1. Perinatal transmission of HBV and HCV in HIV-coinfected women: what are the risks and what can be done?
Claire Thorne
UCL Great Ormond Street Institute of Child Health, University College London

2. Conflict of Interest
Grant recipient: ViiV
Advisory board: ViiV

3. Chronic hepatitis infection
HBV
90% of infected infants will become chronically infected versus 30-50% of 1-4 year olds and 5-10% of adults
Adults with chronic HBV have a 15% lifetime risk of death from cirrhosis or hepatocellular carcinoma
HCV
80-93% of infected infants will become chronically infected, and around 70-85% of infected adults
Adults with chronic HCV: 15-20% will develop liver cirrhosis after 20 years, and 1-5% of those will progress to HCC annually
Development of chronic HBV depends on age at infection

4. Global epidemiology of HBV & HCV
Globally, 257 million people living with chronic HBV.
Viral hepatitis caused 1.34 million deaths in 2015 (comparable to TB mortality and higher than HIV mortality)
7th leading cause of mortality worldwide
deaths in 2015 due to cirrhosis and deaths due to hepatocellular carcinoma
HBV is one of the 10 most important causes of death globally
On a global scale MTCT is the most important route of transmission for HBV and most new HBV cases in LMICs are likely due to vertical transmission
HCV
Globally, 71 million people living with chronic HCV
WHO Global Hepatitis Report 2017

5. HIV and viral hepatitis co-infection
Prevalence of chronic HBV and HCV in PLWH varies substantially by region and within sub-populations
Estimated 5-20% PLWH have chronic HBV
20% in China, 10% in US, >20% in parts of Western Africa
2% of PLWH have chronic HCV in African region as a whole (but in some countries, this reaches 10-15%), whilst in US 20% have HCV co-infection
Among people who inject drugs who are HIV-infected, up to 90% may be HCV seropositive depending on setting
Singh et al 2017, Azevedo et al 2016, US Department of Health and Human Services 2016

6. Perinatal transmission
HIV
HIV
HBV
HCV

7. Successes in PMTCT of HIV
MTCT rates in Europe
UK – 0.27% in
EU cohorts (EPPICC) - 0.7% in 2012
Thailand
eMTCT validated in June ‘16
Peters et al 2017; EPPICC 2017; WHO 2016

8. HBV vertical transmission
Intrapartum transmission most important route, but in utero transmission can occur
MTCT risk and immunoprophylaxis effectiveness (PEP with HBIG and vaccine) depends on maternal HBeAg status
High maternal viral load (HBV DNA) increases risk
HBV DNA >107 IU/ml are at highest risk
With appropriate immunoprophylaxis, breastfeeding does not represent any additional risk of MTCT of HBV
PEP with HBIG and complete vaccine schedule starting within 24 hours of life has 85-95% efficacy
This approach (vaccination at birth) has substantially reduced HBsAg prevalence by 83 to 95% among children in China and Taiwan (Zhang et al. 2010, Ni et al. 2007b). Including a dose of hepatitis B immune globulin (HBIG) at birth to infants can further reduce the risk of transmission to less than 5% (Lee et al. 2006).
Vertical transmission rate
With no intervention
With HBIG and vaccine
HBeAg positive
70-90%
5-10%
HBeAg negative
10-40%
<5%
Stevens et al 1985, Degli Esposti et al 2011; Chen et al 2013; Shi et al 2011; Lin et al 2014, Patton & Tran 2014; Zhang et al 2010; Lee et al 2006

9. HBV PMTCT recommendations
All infants
Use of HBV vaccination within 24 hours of birth for all (regardless of HBsAg status of mother)
Completion of the HBV vaccine schedule within first year of life
For post-exposure prophylaxis
HBIG as adjunct to above if feasible
SSA: some countries do not provide the first vaccine dose until age 6 weeks, HBIG generally not available
Targets
90% childhood vaccine coverage by 2020
50% birth dose coverage or other PMTCT approach by 2020, 90% by 2030

10. Few data on HBeAg prevalence in HIV/HBV co-infected pregnant women
HBV coinfection in pregnant women living with HIV
Few data on HBeAg prevalence in HIV/HBV co-infected pregnant women
African studies – 20-30%
Thai study – 51%
1.6% US ( )
2.1% Tshwane, South Africa ( )
4.4% UK ( )
5.0% Malawi ( )
9.3% Cameroon ( )
9.6% France ( )
12% Italy ( )
13% Thailand ( )
16.3% Temeke, Tanzania (2014)
17% Ukraine ( )
Increased risk in HIV+ vs HIV- ?
UK/US: 5-8 times higher
South Africa: 5 times higher
Tanzania: 2.5-times higher
Cameroon: no difference
Prevalence of HCV co-infection varies, largely depending on the % of women with IDU history and background HCV rates
Salemi et al 2017; Diale et al 2016; Floridia et al 2017; Peters et al 2013; Manyahi et al 2017; Peters et al 2017; Bailey et al 2016; Chasela et al 2014

