Article

Anti-viral therapy for prevention of perinatal HBV transmission: Extending therapy beyond birth does not protect against post-partum flare

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  • Institute for Liver and Digestive Health
Article

Anti-viral therapy for prevention of perinatal HBV transmission: Extending therapy beyond birth does not protect against post-partum flare

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Abstract

Antepartum anti-viral therapy (AVT) is often administered to prevent perinatal transmission of hepatitis B virus (HBV) infection. Little is known about the effect of AVT on post-partum flare rates and severity. To examine whether extending AVT beyond birth influences the post-partum course. One hundred and one pregnancies in 91 women with HBV DNA levels ≥log 7 IU/mL were included. AVT (initially lamivudine, later tenofovir disoproxil fumarate) was commenced from 32 weeks gestation and stopped soon after birth and at 12 weeks post-partum. Outcomes according to post-partum treatment duration were examined: Group 1 = AVT ≤4 weeks (n = 44), Group 2 = AVT >4 weeks (n = 43), Group 3 = no AVT (n = 14). The majority of women were HBeAg+ (97%), median age 29 years, baseline HBV DNA log 8.0 IU/mL and follow-up 48 weeks post-partum. Post-partum treatment duration was 2 weeks for Group 1 and 12 weeks for Group 2, P < 0.01. Flare rates were not significantly different: Group 1 = 22/44 (50%), Group 2 = 17/43 (40%) and Group 3 = 4/14 (29%), P = 0.32. Onset of flare was similar at 8/10/9 weeks post-partum for Groups 1/2/3 respectively, P = 0.34. The majority of flares spontaneously resolved. HBeAg seroconversion (n = 1/5/1 in Groups 1/2/3, P = 0.27) was not associated with treatment duration or the occurrence of a post-partum flare. Post-partum flares are common and usually arise early after delivery. They are often mild in severity and most spontaneously resolve. Extending anti-viral therapy does not protect against post-partum flares or affect HBeAg seroconversion rates.

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... Also, the destruction of immune balance may cause the replication of HBV, which may induce hepatitis flare. Studies have shown that postpartum hepatitis flare is often mild and most spontaneously resolves [8][9][10]. However, severe cases have also been reported [11], Severe flares necessitating liver transplantation when salvage anti-HBV therapy fails have been rarely reported [11][12][13]. ...
... Some studies showed that extending anti-HBV therapy did not protect against postpartum flares or affect hepatitis B e antigen (HBeAg) seroconversion rates [8]. Liu et al. reported that it was safe for most women to withdraw the use of telbivudine after delivery, whereas activating serological response encouraged extended anti-HBV therapy for mothers with ALT elevation during pregnancy [7]. ...
... Postpartum hepatitis flare is more common among women with HBV infection, with an incidence rate between 25 and 44.7% [4][5][6][7]. Most studies found that nucleoside analog therapy in late pregnancy, followed by treatment withdrawal early postpartum, was associated with ALT flare; however, they reported variable changes in HBV DNA levels or rates of HBeAg seroconversion during immediate postpartum up to 1 year of follow-up [8,11,[14][15][16]. e definition of a hepatitis flare varies according to the literature [7,17,18], but a significant increase in serum ALT levels from the baseline level or higher than ULN is generally defined as ALT flare [10]. ...
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Background: Few studies explored whether anti-hepatitis B virus (HBV) therapy should be initiated during postpartum hepatitis flare. Aim: This study aimed to analyze the effect of anti-HBV therapy on postpartum hepatitis flare and evaluate the prognosis within 4 years postpartum. Methods: This retrospective study enrolled hepatitis B surface antigen (HBsAg)-positive and hepatitis B e antigen (HBeAg)-positive pregnant women with HBV DNA ≥ 106 IU/mL. A total of 152 pregnant women were included: 103 in the prophylactic anti-HBV therapy group (PT-G) and 49 in the non-prophylactic anti-HBV therapy group (NPT-G). The women with a postpartum flare were assigned to the anti-HBV therapy group (AT-G) and non-anti-HBV therapy group (NAT-G) to analyze the effect of postpartum anti-HBV therapy on hepatitis flare. Virological and biochemical parameters were assessed. Results: Taking postpartum 12 weeks as the cutoff point, the ALT recovered time for postpartum flare women is shorter in AT-G (n = 16, 42.1%) or PT-G (n = 23, 34.8%) than in NAT-G (n = 14, 23.0%; x 2 = 4.067, P=0.044) or NPT-G (n = 4, 11.1%; x 2 = 5.579, P=0.018). Taking postpartum 26 weeks as the cutoff point, the ALT recovered time is shorter in AT-G (n = 35, 57.3%) or PT-G (n = 44, 66.7%) than in NAT-G (n = 32, 84.2%; x 2 = 7.707, P=0.006) or NPT-G (n = 16, 44.4%; x 2 = 4.749, P=0.029). Postpartum flare recovery time was positively correlated with HBV DNA level at delivery [r = 0.223, P=0.025, 95%CI (0.022~0.41)]. The hepatitis re-flare rates within postpartum 4 years in AT-G (n = 3, 9.68%) is lower than that in NAT-G (n = 24, 45.4%; x 2 = 14.003, P ≤ 0.001). The HBeAg, HBsAg, HBV DNA, and ALT level at postpartum 4 years in AT-G were lower than that in NAT-G (P < 0.001). Conclusion: Anti-HBV therapy for postpartum hepatitis flare of women with chronic HBV could shorten the ALT recovery time and reduce hepatitis re-flare rates within 4 years of postpartum.
... Our results suggested that these adverse events were comparable between the tenofovir and control groups. There were several studies [18,44] reporting data on ALT flares during and after the antiviral treatment in pregnant women; however, their results remained inconsistent. In the study that used telbivudine or lamivudine for the treatment of late pregnancy women [18], it was reported that 17.1% of the mothers in the treated group had severe hepatitis flare (ALT> 10 times the ULN) compared with 6.3% in the untreated mothers [18]. ...
... In the study that used telbivudine or lamivudine for the treatment of late pregnancy women [18], it was reported that 17.1% of the mothers in the treated group had severe hepatitis flare (ALT> 10 times the ULN) compared with 6.3% in the untreated mothers [18]. In another study that used lamivudine or tenofovir, the incidences of postpartum ALT flare (> 95 U/L) in the treatment and no-treatment groups were 40-50 and 29%, respectively [44]. The highly variable and conflicting results could be explained by the different criteria for the definition of ALT flares, different follow-up protocols, different antiviral agents, and lack of controls [44]. ...
... In another study that used lamivudine or tenofovir, the incidences of postpartum ALT flare (> 95 U/L) in the treatment and no-treatment groups were 40-50 and 29%, respectively [44]. The highly variable and conflicting results could be explained by the different criteria for the definition of ALT flares, different follow-up protocols, different antiviral agents, and lack of controls [44]. ...
Article
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Background: The vertical transmission of HBV from mothers to their infants at birth or in early infancy has a significant role in the endemicity of HBV infection. Tenofovir is one of the most potent anti-HBV agents with a high genetic barrier to resistance. The study is to evaluate the efficacy of tenofovir in preventing perinatal HBV transmission, as well as monitoring safety for mothers and infants. Methods: PubMed, Embase, Web of Science, and CNKI (National Knowledge Infrastructure, China) database were systematically reviewed for studies that compared the efficacy and safety of tenofovir with other treatments. Pooled estimates were expressed with weight mean difference (WMD) with 95% confidence intervals (95% CIs) and risk ratio (RR) with 95% CIs. Results: Nine studies involving 1046 pregnant patients met the inclusion criteria and were included in this meta-analysis. Compared with other treatments, tenofovir significantly reduced maternal HBV DNA levels (WMD = 2.33 log10 IU/mL, 95% CI: 1.01, 3.64; P < 0.001), infant HBsAg positivity rate (RR = 0.25, 95% CI: 0.16, 0.38; P < 0.001), infant HBeAg positivity rate (RR = 0.26, 95% CI: 0.14, 0.48; P < 0.001), infant HBV DNA positivity rate (RR = 0.15, 95% CI: 0.07, 0.31; P < 0.001), and immunoprophylaxis failure rate (RR = 0.31, 95% CI: 0.13, 0.73; P = 0.008). Moreover, maternal and infant safety profiles, including ALT, CK, and Cr were comparable between tenofovir and other treatment groups. Conclusion: Based on the current evidence, our study suggested that tenofovir significantly reduced the rate of vertical transmission of HBV, as well as the HBV DNA levels in HBV-infected mothers. Moreover, tenofovir was safe and tolerable for both mothers and their infants.
... Moreover, the rate of postpartum hepatic flare was reported to be 40% to 50% in mothers who stopped antiviral treatment. 24 Accumulating studies have shown that treatment using TDF or LdT during the third trimester is effective and safe for the prevention of MTCT in mothers with high viral loads, [11][12][13][14][15] and this approach has been recommended by major guidelines. [17][18][19][20]25 Although the study by Jourdain et al 16 in Thailand did not show a statistically significant benefit of TDF treatment over a placebo control, the findings might not be generalizable to other countries. ...
... For pregnant women who have normal ALT levels and receive antiviral therapy to prevent MTCT during pregnancy, drugs can be discontinued immediately after delivery (moderate quality, weaker recommendation). 24,25 Close monitoring of maternal ALT levels is warranted after withdrawal of antivirals because postpartum hepatitis may occur. The details of follow-up evaluation are described in section 10.2. ...
... 18 However, extension of antiviral therapy for several weeks or months has not been shown to significantly prevent the occurrence of a postpartum hepatitis flare. 24 Therefore, the Chinese Medical Association guidelines suggest that maternal antiviral therapy can be discontinued at delivery and that regular monitoring of ALT levels should be performed to detect postpartum hepatitis flares. 25 It was reported that ALT flares occurred more frequently in mothers who previously had taken TDF than in those who had not received TDF (45% vs 30%). ...
Article
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In areas where hepatitis B virus (HBV) is endemic, mother-to-child transmission (MTCT) is the major route of infection of children. Blocking MTCT of HBV therefore would reduce its prevalence. The China Foundation of Hepatitis Prevention and Control organized a team of specialists in infectious diseases, hepatology, immunology, obstetrics, and public health to develop an algorithm for interrupting MTCT of HBV, based on the most recent hepatitis B guidelines and latest evidence. This algorithm comprises 10 steps and has been adopted in clinical practice in China. Four aspects (screening, antiviral intervention during pregnancy, immunoprophylaxis, and postvaccination serologic testing) are the core components of preventing MTCT. Although the combination of passive and active immunization in newborns of hepatitis B surface antigen–positive mothers reduces MTCT of HBV, this immunoprophylaxis cannot completely eradicate MTCT. In the past decade, administration of antiviral agents to pregnant women has been shown to be safe and effective in reducing MTCT of HBV in combination with immunoprophylaxis. Aiming to achieve zero MTCT, this algorithm recommends the use of antivirals during pregnancy by women with high viral loads. Preventing MTCT is key to achieving the goal of eliminating HBV as a public health threat by 2030. Implementation and enhancement of the standardized algorithm for pregnant women with chronic HBV infection and their infants is urgently needed to prevent MTCT.
... It is well known that some hormones in pregnant women go through immune changes during pregnancy. For example, the increase of adrenocortical hormone, estrogen, and progesterone may have an immunosuppressive effect, and the immune system tends to recover after delivery quickly [8,9]. It is unknown if immune changes in pregnancy and postpartum impact the natural history of chronic hepatitis B. Higher rates of HBeAg loss (and HBsAg clearance) and biochemical-hepatic flares with increased ALT levels have been reported, especially during early postpartum when immune reconstitution occurs [9]. ...
... Several studies have indicated that women taking anti-HBV therapy during the third-trimester pregnancy had significantly higher postpartum hepatitis flare after delivery than those without prophylactic anti-HBV therapy [6,22]. Other research showed that anti-HBV therapy could not reduce the incidence of postpartum hepatitis flare [8], which was inconsistent with our results. We found that the risk of postpartum hepatitis flare in the prophylactic anti-HBV therapy group was significantly lower than the non-anti-HBV therapy group of pregnant women with high viral load, especially in the relatively severe hepatitis flare women with ALT >5ULN (>200 U/L). ...
