Hepatitis B elimination: from the bench to public health perspectives Pr Karine Lacombe, M.D., PhD Inserm UMR-S1136, IPLESP Sorbonne Université, APHP Paris - France

Chronic Hep B, a silent and neglected killer for years1 15M. 21M. 39M. 7M. 60M. 115M. Incidence of HBV in children < 5 years TOTAL: 257 M. 1Lemoine, J Hepatol 2016. 2Global Hepatitis Report 2017

High disease burden HIV-HBV coinfection affects 2,7M individuals with higher risk of death after ARV initiation in those living in Africa1 ≈ 900 000 deaths due to sequelae of HepB (66% of all 1,34M. deaths from viral hepatitis): 300 000 from HCC, 500 000 from cirrhosis and 100 000 from acute HepB2 Infection thats affect young individuals (30-40 years), women of child bearing age with high risk of transmission to babies 1Kouame, Clin Infect Dis 2018. 2Global Hepatitis Report 2017

SDG for 2030: viral hepatitis elimination 6-10 million infections  (in 2015)  to 900,000 infections (by 2030) 1.4 million deaths (in 2015) to under 500,000 deaths (by 2030)

Effective tools for HBV elimination Without implementation of effective tools, between 2015 and 20301 63 millions new cases of HBV 17 millions HBV-related deaths Prevention Diagnosis HBV Cure HBV Access to Treatment Nagayam, Lancet Glob Health 2016

From the bench: is HBV elimination feasible ? 1Thomas XV. PlosOne 2012.

High efficacy of current treatment… Exemple of HIV-HBV coinfection: Meta-analysis on 23 papers including cohorts and clinical trials, n=516 on TDF A small % continues to have detectable HBV-DNA after extended therapy Price H et al., PLoS One 2013

… but no functional cure Persistence of DNA synthesis despite « viral suppression » New round of infection and/or replenishment of the cccDNA pool occur despite « viral suppression » Boyd, J Hepatol 2016

Multiple targets in host and virus Durantel D. J Hepatol 2016

Upcoming strategies for HBV cure ? Antivirals Host immunity stimulation Prevent viral production and Re-amplification of cccADN Stimulating host immune response or prevent its inactivation HBV functional cure Inhibition of HBV antigen production cccDNA inhibition Inhibits the steps of replication cycle (entry, diffusion, capside formation, HBx functionning and HBsAg release) Decrease or inhibition of cccDNA

From bench to public health: requirements to reach the WHO goals by 2030 How to avert new cases of Hep B ? STATU QUO HBV vaccine scale-up to 90% HBV vaccine scale-up to 90% AND HVB-PMTCT (80% mothers treated + birth dose vaccine) HBV vaccine scale-up to 90% AND HVB-PMTCT (80% mothers treated + birth dose vaccine) AND treatment of cases Nagayam S. Lancet Glob Health 2016

Requirements to reach the WHO targets by 2030 How to decrease HBV mortality ? Statu quo HBV vaccine scale-up to 90% HBV vaccine scale-up to 90% AND HVB-PMTCT (80% mothers treated + birth dose vaccine), treatment AND cure HBV vaccine scale-up to 90% AND HVB-PMTCT (80% mothers treated + birth dose vaccine), treatment of cases HBV vaccine scale-up to 90% AND HVB-PMTCT (80% mothers treated + birth dose vaccine) Nagayam S. Lancet Glob Health 2016

Impact of birth dose vaccine in Asia HBsAg and Anti-HBs Ab dynamics in China after global implementation of immunization1 Impact of immunization in HCC occurrence in the long term (Taiwan)2 1Cui, Emerg Inf Dis 2017 2Chang, Gastroenterol 2016

HBV birth dose, a challenge in Africa Hefferman, OFID 2018

HBV PMTCT, a never-ending story Birth dose is not enough ! AgHBe pos. AgHBe neg. 367 000 newborns infected each year in Africa twice higher than HIV Keane, APT 2017

Screening of HBV, a global challenge in LMIC Failure of effective HBV-PMTC due to lack of screening Technical limit: No mean to accurately identify HBe Ag with POC HBV-DNA measurement out of reach in most countries Political will Screening not provided for free … this also leads to failure in identifying who is in need of treatment globally

Treatment eligibility and coverage, the challenging issue 9% of HBV-infected patients are aware of their status1 4 – 9% of screened patients in Africa are in need of treatment2 8% of those in need of treatment have access to treatment1 1Global Hepatitis Report 2017. 2Lemoine, Lancet Glob Health 2016

WHO Guidelines for global HBV screening and treatment WHO HBV Guidelines 2015

New molecular tools for LMIC Use of DBS for HBV-DNA1: Se = 95%, Sp = 99% Use of in-house quantitative PCR2: Developped within the PROLIFICA project in Western Africa Cost = 21€/test (3 to 5-fold less than commercial assays) Use of in-house semi-qualitative PCR3 Threshold of detection set to 2000UI/mL Detection of 95% of sample >2200UI/mL and 100% of samples < 1800UI/mL compared to commercial kits POC HBV-DNA in the near future ? 1Lange, BMC Infect Dis 2017. 2Ghosh, J Viral Hepat 2016. 3Castéra-Guy, J Virol Meth 2017

A simple score to determine who is in need of treatment ? Shimakawa, J Hepatol 2018

Performance of TREAT-B score Shimakawa, J Hepatol 2018

Take home messages Complex interaction between host and virus: not ALL patients have to be treated (at least in the absence of drugs that cure) NO cure to date BUT vaccine (unlike HCV) Elimination: immunization (birth dose) + screening (POC) + HBV-PMTCT (including treatment of mothers) + universal access to HBV drugs (± HBV cure)

Acknowledgements Maud Lemoine (Imperial College) Yusuke Shimakawa (Pasteur Institute, Paris) Anders Boyd (Inserm UMR-S1136, IPLESP)