse effects. All newborns followed joint immune prophylaxis schedule of hepatitis B vaccine and hepatitis B immunoglobulin after delivery. The Mantel-Haenszel random-effects model was employed for all analyses using odds ratio (OR) and 95% confidence interval. Newborns in the lamivudine group had a 13.0-23.7% lower incidence of intrauterine infection, indicated by newborn hepatitis B surface antigen (0.38, 0.15-0.94, six randomized controlled trials [RCTs], P=.04) and HBV DNA (0.22, 0.12-0.40, four RCTs, P<.001) seropositivity, and a 1.4-2.0% lower mother-to-child transmission rate at 9-12 months, indicated by infant hepatitis B surface antigen (0.31, 0.15-0.63, four RCTs, P<.01) and HBV DNA (0.20, 0.10-0.39, two RCTs, P<.001) seropositivity. No significant higher adverse effects or complications in pregnancy were observed. Lamivudine in HBV carrier-mothers with high degree of infectiousness in late pregnancy effectively prevented HBV intrauterine infection and mother-to-child transmission.
Article
The quantifiable level of HBsAg has been suggested as a predictor of treatment response in chronic hepatitis B. However, there is limited information on HBsAg levels considering the dynamic natural course of HBV-infection. This study aimed to determine HBsAg levels in the different phases of HBV-infection in European HBsAg-positive patients. 226 HBV-monoinfected patients, not undergoing antiviral therapy, were analyzed in a cross-sectional study. Patients were categorized according to the phase of HBV-infection: HBeAg(+) immune tolerance phase (IT, n=30), immune clearance phase (IC, n=48), HBeAg(-) low-replicative phase (LR, n=68), HBeAg(-) hepatitis (ENH, n=68), and acute hepatitis B (n=12). HBsAg was quantified and correlated with HBV-DNA, HBV-genotypes and clinical parameters. In addition, 30 LR-patients were followed longitudinally. HBsAg levels were higher in IT-patients and IC-patients compared to LR-patients and ENH-patients (4.96/4.37/3.09/3.87-log(10)IU/ml, p<0.001). HBsAg showed a strong correlation with HBV-DNA during acute hepatitis B (R=0.79, p<0.01). Correlation of HBsAg and HBV-DNA was weak or missing when analyzing different phases of persistent HBV-infection separately. However, associations between HBsAg and HBV-DNA were observed in patients infected with HBV-genotype D but not with HBV-genotype A. LR-patients with HBV-reactivation during follow-up (increase of HBV-DNA >2000IU/ml) showed >3-fold higher baseline HBsAg levels with a NPV of 95% for an HBsAg cut-off of 3500IU/ml. HBsAg levels show significant differences during the natural course of HBV-infection and between HBV-genotypes. These findings may have important implications for understanding the natural history of HBV-infection and for using quantitative HBsAg as a diagnostic tool, i.e. as a marker for predicting HBV-reactivation.
Article
Most children with chronic hepatitis B virus infection (persistent hepatitis B surface antigen-positive for >6 months) are asymptomatic and do not generally require treatment. These children are, however, at increased risk for severe complications later in life, including advanced liver disease and liver cancer. On November 11, 2008, the Hepatitis B Foundation, a nonprofit research and disease advocacy organization, convened a panel of nationally recognized North American pediatric liver specialists to consider and recommend an approach for the screening, monitoring, initial management, and referral of children with chronic hepatitis B. The panel developed recommendations to provide guidance to practitioners on determining what additional tests to conduct, how often to monitor on the basis of test results, and when to refer to a pediatric liver specialist to build a partnership between the practitioner and liver specialist to enhance the success of management of children with this lifelong infection.
Article
Preventive measures remain the best approach to control the spread of hepatitis B virus (HBV) infection. To evaluate the effectiveness of vaccination against HBV, we conducted a 20-year retrospective study on 100 subjects, born to hepatitis B surface antigen (HBsAg)-positive mothers, who had received postexposure prophylaxis at the Clinic of Infectious Diseases (Siena University, Italy) during 1984-2004. All patients were tested for the presence of HBsAg, anti-HBs and anti-HB core antigen (anti-HBc). Two subjects (2%) acquired the infection as shown by the presence of anti-HBc. Of the 98 patients who did not acquire the infection, 62 of these (63.3%) had an anti-HBs concentration considered protective (> or =10 mIU/ml). The percentage of protected subjects decreased in relation to time from vaccination with a significant reduction (p = 0.009) of anti-HBs geometric mean titre (GMT) after 5 years, which reached the level of 10 mIU/ml after about 15 years. No patients without protective concentration have acquired the infection as of today. Only 12% of the HBsAg-positive mothers were followed in specialized structures after pregnancy, reflecting the scarce knowledge of the problem in the general population. Our data, while confirming the effectiveness of anti hepatitis B vaccination, highlight the need for postvaccination follow-up, particularly in high-risk categories, to prolong protection, through booster doses if necessary. We show, moreover, the importance of maintaining active surveillance in the territory to improve follow-up to chronic carriers and to sensitize families.
Article
Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti-HBc), HB surface antigen (HBsAg), and pre- and postbooster titers of HBsAg antibody (anti-HBs) 15 years after primary neonatal immunization with plasma-derived HB vaccines in 2 cohorts of 15-year-old children. Group A consisted of 78 children who were born to HB e antigen-positive HBsAg carrier mothers and had developed protective levels of anti-HBs antibodies (> or =10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti-HBs titers after vaccination were unknown. Anti-HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (P < .001). Anti-HBc was detected in 33.3 % in group A and 4.4 % in group B (P < .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti-HBs-negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%). Fifteen years after neonatal immunization with plasma-derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects. In conclusion, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma-derived HB vaccine.
Article
During pregnancy several alterations in the immune status allow mothers to tolerate the genetically different foetal tissues. We investigated the evolution of liver disease during and after pregnancy in chronic hepatitis B patients. Between 1998 and 2006 there were 38 pregnancies in 31 chronic hepatitis B 's' antigen-positive women at our liver unit. Twenty-four subjects (63%) were hepatitis B 'e' antigen (HBeAg)-positive, 14 (37%) HBeAg-negative. In 13 pregnancies (34%), lamivudine therapy was started during the last trimester of pregnancy to lower hepatitis B virus (HBV) DNA levels to reduce the risk of vertical transmission. A significant increase in liver disease activity after pregnancy, defined as a three times increase in alanine aminotransferase (ALT) within 6 months after delivery, occurred in 17 of 38 patients (45%). In those treated with lamivudine during the last trimester of pregnancy, this occurred in even 8/13 patients (62%). Prediction during pregnancy of these exacerbations was not possible using HBV DNA, ALT level, HBeAg status or any other characteristic. The median maximal ALT of these exacerbations was 4.0 x ULN and none led to decompensated liver disease. In conclusion, a significant increase in liver inflammation occurs often after pregnancy. This may be due to a reactivation of the immune system after delivery. Based on our data we recommend monitoring closely and if necessary treating women with chronic HBV shortly after delivery.
Update: shortened interval for postvaccination serologic testing of infants born to hepatits B‐infected mothers
  • S Schilllie
  • TV Murphy
  • N Fenlon
  • S Ko
  • JW Ward