Article
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Background: Currently, there are few studies on the effect of prophylactic anti-hepatitis B virus (HBV) therapy (AVT) for mother-to-child transmission during pregnancy on postpartum hepatitis flare (PHF) and the risk factors for postpartum hepatitis flare in women with chronic hepatitis B infection. Aim: To analyze the effect of AVT on the postpartum hepatitis flare and risk factors related to postpartum hepatitis flare. Methods: This study retrospectively enrolled hepatitis B surface antigen (HBsAg)-positive and hepatitis B e antigen (HBeAg)-positive women with HBV DNA ≥ 10 6 IU/mL. Six hundred fourteen pregnant women were included: 444 in the anti-HBV therapy group (T-G) and 170 in the control group (C-G). To analyze the risk factors, women with alanine aminotransferase (ALT) flare ( ALT > 40 U / L ) were assigned to the PHF group (PHF-G, n = 355 ), and all the others were assigned to a non-PHF group (NPHF-G, n = 259 ). Results: At 6 weeks postpartum, ALT and AST levels were higher, and ALB levels were lower in the C-G than those in T-G ( P < 0.05 ). Also, ALT (at baseline, pregnancy 32nd and 36th, intrapartum), AST (at pregnancy 32nd and 36th week, and intrapartum), HBcAb (at baseline, intrapartum), and HBV DNA (at intrapartum) of PHF-G were significantly higher than those of NPHF-G ( P < 0.05 ). Multivariate analysis showed that ALT ( OR = 1.067 , P < 0.001 ) and HBcAb ( OR = 1.213 , P ≤ 0.001 ) in pregnant women were risk factors for PHF. The prophylactic anti-HBV for the prevention of perinatal HBV transmission ( OR = 0.357 , P < 0.001 ) was the protective factor for PHF. Conclusion: Pregnant women with prophylactic anti-HBV during the third trimester of pregnancy had a lower incidence of postpartum hepatitis flare, especially a lower risk of serious hepatitis flare. ALT and HBcAb in pregnant women were risk factors for PHF. Women infected with HBV should be closely monitored ALT during pregnancy and postpartum.
... Therefore, more and more scholars are devoted to explore the optimal time for discontinuation to minimize the incidence of postpartum liver dysfunction. Nguyen et al. (55) found liver dysfunction common after delivery and most of cases were recovered by themselves. Continuing oral antiviral drugs could not reduce the risk of liver dysfunction. ...
... There is no significant difference between two groups in adverse event of grade 3 or 4 or a serious adverse event of maternal and infants (P = 0. 61) function (57)(58)(59)(60). Although the flares are often mild and resolved spontaneously, cases of acute liver failure have been described in the peripartum period (25,55,61). ...
Article
Context: Mother-to-child transmission (MTCT) is one of the main transmission routes of chronic hepatitis B virus (HBV) infection. The successful rate of preventing MTCT has increased to over 90% after the administration of passive-active immunoprophylaxis (vaccine and hepatitis B immunoglobulin (HBIG)) on infants born to hepatitis B surface antigen (HBsAg)-positive mothers. However, 5%-10% of the infants had chronic HBV infection who were born to mothers with high HBV DNA levels. Therefore, the current domestic and international guidelines recommended that antiviral therapy in late pregnancy was to further decrease the MTCT rate. This study aimed at reviewing the mechanisms of MTCT and controversial issues in antiviral therapy for pregnant women with high viral load in order to provide clinicians with some strategies for preventing MTCT of HBV. Evidence Acquisition: Relevant English published papers were searched using online databases, including PubMed and EMBASE from January 2000 to January 2019. We summarized the findings of 61 relevant studies in this review. Results: The mechanism of MTCT is still unclear and further studies are needed. Antiviral therapy for pregnant women with high viral load can reduce the rate of MTCT and provide the appropriate safety for mothers and infants. Conclusions: The mechanisms underlying MTCT of HBV is still unknown and more investigations are required. The efficacy and safety of taking tenofovir disoproxil fumarate (TDF) orally in pregnant women with high viral load in the second or third trimester of pregnancy to block MTCT of HBV have been proved. The withdrawal of antiviral therapy during pregnancy due to MTCT should not exceed 3 months after delivery at the latest. Most pregnant women tend to suffer from increased alanine aminotransferase (ALT) after discontinuing antiviral drugs during pregnancy. Accordingly, close ALT levels monitoring after drug discontinuation is essential.
... Different incidences were reported due to different criteria, which may limit the information needed to explain the natural course of hepatitis flare. The risk of hepatitis flare in HBV carriers without antiviral drug was 1.6-14% in the antenatal period and 3.5-50% in the postpartum period [15,16,19,[35][36][37][38]; it varies depending on the diagnostic criteria of hepatitis flare. The variations in the reports were further suspected to be a result of an unadjusted normal level of ALT; therefore, the American Association for the Study of Liver Diseases (AASLD) recently defined normal ALT as 35 U/L for males and 25 U/L for females [39]. ...
... Therefore, some clinicians do not recommend discontinuation of antiviral drug after delivery [42]. However, delayed discontinuation of antiviral drug after a few months of delivery may not reduce the risk of hepatitis flare [38]. Nevertheless, most standard guidelines recommend discontinuing HBV therapy within three months after delivery [26,28,43,44]. ...
Article
Full-text available
This review aimed to provide an update on the impact of pregnancy on the natural course of hepatitis B virus (HBV) infection and also on the impact of HBV infection on adverse pregnancy outcomes, including mother-to-child transmission (MTCT). For the literature review, original research articles, review articles, and guidelines were narratively reviewed and comprehensively validated. The databases of PubMed, EMBASE, and CINAHL were carefully searched for articles in English on topics related to HBV infection, pregnancy, and vertical transmission from 1960 to May 2021. Immunological changes during pregnancy such as suppression of Th1 response and induction of Th2 immunity lead to an impaired immune reaction to HBV and stimulate viral activity along with the reduction of CD8 T cells to escape immune detection. The impact of pregnancy on the natural course of chronic HBV infection seems to be minimal, while pregnancy can increase morbidity and mortality in the case of advanced HBV hepatitis or cirrhosis. Importantly, hepatitis flare or alanine aminotransferase (ALT) flare can occur during pregnancy and is more common during the postpartum period due to the interaction between HBV and the immune response. Interestingly, the impact of HBV infection on adverse pregnancy outcomes is more serious than ever thought. Updated evidence indicates that pregnancies with chronic HBV infection increase the risk of preterm birth and gestational diabetes, especially in cases of positive hepatitis e antigen (HBeAg).
... Penggunaan antivirus yang diperpanjang hingga 12 minggu postpartum tidak melindungi pasien terhadap kejadian post partum flare, namun fenomena ini lebih banyak terjadi pada penghentian antivirus postpartum kurang dari 4 minggu dibandingkan dengan 12 minggu (50% vs 40%; p<0,01). 40 Oleh karena itu, perlu dilakukan follow up secara ketat selama 6 bulan post partum terutama pada pasien dengan HBeAg positif dan pasien yang sudah secara dini terapi antivirusnya dihentikan. Manajemen flare pada hepatitis B harus disesuaikan dengan panduan tatalaksana hepatitis B yang ada. ...
Article
Hepatitis B merupakan penyebab utama penyakit hati kronik dan dapat menyebabkan sirosis, gagal hati dan karsinoma hepatoselular pada 15-40% populasi. Terhitung sebanyak dua miliar penduduk dunia terinfeksi hepatitis B. Sebanyak 240 juta diantaranya mengidap hepatitis B kronik dan 780.000 jiwa meninggal karena komplikasi akut dan kronik hepatitis B. Transmisi hepatitis B berbeda di berbagai belahan dunia. Pada negara maju, transmisi hepatitis B sebagian besar melalui transmisi horizontal, sedangkan pada negara berkembang transmisi heptitis B 90% melalui transmisi vertikal. Upaya pencegahan transmisi vertikal berupa pemberian imunoglobulin mencapai tingkat keberhasilan hingga 95%, namun menyisakan sebagian kecil populasi yang mengalami kegagalan imunoprofilaksis yang berisiko untuk berkembang menjadi hepatitis B kronik. Pemberian antivirus pada saat antenatal berperan dalam mencegah transmisi vertikal pada populasi yang berisiko mengalami kegagalan imunoprofilaksis.Kata Kunci: analog nukleos(t)ida, hepatitis B, kegagalan imunoprofilaksis, transmisi vertikal Prevention of Hepatitis B Vertical Transmission: Focus on Antenatal Antiviral AdministrationHepatitis B is one of the main cause of chronic liver disease, and potentially cause cirrhosis, liver failure and hepatocellular carcinoma in 15-40% population. Globally, 2 billion people are infected by Hepatitis B. Two hundred and forty million people are suffering from chronic hepatitis B, and more than 780 000 people are dying from both acute and chronic complication of hepatitis B. In developed countries, horizontal transmission is the main mode of virus transmission, while in developing countries vertical transmission occured in 90% population with hepatitis B. Immunoglobulin administration as a prevention strategy for vertical transmission has 95% success rate, but it left 5-10% of those who has immunoprophylaxis failure to be at risk to develop chronic hepatitis B. Antiviral administration during pregnancy is considered to prevent hepatitis B vertical transmission in population at risk on developing immunoprophylaxis failure. Keywords: hepatitis B, immunoprophylaxis failure, nucleos(t)ide analog, vertical transmission
... 23 Furthermore, most of the previous studies started TDF treatment in the third trimester. 1,2,5,6,10,11,20,21,[24][25][26][27][28] However, data regarding the efficacy and safety in mothers whose treatment commenced in the second trimester (24-27 weeks) are sparse. Whether TDF treatment initiated from the second trimester has advantages over TDF treatment starting from the third trimester in highly viraemic pregnant women is not clear. ...
Article
Full-text available
Purpose: To investigate whether tenofovir disoproxil fumarate (TDF) treatment that started from the second trimester had an advantage over TDF treatment that started from the third trimester. Patients and methods: Twenty 35-year-old pregnant women with hepatitis B virus (HBV) DNA >2×106 IU/mL were prospectively enrolled in this study. All participants were divided into two subgroups: the second trimester group who started TDF treatment at 24-27 weeks and the third trimester group who started TDF treatment at 28-30 weeks. The primary outcome was the change in serum HBV DNA level from baseline to delivery. Each parameter was tested every 4 weeks from TDF initiation to 3 months postpartum. Results: There were 80 pregnant women in the second trimester group and 49 pregnant women in the third trimester group. The decline in HBV DNA from baseline to delivery was more obvious in the second trimester group (4.8±1.2 log10 IU/mL) than that in the third trimester group (4.3±1.1 log10 IU/mL, p=0.041). The downward shift of haemoglobin (HB) from baseline to delivery was greater in the second trimester group (10.6±10.7 g/L) than in the third trimester group (6.3±12.3 g/L, p=0.041). The decline in HBV DNA from baseline to delivery was linearly related to the start of TDF treatment from the second trimester (β=0.50 and 95% CI: 0.26-0.75, p<0.001). There were no significant differences between the two groups regarding HBV serologic markers and safety indicators. Conclusion: Starting TDF treatment from the second trimester achieved better viral suppression than starting TDF treatment from the third trimester in highly viraemic pregnant women without increasing additional adverse reactions. HB level needed frequent monitoring during treatment to avoid anaemia. Registry number: Clinical Trial No. NCT02719808.
... Higher rates of HBeAg loss (and HBsAg clearance) and biochemical-hepatic flares with increased ALT levels have been reported, especially during early postpartum when immune reconstitution occurs. (106)(107)(108)(109)(110) Most flares are self-limited and do not require therapy, but some can be severe, resulting in liver failure. (111,112) The reported rates of ALT flares postpartum are variable owing to different definitions of ALT flare, patient characteristics, and antiviral therapy (Table 2). ...
