1. HBV Patient Populations: Treating HBV in the Setting of Pregnancy
HBV, hepatitis B virus.
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2. About These Slides
The full program accompanying these slides is available on the Clinical Care Options Hepatitis Web site: clinicaloptions.com/PRIME
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We are grateful to Heiner Wedemeyer, MD, and Nezam H. Afdhal, MD, FRCPI, for their assistance in developing these slides
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. 2 2 2

3. Hepatitis B and Pregnancy
Mother
Worsening of hepatitis before or during pregnancy?
Worsening of hepatitis after delivery?
Hepatitis B and other disorders during pregnancy
Infant
Transmission of HBV?
Teratogenicity of drugs?
Risk of fulminant hepatic failure?
Breast-feeding?

4. What is the risk for hepatic flares when stopping antiviral treatment?

5. Hepatic Exacerbations Associated With Discontinuation of HBV Agent
Exacerbations of Hepatitis During Off-Treatment Follow-up,* n/N (%)
ETV
LAM
Nucleoside naïve
25/431 (6)
38/392 (10)
HBeAg positive†
2/134 (1)
9/129 (7)
HBeAg negative‡
23/297 (8)
29/263 (11)
*Nucleoside-naive patients in studies AI and AI with ALT elevations > 10 x ULN and > 2 x baseline.
†Median time to off-treatment exacerbation: 23 weeks for ETV-treated patients vs 12 weeks for LAM-treated patients.
‡Median time to off-treatment exacerbation: 24 weeks for ETV-treated patients vs 9 weeks for LAM-treated patients.
Entecavir [package insert].

6. Changes in Chronic HBV Infection During Pregnancy?
No worsening of liver disease in the majority of women during pregnancy; liver enzymes frequently normalize[1]
However, case reports of hepatic exacerbations/fulminant hepatic failures in HBsAg-positive pregnant women[2-4]
1. Terrault NA, et al. Semin Liver Dis. 2007;(suppl 1):18-24.
2. Mahtab MA, et al. Hepatobiliary Pancreat Dis Int. 2008;7:
3. Yang YB, et al. World J Gastroenterol. 2004;10:
4. Rawal BK, et al. Lancet. 1991;337:364.

7. Increased Risk of Maternal Hepatic Flares ≤ 6 Months After Delivery
HBV-infected pregnancies
(N = 38)
LAM treatment during the last trimester
(n = 13)
No antiviral treatment
(n = 25)
ALT > 3-fold postdelivery:
n = 9 (36%)
n = 8 (62%)
P = NS
ter Borg MJ, et al. J Viral Hepat. 2008;15:37-41.

8. Increased Risk of Gestational Diabetes in HBV-Infected Women
HBsAg positive (n = 1138)
P = .418 20
HBsAg negative (n = 12,547)
18.1
17.1 16
P = .019
12.4 12
10.2
Patients (%) 8
P = .035 4
P = .969
2.8
1.8
0.4
0.4
Hypertension
Gestational Diabetes
Pre-eclampsia
Cesarean Section
Lao TT, et al. J Hepatol. 2007;47:46-50.

9. Hepatitis B and Pregnancy
Mother
Worsening of hepatitis before or during pregnancy?
Worsening of hepatitis after delivery?
Hepatitis B and other disorders during pregnancy
Infant
Transmission of HBV?
Teratogenicity of drugs?
Risk of fulminant hepatic failure?
Breast-feeding?

10. HBV Transmission: When Does It Happen?
In utero transmission
Very rare (< 10%); associated with high HBV DNA levels[1]
During amniocentesis
Very rare; no transmission reported in 2 case series[2,3]
At birth!
HBeAg-positive mothers: 85%
HBeAg-negative mothers: 31%[4]
1. Wang Z, et al. J Med Virol. 2003;71: Alexander JM, et al. Infect Dis Obstet Gynecol ;7: Towers CV, et al. Am J Obstet Gynecol. 2001;184: Beasley RP, et al. Am J Epidemiol. 1977;105:94-98.

11. Mode of Delivery Has No Effect on HBV Transmission
No effect of cesarean section on incidence of immunoprophylaxis failure[1]
If immunoprophylaxis cannot be provided, elective cesarean section might reduce mother-to-child- transmission of HBV[2]
1. Wang J, et al. Chin Med J. 2002;115:
2. Yang J, et al. Virol J. 2008;5:100.

