1. HIV/HBV coinfection in HIV-infected children Pope Kosalaraksa, M.D. Department of Pediatrics Faculty of Medicine Khon Kaen University

2. Outline Epidemiology – prevalence Coinfection and risk of transmission Natural history of HBV infection perinatally/adults HBV/HIV coinfection: clinical HBV vaccine: seroprotection, booster Treatment

3. Hepatitis B infection Asymptomatic >>> Symptomatic Recover (immune) >> carrier >> >> cirrhosis >> cancer HIV-infected children more rapid/severe than adult/non HIV children?

4. HBV/HIV co-infection In adults: higher level of HBV viremia increase hepatotoxicity increase liver-related morbidity and mortality In children: little information unique population (immune tolerant) liver-related morbidity, mortality

5. Epidemiology 350 million: chronic HBV infection 0.5–1.2 millions: die each year Pregnant women (Africa) - prevalence : HBV monoinfection 4.0 - 17.1% : HBV/HIV coinfection 0.4 - 7.1%

6. HIV/HBV co-infection in children HIV/HBV coinfection(%)Country 1.2 - 4.9Tanzania, USA,Thailand, China 12.1 - 29.7Ivory Coast, Rwanda, Nigeria, India 43.4 - 49.1Romania, Burkina Faso Healy SA, et al. Expert Rev Anti Infect Ther 2013;11:251-63.

7. HBV and HIV Common transmission routes : perinatal : horizontal : parenteral : sexual Higher prevalence of HBV infection in HIV than non-HIV population

8. Risk of developing chronic HBV Age at time of infection : Neonate (mother HBeAg+) up to 90% : After neonate – 5 years20-30% : Immunocompetent adults < 5-10% Maternal HBeAg/anti-HBe status : < 10% - HBeAg -ve/anti-HBe +ve

9. HBV vaccine in HIV children may have less protection : less robust initial immune response : waning of anti-HBs After cART : poor restore anti-HBs : 1-40% had protective Ab >10 IU/ml

10. Immune response to HBV vaccine in HIV children International Maternal Pediatric Adolescent AIDS Clinical Trial group : 204 HIV children with cART : mean age - 9 years : history of 3 doses of a primary HBV vaccination : 24% had protective anti-HBs antibody : 45%- seropositive at 8 weeks after a booster Abzug MJ, et al. J Infect Dis 2009:200:935-46.

11. Booster response in HIV children 64 HIV-infected children : median age - 10 years : median cART - 31 months : complete HBV vaccination : no seroprotective Ab – 87% Seroprotective Ab after booster : 17.0% after 1 st dose : 82.5% after 2 nd dose : 92.0% after 3 rd dose Lao-Araya M, et al. Vaccine 2011;29:3977-81.

12. Extrapolating from adults’ studies HBV/HIV co-infected children : more active liver disease : more rapid progression to hepatic fibrosis and cirrhosis

13. HBV infection perinatally PhaseCharacteristics Immune tolerant 10-30 years, little host immune response Immune active increase immune activity Inactive HBsAg+ carrier loss of HBeAg, inactive carrier stage HBeAg- chronic hepatitis hepatic inflammation, cirrhosis, liver cancer

14. Phases of chronic HBV infection Phases Immune tolerant Immune active Inactive HBsAg+ve carrier HBeAg-ve chronic hepatitis HBeAg+ve -ve AntiHBeAg-ve +ve HBV DNA10 6 -10 8 10 5 -10 8 10 2 -10 3 10 4 -10 5 ALTnormal normal, Liver inflammation no - minimal mod- severe 0-1 fibrosis may regress mod-severe TreatmentNoYesNoYes

15. Treatment of HBV in children Not cytopathic Immune response: hepatic damage Immune tolerant phase - not recommended : high HBV DNA, normal ALT Immune active phase - recommended : elevated ALT, mod-sever liver inflam. : non-invasive measures – transient elastography

16. Treatment of HBV in HIV children Concern: high risk progression to hepatic fibrosis Hepatic foundation expert: treat all regardless phase of infection Other group: same as non HIV children No published guideline: indication for Rx. Antiviral drugs (HBV) : IFN- α, nucleos(t)ide anlogue

17. Antiviral drugs IFN- α – preferred treatment, 26% efficacy - poor tolerant: flu-like symptom Lamivudine (3TC), FTC - good safety profile - risk of resistance (monotherapy) Adefovir - increase in serum creatinine Entecavir, Tenofovir - high genetic barrier - high efficacy (78-86%)

18. HBV monotherapy in HIV Lamivudine (3TC) resistance 1 : 50% within 2 years : >90% at 4 years In children 2 : 69% HBV DNA > 10 5 copies/ml : rtM204V/I mutation – 75% 1. Healy SA, et al. Expert Rev Anti Infect Ther 2013;11:251-63. 2. Aurpibul L, et al. Pediatr Infect Dis J 2012;31:943-7.

19. Antiviral agents for HBV Generic nameUS FDAHIV activity LamivudineHBV>2 yr, HIV > 0yes EmtricitabineNot labeled, HIV>0yes TenofovirHBV>18 yr, HIV>2 yryes EntecavirHBV>16 yr, HIV - noneyes IFN- -2bHBV>1 yrno PegIFN- 2aHBV>18 yrno AdefovirHBV>12 yrno TelbivudineHBV>16 yrno

20. Treatment strategy: HIV/HBV Not require HBV treatment : use lamivudine sparing ART Require HBV treatment : use tenofovir/lamivudine Hepatic flare after starting ART : 25% in adults : in children – immune tolerant (unknown)

21. HIV/HBV: summary Similar transmission route, drugs Effect of HBV disease progression HBV vaccine response rate : low, need reimmunization Choice of ARV – depend on HBV status Long survival in HIV children : long-term effect of HBV?? Screening and Prevention****