Article
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The hepatitis B virus (HBV) is an important human pathogen. Unvaccinated infants infected through mother‐to‐child transmission (MTCT) are at >95% risk of developing serum hepatitis B surface antigen‐positive chronic hepatitis B (CHB). Despite complete passive‐active HBV immunoprophylaxis, approximately 10% of infants born to mothers who are highly viremic develop CHB, and thus maternal treatment with nucleos(t)ide analogs (tenofovir disoproxil fumarate, lamivudine, or telbivudine) is recommended in the third trimester of pregnancy to reduce MTCT risk. Viral rebound usually occurs after stopping treatment and, in the context of maternal immunologic reconstitution postpartum, can also precipitate host immune‐mediated hepatic (biochemical) flares. In this article, we review the epidemiology of HBV MTCT, discuss management and potential mechanisms of HBV vertical transmission, and highlight recent studies on virologic and immunologic aspects of hepatitis B in pregnancy and postpartum.
... It is therefore suggested that women with high virus load initiate treatment in the earlier part of this period. Treatment with TDF, initiated during weeks 28-32 of pregnancy should end 0-3 months after childbirth, provided the mother is not supposed to undergo continued treatment for chronic HBV infection [82]. There are no reasons to advise against breastfeeding, even for women who continue antiviral therapy after childbirth [83]. ...
Article
Full-text available
Despite access to effective antiviral drugs and vaccines, hepatitis B virus (HBV) infection remains a major health issue worldwide. HBV is highly infectious and may cause chronic infection, progressive liver damage, hepatocellular cancer (HCC) and death. Early diagnosis, proper management and timing of treatment are crucial. The Swedish Reference group for Antiviral Treatment (RAV) here provides updated evidence-based guidelines for treatment and management of HBV infection which may be applicable also in other countries. Tenofovir alafenamide (TAF) has been introduced as a novel treatment option and new principles regarding indication and duration of treatment and characterization of hepatitis B have been gradually introduced which justifies an update of the previous guidelines from 2007. Updated guidelines on HCC surveillance in HBV-infected patients, treatment and prophylaxis for patients undergoing liver transplantation as well as management of pregnant women and children with HBV infection are also provided.
... 16,24,[26][27][28][29][30][31][32][33][34][35] Some of them covered more than one NA (n = 7). 7,15,16,24,26,28,31 Contrary to relatively older studies, the majority of recent studies did not cover LAM. In all studies for the group under treatment, antiviral therapy was initiated in the second or third trimester, while discontinuance occurred at different times. ...
Article
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Background and Aims: The perinatal transmission of hepatitis B virus (HBV) remains an important global health problem. Here, a systematic review and meta-analysis were conducted to evaluate the evidence regarding the efficacy and maternal/fetal safety of treating pregnant women with lamivudine, telbivudine (LdT), and tenofovir (TDF). Methods: A PubMed and Scopus search resulted in 1,076 records, which were reduced to 36, containing 7,717 pregnant women with chronic HBV infection and 7467 infants meeting the inclusion criteria. The latest search was in August 2019. Results: Treatment with LdT, but not lamivudine and TDF, could significantly reduce the hepatitis B virus surface antigen-positive rate (odds ratio (OR) = 0.37) in infants; it also led to higher rates of hepatitis B e antigen loss (OR = 12.14), hepatitis B e antigen seroconversion (OR = 8.93), and alanine aminotransferase normalization in mothers (OR = 1.49). Each of these treatments was able to significantly reduce HBV DNA positivity at birth (total OR = 0.19) and mother-to-child-transmission of HBV (total OR = 0.15), and to cause higher rates of HBV DNA suppression in mothers (total OR = 25.53). However, nucleos(t)ide analogues might also be involved in creatine kinase elevation (total OR = 7.48). In contrast, no significant association was found between nucleos(t)ide analogue therapy and preterm/premature births, congenital malformation, low birth weight, and abortion or fetal/infant death. The results suggested LdT's high capability of preventing mother-to-child-transmission. However, TDF failed to show significant associations to a reduced risk of mother-to-child-transmission, probably due to the low number of patients included. Conclusions: Although using either lamivudine, LdT, or TDF could lead to more favorable maternal/fetal outcomes, LdT seemed to show more potential in resolving certain infant- and maternal-related outcomes. More studies on the safety profile of such treatments are required.
... Most studies of antiviral use to prevent MTCT continue antivirals for 4 to 12 weeks after delivery, and HBV flares can occur in the postpartum period, thought to be due to immunereconstitution after the relative immune-tolerance of the pregnant state. 18 All patients should be monitored in the postpartum setting for disease flare. If HBV flare is persistent or severe, initiation or re-initiation of antiviral therapy should be considered. ...
Article
Antiviral therapy with lamivudine, tenofovir, or telbivudine in the 3rd trimester can decrease mother-to-child transmission (MTCT) to < 5% and should be used in women with high viral loads in the 3rd trimester. Postpartum flares of liver disease are common, and therefore, careful monitoring is warranted in women who stop therapy. The decision to breastfeed while on antiviral therapy should be individualized, but current evidence suggests that it is safe. How to cite this article Kumari SS, Prakash P, Garg R, Agarwal P. Hepatitis B in Pregnancy. J South Asian Feder Obst Gynae 2016;8(3):167-170.
... There are conflicting data about the proportion and severity of flares after discontinuing antiviral therapy. [44][45][46] There are no data in pregnant women regarding flares with longer duration of treatment and lower HBV DNA at delivery, nor is there information about predisposing characteristics to provide recommendations either before, or even after, flares start. We will determine the proportion of woman who have a moderate (ALT >2.5× ULN) or severe (ALT >5× ULN) hepatitis flare after discontinuation of TDF. ...
Article
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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.
... Hepatic flares are detected using ALT but in most RLSs, ALT is not available on site which can cause a delay in identification of the flare. Most, 90%, of the cases resolves spontaneously, but in rare cases, flares could cause severe disease and even death [35,36]. This implies that after stopping tenofovir treatment the woman should be able to follow up in a clinic preferably with the ability to measure ALT. ...
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Background The aim of this manuscript is to highlight challenges in the implementation of maternal tenofovir disoproxil fumarate (tenofovir) for prevention of mother to child transmission (PMTCT) of hepatitis B virus (HBV) in resource limited setting. Current preventive strategies in resource-limited settings fail mainly due to prohibitive costs of hepatitis B immunoglobulin (HBIG) and a high proportion of homebirths, meaning both HBIG and hepatitis B birth dose vaccine are not given. A new strategy for PMTCT without the necessity of HBIG, could be daily tenofovir commenced early in gestation. Implementation challenges to early tenofovir for PMTCT can provide insight to elimination strategies of HBV as the burden of disease is high in resource-limited settings. Methods Challenges encountered during implementation of a study of tenofovir for PMTCT before 20 weeks gestation in rural and resource-limited areas on the Thailand-Myanmar border were identified informally from trial study logbooks and formally from comments from patients and staff at monthly visits. ClinicalTrials.gov Identifier: NCT02995005. Main body During implementation 171 pregnant women were hepatitis B surface antigen (HBsAg) positive by point of-care test over 19 months (May-2018 until Dec-2019). In this resource-limited setting where historically no clinic has provided tenofovir for PMTCT of HBV, information provided by staff resulted in a high uptake of study screening (95.5% (84/88) when offered to pregnant women. False positive point-of-care rapid tests hinder a test and treat policy for HBV and development of improved rapid tests that include HBeAg and/or HBV DNA would increase efficiency. Integrated care of HBV to antenatal care, transport assistance and local agreements to facilitate access, could increase healthcare at this critical stage of the life course. As safe storage of medication in households in resource-limited setting may not be ideal, interactive counseling about this must be a routine part of care. Conclusion Despite challenges, results from the study to date suggest tenofovir can be offered to HBV-infected women in resource-limited settings before 20 weeks gestation with a high uptake of screening, high drug accountability and follow-up, with provision of transportation support. This commentary has highlighted practical implementation issues with suggestions for strategies that support the objective of PMTCT and the World Health Organization goal of HBV elimination by 2030.
... No patients had kidney dysfunction in TDF treatment group. In line with our observations, Nguyen et al. reported that regardless of whether TDF was immediately withdrawn after delivery or continuously used, this medicine did not affect the risk of HBV DNA recovery in pregnancies 40 . However, another study recommended close monitoring up to 6 months after delivery for women who were HBeAg positive or had stopped TDF treatment 41 . ...
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Mother-to-child transmission is the major cause of chronic hepatitis B virus (HBV) infection. This double-blind trial tested the effect of tenofovir disoproxil fumarate (TDF) in preventing vertical transmission. Pregnant women who were HBsAg/HBeAg-positive with a HBV DNA titer ≥ 2×10⁶ IU/mL were randomly assigned to the control (n = 60) and TDF-treated (n = 60) groups. TDF treatment (oral dose 300 mg/day) was initiated at 24 weeks of gestation and continued to 4 weeks after delivery. The subjects were followed up to 28 weeks postpartum. The effects of TDF on vertical transmission, outcomes of the mothers and infants and virological changes were monitored. TDF dynamically reduced the serum HBV DNA level of the mothers, particularly during the first 4 weeks of treatment. The lower viral loads were maintained in the pregnancies until delivery. Approximately 90% and 33.9% of the TDF-treated mothers had viral loads ≤2000 IU/mL after delivery and at 28 weeks postpartum, respectively. No cervical transmission or adverse effects were observed in the TDF-treated individuals, whereas 13.5% of the infants were infected with HBV in the control group. We conclude that TDF treatment initiated at 24 weeks of gestation in high-viremia, HBsAg/HBeAg-positive mothers efficiently prevents mother-to-child HBV transmission without adverse events in mothers and infants.
... [8] It is hypothesized that postpartum hepatic flares in HBV or autoimmune hepatitis are due to immune system reactivation after parturition. [16,17] We selected patients who received antiviral treatment during pregnancy and compared their cytokines in different postpartum ALT groups. We aimed to study the relationship between postpartum ALT abnormalities and cytokines during postpartum non-treatment patients with high viremia. ...
Article
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Alanine transaminase (ALT) abnormalities are common in chronic hepatitis B (CHB) carriers during postpartum period. Disturbances in cytokines are considered to be associated with hepatitis Flares. There are limited data on cytokines changes in HBeAg positive patients with ALT abnormalities.This is an observational study. Pregnant patients with hepatitis B e-antigen (HBeAg) positive were enrolled from January 2014 to September 2018. Patients were assigned into three groups based on ALT levels in postpartum 6 to 8 weeks: ALT in normal range, ALT in 1 to 2-fold upper limits of normal (ULN) and ALT >2-fold ULN. Serum cytokines, ratios of regulatory T cells, and the concentration of cortisol were collected and compared among the three groups.Of the 135 mothers enrolled, 80.7% (109/135) completed the postpartum 6-week study. 13.8% (15/109) patients had postpartum ALT higher than 2ULN, 27.5% (30/109) patients had ALT in 1 to 2ULN and 58.7% (64/109) patients had ALT in normal range. Compared to control group, patients with ALT >2ULN had a higher IL-10 level (P < .05). No differences of IL-10 levels were found in the comparison of other inter comparison among three groups. No differences were found in the levels of other collected serum cytokines, cortisol, and regulatory T cells among three groups. On multivariate analysis, abnormal IL-10 level was independent risk factor for postpartum ALT elevating >2ULN. At the same time, the incidence of postpartum ALT elevated >2ULN were higher in patients with abnormal elevation IL-10 level than in patients with normal IL-10 level (14/68 vs 1/41, P = .008).CHB patients with postpartum ALT abnormalities show higher IL-10 level and postpartum ALT abnormalities were mainly occurred in patients with abnormal IL-10 level. IL-10 may be an underlying predictor and treatment target of hepatitis B, and further studies are needed.
... 15,16 Most studies found that NA therapy in late pregnancy followed by treatment withdrawal early post-partum was associated with ALT flare but reported variable changes in HBV DNA levels or rates of HBeAg seroconversion during immediate post-partum up to 1 year of follow-up. 10,12,[17][18][19][20][21][22] The primary objective of this retrospective real-world cohort study was to evaluate maternal viral markers (ie HBV DNA, HBeAg and HBsAg) and ALT changes during pregnancy, early and long-term follow-up post-partum. Our secondary objectives were to assess: (a) maternal ALT and HBV DNA changes during single or multiple pregnancies, (b) liver stiffness measurement, (c) changes in maternal renal function and phosphate, and (d) infant immunoprophylaxis outcomes. ...
