HBV Patient Populations: Treating HBV in the Setting of Pregnancy HBV, hepatitis B virus. Supported by an unrestricted educational grant from

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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?

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

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 AI463022 and AI463027 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].

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;7:161-164. 3. Yang YB, et al. World J Gastroenterol. 2004;10:2305-2306. 4. Rawal BK, et al. Lancet. 1991;337:364.

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.

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.

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?

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;71:360-366. 2. Alexander JM, et al. Infect Dis Obstet Gynecol. 1999;7:283-286. 3. Towers CV, et al. Am J Obstet Gynecol. 2001;184:1514-1518. 4. Beasley RP, et al. Am J Epidemiol. 1977;105:94-98.

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;115:1510-1512. 2. Yang J, et al. Virol J. 2008;5:100.

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;99:1049-1052. 3. Cornberg M, et al. J Viral Hepat. 2008;15:1-21. 4. Johnson MA, et al. Clin Pharmacokinet. 1999;36:41-66.

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;2:133-145. 2. del Canho R, et al. Vaccine. 1997;15:1624-1630.

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 2008. Abstract 827.

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 12.5% (OR: 2.9; 95% CI: 0.29-28.0)[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;1488-1489. 2. van Zonneveld M, et al. J Viral Hepat. 2003;10:294-297.

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.

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].

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: http://www.fda.gov/fdac/features/2001/301_preg.html. Accessed October 20, 2008.

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

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;132:1775-1782. EASL Clinical Practice Guidelines. J Hepatol. In press.

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