1. CHALLENGES OF HEPATITIS B INFECTION IN CHILDREN TAMMY MEYERS JOCKEY CLUB SCHOOL OF PUBLIC HEALTH AND PRIMARY CARE, CHINESE UNIVERSITY OF HONG KONG AND DEPARTMENT OF PAEDIATRICS AND CHILD HEALTH, UNIVERSITY OF THE WITWATERSRAND

2. Improved hepatitis B virus vaccination coverage has decreased the chronic infection rate in children from 8-15% to <1% in many countries Hepatitis B Fact sheet N°204 Updated July 2015

3. EPIDAEMIOLOGY Prevalence of Chronic Hepatitis B infection among adults (2012 ) Disease data source: Ott JJ, Vaccine. 2012; 30(12):2212– 2219 ~2 billion people infected with HBV 240 million with chronic HBV(90 million in China) 650 000 deaths per year > half of all liver cancers are associated with HBV ~5-15% of 34 million PLHIV coinfected with HBV Hepatitis B Fact sheet N°204 Updated July 2015

4. HBV MONOINFECTION PREGNANT WOMEN HBV Asian pregnant women In Hong Kong routine neonatal immunisation since 1988, anti HBsAg seroprevalance in pregnant women decreased from 11.3% in 1990 to 6.2% in 2014 Surveillance of viral hepatitis in Hong Kong – 2014 Update http://www.info.gov.hk/hepatitis/doc/hepsurv14.pdf HBV in African pregnant women ranges from 4%-17.1% Healy et al, HIV/HBV coinfection in children and antiviral therapy. Expert Rev Anti Infect Ther. 2013

5. HBV/HIV COINFECTION AND MATERNAL-INFANT TRANSMISSION HBV/HIV coinfection ranges from 0.4%-7.1% KZN – 5.3% prevalence of HBV infection and 3.1% prevalence of HBV/HIV co-infection in stored specimens from 570 PW, (Thumbiran et al SAMJ 2014) Soweto - HBsAg positivity in 14/189 (7.4%) preg HIV + women and HBV transmitted to 4 infants (Hoffman CJ et al JIAS 2014) Beghin JC et al. J Med Virol. 2016 Jun 13

6. TRANSMISSION In endemic countries, mother-to child transmission of HBV is the predominant route of transmission Horizontal transmission from an infected child to an uninfected child during the first 5 years of life Traditionally thought to be more common in Africa Breastfeeding not a risk for transmission close contact with mother associated with post-partum transmission

7. http://virology-online.com/viruses/HepatitisB.htm ~ 20-30% of chronically infected will develop complications such as cirrhosis and hepatocellular carcinoma

8. HEPATITIS B VIRUS DNA virus from the Hepadnaviridae family Enveloped and encapsulated Important proteins include An surface protein called surface antigen – HBsAg A structural nucleocapsid core protein – HBcAg A soluble nucleocapsid protein – HBeAg http://medlibes.com/entry/hepatitis-b

9. Immune escape < <> > HBeAg+ve HBeAg–ve ALT HBV-DNA Inactive (carrier) state* HBeAg –ve active chronic hepatitis HBeAg +ve chronic hepatitis Immune tolerance Immune clearance Immune control Natural History of Chronic Hepatitis B infection in children

10. NATURAL HISTORY WITH HIV/HBV COINFECTION Ivory Coast- 34 children followed for 30 months development of anti-HBeAg did not result in control of viral replication children with more active HIV disease have less immune control of HBV Romania- cohort of coinfected adolescents, 1 year follow-up 126/161 (78%) had evidence of HBV infection - anti-HB core Ab 43% HBsAg positive, 25% HBeAg positive Adolescents with more severe immune suppression had higher levels of HBV DNA and were more likely to be HBsAg positive After 1 year, 31% seroconverted to anti-HBe with the clearance rate significantly less in those with severe immune suppression Healy et al, HIV/HBV coinfection in children and antiviral therapy. Expert Rev Anti Infect Ther. 2013

11. NATURAL HISTORY WITH HIV/HBV COINFECTION Extrapolating from HIV/HBV-coinfected adults: Lower rates of clearance of HBeAg Increased serum HBV DNA viral load 1 Reactivation of hepatitis in asymptomatic carriers Increased liver injury More rapid onset fibrosis, cirrhosis and HCC Higher mortality and morbidity Liver-related mortality rate (per 1,000 person-years) Multicenter prospective cohort study of 5293 men who had sex with men (USA) (1) Perillo RP, Regenstein FG, et al. Chronic hepatitis B in asymptomatic homosexual men with antibody to the human immunodeficiency virus. Ann Intern Med 1986:105:382-3 Thio CL, et al. Lancet 2002;360:1921- 6

12. GEOGRAPHIC DISTRIBUTION OF HBV GENOTYPES

14. WHY ARE CHILDREN AND ADOLESCENTS STILL INFECTED WITH HBV? Many countries not yet instituted routine screening of pregnant women and HBIG to babies Birth vaccine dose not implemented averywhere Residual infection transmitted at a rate 5-15% in HBsAg + women Women with high HBV DNA levels may transmit HBV to their neonates despite vaccination Marginalised populations (higher risk) may be missed Some children fail to respond to vaccine HIV-exposed less likely to be immunised HIV-infected children have a less robust initial response to HBV vaccine (Healy et al, HIV/HBV coinfection in children and antiviral therapy. Expert Rev Anti Infect Ther. 2013) In China alone, with <1% transmission rate, an estimated 50 000 children per year still become infected at birth Haruki Komatsu, Journal of Gastroenterology, 2014