Article
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Background: There are limited long-term data on outcomes of chronic hepatitis B (CHB) in untreated and tenofovir disoproxil fumarate (TDF)-treated women during pregnancy. Aims: To assess clinical outcomes in a multiethnic cohort of patients during pregnancy and post-partum in a low HBV endemic region. Methods: Retrospective real-world study of women with CHB (treated or untreated with TDF) from 2011 to 2019; data including ALT, HBV DNA, HBeAg and liver stiffness measurement were collected during pregnancy and post-partum. Results: In 341 women (446 pregnancies) followed for a median of 33 months (IQR: 26.7-39.5) post-partum, 19% (65/341) received TDF (11 initiated pre-pregnancy, 53 for mother-to-child transmission (MTCT) prevention). During follow-up, 72/341 had subsequent pregnancy, including 18/53 on TDF for MTCT risk, of whom 7/18 were re-treated. In all TDF-treated women, HBV DNA declined but rebounded after TDF withdrawal (median baseline, near birth and early follow-up levels were 7.2, 3.0 and 5.5 log IU/mL respectively [P < 0.01]). In HBeAg+ patients (65/341) ALT flares were more common (P = 0.03), especially for those who stopped TDF post-partum, requiring re-treatment in 21% (11/53). In comparison, 54% (116/215) of untreated women had a post-partum ALT flare; one with fulminant hepatitis underwent transplant 13 months post-partum. HBsAg clearance occurred in 2.6% (9/341, 3/9 HBeAg+, 2/9 TDF treated) at median 30 months (IQR: 23-40) and 37% (24/65) of HBeAg+ patients had HBeAg loss at median 17 months (IQR: 12-26) post-partum. Conclusions: Post-partum ALT flares were common, especially after TDF withdrawal. Overall, 37% achieved HBeAg clearance and 2.9% had HBsAg loss during long-term follow-up.
... When antivirals are indicated only to reduce MTCT, treatment may be discontinued at delivery or kept up to 4-12 weeks after delivery to reduce the risk of flares [30]. In a prospective study where 91 women received antiviral therapy to prevent transmission, extending antiviral therapy beyond delivery did not appear to reduce the frequency of HBV flares over a median of a 48 week-follow-up [49]. ...
Article
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Infection with the hepatitis B virus (HBV) is one of the leading global public health issues. Over 250 million people worldwide have chronic HBV infection, out of which roughly 65 million are women in their reproductive age. The most common route of passing the infection in areas of high endemicity is by mother-to-child transmission (MTCT). In children the infection may still occur despite adequate immunoprophylaxis, however, antiviral medication, such as Tenofovir disoproxil fumarate (TDF), may be helpful in reducing the risk of MTCT. A literature review was conducted concerning TDF's role in preventing MTCT and its safety in pregnancy. Studies were identified by researching various databases up to 2020 for variations of the following sentence: "Tenofovir disoproxil fumarate and Lamivudine and Telbivudine and Entecavir and pregnancy and transmission and safety and HBV". Prenatal and perinatal adequate management of maternal HBV infection is of utmost importance, with focus on prevention of MTCT as the key strategy to reduce the global HBV infection burden. This review discusses the most up-to-date evidence from a multidisciplinary perspective of using TDF to reduce MTCT of HBV infection as well as its safety profile for pregnant women.
... This risk of hepatic flare following the cessation of TDF treatment was taken from a study in Australia, which found that 50.0% require additional TDF treatment and lab tests [31]. This is in line with other published studies on post partum flare [38,39]. ...
Article
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Background Hepatitis B Virus (HBV) is transmitted from mother to child which can be prevented via birth dose vaccine combined with three follow up hepatitis B vaccines, hepatitis B immunoglobulins (HBIG), and maternal antiviral treatment with Tenofovir Disoproxil Fumarate (TDF). This study evaluates the cost effectiveness of six strategies to prevent perinatal HBV transmission in a resource limited setting (RLS) on the Thailand-Myanmar border. Methods The cost effectiveness of six strategies was tested by a decision tree model in R. All strategies included birth and follow up vaccinations and compared cost per infection averted against two willingness to pay thresholds: one-half and one gross domestic product (GDP) per capita. Strategies were: 1) Vaccine only, 2) HBIG after rapid diagnostic test (RDT): infants born to HBsAg+ are given HBIG, 3) TDF after RDT: HBsAg+ women are given TDF, 4) TDF after HBeAg test: HBeAg+ women are given TDF, 5) TDF after high HBV DNA: women with HBV DNA > 200,000 are given TDF, 6) HBIG & TDF after high HBV DNA: women with HBV DNA > 200,000 are given TDF and their infants are given HBIG. One-way and probabilistic sensitivity analyses were conducted on the cost-effective strategies. Results Vaccine only was the least costly option with TDF after HBeAg test strategy as the only cost-effective alternative. TDF after HBeAg test had an incremental cost-effectiveness ratio of US$1062; which would not be considered cost-effective with the lower threshold of one-half GDP per capita. The one-way sensitivity analysis demonstrated that the results were reasonably robust to changes in single parameter values. The PSA showed that TDF after HBeAg test had an 84% likelihood of being cost effective at a willingness to pay threshold of one GDP per capita per infection averted. Conclusions We found that TDF after HBeAg test has the potential to be cost-effective if TDF proves effective locally to prevent perinatal HBV transmission. The cost of TDF treatment and reliability of the RDT could be barriers to implementing this strategy. While TDF after RDT may be a more feasible strategy to implement in RLS, TDF after HBeAg test is a less costly option.
... Evidence has supported a favourable safety profile for antiviral use in both mothers and infants [6]. Although post-partum hepatic flares have been observed in several studies and may be associated with the use of antiviral therapy, they are often mild in severity and most spontaneously resolve [28,29]. Also, no serious concerns regarding safety have been raised on antiviral therapy in asymptomatic carriers and immune tolerant individuals [30]. ...
Article
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Abbreviations: AASLD, American Association for the Study of Liver Diseases; AUC, area under the receiver operating characteristic curve; cccDNA, covalently closed circular DNA; CI, confidence interval; CMIA, chemiluminescent microparticle immunoassay; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; LMIC, low- and middle-income country; MTCT, mother-to-child transmission; PEI, Paul Ehrlich Institute; RDT, rapid diagnostic test; RLU, relative light unit; ROC, receiver operating characteristic; S/CO, sample to cut-off; WHO, World Health Organization.
... There have been concerns that the discontinuation of antiviral treatment may exacerbate hepatitis flares. Although there was an increased tendency toward the development of postpartum hepatitis flares after the discontinuation of antiviral agents in the antiviral-treated group compared to the non-antiviral-treated group, the severity of hepatitis was not different, and most patients showed resolution with or without antiviral treatment [71]. The most recent meta-analysis on this topic showed that lamivudine, telbivudine, and TDF can be used safely with no increase in the risk of postpartum hepatitis flares after treatment discontinuation [46]. ...
Article
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Hepatitis B virus (HBV) is a main cause of chronic liver disease worldwide and can lead to severe liver diseases. The World Health Organization has planned to eliminate viral hepatitis, including hepatitis caused by HBV and hepatitis C virus, by 2030. As mother-to-child transmission (MTCT) of HBV is a main cause of chronic HBV infection, MTCT prevention is the main target to reduce the risk of chronic HBV infection and eliminate the disease. Recent clinical trials and meta-analyses found that antiviral therapy could prevent MTCT effectively in mothers with ≥200,000 IU/mL of HBV DNA, in combination with serial vaccination and hepatitis B immune globulin administration in infants. Despite the preventive role of antivirals for MTCT of HBV, there are several concerns regarding antiviral therapy with respect to the safety of the mother and fetus during pregnancy. This review summarizes the benefits and risks of antiviral treatment during pregnancy in women with chronic HBV infection.
... The aim of therapy is to reduce HBV DNA levels below the threshold of transmission or immunoprophylaxis failure at the time of delivery, and for this reason treatment is mainly started around 28 wk to 32 wk of gestation. Earlier may be beneficial and has been suggested for prevention of early placental infection and intrauterine transmission [39]. When the treatment is started only to prevent vertical transmission, it could be discontinued as early as at delivery or, as suggested by the major international societies, prolonged until 12 wk after delivery. ...
Article
Hepatitis B virus (HBV) is the leading cause of chronic viral hepatitis. Annually, almost two million children younger than 5 years acquire the infection, mostly through vertical or horizontal transmission in early life. Vertical transmission of HBV is a high efficacy phenomenon ranging, in the absence of any preventive interventions, from 70% to 90% for hepatitis e antigen positive mothers and from 10% to 40% for hepatitis e antigen-negative mothers. Maternal viraemia is a preeminent risk factor for vertical transmission of HBV. Maternal screening is the first step to prevent vertical transmission of HBV. Hepatitis B passive and active immunoprophylaxis at birth together with antiviral treatment of highly viraemic mothers are the key strategies for global elimination of HBV infection. Strategies are needed to promote implementation of birth-dose vaccination and hepatitis B immunoglobulins in low- and middle-income countries where the prevalence of the infection is at the highest.
... The point is to strike a balance between the potential risk of interfering with breastfeeding and the benefit on possible postpartum hepatitis flares [35] . More con servative recommendations [45] rely on a prospective study recruiting 91 women (101 pregnancies), showing no advantages in terms of hepatitis flare rate for gravid subjects who extended antiviral prophylaxis with TDF beyond 4 wk after delivery [79] . Nevertheless, prolongation of antiviral prophylaxis [38] might be useful at least for women with elevated ALT during pregnancy, since they present a higher risk of postpartum hepatitis flare, as showed by a Chinese study wherein mothers were administered LdT [80] . ...
Article
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Hepatitis B virus (HBV) infection is one of the main public health problems across the globe, since almost one third of the world population presents serological markers of contact with the virus. A profound impact on the epidemiology has been exerted by universal vaccination programmes in many countries, nevertheless the infection is still widespread also in its active form. In the areas of high endemicity (prevalence of hepatitis B surface antigen positivity > 7%), mother-to-child transmission represents the main modality of infection spread. That makes the correct management of HBV in pregnancy a matter of utmost importance. Furthermore, the infection in pregnancy needs to be carefully assessed and handled not only with respect to the risk of vertical transmission but also with respect to gravid women health. Each therapeutic or preventive choice deserves to be weighed upon attentively. On many aspects evidence is scarce or controversial. This review will highlight the latest insights into the paramount steps in managing HBV in pregnancy, with particular attention to recommendations from recent guidelines and data from up-do-date research syntheses.
... Approximately 17.2-62% of patients might develop hepatitis flares after discontinuation, which usually occurs within 24 weeks. [187][188][189] Postpartum monitoring is needed. Blood biochemical indexes for the liver and HBV DNA should be rechecked 4-6 weeks after delivery. ...
Article
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To achieve the goal of the World Health Organization to eliminate viral hepatitis as a major public health threat by 2030, the Chinese Society of Infectious Diseases and the Chinese Society of Hepatology convened an expert panel in 2019 to update the guidelines for the prevention and treatment of chronic hepatitis B (CHB). The current guidelines cover recent advances in basic, clinical, and preventive studies of CHB infection and consider the actual situation in China. These guidelines are intended to provide support for the prevention, diagnosis, and treatment of CHB.
... 5,16 Notably, delay in stopping antiviral therapy until the first few months after delivery has not been shown to reduce risk for HBV flare. 17 The treatment course for women with immune-active hepatitis B, or with advanced fibrosis, should follow that of nonpregnant populations (Fig. 1). ...
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... Although most mothers with CHB are HBeAg-positive, we want to briefly mention pregnancy-associated flares that obviously result from immunologic alterations [12]. In pregnant patients with CHB who are treated with Nucs, postpartum flares are common after the cessation of Nuc treatment [52]; however, these flare episodes are often mild and resolve spontaneously [53]. In untreated pregnant females with CHB, spontaneous flares are also mild and self-limited in both the prepartum and postpartum periods [54]. ...
Article
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Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.
