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February
2012: VOLUME 2, ISSUE 3


Hepatitis B and Pregnancy

In this Issue...


Mother-to-child-transmission of hepatitis B remains a significant problem worldwide. In this issue, we review recent data from Asia that suggest hepatitis B e antigen (HBeAg) as a factor in perinatal transmission and its possible relationship to global immunoprophylaxis strategies and recommendations. Several studies over the last several years have looked at HBV transmission rates, even with appropriate vaccination and the role played by high maternal viremia in transmission. More recent studies have identified maternal viremia levels > 108 copies/mL as a risk factor, with transmission rates approaching 9% in these patients. These findings have led to therapeutic trials of oral antiviral agents for use in women with hepatitis B in pregnancy, specifically in the third trimester, in the hopes of reducing transmission rates in these highly viremic mothers. Other key issues related to pregnancy, including breastfeeding, are also addressed in a meta-analysis.

     
   LEARNING OBJECTIVES
 
    After participating in this activity, the participant will demonstrate the ability to:

 Review current data on hepatitis B vertical transmission
 Assess hepatitis B virus (HBV) vaccination strategies
 Evaluate data on therapies used for the prevention of mother-to-child transmission (MTCT) of HBV

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.
   
   
  IMPORTANT CME/CE INFORMATION
Program Begins Below
Accreditation Statements
Physicians
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Nurses
The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

The Institute for Johns Hopkins Nursing and the American Nurses Credentialing Center do not endorse the use of any commercial products discussed or displayed in conjunction with this educational activity.


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Physicians
eNewsletter: The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Podcast: The Johns Hopkins University School of Medicine designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses
eNewsletter: This 1 contact hour Educational Activity is provided by The Institute for Johns Hopkins Nursing. Each newsletter carries a maximum of 1 contact hour or a total of 7 contact hours for the 7 newsletters in this program.

Podcast: This 0.5 contact hour Educational Activity is provided by the Institute for Johns Hopkins Nursing. Each podcast carries a maximum of 0.5 contact hour or a total of 2.5 contact hours for the 5 podcasts in this program.


successful completion
To successfully complete this activity, participants must read the content, and then link to the Johns Hopkins University School of Medicine's website or the Institute for Johns Hopkins Nursing’s website to complete the post-test and evaluation. Once you receive a passing grade, you can access and print your certificate of credit.

NOTE: If you have already registered for other Hopkins CME programs on their prospective websites simply enter the requested information when prompted.

There are no prerequisites for this activity.

This activity is supported by an educational grant from Gilead Sciences, Inc. and Vertex Pharmaceuticals.

Launch Date
January 31, 2012; activities expire 2 years from the date of publication.

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The Office of Continuing Medical Education (CME) at the Johns Hopkins University School of Medicine is committed to protecting the privacy of its members and customers. The Johns Hopkins University SOM maintains its Internet site as an information resource and service for physicians, other health professionals, and the public.

Continuing Medical Education at the Johns Hopkins University School of Medicine will keep your personal and credit information confidential when you participate in an Internet-based CME program. Your information will never be given to anyone outside of the Johns Hopkins University School of Medicine program. CME collects only the information necessary to provide you with the services that you request.


Disclaimer Statement
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of the Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information for specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.
Statement of Responsibility
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

Intended Audience
This activity has been developed for hepatologists, primary care physicians, infectious disease specialists, nurses, nurse practitioners, and others involved in the care of patients with viral hepatitis.

