HEPATITIS B: PREGNANCY AND LABOR MANAGEMENT MICHAEL P. NAGEOTTE, M.D.

HEPATITIS B: PREGNANCY AND LABOR MANAGEMENT MICHAEL P. NAGEOTTE, M.D.

Disclosures I have no relevant financial relationships to disclose or conflicts of interest to resolve. I will not discuss any unapproved or off label, experimental or investigational use of a product, drug, or device.

HEPATITIS B VIRUS (HBV) Caused by the hepatitis B virus (HBV) HBV is a double-stranded DNS virus that primarily effects the liver The HBV virion is also known as the Dane particle

Small DNA virus Three principle antigens Surface antigen (HBsAg) Core antigen (HBcAg) Hepatitis B e antigen (HBeAG) What is Hepatitis B?

HBV DNA ENCODES: HBV polymerase (enzyme with reverse transcriptase activity) Hepatitis B core antigen (HBcAg) Pre-core protein cleaved in the endoplasmic reticulum of the infected cell and secreted as hepatitis B e antigen (HBeAg) Large, middle and small surface antigens (HBsAg) The X protein; required to initiate and maintain virus replication after infection

INFECTION Sexual transmission accounts for most HBV infections in the U.S. Risk is 25% for regular sexual contacts of infected individuals to become seropositive; chronic HBV has 15-25% mortality from cirrhosis or hepatocellular carcinoma; 250 million people worldwide with chronic HBV Mother to child transmission is the predominate mode of transmission in areas of high HBV prevalence (Asia, Africa and South Pacific) Vertical transmission can occur in 10% of neonates with first trimester acute infection and in 80-90% with third trimester acute infection In women chronically seropositive for both HBsAg and HBeAg, vertical transmission occurs in approximately 90% 10-20% of HBsAg seropositive women will transmit the virus to their neonates in the absence of immunoprophylaxis; neonatal/pediatric acquisition additional risk without vaccination

INFECTION Average incubation period is 90 days from exposure to symptoms but may vary from 6 weeks to 6 months HBV found in highest concentrations in the blood with lower concentrations in saliva, semen, vaginal secretions and wound exudates HBV can remain viable on environmental surfaces or at room temperature for greater than 7 days Acute HBV infection in adults is symptomatic in only 50% (anorexia, nausea, vomiting, fever, abdominal pain and jaundice); 1% of cases result in acute liver failure and death Chronic infection occurs in 90% of infected infants, 30% of infected children < 5 years and 2% - 6% of adults

Acute Hepatitis B with Recovery

Progression to Chronic Hepatitis B

Adult Infection Mortality associated with Hepatitis B is only 1% Of adults infected, 85-90% have resolution However, 2% - 6% develop chronic infection 15-30% of chronically infected have continued viral replication with persistence of the e Ag Develop cirrhosis and persistent hepatitis Can develop hepatocellular carcinoma Likely have high viral DNA load

Acute Hepatitis in Pregnancy As with any adult, hospitalize with: Encephalopathy Coagulopathy Severe debilitation Correct coagulopathy Supportive care/limit activity Protect from upper abdominal trauma

Prenatal Diagnostic Testing Transmission through amniocentesis or CVS appears low with chronic Hepatitis B or C 115 women known HBsAg positive at test Neonatal infection rates were no different However, very small number of cases Alternative genetic screening options should be considered

Efforts to Mitigate Risk of Vertical Transmission of Hepatitis B During Pregnancy and Birth

Immunization of Neonates Screen negative (HBSAg negative) mother: active immunization before discharge but no later than 2 months of age; total of three injections at 0, 1 and 6 months Neonates <2000 gms with negative mother, vaccine should be delayed until 1 month of age or discharge with subsequent vaccination

Vaccination Seroconversion occurs in 95% of recipients Should be given in the deltoid Intragluteal and intradermal injections result in lower rates of seroconversion

Immunization of Neonates HBsAg positive or unknown at delivery HBIG (0.6 ml/kg) plus-- Hepatitis B vaccine Give simultaneously at different sites IM Give within 12 hours of birth Two more Hepatitis B vaccines within 6 months Immunoprophylaxis will do nothing if the neonate was already infected in utero

INFECTION Immunoprophylaxis failure against vertical transmission appears to occur more frequently in mothers who are HBeAg-positive and/or have high viral loads The presence of HBeAg generally indicates the person has high levels of virus and greater infectiousness; the absence of e-antigen does not exclude active viral replication Maternal HBV-DNA level has been demonstrated to be the strongest predictor of neonatal immunoprophylaxis failure, with a lower prophylaxis effective rate directly related to a higher maternal viral load/positive HBeAg status