15. CLINICAL MANIFESTATIONS IN CHILDREN Children are typically in the immune tolerant phase (usually asymptomatic) Cirrhosis and hepatocellular carcinoma are infrequent in children and adolescent estimated annual incidence of cirrhosis of 2-3% Unclear which cases will progress to cirrhosis

16. CLINICAL MANIFESTATIONS Fulminant hepatitis in a newborn (more common in women HBsAg + but HbeAg –ve) Gianotti-Crosti syndrome Polyarteritis nodosa Membranous or mebranoproliferative nephropathy – nephrotic syndrome

17. HCC IN CHILDREN

18. POSTVACCINATION SEROLOGIC TESTING (PVST)

19. MONITORING SEROLOGY IN CHILDREN CDC now recommends PVST from 9-12 months, (1-2 months after vaccination course completed) PVST can identify early those who have not responded to vaccine, and require revaccination Identify those infants who have been infected PVST not commonly performed in low resource settings

20. DURATION OF IMMUNITY POST VACCINATION Many studies confirm the long term immunity afforded by Hep B vaccination 20 years after vaccination Despite waning titres, most have an anamnestic response after 1 booster dose (Bagheri-Jamebozorgi M, Human Vacc Immunotherapy 2014) Evidence of HBsAg specific cell-mediated immunity in up to 80% (Saffer H Hepat Mon 2014) No recommendation for routine booster dose

21. IMMUNE RESPONSE TO VACCINATION IN KZN In SA concerns that immune response to Hep B vaccine may be suboptimal in children 210 paed oncology patients included (median age 6.5 years), 84 (40%) had no immunity to hepatitis B despite presumed vaccination Six patients had anti-HBc positivity, consistent with previous infection No patients had active hepatitis B infection (hepatitis B surface antigen-positive) Most HIV-infected patients were not immune to HBV (80.0%). (Büchner A et al SAMJ 2014;104 Beghin JC et al. J Med Virol. 2016 Jun 13

22. BOOSTER VACCINATION The following should be monitored and receive booster dose if anti-HBs antibodies <10mIU/mL Health care providers including laboratory staff HIV-infected patients Haemodialysis patients Immunocompromised patients MSM or multiple sexual partners Chronic hepatitis/liver disease (non - HBV) Injection drug users Inmates/staff; staff for mentally disabled

23. EVALUATION OF CHILDREN WITH HBV Clinical evaluation routine for all with CHB Liver function tests, PTT, FBC and platelets Non-invasive tests may reduce need for liver biopsy WHO

24. Loss of HBeAg Loss of HBV DNA Anti-HBe+ Loss of HBsAg Anti-HBs+ Improved survival Improved histology Therapeutic Endpoints = HBeAg seroconversion With current drugs available cure is not possible

25. ANTIVIRALS ACTIVE AGAINST HBV IN ORDER OF POTENCY AND BARRIER TO RESISTANCE WHO Tenofovir recommended for children ≥12 years Entecavir approved for 2-11

26. INVESTIGATIONS WHO

27. TREATMENT FOR HIV/HBV COINFECTED ADULTS, ADOLESCENTS AND CHILDREN WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Recommendations for a public health approach - Second edition) Treat all with ART Severe chronic liver disease prioritised if necessary CHB + cirrhosis regardless of ALT levels, HBeAg status or HBV DNA NRTI drugs for ART – TDF with 3TC or FTC – are active against HBV (including children ≥ 3years) Treatment of HIV/HBV coinfection without TDF  flares of hepatitis B due to IRIS Treatment discontinuation, especially 3TC, associated with HBV reactivation, ALT flares and, rarely, hepatic decompensation TDF + 3TC or FTC should be continued when ARV’s regimen changed WHO Guidelines for the prevention, care and treatment of persons with Chronic hepatitis B infection HBV/HIV coinfected adults, adolescents and children ≥ 3years – TDF + 3TC/FTC + EFV FDC preferred option (Strong recommendation, moderate quality of evidence

28. SPECIFIC ISSUES IN PAEDIATRIC TREATMENT OF CHB Generally children in the immune tolerant phase do not require treatment Children with ALT values >10 times the ULN may be in the process of spontaneous HBeAg seroconversion and should be observed for several months before treatment is begun Children with HIV or undergoing immune therapy should be considered for antiviral therapy Children should be included in clinical trials for newer drugs such as tenofovir alafenamide (TAF) and agents which are being investigated for cure

29. SUMMARY AND RECOMMENDATIONS Paediatric HBV infection has declined dramatically following increased HBV vaccination Ending HBV transmission to babies is a real possibility: Routine screening for high risk pregnant women and HBIG Birth dose should be implemented globally Increased awareness of risk of HBV/HIV coinfection in children in high burden regions PVST for infants 1-2 months after last vaccine can identify sero- response to vaccine and identify infected children

30. SUMMARY AND RECOMMENDATIONS Identification and follow up of CHB infected children and adolescents into adulthood is necessary to ensure timeous treatment if indicated Cohort studies to determine the natural progression of CHB in children and adolescents in the era of routine HBV vaccination Coinfected HIV/HBV infected children are more vulnerable need booster vaccination more intense follow up as CHB disease severity may be worse Paediatric clinical trials should be expedited investigating improved strategies to prevent transmission, treat and/or cure CHB Discrimination of people living with chronic hepatitis B infection must end