Mother to Child Transmission (MTCT) of

Hepatitis B: Prevention and Management

Strategy
Maisuri T. Chalid
Faculty of Medicine-Hasanuddin University-Makassar
Outline
 Epidemiology
 Impact of Mother-to-Child Transmission (MTCT) of hepatitis B
 Factors associated with MTCT transmission
 Management
 Conclusion: Key points
Estimated annual deaths from selected causes by region, 2010

Lozano et al. Lancet. Vol 380. 2012

Courtesy of IHME – Global Burden of Disease Study
 GLOBAL ANNUAL MORTALITY FROM HEPATITIS, HIV, TUBERCULOSIS
AND MALARIA, 2000–2015

Unlike HIV, tuberculosis and malaria, the trend in mortality from viral hepatitis is
increasing

Source: Global Burden of Disease and WHO/UNAIDS estimates

http://ihmeuw.org/3pms, http://ihmeuw.org/3pmt (accessed 28 July 2017).
 Hepatitis B

Hepatitis B is a major public health problem:

• 2 billion people globally have been infected by hepatitis B virus
(HBV)
• In 2015: More than 257 million have chronic hepatitis B, with
development to severe complications, cirrhosis, and cancer,
resulting in >887 000 deaths each year

World Health Organization. Fact Sheet #2017.

Lozano et al. Global Burden of Disease Study 2010. Lancet. 2012; 380
Immunization Program in Indonesia

HB Vaccination in Indonesia
WHO Pilot Project in Lombok Island. Indonesia was selected as the
first model of HB vaccination integrated to EPI. Reduction of HBsAg
prevalence infants from 6.2% to 1.4%

Expanded to 4 Provinces: NTB, Bali,

Jogja & East Java

Added: 3 provinces (Papua, NTT & East Timor)

Added: 6 Provinces (Central Java, West

Java, DKI, Lampung, West Sumatra &
West Borneo)
National Program

Birth-dose
Immunization

1987 1991-1992 1992-1993 1996-1997 April 1997 April 1999

 Hepatitis B in Indonesia
(Basic Health Survey 2007 - west and middle region)

HBsAg Distribution of HBsAg (+) According to Age Group #

16
%
14

12

10

0
5–9

10 – 14

25 – 29

30 – 34

35 – 39

50 – 54

55 – 59

> 60
1–4

15 – 19

20 – 24

40 – 44

45 – 49
Age group HBsAg (+)

 HBsAg (+): 9.4% (N = 10,391); Male: Female = 9,68 : 9,28

 HBsAg in 1-4 years group: 7,32%
# Provisional data
 Possibility I:

many provinces
• Low coverage in
WHO Target

20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0

10.0
0.0
ACEH 77.5
SUMATERA UTARA 76.7
SUMATERA BARAT 72.7
RIAU 67.1
JAMBI
SUMATERA SELATAN 88.6
BENGKULU 65.7
LAMPUNG 79.4
DKI JAKARTA 74.9
JAWA BARAT 99.9
JAWA TENGAH 97.4
DI YOGYAKARTA
JAWA TIMUR 98.2
KALIMANTAN BARAT 58.8
KALIMANTAN TENGAH 60.3
WHY?

KALIMANTAN SELATAN 62.6

KALIMANTAN TIMUR 64.6
SULAWESI UTARA 76.6
SULAWESI TENGAH 57.0
SULAWESI SELATAN 87.7
SULAWESI TENGGARA 46.1
BALI 95.0
under-five children

NUSA TENGGARA BARAT 98.2

NUSA TENGGARA TIMUR 60.9
MALUKU 56.1
PAPUA 43.3
BANTEN 89.9
MALUKU UTARA 66.1
GORONTALO 76.8
BANGKA BELITUNG 92.7
New cases continue to occur in

Coverage of Birth-dose Hepatitis B immunization in Indonesia 2012 (By Province)

PAPUA BARAT 38.1

KEPULAUAN RIAU 79.9
SULAWESI BARAT 64.3
INDONESIA 85.6
 New cases continue to occur in
under-five children

WHY?

