Vertical Transmission of HBV Stephan Ehrhardt MD, MPH Associate Professor Department of Epidemiology

Outline Background on vertical transmission Prevention strategies Failure of current prevention strategies Opportunities to improve prevention of vertical transmission

Background Hepatitis B virus (HBV) infection poses a significant global health problem with an estimated 350-400 million chronically infected individuals worldwide.

Background continued Majority of new cases in low-income countries are likely due to MTCT Contrasting patterns: majority of new cases in high-income countries are due to horizontal transmission in adulthood The risk of developing CHB is inversely proportional to age at time of exposure: About 85-95% of infected infants become chronic HBV carriers 20% to 30% of children infected between age 1 year and 5 years become chronic HBV carriers < 5% of immunocompetent infected adults become HBV carriers The risk of MTCT increases with higher maternal HBV DNA levels

Prevention strategy Estimate: 15-45% of CHB patients will die of Liver-related complications or Progress to hepatocellular carcinoma Before the introduction of active plus passive vaccination: 70-90% of infants of HBsAg and HBeAg + mothers became chronically infected Current recommendation: active RV plus HBIg within the first 12 hours if life (plus subsequent completion of the RV series) MTCT rate reduced to 5-15% due to active plus passive vaccination

Prevention strategy Protective efficacy rates in neonates born to HBeAg positive mothers after passive Immunization (HBIg), active immunization (PV: plasmatic vaccine, RV: recombinant vaccine) and combination

Failure of immunoprophylaxis Main factor: High maternal serum HBV DNA levels Among 869 infants born to HBsAg positive mothers found the immunoprophylaxis failure rates were 0%, 3.2%, 6.7% and 7.6% when mothers’ HBV DNA levels were <106, 106-<107, 107-<108 and ≥108 IU/mL Delayed delivery of RV/HBIg Intrauterine transmission of HBV Genetic mutations in the HBV surface antigen Failure of the infant to respond to vaccine for immunologic reasons

Antiviral treatment Concept: To suppress maternal HBV DNA before delivery to decrease transmission risk No antiviral agent has been approved for use in pregnancy The health of the mother and the fetus must be considered independently Infants: risk of exposure to medication during early embryogenesis Mothers: stopping or switching medication may adversely affect both short- and long-term liver disease outcomes Randomized clinical trials have been conducted to study the additive efficacy and safety of: Lamivudine Telbivudine Tenofovir

Lamivudine (LAM) and MTCT of HBV Pregnancy risk Class C agent by FDA A meta-analysis examined 15 RCTs including 1693 HBV-carrier mothers reported the efficacy and safety of LAM in late pregnancy to interrupt MTCT of HBV: Most studies (13/15): low methodological quality Most studies: sample size < 100 LAM was administered in 2nd or 3rd trimester Pooled RR: 0.43 (95% CI, 0.25-0.76; 8 RCTs) and 0.33 (95% CI, 0.23-0.47; 6 RCTs) indicated by newborn HBsAg or HBV DNA Pooled RR: 0.33 (95% CI, 0.21-0.50; 6 RCTs) and 0.32 (95% CI, 0.20-0.50; 4 RCTs) indicated by serum HBsAg or HBV DNA of infants 6-12 months after birth Only 1 study reported side effects of LAM in newborns Epivir

Lamivudine (LAM) and MTCT of HBV Yet … in 20% of the pregnant women, the viral load remained high (>1 x 107 IU/ml) and resistant mutations were detectable after only three months of treatment Case for more potent antiviral drugs to be used to prevent transmission. Ref: Han L, Zhang HW, Xie JX, et al. A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus. World J Gastroenterol 2011;17(38):4321-33

Telbivudine and MTCT of HBV Pregnancy risk Class B agent by FDA A meta-analysis examined 2 RCTs and 4 non-randomized controlled trials (NRCTs) including 576 HBV-carrier mothers reported the efficacy and safety of Telbivudine in late pregnancy to interrupt MTCT of HBV: Most studies are of low methodological quality. Most studies have sample size < 100 All newborns received hepatitis B vaccine and HBIg after birth. Pooled RR: 0.31 (95% CI, 0.20-0.49; 3 NRCTs) and 0.18 (95% CI, 0.08-0.40; 2 RCTs and 3 NRCTs) indicated by newborn HBsAg or HBV DNA Tyzeka

Telbivudine and MTCT of HBV Pooled RR: 0.11 (95% CI, 0.04-0.31; 2 RCTs and 3 NRCTs) and 0.09 (95% CI, 0.02-0.30; 1 RCT and 2 NRCTs) indicated by serum HBsAg or HBV DNA of infants 6-12 months after birth No study reported significant adverse effects More high quality, well-designed, double-masked, randomized controlled and large size clinical trials are needed for further investigation and more convincing results on the efficacy and safety of Telbivudine Ref: Deng M, Zhou X, Gao S, et al. The effects of telbivudine in late pregnancy to prevent intrauterine transmission of the hepatitis B virus: a systematic review and meta-analysis. Virol J. 2012; 9: 185.

Tenofovir (TDF) and MTCT of HBV Pregnancy risk Class B agent by FDA Compared to LAM and Telbivudine, TDF: Has higher efficacy in treating CHB1 Has lower potential for the development of resistance2 TDF has been used widely in HIV positive mothers to prevent MTCT, providing sufficient numbers of 1st trimester exposures in pregnant women with no increased risk in birth defects. Data of safety of Telbivudine in pregnant women are limited3 One RCT ongoing to study the efficacy and safety of TDF in pregnant women in Thailand 1 Wiens A, Lenzi L, Venson R, et al. Comparative efficacy of oral nucleoside or nucleotide analog monotherapy used in chronic hepatitis B: a mixed-treatment comparison meta-analysis. Pharmacotherapy 2013;33(2):144-51. 2 Peng CY, Chien RN, Liaw YF. Hepatitis B virus-related decompensated liver cirrhosis: benefits of antiviral therapy. J Hepatol 2012;57(2):442-50. 3 Pan CQ, Lee HM. Antiviral therapy for chronic hepatitis B in pregnancy. Semin Liver Dis 2013;33(2):138-46. Viread

HBIg withdrawal strategy? is often not available in low-resource areas due to production and storage problems is often very expensive cannot prevent in utero transmission often fails when the maternal HBV DNA is high TDF has been used in liver transplant patients as a safe and effective substitute for HBIg against HBV recurrence. Since first trials in liver transplant recipients have shown promise, we are currently debating HBIg withdrawal strategies in a broad context The efficacy of antiviral drugs compared to HBIg in newborns has never been studied.

HBIg withdrawal strategy? Drug can be delivered in the maternal-child care context (usually well developed) May be integrated into HIV-MTCT programs