11. Reasons for vertical HBV transmissions despite interventions
High maternal viral load
Delayed delivery of HBIG / vaccine
Intrauterine transmission of HBV
Failure of the infant to respond to vaccine for immunologic reasons
March 2015
Pan et al NEJM 2016
Efficacy of TDF from GW for PMTCT of HBV
No time to go into details re the Pan et al trial. HBIG at birth and 4 weeks and vaccine at birth, week 4 and week 24

12. MTCT of HBV in HIV/HBV co-infection in pre Option B+ era
Setting
MTCT Interventions
HBV MTCT (95% CI)
Thailand
Khamduanget et al 2013
N=230
Vaccine +/- HBIG
No cART (sdNVP and ZDV only)
4.8% (2.4, 8.4%)
(no HBV/HIV MTCT, HIV MTCT: 2.2% [0.7, 5.0])
Malawi BAN trial
Chasela et al 2014
N=51
Vaccine from 6 wks
7 days 3TC+ZDV (mother and infant); maternal postnatal cART with 3TC for 28w in 1 of the 3 arms
9.8% (3.3, 21.4%)
No data yet to assess the impact of life-long ART with HBV-active drugs on MTCT of HBV
Thai study: 6.7% (2.9, 12.8%) among HBeAg positive and HBV DNA >6 log10
2.7% (0.6, 7.7%) among HBeAg negative

13. HCV seroprevalence in pregnant women living with HIV
1.5% Nigeria ( )
2.1% Uganda/Rwanda (2007)
2% UK (2013)
2.8% US ( )
3.0% Rwanda (2011)
3.7% Thailand ( )
4.8% Burkina Faso (2006)
13.7% Switzerland ( )
29% in 2000, 8% in 2008 Italy
33% Ukraine ( )
50% St Petersburg, Russia (2010)
Higher seroprevalence in HIV+ vs HIV- ?
W.Europe/US: times higher
Sub-Saharan Africa: no difference in several studies
Prevalence of HCV co-infection varies, largely depending on the % of women with IDU history and background HCV rates
Floridia et al 2010, Ezechi et al 2014 ; Rouet et al 2004; Kissin et al 2010; Simpore et al 2006; Pirillo et al 2007; Salemi et al 2017; Mutagoma et al 2017; Khamduang et al 2013; Bailey et al 2014; Aebi-Popp et al 2016

14. HCV vertical transmission
Most (~70%) transmission occurs around time of delivery
Rates of HCV vertical transmission from meta-analysis of 109 studies
HIV-negative mothers: 5.8% (95% CI %)
HIV-positive mothers: 10.8% (95% CI %)
HCV viremia / high viral load is a risk factor, but not maternal genotype, mode of delivery or breastfeeding
No interventions to prevent HCV vertical transmission
Exception: treating HIV in HIV/HCV co-infected women
Dutch study: HCV MTCT rate 4% among HIV/HCV pos women on successful cART
Mok et al 2005 Arch Dis Child; Benova et al 2014 Clin Infect Dis; Snijdewind et al 2014 J Clin Virol;
Pembrey et al 2003

15. MTCT of HCV in HIV/HCV co-infection
Switzerland (MoCHiV) N=75
80% HIV/HCV co-infected women on ART at conception, 93% HIV VL <400 copies/ml at delivery
2.8% (95% CI 0.3, 9.8) HCV transmission rate, no HIV transmissions
The Netherlands (ATHENA) N=24
All HIV/HCV co-infected women on cART by delivery, 75% had HIV VL <500 copies/ml at delivery
4.2% (95% CI 0.1, 24.1) (1/24) HCV transmission rate, no HIV transmissions
Aebi-Popp et al 2016, Snijdewind et al 2015

16. HCV treatment in pregnancy?
In studies of HIV/HCV co-infected pregnant women, lower HCV MTCT rates with widespread use of ART and resultant HIV suppression observed
Direct acting antivirals (DAAs) for HCV treatment are potent, tolerable and efficacious
Lack of human pregnancy data on DAAs; animal reproductive toxicity data available
No DAA has approval for use in pregnancy currently
Sofosbuvir and ledipasvir show “promising” safety and PK profiles for potential use in pregnancy
Spera et al 2016; Kanninen et al 2015

17. HCV treatment in pregnancy?
Double dividend – we can cure the mother and prevent HCV vertical transmission at the same time
COST ?
DIAGNOSTICS ?
SAFETY ?
ACCEPTABILITY ?
If we treat woman BEFORE pregnancy then we can prevent fetal exposure to DAAs
But most pregnancies are unplanned
Why not wait until after delivery to treat the mother – and the baby if vertical transmission occurred?
What about postnatal loss to follow-up? In pregnancy we have an opportunity to treat while a woman is in touch with heath services

18. Conclusion
Burden of viral hepatitis/HIV co-infection varies by geographic setting and within sub-populations (e.g. high burden in WWID)
What can be done for PMTCT?
Approach depends on setting
Optimal implementation of Option B+ and infant HBV vaccination
Research needed on DAAs in pregnancy
Prevent HBV and HCV infections in girls and women living with HIV (e.g. HBV vaccination, harm reduction for PWID)
Treat and cure HCV in HIV-co-infected girls and women prior to pregnancy

19. Many thanks to Giuseppe Indolfi, Gareth Tudor-Williams, Ali Judd, Anna Turkova and Heather Bailey for their help with this presentation.