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Nucleo(t)side analogues (NAs) have been administered as adjunctive therapy to interrupt the mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV). The efficacy and safety of this method remain controversial. A Meta‐analysis was conducted to evaluate the efficacy and safety of NAs treatment during pregnancy. The differences among different agents and initiation trimesters were analysed. A total of 9228 mother‐infant‐pairs in 59 studies (32 RCTs and 27 non‐RCTs) were included in this meta‐analysis. NAs significantly reduced the risk of MTCT, as indicated by seropositivity of hepatitis B surface antigen (HBsAg) (risk ratio (RR)=0.51, 95% confidence interval (CI) 0.45 to 0.57) and HBV DNA in newborns (RR=0.22, 95% CI 0.18 to 0.26). No differences in the efficacy of interrupting HBV MTCT were evident among lamivudine, telbivudine, and tenofovir disoproxil fumarate. NA was more effective when administered from the second than from the third trimester as indicated by HBV DNA (RR: the second vs. the third 0.08 vs. 0.22, P=0.010), but this effect was not evident as indicated by HBsAg (RR: the second vs. the third 0.46 vs. 0.53, P=0.596). Antiviral treatment initiated from the second trimester did not confer a higher risk of safety problems in the newborns compared with treatment from the third trimester, as indicated by weight (P=0.064), length (P=0.491), and malformation rate (P=0.635) of newborns. Conclusions Lamivudine, telbivudine, and tenofovir disoproxil fumarate are equally effective in blocking HBV MTCT. Antiviral treatment can be applied from the second trimester, without obvious safety concerns. This article is protected by copyright. All rights reserved.
Article
Liver diseases during pregnancy pose a unique clinical challenge because they can affect the lives of both the mother and unborn child. Although severe liver disease is rare, pregnancy-related liver disease affects approximately 3% of pregnancies and can be fatal. Timely recognition and diagnosis are essential in order to institute appropriate management strategies. This article provides an overview of liver diseases during pregnancy and is divided into 2 sections: (1) liver diseases specific to pregnancy, and (2) preexisting or coincident liver diseases during pregnancy.
Article
Introduction: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. Methods: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy. Results: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation. Discussion: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.
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Hepatitis virus infection is often initiated in infancy or childhood. Mother-to-infant transmission is an important transmission route for a large number of patients, with subsequent chronic hepatitis and associated long-term complications including cirrhosis, liver cancer, and mortality. In the past 30 years, measures to prevent mother-to-infant transmission have been investigated extensively especially in hepatitis B virus infection, including screening of pregnant women with HBsAg and/or HBeAg, neonatal immunization with HBV vaccines and hepatitis B immunoglobulin, and postimmunization surveillance for children with breakthrough infection. For up to 10% of infants born to HBsAg-/HBeAg-positive mothers, neonatal immunization may not offer effective protection, and these infants may become chronically infected. Recently, studies have shown that short-term antiviral therapy for HBV-infected pregnant women with a high viral load has effectively prevented mother-to-infant transmission. Mother-to-infant transmission of hepatitis C virus occurs in about 5% of HCV-infected mothers. Screening of pregnant women for HCV is still a controversial issue because no effective preventive measure is currently available. Surveillance of children born to HCV-infected mothers is recommended. Acute HAV and HEV infection in pregnant women is rare, but these infections should be considered when icteric illness occurs in pregnant women. HAV vaccination helps to decrease the susceptible population. Acute HEV infection in pregnant women frequently leads to fulminant hepatic failure, with a high mortality rate for the mother, fetus, and neonates. Most reported cases occurred in an endemic area. Safe drinking water, public health improvement, and newly developed HEV vaccines are effective measures to prevent infection. In conclusion, efforts toward interrupting mother-to-infant transmission of viral hepatitis will effectively improve maternal/fetal/neonatal outcomes, as well as preventing a large population in the world with chronic hepatitis and associated complications.
Article
Introduction: Hepatitis B infection in pregnancy mandates careful monitoring and specialized management according to the phase of hepatitis B infection. Perinatal transmission may be prevented by antiviral therapy in mothers with high viral load and timely immunoprophylaxis of the infant. Areas covered: This review focuses on the current first-line therapies for treating hepatitis B in pregnancy, timing of therapy, and prevention of perinatal transmission. Strategies to manage disease at the various phases and potential emerging therapies in phase III of development are also covered. Medline/PubMed and Cochrane databases were searched systematically from 1990 to April 2018 with the relevant articles selected for the review. Expert opinion Universal antenatal screening for hepatitis B and strict immunoprophylaxis for infants form the cornerstones to prevent hepatitis B virus (HBV) perinatal transmission. Tenofovir is the preferred drug for treatment in pregnancy in view of its good efficacy and high barrier to resistance. Most of the data on antivirals are from cohort studies which are prone to bias and more randomized controlled trials (RCTs) are needed to establish the benefits and safety of these drugs in pregnancy. Various novel drugs are in the pipeline which may pave the way for a cure in the near future.
Article
Objective To investigate the effect of antiviral therapy and drug withdrawal on the incidence of hepatitis B after delivery in pregnant women with chronic hepatitis B virus (CHB) infection who received tenofovir disoproxil fumarate (TDF) treatment.Methods Eligible CHB pregnant women were enrolled, and received TDF at 32 weeks gestation. The drug was stopped immediately or at 6 weeks after delivery. The HBV biomarkers and clinical biochemical parameters were monitored during gestation and 24 weeks after delivery.ResultsThere were 264 women completed the observation, including 96 untreated subjects in control group. Among 168 treated subjects, 131 cases stopped drug immediately after delivery and 37 cases delayed the drug withdrawal at 6 weeks after delivery. The incidence of postpartum hepatitis in control, immediate drug withdrawal, and delayed drug withdrawal were 28.1% (27/96), 23.7% (31/131), and 24.3% (9/37), showing no significant difference (χ2 = 0.607, p = 0.738). No factor was found to be associated with the occurrence of postpartum hepatitis. It’s noteworthy that 96.3% of postpartum hepatitis in control group and 92.3% of postpartum hepatitis in immediate drug withdrawal group occurred within 12 weeks after delivery. While in delayed drug withdrawal group, the rate of postpartum hepatitis occurred within 12 weeks after delivery was 77.7%.Conclusion Withdrawing antiviral drug immediately or at 6 weeks after delivery did not affect the incidence of postpartum hepatitis in CHB women, but delaying drug withdrawal might delay the onset of postpartum hepatitis.Clinical trial registration number: NCT03214302.
Article
Mother‐to‐child transmission (MTCT) is responsible for the majority of chronic hepatitis B virus (HBV) infections worldwide. Despite timely HBV immunoprophylaxis of neonates, MTCT can occur in infants born to mothers with high levels of HBV viremia. We performed a retrospective cross‐sectional analysis of Asian American women with chronic HBV evaluated with HBV DNA during prenatal care at two community health sites in New York City from 2007 to 2017. We described patient's demographic and clinical characteristics, categorized their HBV disease phase, and analyzed for variables associated with high MTCT risk (defined by HBV DNA level > 200,000 IU/mL) using multivariable logistic regression. A total of 1298 pregnancies among 1012 mostly China‐born (97.6%) women with chronic HBV were included in the study. Of the 1241 pregnancies among women not on antiviral treatment, 22.4 % were considered high‐risk for MTCT and of these, 255 (91.7%) were HBV e antigen (HBeAg)‐positive and 19 (6.8%) were HBeAg‐negative. HBeAg‐positive status and ALT levels between 26 to 50 U/L were associated with higher likelihood for being high‐risk for MTCT. Only 0.8% of pregnancies low‐risk for MTCT were in the immune active phase while the majority (58.4%) were in the inactive chronic HBV phase of infection. Approximately one in five (22.4%) pregnancies among Asian American women with chronic HBV was considered high‐risk for MTCT and met criteria for antiviral therapy. Full assessment of HBV pregnant women and early coordinated care is needed to deliver interventions to prevent MTCT during critical windows of time.
Article
Importance: Vertical hepatitis B virus (HBV) transmission is the important route of chronic HBV infection. Although infant immunoprophylaxis is effective, a significant number of infants still become infected, most are associated with intrauterine infection. New evidences support intrauterine treatment in cases of high risk. Objective: The aim of this study was to review the current evidences and recommendations for management of HBV infection in pregnancy. Evidence acquisition: Original research articles, review articles, and guidelines were reviewed. Results: The management can be summarized as follows: (1) all pregnant women should be screened for hepatitis B surface antigen (HBsAg) and antibody to HBsAg. High-risk HBsAg-negative pregnant women without immunity should be vaccinated during pregnancy. (2) HBsAg-positive pregnant women should undergo further workup for liver status and indicative factors for immunoprophylaxis failure. (3) Pregnant women should be treated with HBV DNA levels greater than 200,000 IU/mL or 6 log copies/mL. (4) Antiviral drug should be started around 28 to 32 weeks. The first-line drug is tenofovir disoproxil fumarate. (5) Delivery route should be chosen based only on obstetric indications. (6) Breastfeeding is not contraindicated because it does not increase the risk of transmission in neonates with HBV vaccine and immunoglobulin administration. (7) Neonates born to HBsAg-positive mothers should receive HBV vaccine and immunoglobulin after birth as soon as possible. (8) Follow-up of the mothers and neonates is important. Beware of hepatitis flare after birth and after antiretroviral drug discontinuation; alanine transaminase assessment every 1 to 3 months until 6 months is suggested. Also, the schedule of infant vaccination and follow-up of serologic testing at 9 to 12 months old is needed.
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.
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Chronic liver disease poses various challenges for women of reproductive age. Cirrhosis, particularly if decompensated, and liver transplantation may impact gestation and perinatal outcomes. Tailored management of underlying liver disease is critical to optimize maternal and fetal wellbeing. Early education, timely intervention, close monitoring, and a multidisciplinary approach are key elements required to minimize complications and increase chances of a safe and successful pregnancy. In this review, we focus on the pregnancy-related implications of chronic liver disease and liver transplantation on women of reproductive age and highlight disease-specific management considerations.
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Chronic hepatitis B virus (HBV) infection is a substantial global health burden. Despite immunoprophylaxis and advancement in antiviral therapies in the past decades, there is still an enormous load of afflicted people, mostly adults born before the HBV universal vaccination program and children without timely vaccination or immunization failure. Like adults, infected children may experience hepatitis activity and chronic consequences without awareness and thus require screening, followed by close monitoring and proper treatment. As of 2021, most antivirals licensed for adults are approved for children (including pegylated interferon and tenofovir). HBV-infected pregnant women are a particular group that needs screening to identify and monitoring hepatic inflammation and viral loads during pregnancy and postpartum to implement appropriate management for maternal/fetal health and to prevent mother-to-infant transmission of HBV. The best practice and long-term impacts in children and pregnant women/offspring are still evolving. To reach the goal of eliminating viral hepatitis of the World Health Assembly by 2030, infant vaccination should be aided with maternal late pregnancy prophylaxis. Screening, monitoring, antiviral therapy, and surveillance of cirrhosis and hepatocellular carcinoma are the secondary strategies toward the global elimination of chronic hepatitis B. They should include children and pregnant women as a whole.
Article
Background Tenofovir disoproxil fumarate (TDF) is recommended for the prevention of perinatal transmission of the hepatitis B virus (HBV). This study aimed to systematically assess the efficacy and safety of TDF in pregnant women with chronic HBV and their infants. Material and methods Database searches were performed to identify studies blocking the mother-to-child transmission of the hepatitis B virus with tenofovir. The search included pregnant women with chronic HBV infection administered with TDF compared to the no treatment controls, and data from individual studies were pooled using RevMan v5.3 for meta-analysis. Results Seven studies with a total of 911 patients met the inclusion criteria: 433 patients in the TDF group and 478 patients in the non-TDF group. The HBV mother-to-child transmission rate in the tenofovir group was effectively reduced compared to the control group (RR: 0.18, 95% CI: 0.08-0.40). HBV-DNA positivity was also significantly low in infants from TDF group (RR: 0.17, 95% CI: 0.10-0.30) and the TDF treatment resulted in significantly higher anti-HBs production (RR: 1.11, 95% CI: 1.04-1.18). Similarly, maternal HBV-DNA was suppression was significantly high in the TDF group (RR: 34.16, 95% CI: 16.40-71.13). Women treated with TDF and their infants did not result in serious adverse events that are statistically different as compared to the women who did not receive any treatment. Conclusion Treatment of HBV infected pregnant women with TDF can effectively and safely prevent the perinatal transmission of chronic hepatitis B.
