1. Pathogenesis of HIV-hepatitis B co-infection Sharon R Lewin, FRACP, PhD Infectious Diseases Unit, Alfred Hospital Department of Medicine, Monash University Centre for Virology, Burnet Institute, Melbourne, Australia

2. Outline  Natural history of HIV-HBV co-infection  HBV-active HAART  Pathogenesis of disease progression in HIV-HBV co- infection  Virological factors  Immunological factors  Hepatic factors  Treatment  Emerging research issues

3. Liver related mortality rate/100 py 0 2 4 6 8 10 12 14 16 HBVHIVHIV/HBV HIV/HBV co-infection: mortality Thio et al Lancet 2002; 360:1921;

4. DrugHBVHIV 3TC / FTC++ Tenofovir+++ Adefovir++? Entecavir++++ Telbivudine+++? IFN / PEG-IFN++++ Treatment of HIV-HBV co-infection

5. Immune responses in HBV mono-infection post treatment 2-5% 1-2%

6. HIV-HBV co-infection: HBV-active HAART  Excellent HBV virological control on tenofovir combination regimens  Benhamou et al., Hepatology 2006; Peters et al., Hepatology 2006; Schmutz et al., AIDS 2006; Matthews et al., Hepatology 2008; Lacombe et al., Antiviral Therapy 2008; Lewin et al., Hepatology 2008; Matthews et al., AIDS 2009  HBV resistance to tenofovir is extremely rare  Sheldon et al., Antiviral Therapy, 2005; Benhamou et al., Hepatology 2006; Audsley et al., HIV Med 2008  HBeAg seroconversion rates high  Avahingson et al., 5 th IAS Conference, poster # WEPEB226

7. Longitudinal Thai cohort (n=47); HBeAg-positive (n=30); median follow up = 27 months HBeAg loss = 46%; HBsAg loss = 13% Avahingson et al., 5 th IAS Conference, Capetown 2009, Poster # WEPEB226 High rates of HBeAg seroconversion following HBV active HAART

8. HIV-HBV co-infection: HBV-active HAART  Excellent HBV virological control on tenofovir containing regimens  Benhamou et al., Hepatology 2006; Peters et al., Hepatology 2006; Schmutz et al., AIDS 2006; Matthews et al., Hepatology 2008; Lacombe et al., Antiviral Therapy 2008; Lewin et al., Hepatology 2008; Matthews et al., AIDS 2009  HBV resistance to tenofovir is extremely rare  Sheldon et al., Antiviral Therapy, 2005; Benhamou et al., Hepatology 2006; Audsley et al., HIV Med 2008  HBeAg seroconversion rates high (20-30%)  Avahingson et al., 5 th IAS Conference, poster # WEPEB226  Liver related mortality remains elevated  Thio et al., Lancet 2002; Hoffman et al., AIDS 2009; Salmon-Carron, J Hepatol 2009

9. Thio et al Lancet 2002 Liver related mortality rate/100 py 0 5 10 15 20 25 30 35 HIV/HBV co-infection: mortality <19961996-2000 HBV 1996-2007 Hoffman et al., AIDS 2009 HAART HBV-active (95%)

10. Increased liver mortality on HBV-active HAART Hoffman et al., AIDS 2009

11. HIV-HBV pathogenesis  Virological factors  Immunological factors  Hepatic factors  Treatment

12. High Baseline HBV DNA Associated With Increased Risk of HCC and Cirrhosis ≥ 100,000 10,000- 99,999 Patients (%) Cumulative Incidence of HCC at Year 13 Follow-up [1] (N = 3653) 50 40 30 20 10 0 1.3 1.4 3.6 12.2 14.9 Cumulative Incidence of Cirrhosis at Year 13 Follow-up [2] (N = 3582) 4.5 5.9 9.8 23.5 36.2 < 300 300- 999 1000- 9999 < 300 300- 9999 10,000- 99,999 100,000- 999,999 ≥ 1 million Baseline HBV DNA (copies/mL) 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. REVEAL: Long-term follow-up of untreated HBsAg+ve individuals in Taiwan

13. HBV Replication: HBV DNA Pathway Adapted from: Diestag, N Engl J Med, 2008

14. HBV Replication: HBsAg (Envelope) Pathway Adapted from: Diestag, N Engl J Med, 2008 Reverse transcriptase inhibitors

15. Cumulative Risk for HCC and HBsAg in HBV mono-infection Yuen M-F, et al. Gastroenterology 2008; 135:1192

16. HBV DNA and HBsAg following HBV-active HAART Iser, Matthews, Bowden et al., unpublished; Avahingson et al, 5 th IAS, poster #WEPEB226 n=36; Thai cohort; genotype B and C

17. HIV-HBV pathogenesis  Virological factors  Immunological factors  Hepatic factors  Treatment

18. T cell immunity and HBV

19. 7 13 14 Chang et al., J Virol 2005;79:3038-3051; Chang, Sirivichayakul et al., J Virol 2009; 83(15):7649-58 Reduced HBV-specific CD4+ T-cells in HIV-HBV co-infected patients on HAART % of patients with HBV-specific T-cell responses HBV (naïve) HBV (treated) HBV/HIV (treated) n= 7 13 14