Prevalence of HBsAg (+) in several cities in Indonesia

Jakarta 1985 4%
Possibility 2:
 Mother-to-child Surabaya 1989 4,6%
transmission (MTCT) Denpasar 1981 2,46%
Mataram 1993 3,4%
Bali 1996 5%
Jakarta 2009 2,2%
Makassar 2014 6.8% (64/943)
Jakarta 2013 3.5%
Ongoing research in
Indonesia
 Shifting to intermediate endemic countries
 Of 70,000 pregnant mothers (2014) => 2.76% HBsAg (+)
 If pregnancy rate 5,000,000/year => 150,000 pregnant
mothers /year potential transmit to their babies => 95%
Chronic HepB
Prevalence of HBsAg (+) among Health Workers and Pregnant Women in 13
Provinces in Indonesia (2014)
11
9.00

8.00
8.00

7.00

6.00

5.00

4.37

4.24
4.08

3.76
3.76

3.61
4.00

3.33
3.03

3.50
2.80
2.78

2.76
2.67
2.65

2.56
3.00

2.43
2.42
2.39
1.93

1.79

1.79
1.73

1.66
2.00
1.46

1.57
0.80

0.79

1.00

0.00
Sumbar Jambi DKI Jateng Jatim Sulsel Kalbar Sumut Bengkulu Papua NTB Jabar Sulut Total
Jakarta Barat

Bumil Nakes
 WHO Global Strategy on Viral
Hepatitis (2016)

 Vision: “A world where viral hepatitis transmission is

halted and everyone living with viral hepatitis has
access to safe, affordable and effective prevention, care
and treatment services”

 Goal: Eliminate viral hepatitis as a major public health

threat by 2030.
Outline
 Epidemiology
 Impact of Mother-to-Child Transmission (MTCT) of hepatitis B
 Factors associated with MTCT transmission
 Management
 Conclusion: Key points
Hepatitis B Virus
(Dane particle)

 42-nm double shelled

DNA virus
 outer component:
HBsAg
 Inner component:
HBcAg (27 nm)
 Circular double
stranded DNA
 DNA polymerase
Current diagnostics: all
laboratories
 HBsAg – marker of infection
 IgM anti-HBc – marker of recent infection
 IgG anti-HBc – marker of past infection
 Anti-HBs – marker of past infection,
response to vaccine
 HBeAg/Anti-HBe – helps to characterise disease
stage
 HBV DNA – helps to characterise disease
stage, response to Rx
 Interpretation of screening test for HBV
HBV Infection status:
 Current infection of HBV: HBsAg+
 Past/life-time exposure to HBV: anti-HBc +
 Immunity against HBV: anti-HBs+
• Resolved infection (HBsAg-, anti-HBc+, anti-HBs+)
• Immune due to vaccination (HBsAg-, anti-HBc-, anti-HBs+)
L L
I I
V V
E E
R R

D D
A A
M M
A A
G G
E E
Outcome of HBV infection

Compensated
Resolution Stabilisation cirrhosis

Acute Chronic
infection hepatitis Cirrhosis Liver cancer Death

Chronic Carrier Progression Decompensated

Cirrhosis
(Death)
30–50 years
Course of HBV Infection After Neonatal or Adult Exposure

80% Inapparent disease

90-99% Recovery
Childhood and Adult 20% Acute Hepatitis
1-12% Carriers
1% Fulminant Hepatitis
1-12% Per year Very low risk

HBV Infection Cirrhosis HC Carcinoma

1-12% Per year 0.5% Per Year

Neonatal Inapparent Disease 95% Carriers

 Outcome of Hepatitis B Infection by Age of Infection

100 Predominantly 100

neonatal infection
in Asia

80 Chronic Infection 80

Symptomatic Infection (%)

Chronic Infection (%)

60 60
Predominantly
adult infection
in Western
40 countries 40

20 20
Symptomatic Infection

0 0
Birth 1-6 months 7-12 months 1-4 years Older Children
and Adults
Age at Infection
 How HBV Is Transmitted？

MTCT
Blood Sexual
Mother-to-child transmission
transmission

Intrauterine At birth Postnatal

Outline
 Epidemiology
 Impact of Mother-to-Child Transmission (MTCT) of hepatitis B
 Factors associated with MTCT transmission
 Management
 Conclusion: Key points
Factors associated with 24