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
Perinatal transmission of hepatitis B virus continues to be a serious global public health concern. Transmission failures are related to high maternal viremia. Several antiviral therapies reduce maternal viremia around the time of delivery and decrease maternal-to-child-transmission. This chapter is a review of current studies that, ultimately, have provided strong evidence for the efficacy and safety of 3 antiviral drugs in pregnancy-lamivudine, telbivudine and tenofovir. The latter drug is the particular focus of this chapter which will show that tenofovir is the preferred antiviral therapy in pregnant women because of its potency, safety profile, and low risk of resistance.
Article
Background: Tenofovir disoproxil fumarate (TDF) is recommended for the prevention of perinatal transmission of the hepatitis B virus (HBV). This study aimed to systematically assess the efficacy and safety of TDF in pregnant women with chronic HBV and their infants. Material and methods: Database searches were performed to identify studies blocking the mother-to-child transmission of the hepatitis B virus with tenofovir. The search included pregnant women with chronic HBV infection administered with TDF compared to the no treatment controls, and data from individual studies were pooled using RevMan v5.3 for meta-analysis. Results: Seven studies with a total of 911 patients met the inclusion criteria: 433 patients in the TDF group and 478 patients in the non-TDF group. The HBV mother-to-child transmission rate in the tenofovir group was effectively reduced compared to the control group (RR: 0.18, 95% CI: 0.08-0.40). HBV-DNA positivity was also significantly low in infants from TDF group (RR: 0.17, 95% CI: 0.10-0.30) and the TDF treatment resulted in significantly higher anti-HBs production (RR: 1.11, 95% CI: 1.04-1.18). Similarly, maternal HBV-DNA was suppression was significantly high in the TDF group (RR: 34.16, 95% CI: 16.40-71.13). Women treated with TDF and their infants did not result in serious adverse events that are statistically different as compared to the women who did not receive any treatment. Conclusion: Treatment of HBV infected pregnant women with TDF can effectively and safely prevent the perinatal transmission of chronic hepatitis B.
Article
This first Practice Guidance on Reproductive Health from the American Association for the Study of Liver Diseases (AASLD) is intended to be a comprehensive reference on adolescents and adults with chronic liver disease. The Guidance specifically (1) addresses management of reproductive health in women and men from puberty to senescence and (2) summarizes the natural history, risk factors, evaluation, and optimal management of liver diseases during pregnancy and after birth.
Article
Background and aims: Achieving HBeAg seroconversion (HBeAgSC) at an earlier age confers better prognosis. We examined baseline and post-partum factors associated with HBeAgSC after pregnancy. We developed a tool, the SydPregScore, to estimate the likelihood of HBeAgSC in the years after pregnancy. Methods: A retrospective analysis of a HBeAg positive pregnant cohort was conducted. Variables including baseline age, parity, alanine aminotransferase level, HBV viral load, quantitative HBsAg, use of antiviral therapy and post-partum flare were collected. Univariate and multivariate cox-regression analysis to determine predictors of HBeAgSC and develop a predictor score was performed. Results: We analysed HBeAgSC rates in 220 pregnancies to 149 HBeAg positive women from 2006 to 2019. At baseline their median age was 33 (IQR29-37), ALT 23U/L (IQR17-33) and viral load 8 log10 IU/mL (IQR6.3-8.2 log10 IU/mL). The majority (133/198, 67.2%) received short-course antiviral therapy to prevent mother-to-child transmission. 109/192(56.8%) had a post-partum flare. HBeAgSC occurred in 74/220(33.6%) after pregnancy (median follow-up 814 days IQR405-1531). Multivariate analysis identified baseline viral load <8 log10 IU/mL (HR2.426 (1.224-4.809), p0.011), baseline ALT ≥2ULN (HR2.726 (1.299-5.721), p0.008) and age <35 (HR2.859 (1.255-6.513), p0.012) to be positive predictors of HBeAgSC. The "SydPreg Score" estimated the probability of HBeAgSC at 2000 days as 10%, 30%, 70% and 80% for 0, 1, 2, and 3 predictors respectively. Conclusion: The SydPreg Score allows prediction of HBeAgSC in the years after pregnancy. Even in those without elevated ALT, age <35 and viral load <8 log10 IU/mL can identify women with a good chance of subsequent HBeAgSC. Those without a chance may benefit from viral suppression.
Article
The efficacy of prenatal antiviral therapy (AVT) for preventing the vertical transmission of hepatitis B virus (HBV) is well demonstrated. However, data are limited regarding the safety of postpartum cessation of AVT, which may induce alanine aminotransferase (ALT) elevation. We aimed to investigate the necessity of prolonging maternal AVT after delivery. Chronic hepatitis B mothers at the immune-tolerant phase with HBV DNA levels >6 log10 IU/mL were prospectively enrolled and received AVT during the third trimester until delivery. Patients were offered to discontinue AVT either at delivery or postpartum week (PPW) 6. In addition, mothers who deferred AVT during pregnancy served as the control group. All mothers were followed until PPW 52 for clinical and virological parameters of hepatitis flares. Among 118 mothers recruited, 91 received AVT with 53 (group A) and 24 (group B) discontinue their treatment at delivery and PPW 6, respectively. Twenty-seven mothers who deferred AVT during pregnancy were followed as the control (group C). A total of 104 of 118 mothers who completed the study, 50% (52/104) had postpartum-elevated ALT levels, which were mild and moderate except 6 of 104 (5.77%) of patients had levels ≥5 times the upper limit of normal; 70% (36/52) of the ALT flares occurred within 12 weeks after delivery. In subgroup analyses, the frequency of ALT elevation was similar among the groups A vs B vs C (50.9% [27/53] vs 58.3% [14/24] vs 40.7% [11/27], respectively; P = .447), as well as the mean peak ALT level (108.4/74.1/126.7 U/L in groups A/B/C, respectively; P = .291). Although postpartum ALT flares were common for mothers with or without AVT during pregnancy, most cases of ALT elevation were mild to moderate. Our study observed that extending AVT to PPW 6 did not affect maternal outcomes and ATV should be discontinued at birth. Close monitoring is warranted as severe flares rarely occurred.
Article
Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares might occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and might mark transitions to inactive disease or clearance of infection, but in certain scenarios they might also lead to hepatic decompensation or death. As such, understanding of the clinical significance of flares in different patient populations and different scenarios is important for optimal management. In this Review, we summarise what is known about flares in different stages of chronic HBV infection; describe flares in the context of the natural history of chronic infection; summarise the immunological mechanisms underlying flares, and describe flares in different clinical scenarios. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve the understanding of flares, hopefully providing insights into their pathogenesis that can be used to improve current clinical management and ideally to further develop new curative therapeutic approaches for HBV infection. We also propose a working definition of an ALT flare to facilitate future research.
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
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Background/aims Little is known about the long-term outcome of chronic hepatitis B (CHB) patients who discontinued antiviral therapy. We intended to analyze the long-term outcome of CHB patients who discontinued lamivudine therapy and to evaluate predictors for post-treatment outcome. Material/methods From 2007 to 2008, 138 lamivudine off-treated CHB patients with alanine aminotransferase normalization were consecutively enrolled. Post-treatment virologic relapse, biochemical breakthrough, hepatitis flare, and retreatment results were retrospectively analyzed. Results Among 138 patients, 102 were initially HBeAg-positive at the start of lamivudine treatment. Virologic relapse, biochemical breakthrough, and hepatitis flare were observed in 45.2, 52.9, and 12.7% of HBeAg-positive and 29.4, 30.6, and 8.3% of HBeAg-negative patients during the median follow-up of 28 and 30 months, respectively. The cumulative virologic relapse and biochemical breakthrough rates were significantly lower in patients with HBV DNA <50 copies/mL than 50-104 copies/mL at lamivudine cessation. Hepatitis flare was observed in 4.8 and 11.8% of HBeAg-positive and HBeAg-negative patients with HBV DNA <50copies/mL, respectively. Thirty-eight among 138 patients received retreatment and most of them achieved biochemical (37/38) and virologic response (35/38) within 1 year of retreatment. Undetectable serum HBV DNA (<50 copies/mL) and young age at lamivudine cessation were inversely associated with virologic relapse. Undetectable HBV DNA at cessation, female, and initial HBeAg-negative were inversely associated with biochemical breakthrough. Conclusions Post-treatment virologic relapse and biochemical breakthrough incidence were low in patients who achieved undetectable viral titer at lamivudine cessation. Retreatment after biochemical breakthrough or virologic relapse was safe and effective. Intermittent antiviral therapy might be cautiously considered in appropriately selected CHB patients.
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Article
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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
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Hepatitis B virus infection is a global health problem. Worldwide, about 360 million people are chronically infected with the virus. They continue to spread the virus to others and are themselves at risk of chronic liver diseases and hepatocellular carcinoma. The infection can now be treated by antivirals or interferons and the transmission route can be interrupted. Nevertheless, the most effective means is to immunize all susceptible individuals, especially young children, with safe and efficacious vaccines. The combined efforts of vaccination, effective treatment and interruption of transmission make elimination of the infection plausible and may eventually lead to eradication of the virus. Because hepatitis B vaccination has a key role in the control of hepatitis B, properties of this vaccine, its effectiveness in pre-exposure and post-exposure settings, duration of protection after vaccination and the need of booster doses are discussed. Mass hepatitis B vaccination in children decreases the carriage of the virus, and the diseases associated with acute and chronic infection, including hepatocellular carcinoma. Challenges that need to be solved to expand mass vaccination, and the strategies towards elimination and eventual eradication of hepatitis B in the world are also discussed.
Article
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Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.
Article
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Among the many viruses that are known to infect the human liver, hepatitis B virus (HBV) and hepatitis C virus (HCV) are unique because of their prodigious capacity to cause persistent infection, cirrhosis, and liver cancer. HBV and HCV are noncytopathic viruses and, thus, immunologically mediated events play an important role in the pathogenesis and outcome of these infections. The adaptive immune response mediates virtually all of the liver disease associated with viral hepatitis. However, it is becoming increasingly clear that antigen-nonspecific inflammatory cells exacerbate cytotoxic T lymphocyte (CTL)-induced immunopathology and that platelets enhance the accumulation of CTLs in the liver. Chronic hepatitis is characterized by an inefficient T cell response unable to completely clear HBV or HCV from the liver, which consequently sustains continuous cycles of low-level cell destruction. Over long periods of time, recurrent immune-mediated liver damage contributes to the development of cirrhosis and hepatocellular carcinoma.
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
A randomised blind controlled trial of hepatitis B immune globulin (HBIG) plus hepatitis B vaccine for the prevention of the perinatally transmitted HBsAg carrier state was conducted in Taipei. Infants of e-antigen-positive HBsAg carrier mothers were given HBIG immediately after birth, and then one of three schedules of vaccination. There was no difference in efficacy between the three schedules; the combined efficacy was 94%, compared with that of HBIG alone (71%) or of vaccination alone (75%). Persistent HBs antigenaemia developed in only 9 (6%) of the 159 infants receiving prophylaxis, but in 88% of the controls. Antibodies developed in all those who did not become antigenaemic and presumably will provide long-term protection from hepatitis B virus infection. HBIG should be given as soon as possible after birth and need not be given again if the infant is subsequently vaccinated. With HBIG coverage from birth, the timing of the start of vaccination does not seem to be of importance within the first month of life, but to maximise compliance and minimise costs hepatitis B vaccination should be initiated during the confinement.
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
Hepatitis B infection is best controlled by prevention rather than treatment, as chronic infection is usual once infected at a young age. Infant immune-prophylaxis is highly efficacious, although in the setting of high maternal viral load, breakthrough infection still occurs in almost 10 % of babies. Ante partum antiviral therapy for the purpose of preventing mother to child transmission in this group is important to consider. This article provides an up-to-date account of the available evidence of the safety and efficacy of ante partum antiviral therapy options and a management plan is proposed. Mothers with HBV infection and high viral load should have the opportunity to consider this evidence. Post-partum HBV flares are common but usually mild. It is unclear whether post partum flares are best ignored till they settle or if they represent an opportunity for intervention to increase the chance of HBV clearance.
