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

Conflict of Interest Grant recipient: ViiV Advisory board: ViiV

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

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 720 000 deaths in 2015 due to cirrhosis and 470 000 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

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

Perinatal transmission HIV + + - - + - + - HIV + + - - + - + - HBV HCV

Successes in PMTCT of HIV MTCT rates in Europe UK – 0.27% in 2012-14 EU cohorts (EPPICC) - 0.7% in 2012 Thailand eMTCT validated in June ‘16 Peters et al 2017; EPPICC 2017; WHO 2016

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

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

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 (1998-2011) 2.1% Tshwane, South Africa (2008-2013) 4.4% UK (2010-2016) 5.0% Malawi (2004-2009) 9.3% Cameroon (2000-2003) 9.6% France (2000-2012) 12% Italy (2001-2016) 13% Thailand (2005-2007) 16.3% Temeke, Tanzania (2014) 17% Ukraine (2007-2012) 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

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 30-32 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

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

HCV seroprevalence in pregnant women living with HIV 1.5% Nigeria (2006-2011) 2.1% Uganda/Rwanda (2007) 2% UK (2013) 2.8% US (1998-2011) 3.0% Rwanda (2011) 3.7% Thailand (2000-2004) 4.8% Burkina Faso (2006) 13.7% Switzerland (2000-2014) 29% in 2000, 8% in 2008 Italy 33% Ukraine (2007-2012) 50% St Petersburg, Russia (2010) Higher seroprevalence in HIV+ vs HIV- ? W.Europe/US: 10-20 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

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 4.2-7.8%) HIV-positive mothers: 10.8% (95% CI 7.6-15.2%) 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

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

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

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

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

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