In Utero Fetal Infection 85-95% of perinatal transmission occurs intrapartum from infected maternal blood and GU secretions 5-15% are from hematogenous transplacental dissemination and postnatal contact Risks for in utero infection include: Threatened preterm labor/maternal hemorrhage Higher HBsAg and HBV DNA titres HBeAg positivity HBV DNA in villous capillary endothelial cells

Failure of Immunoprophylaxis at Birth What can be done to limit the in utero acquisition of hepatitis B? Is post-exposure prophylaxis indicated in pregnancy? Are there specific risk factors or populations which are at greater risk for infection before labor and delivery? Is there any evidence of efficacy with antenatal treatment resulting in a lower failure of immunoprophylaxis at birth?

Prophylaxis for Susceptible Pregnant Women Sexual contact, percutaneous or mucosal exposure, needle sharing or sexual assault/abuse with HBSAg-positive individual within 14 days: --if previously vaccinated, administer hepatitis B vaccine booster dose --if unvaccinated, administer hepatitis B vaccine series and HBIG --if contact has unknown HBSAg status, no treatment if previously vaccinated; hepatitis B vaccine series if unvaccinated

Antepartum Fetal Therapy--HBIG Randomized 112 women into: HBIG treatment q4 weeks from 28 weeks Control group IU infection rate 10.5% vs 27.3% (p<0.05) Ascendant trend as HBV DNA levels increases Risk increases with HBV-DNA > 10 8 copies/ml Li XM, Shi MF, Yang YB, Shi ZJ, Hou HY, Shen HM, Teng BQ. Effect of hepatitis B immunoglobulin on interruption of HBV intrauterine infection. World J Gastroenterol. 2004;10(21):3215.

Antiviral Treatment in Pregnancy Indications for treatment: Chronic liver disease in the mother Decrease the vertical transmission rate Can we affect the intrauterine fetal infection rate by treating mother during pregnancy?

Nuceloside Analogues Lamivudine Category C History of safety in HIV infection but high risk for resistance Tenofovir Category B First line agent and low risk for resistance Telbivudine Category B High risk for resistance and very few studies of efficacy

Antepartum Treatment: HBIG or Lamivudine HBIG group 56 cases Q4 weeks: 28 weeks until delivery Lamivudine 43 cases 100 mg daily: 28 weeks to 30 days after labor Control group 52 cases No specific treatment HBsAg, HBeAg, HBV-DNA tested 28 weeks Before delivery In newborns 24 hour before immunoprophylaxis Li XM, Yang YB, Hou HY, Shen HM, Teng BQ, Li AM, Shi MF, Zou L. Interruption of HBV intrauterine transmission: a clinical study. World J Gastroenterol 2003 Jul;9(7):1501-3.

Antepartum Treatment Group n HBsAg (+) n HBeAg (+) n Intrauterine infection n % HBIG 56 3 7 9 16.1 a Lamivudine 43 1 7 7 16.3 a Control 52 8 11 17 32.7 b a P>0.05 between HBIG and lamivudine group; b P<0.05 Control vs HBIG or lamivudine group Li XM, Yang YB, Hou HY, Shen HM, Teng BQ, Li AM, Shi MF, Zou L. Interruption of HBV intrauterine transmission: a clinical study. World J Gastroenterol 2003 Jul;9(7):1501-3.

ANTEPARTUM HBIG vs. LAMIVUDINE Rate of neonatal HBV positivity 16.1 % in HBIG group vs. 16.3% in lamivudine group vs.32.7% in controls HBV DNA significantly reduced in both treatment groups compared to controls Despite immunoprophylaxis, there continued to be a significant rate of newborn HBSAg positivity

Antepartum Lamivudine Treatment Multi-center, double blind, RCT of 155 HBSAg + mothers Arm 1: lamivudine + infant HBIG/vaccine (n=89) Arm 2: placebo + infant HBIG/vaccine (n=61) Arm 3: lamivudine + infant vaccine only 154/155 were HBeAg positive Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, Zhang SL, Qiao FY, Campbell F, Chang CN, Gardner S, Atkins M 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.