Faculty Disclosure
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine Office of Continuing Medical (OCME) to require signed disclosure of the existence of financial relationships with industry from any individual in a position to control content of a CME activity sponsored by OCME. Members of the Planning Committee are required to disclose all relationships, regardless of their relevance to the activity content. Faculty are required to disclose only those relationships that are relevant to their specific presentations. The following relationships have been reported for this activity:

Mark S. Sulkowski, MD, has disclosed that he has served as a consultant for Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers-Squibb, Gilead, Janssen/Tibotec, Merck, Pharmasset, and Roche. He also has received grants and research support from, Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers-Squibb, Gilead, Janssen/Tibotec, Merck, Pharmasset, and Roche/Genentech.
Raymond T. Chung, MD, has disclosed that he has received grants/research support from Gilead, Pfizer, Roche/Genentech, Merck, and Romark.
No other planners have indicated that they have any financial interests or relationships with a commercial entity.
Guest Authors Disclosures

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I understand that while I am attending in this capacity, I may be exposed to "protected health information," as that term is defined and used in Hopkins policies and in the federal HIPAA privacy regulations (the Privacy Regulations). Protected health information is information about a person's health or treatment that identifies the person.

I pledge and agree to use and disclose any of this protected health information only for the training and/or educational purposes of my visit and to keep the information confidential.

I understand that I may direct to the Johns Hopkins Privacy Officer any questions I have about my obligations under this Confidentiality Pledge or under any of the Hopkins policies and procedures and applicable laws and regulations related to confidentiality. The contact information is Johns Hopkins Privacy Officer, telephone: 410-735-6509, e-mail: HIPAA@jhmi.edu.

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Johns Hopkins University School of Medicine
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Updated 4/09

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   this issue
  COMMENTARY from our Guest Author
  Maternal Screening and Universal Immunization for the Prevention of Mother-to-Infant HBV Transmission
  HBV Perinatal Transmission Among Mothers with High Viral Loads
  Lamivudine Use in Late Pregnancy for the Prevention of Perinatal HBV Transmission
  Efficacy and Safety of Telbivudine During Pregnancy for the Prevention of HBV Transmission
  Breastfeeding of Newborns by HBV-Infected Mothers

Program Directors

Mark S. Sulkowski, MD
Associate Professor of Medicine

Medical Director
Viral Hepatitis Center
Divisions of Infectious Disease
and Gastroenterology/Hepatology
The Johns Hopkins University
School of Medicine
Baltimore, Maryland


Raymond T. Chung, MD
Associate Professor of Medicine

Director of Hepatology,
Medicine Services
Harvard Medical School
Vice Chief of Gastroenterology
Massachusetts General Hospital
Boston, Massachusetts

Julie McArthur, MS, CRNP
Adult Nurse Practitioner

Division of Infectious Disease
The Johns Hopkins University
School of Medicine
Baltimore, Maryland

   GUESTS AUTHORs OF THE MONTH
 Commentary:

Tram T. Tran, MD  Tram T. Tran, MD
Associate Professor of Medicine
David Geffen School of Medicine at UCLA
Medical Director
Liver Transplantation Program
Comprehensive Transplant Center
Cedars-Sinai Medical Center
Los Angeles, California
Guest Faculty Disclosures

Tram T. Tran, MD, has disclosed that she has served as a consultant and advisor for Gilead Sciences and Bristol- Myers Squibb.

Unlabeled/Unapproved Uses

The author has indicated that there will be references to unlabeled/unapproved uses of tenofovir and lamivudine in pregnancy in this presentation.


Program Directors’ Disclosures
 
 Program Information
CME Info
Accreditation
Credit Designations
Intended Audience
Learning Objectives
Internet CME Policy
Faculty Disclosures
Disclaimer Statement


Length of Activity

1.0 hour Physicians
1 contact hour Nurses


Launch Date
February 28, 2012

Expiration Date
February 27, 2014
TO ACCESS THE
POST-TEST


Step 1.
Review the CE Information and study the educational content.

Step 2.
Click the post-test link at the end of the newsletter.

Step 3.
Follow the instructions to access a post-test.