MTCT
 Maternal Viral load (HBV DNA level)
 Maternal HBeAg status
 Mode of delivery
 HBV S gene variation (mutant)
 Neonatal immune deficiency
Factors associated with
MTCT
 Maternal Viral load (HBV DNA level)

 Higher Maternal HBV DNA levels [<6, 6–6.99, 7–

7.99, and ≥8 log10 copies/mL]  higher rates of
immunoprophylaxis failure: [0%, 3.2%, 6.7%, and
7.6%, respectively];
 antenatal HBV DNA level >6 log10 copies/mL
(>200,000 IU/mL) is the most important predictor
for MTCT.
Factors associated with
MTCT
 Maternal HBeAg status
 Transplacental HBeAg from the mother
induces a specific unresponsiveness of helper
T cells to HBeAg and HBcAg in neonates born
to HBeAg-positive HBsAg carrier mothers
Routes of mother-to-child HBV
transmission

 Intrauterine transmission:
 Practicaldefinition: “The detection of
HBsAg or HBV DNA in neonatal peripheral
venous blood or cord blood”.
Routes of mother-to-child HBV
transmission

Intrapartum transmission (transmission

during delivery)

 Is the main route of MTCT of HBV infection

 Association with duration of the first stage of labour lasting >9
hours.
 Occurs through:
 Exposure of baby to HBV-containing maternal body fluids when
passing through the birth canal
 Partial placental leakage due to uterine contractions or
instrumentation trauma during labour
Routes of mother-to-child HBV
transmission

Postpartum transmission

 HBV infection (of newborns and infants)

through exposure to maternal body fluids,
breastfeeding, and other contacts in daily
life.
 Post partum MTCT with breastfeeding is
controversial:
 HBsAg is detected in 72% of breast milk and can
be transmitted if mothers have abrasion on
nipple.
 Published data does not support this route.
Outline
 The magnitude of the problem
 Impact of Mother-to-Child Transmission (MTCT) of hepatitis B
 Factors associated with MTCT transmission
 Management
 Conclusion: Key points
Mother-to-Child Transmission of
HBV can be Eliminated
 Screen pregnant women for HBsAg
 Communicate HBV status to delivery unit
 Provide timely birth dose HBV vaccine to
all newborns
 Provide HBIG to infants of HBsAg+ mothers
 Provide antiviral therapyto HBsAg+
mothers with high viremia in 3rd trimester
 Complete 3 dose HBV vaccine series

Lok, A personal communication, AASLD 2016

Management:
ANTENATAL STRATEGY

 Screening of
mothers:
 HBsAg: at least
before the 3rd
trimester
 HBeAg (for
HBsAg-positive
mothers)
 Viral load/HBV
DNA level (for
HBsAg-positive
mothers)
PATIENT AND FAMILY EDUCATION
Prevention of MTCT: At delivery
 For mothers: Caesarean section:
 Still controversial:
 One study: 17.5% risk reduction of MTCT when compared with
immunoprophylaxis alone
 Other studies: elective caesarean section offers no benefit.
 Beijing (2007-2011) from 1,409 infants born to HBsAg (+) positive
mothers, with appropriate immunoprophylaxis at birth:
• 1.4% after elective caesarean section
• 3.4% after vaginal delivery
• 4.2% after emergency caesarean section (P <0.05).
 When stratified according to HBV DNA levels:
 delivery mode did not affect MTCT rates for HBV DNA levels <6
log copies/ ml).
 MTCT: With and Without Intervention?
MTCT in HBeAg(+) pregnant women

90% 20% 5-10% 0%?

Risk Risk Risk Risk

No Vaccine Vaccine Only Vac+HBIG Vac+HBIG+Nuc

Prevention of MTCT:
At delivery

2. For babies: Immunoprophylaxis

 Active immunization: 2 strategies
 3-dose schedule
 1st dose (birth dose) – monovalent vaccine
 2nd and 3rd doses together with other vaccination
 4 dose schedule:
 1st dose (birth dose) – monovalent
 2nd, 3rd, 4th doses together with other vaccines.