HBV DNA Level Lamivudine (n=89) Placebo (n=61) n Mean (SD) Meq/mL n Mean (SD) Meq/mL Baseline 89 2220 (1610.9) 61 2692.7 (1627.0) Week 4 (ante) 76 41.7 (177.4) 53 2147.4 (1447.6) Week 8 (ante) 28 28.5 (93.5) 23 1955.4 (1480.1) At labor and delivery 80 51.4 (308.5) 58 2168.8 (1646) Week 4 (pp) *End of tx 76 191.1 (760.6) 54 3769.9 (3274.5) Week 9 (pp) 64 3035.8 (3200.4) 50 2638.5 (2446) Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, Zhang SL, Qiao FY, Campbell F, Chang CN, Gardner S, Atkins M 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.

Results At birth: 7/56 (12.5%) of infants in the lamivudine group were HBsAg seropositive 14/59 (24%) infants in the placebo group At 52 weeks: 10/56 (18%) of infants in the lamivudine group were HBsAg seropositive 23/59 (39%) in the placebo group (p = 0.014) Xu WM, Cui YT, Wang L, Yang H, Liang ZQ, Li XM, Zhang SL, Qiao FY, Campbell F, Chang CN, Gardner S, Atkins M 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.

Antepartum Lamivudine Treatment Meta-analysis of 15 RCTs 1693 HBV carrier mothers Started treatment at 28 weeks Interruption of MTCT at birth and at 6-12 months of age Han L, Zhang HW, Xie JX, Zhang Q, Wang HY, Cao GW. A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus. World J Gastroenterol 2011; 17(38): 4321 4333.

Concluded Lamivudine treatment from 28 weeks of gestation efficiently interrupts MTCT Treatment is safe and more efficient than HBIG at delivery in interrupting MTCT If maternal viral load is reduced to < 10 6 copies/ml by lamivudine treatment, HBV MTCT can be more frequently prevented

Antepartum Lamivudine Treatment Meta analysis of 10 RCTs including 951 mothers Included studies with an HBIG arm Interruption of intrauterine infection significant Interruption of MTCT at 9-12 months significant Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):147.

Lamivudine versus control for interruption of intrauterine infection Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):147.

Lamivudine versus HBIG for interruption of intrauterine infection Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):147.

Lamivudine vs. control in interruption of HBV mother-to-child transmission at 9 12 months Shi Z, Yang Y, Ma L, Li X, Schreiber A. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010;116(1):147.

Concluded Lamivudine is effective in interruption of HBV intrauterine infection and MTCT at 9-12 months Should be recommended to mothers with viral loads of >10^3 copies/ml Problem is with establishment of high resistance to lamivudine treatment in high percentage of patients Not recommended antiviral because of this concern

Current Interventions HBIG and HBV vaccination at birth Decreased the MTCT to 5-10% 8-30% of mothers with HBeAg positivity or high viral loads still pass HBV to their babies What options are there for treating in utero? Maternal HBIG administration Maternal antiviral treatment--options

Which Fetuses are at Higher Risk of Intrauterine Infection? Two nested case-control studies in 773 hepatitis B surface antigen (HBsAg)-positive Taiwanese women and their infants As the serum HBV DNA levels increased: HBeAg positive moms: OR increased from 1-147 for persistent neonatal infection HBeAg negative mom: OR 19 for high vs low viral load Burk RD, Hwang LY, Ho GY, Shafritz DA, Beasley RP. Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load. J Infect Dis. 1994;170(6):1418.

Failure of Neonatal Treatment Retrospective review between 2007-2010 869 HBsAg + mother infant pairs Dose dependent correlation with HBV-DNA levels and neonate immunoprophylaxis failure All failed cases had mothers with HBeAg positivity and high DNA levels (>10 6 copies/ml) Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepat 2012; 19(2): e18 e25.

Failure of neonatal treatment Meta-analysis in the Netherlands HBV-DNA level was only factor affecting treatment efficacy 100% efficacy with viral DNA levels < 10 7 IU/mL at birth 68% efficacy with viral DNA levels > 10 7 IU/mL at birth del Canho R, Grosheide PM, Schalm SW, de Vries RR, Heijtink RA. Failure of neonatal hepatitis B vaccination: the role of HBV-DNA levels in hepatitis B carrier mothers and HLA antigens in neonates. J Hepatol 1994; 20(4): 483 486.

HBV DNA Viral Load Observational study within Kaiser Northern California 4446 infants born to 3253 HBV positive mothers Viral load determined in third trimester in all patients 1997-2010; all neonates treated with HBIG and vaccine Lowest viral load with transmission was 6.32 x 10 7 IU/mL No mother with viral load less than 5 x 10 7 IU/mL transmitted the virus regardless of HEV status Kubo A, Shlager L, Marks AR, Lakritz D, Beaumont C, Gabellini K, Corley DA. Prevention of vertical transmission of hepatitis B: an observational study. Ann Intern Med. 2014 Jun;160(12):828-35.

Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load (Pan, CQ, Duan Z, Dai, E, et al. N Engl J Med 2016; 374:2324-34.) 200 mothers positive for HBeAg with HBV DNA level higher than 200,000 IU/ml (between 5 and 6 log 10 copies/ml) Randomized to usual care or tenofovir disoproxil fumarate (TDF) 300 mg/day from 30-32 weeks of gestation until postpartum week 4 All infants received immunoprophylaxis Primary outcomes were the rates of MTCT and birth defects Secondary outcomes were safety of TDF, % of mothers with an HBV DNA level less than 200,000 IU/ml at delivery and loss or conversion of HBeAg or HBSAg at postpartum week 28

RESULTS At delivery, 68% in the TDF group (66 of 97 women) as compared with 2% in the control group (2 of 100) had an HBV DNA level less than 200,000 IU per ml (P<0.001) At postpartum week 28, the MTCT was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (with transmission of virus to 5% of infants [5 of 97] vs. 18% [18 of 100], P=0.007) and the per-protocol analysis (with transmission of virus to 0 vs. 7% [6 of 88], P=0.01). Maternal and infant safety profiles similar although more mothers in the TDF group had an increase in the creatine kinase level and elevated LFTs. The maternal HBV serologic outcomes did not differ significantly between the groups.

CONCLUSIONS In a cohort of HBeAg-positive mothers with and HBV DNA level of more than 200,000 IU/ml during the third trimester, the rate of MTCT was significantly lower among those who received TDF therapy than among those who received usual care without antiviral therapy There were no differences in the maternal and infant safety profiles; this included birth defects but there was noted an increase in maternal creatine kinase and alanine aminotransferase (SGPT) both during and following TDF treatment

STUDY CONCERNS Was initiation of TDF therapy done too late? Current international guidelines recommend that antiviral treatment start at 28-32 weeks. Would earlier treatment further reduce the almost one third of mothers who continued to have levels above the HBV DNA threshold? Was avoidance of breast-feeding while taking TDF appropriate? Women being treated with TDF-containing antiretroviral regimens for HIV are encouraged to breast-feed. In this report, 49% of the infants in the TDF group and 57% in the control group were born by cesarean section. The rate of elective cesarean section was 34% (67 of 197) with the TDF rate no different from the control (64% [30 of 47 mothers] and 74% [37 of 50], respectively; P=0.28). Did bias effect the choice of elective cesarean section and effect in any way the results?

CURRENT TREATMENT RECOMMENDATIONS SMFM recommends antiviral therapy be considered in pregnant women with HBV infection and viral load > 6-8 log 10 copies/ml; currently no official ACOG position Consider HBeAg as well as HBV DNA level in HBSAg positive women in second trimester of pregnancy, particularly if first generation immigrants from SE Asia or Africa Antiviral treatment generally started at 28 weeks with the nucleotide analogue tenofovir disoproxil fumarate (TDF) 300 mg orally/day until delivery as the preferred antiviral because of its better resistance profile and safety data in pregnancy Delivery by cesarean section for the purpose of reducing MTCT of HBV is not recommended by the CDC or ACOG

Pan CQ, Duan ZP, Bhamidimarri KR, Zou HB, Liang XF, Li J et al. An algorithm for risk assessment and intervention of mother to child transmission of hepatitis B virus. Clin Gastroenterol Hepatol 2012; 10(5): 452 459.

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Vertical Transmission Perinatal transmission is the greatest cause of chronic infection worldwide Without prophylaxis at birth: 10-20% seropositive for HBsAg alone will transmit the virus to their neonates 90% of women seropositive for HBsAg AND HBeAg will transmit the virus to the neonate

Adult versus Perinatal Acquisition Risk of developing chronic HBV is inversely proportional to the age at exposure Risk of chronic infection for adults is 5-10% If acquired perinatally: Risk of chronic infection is 85-95% 25-30% lifetime risk of serious or fatal liver disease

Vertical Transmission Gestational age timing of maternal acute hepatitis B affects the transmission rate: 1 st trimester: up to 10% of patients will be seropositive at delivery (+ HbSAg) 3 rd trimester: 80-90% of patients will be seropositive at delivery