   COMMENTARY
  Hepatitis B therapy has advanced significantly over the past decade with the use of antiviral therapies that can suppress the virus and mitigate histologic injury without long-term viral resistance. The reduction in rates of mother-to-child-transmission of HBV infection is still attributed predominantly to the safe, efficacious, and widely available HBV vaccine, and the studies have shown that with the use of the vaccine, approximately 90% of infants born to HBV- infected mothers will be protected from getting the virus.1

The remaining 10% of infants, likely born to mothers with high levels of viremia , as seen in the papers presented here, have either experienced vaccine failure or are exposed in utero to the virus. Data presented here suggest that antiviral therapy with lamivudine, tenofovir, or telbivudine during pregnancy may reduce maternal viral levels and reduce the risk of transmission. Although data is still limited by the paucity of high-quality, randomized, controlled trials in this population, evidence seems to suggest that treatment with antivirals may be an effective strategy.

Once these high-risk infants are born, immediate administration of the HBV vaccine plus hepatitis B immune globulin (HBIg) should be carried out and completed according to protocol, although it is possible that HBeAg-negative patients may not require the addition of HBIg. Breastfeeding in this population has been controversial, but numerous studies, including the meta-analysis presented herein, reaffirm the safety and low risk for HBV transmission associated with breastfeeding, which has proven health benefits among newborn infants.

Safety should be considered of utmost concern in this sensitive population. The Antiretroviral Pregnancy Registry, which comprises mainly patients with human immunodeficiency virus (HIV), is limited both in its scope and by its self-reported, short-term nature, but it does release findings on the safety of these HBV agents.

When contemplating the use of antiviral therapy, the clinician must always separate the issue of treatment for the mother's benefit from treatment to prevent disease transmission. Treatment strictly for the mother's benefit is rarely needed in the short term, so therapy can likely be deferred until after pregnancy. Treatment to reduce the risk of mother-to-child transmission must be undertaken with consideration of the available data, along with the mother's clear understanding of the associated risks and benefits.

Commentary References

1. Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. . N Engl J Med. 1976;294(14):746-749.
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   Maternal Screening and Universal Immunization for the Prevention of Mother-to-Infant HBV Transmission
Chen HL, Lin LH, Hu FC, et al. Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV. Gastroenterology. 2011 Dec 22. [Epub ahead of print] .

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)


View journal abstract  View journal abstract  View full article  View full article
Mother-to-child-transmission has been and remains worldwide one of the most common modes of spreading chronic HBV infection. The HBV vaccine was made widely available in 1982, and since that time, acute hepatitis B infection has declined by 94% among children and adolescents in the United States, attributed mainly to implementation of vaccination protocols.1 It had been established that mothers who are HBeAg-positive have a higher risk for HBV transmission to their unborn infant than do mothers who are HBeAg-negative (70% to 90% vs. < 10%, respectively, without prophylaxis).2 This is due in part to higher HBV DNA levels in the HBeAg-positive woman. The Advisory Committee on Immunization Practices currently recommends that any infant born to a mother with hepatitis B receive HBV vaccination plus HBIg within 12 hours of birth, and complete the three-dose vaccination series by six months of age.3 With this strategy of immunoprophylaxis, 85% to 95% of infants born to hepatitis B surface antigen (HBsAg)–positive/HBeAg-positive mothers subsequently become HBV- negative.3 The use of HBIg in all HBV-positive mothers is still controversial, with HBIg administration either difficult or cost-prohibitive in many areas of high disease prevalence.

The current review by Chen and colleagues analyzed data on the use of HBIg in 2356 children born to HBsAg-positive mothers. HBIg and HBV vaccination were administered to all mothers who were prenatally determined to be HBsAg-positive/HBeAg-positive (n = 583). In mothers who were HBsAg-positive/HBeAg-negative, HBV vaccine was administered, but HBIg was not given unless by parental choice. Of those who were HBeAg-negative, 1050 of 1773 mothers were not given HBIg, whereas 723 did receive HBIg. The overall HBV infection rate in this large cohort was 2.5%, with the HBeAg-positive group having a transmission rate of 9.26%, vs. 0.23% in HBeAg-negative mothers. In the HBeAg-negative group, there was no statistical significance in transmission between those who had received the HBV vaccine plus HBIg and those who had received only the HBV vaccine at birth. Antibodies against the hepatitis B core antigen (anti-HBc) were also examined in this study, with rates of positive anti-HBc also much higher in the HBeAg-positive group than in the HBeAg-negative group (16.7% vs. 1.58%, respectively), suggesting that infection and subsequent seroconversion occurred much more frequently.