Article
To elucidate the effects of pregnancy and delivery on hepatitis B e antigen (HBeAg)-positive carrier mothers, 31 HBeAg-positive carrier mothers were followed-up postpartum 1 year, with 30 HBeAg-positive nonpregnant female carriers as controls. Serum hepatitis B surface antigen (HBsAg), HBeAg titer, and hepatitis B virus (HBV)-DNA concentration were studied at defined intervals. The results revealed that in the control group HBeAg titers and HBV-DNA concentrations fluctuated, whereas the HBsAg titers showed little change, but HBeAg clearance or seroconversion to anti-HBe were not noted on follow-up. In contrast, one carrier mother sero-converted to anti-HBe during pregnancy and the antibody persisted thereafter. Five of the remaining 30 carrier mothers cleared HBeAg postpartum, and among these five cases, one also seroconverted to anti-HBe. In addition, in another five of the 30 cases, the HBV-DNA fell to undetectable level (< 0.04 ng/ml). All these ten cases had a common tendency of showing a decrease in HBeAg titers and/or HBV-DNA concentrations 1–2 months after delivery. The HBeAg titers and HBV-DNA concentrations in the other 11 cases remained unchanged, whereas the remaining nine cases had increased levels. It is concluded that subsidence of HBV replication is precipitated by delivery in one-third of HBeAg-positive carrier mothers in Taiwan, and this occurs most frequently 1–2 months postpartum.
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
Unlabelled: It is estimated that 350 to 400 million individuals worldwide are chronically infected with hepatitis B virus (HBV). In regions of high endemicity, many of these are females of reproductive age who are an important source for perinatal transmission. There are a number of issues specific to the women of childbearing age who have chronic HBV infection, including the safety of antiviral therapy during pregnancy and breast-feeding, the changes in the immune system during pregnancy and postpartum that may impact on the natural history of HBV, and the emerging role of antivirals to reduce perinatal transmission of HBV. For women in their reproductive years who require treatment, many of the available antivirals have not been studied in pregnant or breast-feeding women and their use requires the development of a carefully considered strategy, considering the impact of both the disease and treatment on the mother and fetus/infant. The purpose of this article is to (1) review data regarding the mechanisms and timing of perinatal HBV infection; (2) review data on interventions, particularly antiviral therapy, to reduce perinatal transmission beyond the protection afforded by hepatitis B immunoglobulin and vaccination; (3) summarize the immunological changes associated with pregnancy and the potential effect these may have on the natural history of HBV infection; and (4) summarize the information currently available for antiviral therapy available for HBV treatment, focusing specifically on safety data pertaining to reproduction, pregnancy, and breast-feeding. Target audience: Obstetricians & Gynecologists and Family Physicians. Learning objectives: After completing this CME activity physicians should be better able to classify the interventions to reduce mother-to-child transmission of hepatitis B including antivirals, caesarean section, hepatitis B immunoglobulin and hepatitis B vaccine, assess the immunological changes associated with pregnancy and the potential effect this may have on the natural history of HBV infection and apply the information currently available for antiviral therapy licensed for HBV treatment, focusing specifically on safety data in pregnancy and during breastfeeding.
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
In the Asia-Pacific region, perinatal transmission of the hepatitis B virus (HBV) is the primary cause of chronic hepatitis B infection. Despite the use of HBIG and HBV vaccination, HBV perinatal transmission (PT) occurs in 10-30% of infants born to highly viremic mothers. We evaluated the efficacy and safety of LTD use during late pregnancy in reducing HBV transmission in highly viremic HBeAg+mothers. Two hundred and twenty-nine HBeAg+HBV DNA levels>1.0×10(7) copies/ml mothers received telbivudine 600 mg/day from week 20 to 32 of gestation (n=135) or served as untreated controls (n=94). All infants in both arms received 200 IU of HBIg within 12 h postpartum and recombinant HBV vaccine of 20 μg at 0, 1, and 6 months. HBsAg and HBV DNA results of infants at week 28 were used to determine perinatal transmission rate. All telbivudine treated subjects were registered in the Antiretroviral Pregnancy Registry. Telbivudine treatment was associated with a marked reduction in serum HBV DNA and hepatitis B e antigen (HBeAg) levels and normalization of elevated ALT levels before delivery. A striking decline of HBV DNA levels started from treatment onset to week 4, and sustained in a low level since week 12. Forty-four (33%) of the 135 telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction-undetectable viremia (DNA<500 copies/ml) at delivery. Seven months after delivery, the incidence of perinatal transmission was lower in the infants that completed follow-up born to the telbivudine-treated mothers than to the controls (0% vs. 8%; p=0.002). HBV DNA levels were only detectable in HBsAg+infants. No significant differences in anti-HBs levels were observed during postnatal follow-up. No serious adverse events were noted in the telbivudine-treated mothers or their infants. Telbivudine used during pregnancy in CHB HBeAg+highly viremic mothers can safely reduce perinatal HBV transmission. Telbivudine was well-tolerated with no safety concerns in the telbivudine-treated mothers or their infants on short term follow up. These data support the use of telbivudine in this special population.
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
Maternal screening and active and passive immunoprophylaxis have reduced the perinatal, or vertical, transmission of hepatitis B virus (HBV) dramatically. Without immunoprophylaxis, chronic HBV infection occurs in up to 90% of children by age 6 months if the mother is positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Even with immunoprophylaxis, perinatal transmission is possible when the mother is highly viremic and HBeAg positive. Antiviral therapy during the third trimester of pregnancy in high-risk women with chronic HBV infection reduces viral load in the mother and may decrease the risk of perinatal transmission, although data are lacking. Safety data in pregnancy are most robust with lamivudine and tenofovir compared with other therapies. Careful discussion with the patient regarding the risks and benefits of therapy is warranted. Prophylaxis remains the best method of prevention of perinatal transmission.
Article
Unlabelled: Alpha interferon is the only licensed drug for hepatitis B with immunomodulatory as well as viral inhibitory properties. Potential advantages of interferon compared to nucleoside analogs include a lack of drug resistance, a finite and defined treatment course, and a higher likelihood for hepatitis B surface antigen (HBsAg) clearance. Approximately 30% of hepatitis B e antigen (HBeAg)-positive and 40% of HBeAg-negative cases have a sustained virological response (when defined as HBeAg seroconversion and/or hepatitis B virus (HBV) DNA levels below 20,000 copies/mL, respectively) 6 months after completion of a 48-week course of peginterferon alfa-2a These responses remain durable in 80% and 50% of cases, respectively, when evaluated several years later. Recent studies have shown that changes in HBsAg and HBeAg concentration during treatment predict sustained virological response and serial monitoring of HBsAg is helpful in predicting HBsAg clearance. HBeAg-positive patients with genotype A have higher rates of HBeAg and HBsAg clearance, whereas HBeAg-negative patients with genotype D have the lowest rate of response to interferon therapy. Long-term follow-up of virological responders to either standard alpha interferon or peginterferon has demonstrated a progressive increase in the rate of HBsAg clearance, particularly in patients who were initially HBeAg-positive. Future studies need to address if specific virological benchmarks during therapy can be used to tailor treatment duration. Conclusion: Peginterferon alfa has a place as first-line therapy of hepatitis B in patients who are carefully selected on the basis of pretreatment serum HBV DNA and aminotransferase levels, safety considerations, and viral genotype.
Article
This randomized, double-blind, placebo-controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26-30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine-treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo-treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.
Article
235 infants of HBeAg-carrier mothers in Hong Kong were assigned to four study groups. Groups I, II, and III received hepatitis-B (HB) vaccine at birth and at 1, 2, and 6 months. Group I also received seven monthly injections of HB immunoglobulin (HBIg), and group II received one HBIg injection at birth. Group III received vaccine only and group IV received placebo for both vaccine and HBIg. At the age of 3 years, all infants of the three treatment groups were significantly protected against the HB virus (HBV) carrier state compared with the placebo group (p less than 0.0001); the protective efficacy rates in groups I, II, and III were 87%, 80%, and 65%, respectively. At all times, group I was significantly better protected than group III. In groups III and IV, infants of mothers with serum HBV DNA levels of 5 pg/ml or above were at a significantly higher risk of acquiring the HBV carrier state than those whose mothers had HBV DNA levels below 5 pg/ml. This difference was not significant in groups given HBIg. Of the 183 infants who initially escaped HBV infection, 73 (40%) had transient and 8 (4%) chronic HBV infection between 6 and 36 months. Vaccinated infants who had actively formed anti-HBs remained well protected against the HBV carrier state. However, infants in groups I and II with no active anti-HBs response to vaccine became at risk for the HBV carrier state when the passively acquired anti-HBs antibodies had disappeared. HBIg should be included in HB vaccination schedules for all infants of HBeAg-positive mothers.
Article
A randomised blind controlled trial of hepatitis B immune globulin (HBIG) plus hepatitis B vaccine for the prevention of the perinatally transmitted HBsAg carrier state was conducted in Taipei. Infants of e-antigen-positive HBsAg carrier mothers were given HBIG immediately after birth, and then one of three schedules of vaccination. There was no difference in efficacy between the three schedules; the combined efficacy was 94%, compared with that of HBIG alone (71%) or of vaccination alone (75%). Persistent HBs antigenaemia developed in only 9 (6%) of the 159 infants receiving prophylaxis, but in 88% of the controls. Antibodies developed in all those who did not become antigenaemic and presumably will provide long-term protection from hepatitis B virus infection. HBIG should be given as soon as possible after birth and need not be given again if the infant is subsequently vaccinated. With HBIG coverage from birth, the timing of the start of vaccination does not seem to be of importance within the first month of life, but to maximise compliance and minimise costs hepatitis B vaccination should be initiated during the confinement.
Article
From 1982 to 1989, 705 infants born to HBsAg-positive mothers entered the Dutch neonatal hepatitis B vaccination program and received passive-active hepatitis B immunization in three randomized controlled trials testing variations in time of starting active vaccination, dose and type of vaccine, and number of hepatitis B immunoglobulin (HBIg) injections. A meta-analysis of individual patient data of the three randomized trials was performed to determine which independent host and vaccination related factors influence protective efficacy and long-term immunogenicity, and to assess whether hepatitis B vaccination concomitant with standard DKTP vaccination provides optimal protection. Statistical methodology included multivariate logistic regression analysis. Eight infants (1.1%), all born to HBeAg-positive mothers, became HBsAg carriers within the first year of life. The protective efficacy rate (PER) of passive-active immunization at 12 months follow-up was 92% for the total group of children from 114 HBeAg-positive mothers with no significant differences between children starting active immunization at birth or at 3 months of age, between infants starting at 3 months of age receiving one or two doses of HBIg or between those receiving plasma derived or recombinant vaccine. The only factor that affected the PER significantly was the level of maternal HBV DNA; PER was 100% if maternal HBV DNA was < 150 pg ml-1 and 68% for HBV DNA levels > 150 pg ml-1. After 5 years of follow-up, the group that started active immunization at birth had significantly more infants with loss of seroprotection (anti-HBs levels < 10 IU l-1, 15%) than the corresponding group starting at 3 months of age (anti-HBs < 10 IU l-2, 2%). One of 35 children with loss of seroprotection at 2 years became a HBsAg carrier in the fifth year of follow-up. This meta-analysis shows that the protective efficacy of passive-active hepatitis B vaccination is mainly influenced by material HBV DNA levels, and independent of the time of starting active vaccination at birth or at 3 months of age; long-term immunity was enhanced by starting active vaccination concomitant with DKTP vaccination. These findings allow incorporation of hepatitis B vaccine into the standard infant immunization programs for countries with a passive-active immunization strategy for the control of hepatitis B. Additional measures are needed to protect neonates of highly viremic women.