20. No change in HBV-specific T-cells following HBV-active HAART HBV peptides Crane et al., submitted Weeks following HBV-active HAART 0 4 8 24 48 IFN-  TNF-  IFN-  and TNF-  n=24; Thai cohort; median CD4=60 pre-HAART

21. HIV-HBV pathogenesis  Virological factors  Immunological factors  Hepatic factors  Treatment

22. HIV and the liver  In vitro (cell lines and primary cells)  Hepatocytes (HC)  Kupffer cells (KC)  Stellate cells (HSC)  Endothelial cells (EC)  In vivo  Hepatocytes  Kupffer cells Housset C., Res Virol 1990; 141: 153; Cao Y., AIDS 1992; 6: 65; Housset C., J Hepatol 1993; 19: 252; Schmitt M., Res Virol 1990; 141: 143; Steffan A., Proc Natl Acad Sci 1992; 89: 1582; Cao Y., J Virol 1990; 64: 2553; Banerjee R., AIDS 1992; 6: 1127; Vlahakis S., J Infect Dis 2003; 188: 1455.

23. Hepatic Stellate Cells express high levels of CXCR4 Hong et al, Hepatology 2009;49:2055-2067 0 0.5 1 1.5 2 2.5 3 3.5 4 controlSDF-1 Fold increase in  SMA protein ** ** p<0.05

24. HIV infection increases stellate cell activation 0 0.5 1 1.5 2 2.5 mockHIV IIIBgp120mockHIV IIIB Collagen I  -SMA (smooth muscle actin) Fold change qRT-PCR Tuyama et al CROI Boston 2008

25. Immune activation and liver disease HIV -> GIT CD4+ T-cell depletion Immune activation IL-1 TNF-  IFN-  IL-12 Hepatic fibrosis HSC activation Microbial translocationLPS DCs macrophage Cirrhosis HCV Alcohol Altered portal vein circulation Mathurin et al., Hepatology 2000; 32:1008-1017; Paik et al., Hepatology 2003; 37:1043-1055; Balagopal et al., Gastroenterology 2008; 135:226-233..

26. HIV-HBV pathogenesis  Virological factors  Immunological factors  Hepatic factors  Treatment

27. Hepatotoxicity post HAART  Drug related  Mitochondrial toxicity  didanosine  Hypersensitivity  Nevirapine, abacavir  Direct toxicity  Protease inhibitors eg., ritonavir  Anti-HBV drug withdrawal  Immune mediated  Early – immune restoration disease (IRD) Wit et al., J Infect Dis 2002; 186:23-31; Sulkowski MS, J Infect Dis 2008; 197:S279-93

28. Hepatic flare: Case definition: ALT > 5x ULN or > 100 IU/ml increase from baseline (within 12 weeks of HAART initiation) HBV IRD Case n=8 Control n=28 Hepatic flare following initiation of HBV- active HAART is common n=36 Wk 12Wk 48 Inclusion: HIV- HBV co-infected, HBV DNA > 10 5 IU/ml, ARV naïve, HBV Rx naive Wk 0 Wk 4 Wk 8 AZT / LAM / EFV AZT / TDF / EFV LAM / TDF / EFV Matthews et al., Hepatology 2008; 48(4):1062-9

29. Hepatic flare (cases) n=8 Non hepatic flare (controls) n=28 P value Baseline CD4 (/mm 3 )5232NS Baseline CD8 (/mm 3 )603588NS Baseline HIV-1 RNA (log 10 ) 4.94.7NS Baseline ALT79360.008 Baseline HBV DNA (log 10 )9.98.30.011 CD4 change to week 125760NS Risk factors for hepatic flare Crane et al., J Infect Dis 2009;199(7):974-81

30. CXCL-10 elevated in hepatic flare consistent with immune restoration disease Crane et al., J Infect Dis 2009;199(7):974-81; Oliver et al., 5th IAS, poster #TUPEB160 Gradient T-cell CXCR3 CXCL-10

31. Summary and future research directions  Liver related mortality remains elevated post HBV-active HAART  HBV DNA major determinant of liver disease progression in HBV mono-infection  Age of HBsAg loss important for HCC risk  HIV infection of liver cells may drive fibrosis  Role of immune activation and microbial translocation in HIV-HBV co-infection  New management strategies needed to reduce HBV IRD

32. Acknowledgements  Monash University, Melbourne, Australia  Alfred Hospital  Judy Chang  David Iser  Megan Crane  Monash Medical Centre  Kumar Visvanathan  VIDRL, Melbourne, Australia  Stephen Locarnini  Scott Bowden  NCHECR, UNSW, Sydney, Australia  Greg Dore  Gail Matthews  HIVNAT, Bangkok, Thailand  Kiat Ruxrungtham  Anchalee Avihingson  Sunee Sirivichayakul  Royal Perth Hospital, Perth, Australia  Martyn French  Patricia Price  Ben Oliver  Johns Hopkins, Baltimore, MD  Chloe Thio