This analysis confirms previous smaller studies that demonstrated higher rates of transmission in HBeAg positive mothers. More important, however, in the HBeAg- negative cohort, HBIg did not appear to affect disease transmission rates, which were low overall. Interestingly, HBV genotyping was compared between mother-infant pairs and surface mutants were found in 32% of 25 infants tested, suggesting HBIg immune pressure on selection of viral strains. One case of fulminant HBV was reported in an infant born to a mother with HBeAg-negative disease. The implications of this study may be important in the worldwide development of testing and vaccination strategies with regard to global prevention of HBV infection.

References

1. Centers for Disease Control and Prevention (CDC). Implementation of newborn hepatitis B vaccination worldwide, 2006. MMWR Morb Mortal Wkly Rep. 2008;57(46):1249-1252.
2. Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med. 1976;294(14):746-749.
3. Mast EE, Margolis HS, Fiore AE, et al A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):1-31.
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   HBV Perinatal Transmission Among Mothers with High Viral Loads
Wiseman E, Fraser MA, Holden S, et al. Perinatal transmission of hepatitis B virus: an Australian experience. Med J Aust. 2009;190(9):489-492.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract  View journal abstract  View full article  View full article
With the widely available HBV vaccine, mother-to-child transmission of acute and chronic HBV infection has been dramatically reduced, with the impact being achieved even with respect to associated hepatocellular carcinoma rate reductions.1 As noted in the previous article, determination of HBV perinatal transmission risk has been performed mainly via HBsAg and HBeAg status. More recently, however, the use of quantitative HBV DNA in clinical practice has led to the study of HBV DNA levels as a predictor of perinatal transmission, specifically among HBeAg-positive women, who are expected to have higher HBV DNA levels. A 10-year meta-analysis from the Netherlands examined 705 newborns born to HBsAg-positive mothers between 1982 and 1989.2 In this study; the only factor that significantly affected the protective efficacy rate of passive-active immunoprophylaxis was maternal HBV DNA level. In this earlier analysis, albeit with different HBV DNA assays than those currently used, 100% protective efficacy was achieved in women with maternal HBV DNA levels < 150 pg/mL-1. 2 In contrast, the protective efficacy rate was only 68% if the maternal HBV DNA level was > 150 pg/mL-1. 2 Eight of the 705 children from this meta-analysis became HBsAg- positive within the first year of life. Compared with noninfected responders to standard passive-active immunoprophylaxis, 7 of the 8 children were noted to have had significantly higher maternal HBV DNA levels before birth. This prompted the authors of the study to conclude that the extent of viremia was likely to play a large role in the failure of standard immunoprophylaxis.2 In 1989, Ip and associates reported similar results, in which infants born to mothers with HBV DNA levels < 150 pg/mL-1 were all HBsAg-negative at 12 months, whereas those born to mothers with HBV DNA levels > 150 IU/mL had a 25% to 50% risk for developing chronic HBV infection (CHB), regardless of immunization status.3

More recently, the review by Wiseman et al4 discusses one of the largest studies of this kind in a prospective, observational study of perinatal HBV transmission in Australia conducted between 2002 and 2008. Pregnant women who tested positive for HBsAg and their babies, all of whom were offered standard HBV vaccine plus HBIg, were followed during and after delivery. In this study, of 313 mother-infant pairs who were evaluated, 68% were HBV DNA-positive and 29% were HBeAg-positive. A total of 138 of the 213 babies born to HBV DNA-positive mothers (138/213) were tested for HBsAg at 9 months, and four cases of HBV transmission were identified. In those four infants, the mothers were all HBeAg-positive, and all the mothers had high viremia levels (> 108 copies/mL).