Article
There is a wide variation of hepatitis B virus (HBV) infection in the Asia-Pacific region. The prevalence of chronic HBV infection is lowest (<1%) in North America, Australia and New Zealand, 2-4% in Japan, 5-18% in China and highest (15-20%) in Taiwan as well as several other countries in South East Asia. Perinatal transmission is common in HBV-hyperendemic areas. Geographical clusters of horizontal HBV infection have been reported in both high- and low-risk countries. Common sources of infection, including iatrogenic and sexual transmission, have been implicated. Migrant studies indicate the importance of childhood environments in the determination of HBV infection. Rural urban and ethnic differences in the prevalence of HBV infection have also been reported. There has been a decrease in the prevalence of HBV infection after mass HBV vaccination programmes in some Asia-Pacific countries, which may be due to the intervention of possible transmission routes through the use of disposable syringes and needles, screening of HBV infection markers in blood banks, and prevention of high-risk tattooing, acupuncture, ear-piercing and sexual contact. A striking decrease in the incidence of HBV infection and hepatocellular carcinoma has been observed among children in Taiwan and other areas where mass vaccination programmes have been implemented.
Article
Acute exacerbations of chronic hepatitis B virus (HBV) infection occur after withdrawal of lamivudine therapy in approximately 16% of patients and are considered of little clinical significance. We observed "lamivudine withdrawal hepatitis" accompanied by jaundice and incipient liver failure, but also followed by complete recovery and viral clearance. To investigate the incidence, severity, timing, and virologic characteristics of "lamivudine withdrawal hepatitis" we monitored 41 patients for at least 6 months after discontinuation of nucleoside analogue therapy. The incidence of hepatitis flares was estimated to be 7 of 41 (17%); in 2 of 41 cases (5%), hepatitis flares were associated with jaundice and incipient liver failure. A noticeable feature of the "lamivudine withdrawal hepatitis" flares were the high HBV-DNA levels at the time of the alanine transaminase (ALT) peak. All were wild-type HBV, even the one that emerged from a lamivudine-resistant strain during therapy. To minimize the risk of liver failure and to enhance the elimination of HBV following flares, lamivudine therapy was reinstituted in an icteric patient. Clinical and biochemical remission ensued, followed by loss of HBV DNA and hepatitis B e antigen (HBeAg) seroconversion. Such a virologic response did not occur in 5 other patients with a nonicteric "lamivudine withdrawal hepatitis," who were not retreated with lamivudine. Hepatitis after withdrawal of lamivudine resembles acute hepatitis B with a predominance of anicteric flares within a time frame of 6 months. Active management of hepatitis flares following withdrawal of nucleoside analogue therapy should be investigated further.
Article
The hepatitis B virus (HBV) cytotoxic T lymphocyte (CTL) response in patients with chronic HBV infection is generally weak or totally undetectable. This inability to mount protective CTL responses is believed to be a crucial determinant of viral persistence, and its correction represents an important objective of immune therapies for chronic hepatitis B. However, amplification of CTL responses in vivo may be ineffective if HBV-specific CD8 cells are either absent or nonresponsive to exogenous stimulation. In this study, we asked whether antiviral treatments able to inhibit viral replication and to reduce viral and antigen load can successfully reconstitute CTL responses creating the appropriate conditions for their therapeutic stimulation. For this purpose, the HBV-specific CTL response before and during lamivudine therapy was studied longitudinally in 6 HLA-A2-positive patients with HBeAg+ chronic hepatitis B. Both HBV-specific cytotoxic T cell activity measured by chromium release assay on peptide stimulation in vitro and CD8+ T cell frequency measured ex vivo by HLA-A2/peptide tetramer staining were significantly augmented by lamivudine therapy. This enhancement followed the reconstitution of CD4 reactivity and the decline of viral load induced by therapy. Our study shows that lamivudine treatment in chronic hepatitis B can restore CTL reactivity, making CTL susceptible to exogenous stimulation. This effect may enhance the probability that T cell-based immune therapies delivered after lamivudine treatment can successfully reconstitute a protective CTL response able to cure chronic HBV infection.
Article
Why is the fetus not rejected as foreign tissue? The maternal and fetal immune systems temporarily coexist; both are precisely tuned to detect and reject foreign invasion and yet somehow achieve a symbiotic relationship. This mutual state of tolerance is obviously critical for carrying pregnancy to full term. Two active arms of the immune system maintain protection of the host: the first of these involves a humoral immune system in which foreign tissue invokes an antibody response by recognition of antigenic surfaces by the B-cell, the second arm involves cell-mediated immunity in which T-cells and natural killer (NK) cells seek out and destroy foreign tissue. Several mechanisms are thought to invoke the immune tolerance of the fetus. These include: absence of major histocompatibility complex (MHC)-I antigens, presence of unique human lymphocyte antigen (HLA) surface molecules, nonspecific reduction of systemic immunoreactivity, possible role of blocking antibody, expressions of complement regulatory proteins, and factors of locally reduced immunoreactivity. Ultimately, developing regimens to control these elements in the clinical setting may help us overcome preterm labor, infertility, and preeclampsia. Available evidence regarding immune tolerance of the human fetus, integrated into a workable model, and focused at an overview level are systematically reviewed in this article.
Article
Vertical transmission of hepatitis B virus (HBV) can occur occasionally despite vaccination of the child. This vaccination breakthrough has been associated with high maternal viraemia. We treated eight highly viraemic (HBV-DNA >/= 1.2 x 10(9) geq/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc of their offspring were measured at birth and at 3, 6 and 12 months, respectively. Twenty-four children, born to untreated HBsAg-positive mothers with HBV-DNA levels >/=1.2 x 10(9) geq/mL served as historical controls. All children received passive-active immunization at birth and were followed-up for 12 months. In the lamivudine group one of the eight children (12.5%) was still HBsAg and HBV-DNA positive at the age of 12 months. All other children seroconverted to anti-HBs and maintained seroprotection. In three children, HBV-DNA was temporarily detected by polymerase chain reaction. In the untreated historical control group, perinatal transmission occurred in seven of 25 children (28%). In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough. This approach should be evaluated in a large controlled trial.
Article
Lamivudine therapy in patients with chronic hepatitis B can induce the recovery of antiviral T cell responses. It is unknown whether the recovery of T cell responsiveness is long-lasting and persists throughout the treatment and whether the elevation of viremia which follows therapy withdrawal can restore a condition of T cell unresponsiveness. Frequency and function of circulating hepatitis B virus (HBV)-specific CD4 and CD8 cells from 12 hepatitis e surface antigen + patients with chronic hepatitis B were studied longitudinally before, during and after lamivudine therapy by intracellular cytokine staining, proliferation and cytotoxicity assays against HBV proteins and peptides. CD4-mediated responses were analyzed in all patients, whereas CD8 cells were studied in 6 HLA-A2+ patients. HBV-specific CD4 and CD8 reactivity showed a bi-phasic behavior under lamivudine therapy with an early enhancement of T cell frequency and intensity of responses followed by a persistent decline starting from the 5th to 6th month of treatment. Since restoration of HBV-specific T cell reactivity is only transient, our study indicates that therapeutic stimulation of HBV-specific T cell responses to complement lamivudine treatment should be done early after the initiation of lamivudine. Moreover, the transient nature of the immune reconstitution may represent a favorable condition for virus reactivation once lamivudine therapy is withdrawn.
Article
Little is known about how pregnancy influences viremia levels in women with chronic hepatitis B virus infection. In this study, we first retrospectively analysed changes in HBV DNA levels during and after 55 pregnancies in HBsAg-positive women, of whom 9 were HBeAg-positive. Secondly, HBV DNA levels in 3 HBeAg-positive mothers whose babies became chronic HBV carriers, were compared with levels in 18 mothers whose babies were not infected by HBV. We found that HBV DNA ranged from 10(8.1) to 10(9.5) copies/mL in HBeAg-positive, and from undetectable (< 100) to 10(6.8) copies/mL in HBeAg-negative mothers. HBV DNA increased by a mean of 0.4 log late in pregnancy or early post partum; in 4 out of 16 HBeAg negative mothers by > 1 log during pregnancy. Post partum ALT increased in both HBeAg-positive and negative women. HBV DNA was 10(9.4)-10(10.4) copies/mL in 3 HBeAg-positive mothers whose babies were, as compared to < 100-10(10.4) copies/mL in 18 whose babies were not, vertically infected. Although the majority of HBeAg-negative women had low and relatively stable HBV DNA during pregnancy, viremia was also relatively high in some HBeAg-negative mothers, and both viremia and ALT increased significantly late in pregnancy or shortly after delivery. Vertical transmission was only seen in HBeAg-positive mothers with very high levels of viremia. The value of measuring HBV DNA in the pregnant woman to modify immunoprophylaxis to her infant needs further study.
Article
This chapter describes the methodology, analysis, and assessment of the significance of hepatitis B virus (HBV) mutations selected during antiviral therapy. Included in this description is the methodology for genotype classification. The major area of sequence-analysis methodology focuses on the reverse transcriptase region of the polymerase gene, in particular the catalytic domains A–E. This region coincides with the “a” determinant of the S gene in the overlapping reading frame. Other clinically significant HBV mutations, which are located in other genes and regulatory regions such as the basal core promoter and precore gene [(both of which are associated with loss or reduction in the production of hepatitis Be antigen (HBeAg)], may also be identified. Multiple mutations within a gene and the combination of mutations from other areas of the genome may act in a compensatory manner, altering the resistance pattern, replication phenotype, and pathogenesis profile of viral infection. Thus, the crosslinking of genomic data has potentially important implications for patient management.
Article
The pregnant woman experiences physiological changes to support fetal growth and development. Particularly the physiological changes of the liver are the results of the increment of estrogens and progesterone during the pregnancy, and also the hemodynamics changes. (hemodilution). Telangiectasia may appear in up to 60% of normal pregnancies. Liver function test (LFT) abnormalities occurs in 3% of the pregnancies, and the Preeclampsia is the most frequent cause. Most of the articles agree that in normal pregnancy the LFT are either normal or slightly increase o decrease but within normal range. Thus, an increase in serum ALT, AST and GGT activities and serum bilirubin and total bile acid concentration during pregnancy may be pathologic and should prompt further evaluation. In the same way the serum albumin levels is significantly low and the serum alkaline phosphatase concentrations are considerably higher and are a normal component of the pregnancy , and if they are within normal range, do not usually indicate the presence of liver disease. The prothrombine time and the partial prothrombine time remain unchanged during pregnancy and serum fibrinogen increase in late pregnancy. Most of the articles related to plasma lipids in pregnancy agree that cholesterol. Triglyceride and lipoprotein increase during pregnancy. Use of gestational age of the pregnancy are the best guide to the differential diagnosis of liver disease in the pregnancy.
Article
In spite of adequate immunoprophylaxis, perinatal transmission of hepatitis B virus (HBV) has not been completely eliminated. This study evaluated the factors associated with the failure of HBV immunoprophylaxis. The study participants were 144 children who were born to HBsAg-seropositive mothers of known HBeAg status and they had received HB immune globulin and HB vaccine within 24 hours after birth followed by two further administrations of HB vaccine as recommended. Seventeen of the children (11.8%) suffered immunoprophylaxis failure, defined by HBsAg-seropositivity. The rate of HBV immunoprophylaxis failure was 12%, 0%, 21%, 0%, and 27% among the children born to HBsAg-seropositive, HBeAg-seronegative, HBeAg-seropositive, undetectable HBV DNA, and detectable HBV DNA mothers, respectively. The failure of HBV immunoprophylaxis was significantly associated with maternal HBeAg-seropositivity and HBV DNA seropositivity. To identify those children at high risk of HBV immunoprophylaxis failure, maternal HBeAg and HBV DNA need to be assessed prior to childbirth.
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.
European Association For The Study Of The L. EASL clinical practice guidelines: management of chronic hepatitis B virus infection
European Association For The Study Of The L. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167-85.
Clinical and virological factors that predict post partum flares in pregnant women with chronic HBV. (2013) HBV Natural History and Outcomes
  • M Giles
  • K Visvanathan
  • S R Lewin
Giles M, Visvanathan K, Lewin SR, et al. Clinical and virological factors that predict post partum flares in pregnant women with chronic HBV. (2013) HBV Natural History and Outcomes. Hepatology 2013; 58: 638A.