 Passive immunization:
 Hepatitis B immune globulin (HBIG): in 12 hours after birth
(Provides temporary protection for 3 to 6 months).
Treatment of mothers:
 Has not been a general
treatment policy
 Indications are judged by:
 HBV DNA level status
 HBeAg
 Evidence of liver injury (by alanine
aminotransferase [ALT] level and/or liver
histology).
Flowchart for treatment of HBsAg positive mothers (for low
resource)
HBsAg (quantitative)

Low titer <3 Log10 IU/mL High Titer ≥ 3 Log10 IU/mL

HBeAg

HBeAg positive HBeAg negative

Treatment DNA VHB

antiviral quantitative

≥ 6 Log10 IU/mL < 6 Log10 IU/mL

Treat antiviral Observ the Observ the

babies refers mother refers
to to internist
perinatologist
Conclusion: LdT and TDF use in late pregnancy is safe and
effective to prevent Mother-to-child transmission
 Drugs already used in pregnancy

Drug name Drug Effectiveness Remark

category
Lamivudine C Start at week 32: Frequent
(LAM) Significant reduction of resistant for long-
MTCT term use
(15%/year)

Tenovofir B Effective: preferred Better resistance

(TDF) than LAM profile
Good safety:
Experience in HIV-
treatment program

Telbivudine B Given in 2nd or 3rd No resistance, no

(LTD) semester, significantly deformities
lowers MTCT than
controls (0 vs 8%)
Guidelines recommended high HBV DNA level pregnant woman
take NAs for reduction of risk of mother-to-infant transmission

2015 2015 2012 2015

China Guidelines 1 APASL Guidelines 2 EASLGuidelines 3
AASLD Guidelines 4

HBV DNA＞ HBV DNA＞ HBV DNA＞ HBV DNA＞

WHO
2x106IU/ml 6-7log10IU/ml 6-7log10IU/ml 2x105IU/ml

from 24 to 28 from 28 to 32 from 28 to 32

WHEN weeks of
the last trimester of
weeks of
weeks of pregnancy
gestation gestation gestation
Pregnancy Pregnancy Pregnancy Pregnancy
HOW category B category B category B category B
Or LAM(A1) (B2) Or LAM(B1) Or LAM
1. 中华医学会肝病学分会,中华医学会感染病学分会.中华肝脏病杂志,2015,23(12): 888-905.
2. Sarin SK,et al. Hepatol Int. 2016 Jan;10(1): 1-98.
3. European Association For The Study Of The Liver .J Hepatol. 2012 Jul;57(1):167-85.
4. Terrault NA, et al. Hepatology. 2016 Jan;63(1): 261-83.
Outline
 Epidemiology
 Impact of Mother-to-Child
Transmission (MTCT) of hepatitis B
 Factors associated with MTCT
transmission
 Management
 Conclusion: Key points
Kontrasepsi
 WHO Medical Eligibility Criteria for Contraceptive
Use 2015, penggunaan semua jenis kontrasepsi
hormonal tidak memperberat perjalanan
penyakit hepatitis akut, sirosis, ataupun risiko
karsinoma hepatoseluler.
Conclusion 46

 HBV MTCT deserves full attention.

 Screening women for HBV infection, HBV birth dose
vaccine, increasing overall coverage of vaccine are all
feasible.
 Antiviral therapy for HBV-infected mothers need to be
discussed and considered by relevant associations of
experts.
 Urgent needs: Roles of health providers, political
commitment and financial investment, to the elimination
of HBV MTCT in Indonesia
 Dimension of Disease Burden

Social effect Economic effect

Loss of work and

Death, Premature loss of life

productivity
HCC,
Transplant

Decompensated Repeated
Reduced quality of life

Cirrhosis hospitalization, high

treatment cost
Compensated Frequent out-patient
Cirrhosis visits, treatment cost

Chronic Hepatitis Out-patient visits,

treatment cost

Out-patient visits,
Acute hepatitis
treatment cost
Disease development: From baseline risk to disease manifestation

Define and Control Risk • Predict • Monitor Progression

remove Risk • Diagnose • Predict Events
• Treat • Determine Therapeutics

Baseline Risk Initiating Events Subclinical Early signs & Disease

(Mother’s MTCT Stage symptoms Manifestation
HBsAg positivity) Infected babies Asymptomatic Cirrhosis, HCC
Disease Burden

– young adult Hep

reversibility
Cost
Control of hepatitis should start from the mothers