The overall transmission rates were 3% in infants born to HBV DNA-positive mothers, 7% in those born to HBeAg-positive mothers, and 9% in those whose mothers had high viremia levels (> 108 copies/mL).

This study and the preceding ones suggest that immunoprophylaxis failures occur at higher rates in infants whose mothers have high levels of viremia. With observed rates of MTCT approaching 10% in this subpopulation, the concept of antiviral therapy during pregnancy has subsequently emerged.

References

1. Chang MH, Chen CJ, Lai MS et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997;336(26):1855-1859.
2. del Canho R, Grosheide PM, Mazel JA, et al. Ten-year neonatal hepatitis B vaccination program, The Netherlands, 19821992: protective efficacy and long-term immunogenicity. Vaccine. 1997;15(15):1624-1630.
3. Ip HM, Lelie PN, WongVC, Kuhns MC, Reesink HW.et al. Prevention of hepatitis B virus carrier state in infants according to maternal serum levels of HBV DNA. Lancet. 1989;1(8635):406-410.
4. Wiseman E, Fraser MA, Holden S, et al. Perinatal transmission of hepatitis B virus: an Australian experience. Med J Aust. 2009;190(9):489492.
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   Lamivudine Use in Late Pregnancy for the Prevention of Perinatal HBV Transmission
Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat. 2009;16(2):94-103.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
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Given data regarding high maternal viremia levels and transmission of HBV and experience with prevention of HIV transmission with antiviral therapy, treating HBsAg-positive pregnant women was considered a logical therapeutic option to reduce viral transmission and possibly lower disease transmission rates. Lamivudine appeared to be the most viable candidate, as data regarding use of that agent in pregnancy were available from the treatment of HIV-infected pregnant women. Since no changes in drug pharmacokinetics attributable to pregnancy are observed with the use of lamivudine, it appears as if the agent can be used in pregnancy without any dosing adjustments.

van Zonneveld and colleagues analyzed eight pregnant women with HBV DNA levels > 1.2 x 109 copies/mL who were treated with lamivudine 150 mg/day beginning at week 34 of pregnancy through delivery.1 The infants received HBIg at birth and completed the HBV vaccine series. Among these treated women, the median drop in HBV DNA levels was 98.9%. Of the eight infants born to treated mothers, four were HBsAg-positive at birth, but only one remained positive at 1 year of life. The authors compared this treatment cohort with a historical cohort and found that with the use of lamivudine, the risk for perinatal transmission decreased by a factor of 2.9. No adverse effects were observed in mothers or infants.1

In the current review, which is one of the only published randomized, double-blind studies conducted in pregnant HBV women with HBV, Xu and colleagues randomized 150 mothers with HBV DNA levels greater than > 1000 mEq/mL to lamivudine (100 mg/day daily or placebo, from week 32 of their pregnancy until four weeks postpartum. The newborns received recombinant HBV vaccine with or without HBIg. Within the group of infants in whom the mother received lamivudine plus passive-active immunoprophylaxis (n = 56), the frequency of HBsAg-positive infants was 10 of 56 (18%). In contrast, in the placebo group, in which the infants received passive-active immunization beginning at birth (n = 59) with no maternal antiviral treatment, the incidence of HBsAg-positive infants was 23 of 59 (39%; P = .014). The number of infants with detectable HBV DNA levels was 11 of 56 (20%) among lamivudine-treated mothers vs. 27 of 59 (46%) among placebo-treated mothers (P = .003). These data demonstrated a significant decrease in the risk for HBV transmission when lamivudine therapy was initiated in the third trimester of pregnancy.

In this study, newborns that were lost to follow-up were considered a failure in the statistical analysis. More newborns in the placebo group (18 of 59; 31%) compared with the lamivudine group (7 of 56; 13%) had missing follow-up data. Taking into account this information, without adjusting for missing data, no statistically significant difference in HBsAg positivity was observed between the two groups of infants (P = .368).

