Vertical Transmission of HBV
Stephan Ehrhardt MD, MPH
Associate Professor
Department of Epidemiology
1
Outline

Background on vertical transmission

Prevention strategies

Failure of current prevention strategies

Opportunities to improve prevention of vertical
transmission
2
Background
Hepatitis B virus (HBV) infection poses a significant global
health problem with an estimated 350-400 million chronically
infected individuals worldwide.
3
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
4
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: 7090% 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
5
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
6
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

7
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
8
Lamivudine (LAM) and MTCT of HBV


Pregnancy risk Class C agent by FDA
A meta-analysis examined 15 RCTs including 1693 HBVcarrier 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
9
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-tochild transmission of hepatitis B virus. World J Gastroenterol 2011;17(38):4321-33
10
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
11
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.
12
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 resistance 2
 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.
13
HBIg withdrawal strategy?



HBIg
 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.
14
HBIg withdrawal strategy?

Drug can be delivered in the maternal-child care context
(usually well developed)

May be integrated into HIV-MTCT programs
15