12. Breast-feeding and Risk of HBV Transmission
HBV can be detected in breast milk[1]
Neonates that are correctly immunized may be breast- fed[2,3]
Caveat: nucleos(t)ide analogues can be detected in breast milk[4]
1. Linnemann CC, et al. Lancet. 1974;2:155.
2. Hill JB, et al. Obstet Gynecol. 2002;99:
3. Cornberg M, et al. J Viral Hepat. 2008;15:1-21.
4. Johnson MA, et al. Clin Pharmacokinet. 1999;36:41-66.

13. Prevention of HBV Transmission by Postnatal Vaccination
Active plus passive immunization most effective[1]
Role of maternal HBV DNA on transmision[2]
HBV DNA < 150 pg/mL (1.1 x 107 IU/mL) = 0% transmission
HBV DNA > 150 pg/mL = 32% transmission
No Vaccine
Passive Immunization
Passive + Active Immunization
Infants without HBV, % 5 72 95
1. Ranger-Rogez S, et al. Expert Rev Ant Infect Ther. 2004;2:
2. del Canho R, et al. Vaccine. 1997;15:

14. Perinatal Transmission of Hepatitis B: Risk Factor HBV DNA
138 HBsAg positive, HBV DNA–positive women
Active/passive vaccination
HBeAg positive (n = 61)
4 transmissions (6.6%)
HBeAg negative (n = 77)
0 transmissions (0%)
HBV DNA cutoff: 8 log10 copies/mL
Wiseman E, et al. AASLD Abstract 827.

15. Can Antiviral Treatment Reduce Vertical HBV Transmission?
No complete prevention of transmission, even in case of successful LAM treatment[1]
LAM given 1 month before delivery decreased HBV transmission from 28.0% in untreated historical controls to % (OR: 2.9; 95% CI: )[2]
All received standard prophylaxis
High maternal viremia associated with vaccination failure
No adverse events noted with LAM
1. Kazim SN, et al. Lancet. 2002;359;
2. van Zonneveld M, et al. J Viral Hepat. 2003;10:

16. HBV Treatment During Pregnancy
From 32 ± 2 weeks of gestation
To 4 weeks postpartum
All infants received HBV vaccine (10 g/0.5mL) and HBIG (200 IU, single dose)
Primary endpoint: HBsAg- positive infant at 1 year
Secondary endpoint: HBsAb+, HBV DNA+
HBsAg-positive pregnant women, HBV DNA > 1000 mEq/mL
(N = 114)
LAM 100 mg/day (n = 56)
Placebo (n= 58)
Improved outcomes for the infants receiving LAM
Infant Status at 52 Wks, %
LAM (n = 56)
Placebo (n = 59)
P Value
HBsAg positive 18 39
.014
HBV DNA positive 20 46
.003
HBsAb positive 84 61
.008
Xu WM, et al. Hepatology. 2004;40:272A. Abstract 246.

17. Pregnancy Category of FDA-Approved Treatments for Chronic HBV
Drug
Pregnancy Category
IFN alfa-2b C
PegIFN alfa-2a
Adefovir
Entecavir
Lamivudine
Telbivudine B
Tenofovir
Drugs [package insert].

18. FDA Classification of Drug Safety During Pregnancy
Controlled studies in women fail to demonstrate a risk to the fetus and the possibility of fetal harm appears remote B
Either animal reproduction studies have not demonstrated a fetal risk, but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies C
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other), and there are no controlled studies in women or studies in women and animals are not available; drugs should be given only if the potential benefit justifies the potential risk to the fetus D
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (eg, if the drug is needed in a life-threatening situation or for a serious disease in which safer drugs cannot be used or are ineffective) X
Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit; the drug is contraindicated in women who are or may become pregnant
FDA. Available at: Accessed October 20, 2008.

19. Take Home Points Best prevention for transmission is vaccination/HBIG
Maternal HBV DNA levels are likely associated with increased risk of transmission
Family planning must be discussed with women of childbearing age before initiating HBV therapy
Assess necessity of treatment; wait if possible
Treatment may be indicated in advanced disease
Few data exist for safety of HBV treatment during pregnancy
Treatment in the third trimester may be considered
If HBV treatment discontinued for pregnancy, monitor for flare

20. Recommendations for HBV-Infected Women Who Desire Pregnancy
Women with mild liver disease, low viremia
Pregnancy before treatment
Women with moderate liver disease, no cirrhosis
Treatment before pregnancy; if response, stop treatment before pregnancy
Women with advanced liver disease
Treatment before and during pregnancy; continue treatment after delivery
Women with mild liver disease, very high viremia
Treatment in last trimester with “B” category drug
Wedemeyer H, et al. Dtsch Med Wochenschr. 2007;132:
EASL Clinical Practice Guidelines. J Hepatol. In press.

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