The seven antiviral agents approved for the treatment of HBV infection include adefovir dipivoxil (pregnancy category C), interferon alfa-2b (pregnancy category C), pegylated interferon alfa-2a (pregnancy category C), entecavir (pregnancy category C), lamivudine (pregnancy category C), tenofovir (pregnancy class category B), and telbivudine (pregnancy category B). According to the Antiretroviral Pregnancy Registry 2011 interim report, the most of the available data regard treatment during pregnancy currently with focus on lamivudine and tenofovir in the Antiretroviral Pregnancy Registry 2011 Interim Report on antiretroviral use in pregnant women from January 1, 1989, through July 31 2011,2 when a fetus is exposed to lamivudine during the second or third trimester of pregnancy, there is a 2.8% prevalence of birth defects (178 of /6427).2 Tenofovir demonstrated similar results, with a 2.1% prevalence of birth defects (15 of /714). 2 These data are similar to the overall risk of for birth defects reported in the general population.2 Telbivudine has been shown in animal studies to be safe during pregnancy, with no effects on male or female fertility; however, limited human data are available, and those are presented in the review that follows. Clinicians should note that the use of interferon and peginterferon is not considered safe during pregnancy because of the antiproliferative effects of these agents.

References

1. van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2003;10(4):294-297.
2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2011. Wilmington, NC: Registry Coordinating Center; 2011. Accessed February 2, 2012.
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   EFFICACY AND SAFETY OF TELBIVUDINE DURING PREGNANCY FOR THE PREVENTION OF HBV TRANSMISSION
Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. 2011;55(6): 1215-1221.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
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Han and collaborators recently presented data on the efficacy and safety of telbivudine use during late pregnancy in reducing HBV transmission among highly viremic, HBeAg-positive mothers. In this open-label study, a total of 229 Chinese women with HBeAg-positive chronic HBV infection and high viremia (HBV DNA levels > 1.0×107 copies/mL) were treated with telbivudine 600 mg/day from 20 to 32 weeks' gestation (n = 135) or served as untreated controls (n = 94). All infants in both treatment arms received 200 IU of HBIg within 12 hours postpartum and 20μg of recombinant HBV vaccine at 0, 1, and 6 months. The results of the study showed that telbivudine treatment was associated with a significant reduction in serum HBV DNA levels and biochemical normalization of elevated alanine aminotransferase levels prior to delivery. Of the 135 telbivudine-treated mothers, 44 (33%) had DNA levels < 500 copies/mL at delivery, compared with none (0%) of the untreated controls. Seven months after delivery, perinatal transmission rates were lower among the infants born to telbivudine-treated mothers who completed follow-up than among the controls (0% vs. 8%; P = .002). No serious adverse events were reported among the telbivudine-treated mothers or their infants. The authors concluded that telbivudine appeared to reduce mother-to-child HBV transmission and was well tolerated when administered during pregnancy.

The safety concerns over the effects of antiviral therapy on the developing fetus may be partially mitigated by restricting antiviral therapy to use in the third trimester, as opposed to use throughout the duration of a woman's pregnancy. Recent data on antiviral use in the second trimester yielded no additional transmission benefits among pregnant patients.1 Other concerns do remain, however, regarding antiviral use in pregnant women. There are reports of lactic acidosis and hepatic steatosis among pregnant patients receiving nucleoside/nucleotide analogues. For this reason, it is important to monitor liver enzymes and serum electrolytes if women are to receive such treatments during pregnancy. Development of rapid and frequent drug-resistant HBV has been well documented with lamivudine, and this is a particularly relevant issue in among patients with high levels of HBV DNA levels. For this reason, lamivudine is not the optimal drug of choice if a mother has an indication for a long-term CHB chronic HBV treatment beyond pregnancy. Acute exacerbations have also been reported after following discontinuation of antiviral therapy after delivery. Withdrawal flares in the general population have been associated with discontinuation of lamivudine and occur in up to 25% of patients.2 This is in contrast to 62% of patients who developed postpartum flares after receiving amivudine during the last four weeks of pregnancy.3

References

1. Han G, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011; Abst. 236.
2. Wong VW, Chan HL, Wong ML, Tam JS, Leung NW. Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine-resistant mutants. Aliment Pharmacol Ther. 2004 Feb 1;19(3):323-9
3. ter Borg MJ, Leemans WF, de Man RA, Janssen HL. Exacerbation of chronic hepatitis B infection after delivery. J Viral Hepat. 2008;15(1):37-41.
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   Breastfeeding of Newborns by HBV-Infected Mothers
 
Shi Z, Yang Y, Wang H, et al. Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-analysis and systematic review. Arch Pediatr Adolesc Med. 2011;165(9):837-846.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
View journal abstract  View journal abstract  View full article  View full article
Breastfeeding of newborns by HBV-infected mothers has been controversial, as data have shown that HBV is present in breast milk.1 Given the lack of data demonstrating increased transmission risk, the American College of Obstetricians and Gynecologists now recommends that HBV-infected mothers be allowed to breastfeed their infants.2

Shi and associates undertook a meta-analysis of all relevant studies conducted on HBV infection specifically with respect to breastfeeding in the English and Chinese peer-reviewed literature from 1990 to 2010. In their analysis, the authors included only studies that contained extensive data on intrauterine infection (i.e., infant data collected at the time of birth), appropriate immunoprophylaxis administration, breastfeeding for at least one month, and follow-up through 6 to 12 months of age. The primary outcome of this analysis was the rate of mother-to-child transmission of HBV and anti-HBC production in infants at 6 to 12 months of age. Other secondary analyses included rates of newborn infection at the time of birth and presence of HBV in breast milk and maternal blood.

Ten studies, all conducted in Chinese mothers, were included in the meta-analysis; eight in which HBIg was administered to the newborn and three in which only HBV vaccine was given. The studies included a total of 1624 subjects. No significant difference was reported in mother-to-child transmission of HBV among breastfed babies compared with nonbreastfed babies (odds ratio, 0.86; 95% confidence interval, 0.51 to 1.45), even when vertical transmission risks were taken into account. According to the authors, this meta-analysis provides strong evidence that breastfeeding does not contribute to mother-to-child transmission of HBV in the setting of appropriate immunoprophylaxis.

In current practice, all pregnant women should be screened for HBV in the first trimester. If they test positive for HBsAg, further management should be initiated. At this time, no recommendations have been made to change the mode of delivery, as there is little convincing evidence that Caesarean section reduces a woman's risk for mother-to-child transmission of HBV infection compared with vaginal delivery.3

Once delivery occurs, a multidisciplinary effort must be made to initiate HBV vaccination and HBIg administration to the neonate as soon as possible, preferably within the first 12 to 24 hours.4 As highlighted in the current study, breastfeeding can be initiated; however, the mother should be educated that cracked or bleeding skin or nipples should prompt immediate care and deferral of breastfeeding until healed. The infant should then complete the recommended vaccination schedule, and at 9 to 18 months of age, the infant should be assessed for exposure to HBV and the child's chronic infection status should be determined.

This meta-analysis appears to confirm the current practice of allowing breastfeeding in women chronically infected with HBV who give birth. Future prospective studies are needed to stratify risk factors for mother-to-child transmission of HBV.

References

1. Linnemann CC, Goldberg S: HBAg in breast milk Lancet 1974, (2):155)
2. 2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 86: viral hepatitis in pregnancy. Obstet Gynecol. 2007;110(4):941-956.
3. Wang J, Zhu Q, Zhang X. Effect of delivery mode on maternal-infant transmission of hepatitis B virus by immunoprophylaxis. Chin Med J (Engl). 2002;115(10):1510-1512.
4. Centers for Disease Control and Prevention (CDC). Implementation of newborn hepatitis B vaccination worldwide, 2006. MMWR Morb Mortal Wkly Rep. 2008;57(46):1249-1252.
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