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Pathogenesis of HIV-hepatitis B co-infection

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. Outline. Natural history of HIV-HBV co-infection HBV-active HAART

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Pathogenesis of HIV-hepatitis B co-infection

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

  4. 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., 5th IAS Conference, poster # WEPEB226

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

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

  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 REVEAL: Long-term follow-up of untreated HBsAg+ve individuals in Taiwan Cumulative Incidence of HCC at Year 13 Follow-up[1] (N = 3653) Cumulative Incidence of Cirrhosis at Year 13 Follow-up[2] (N = 3582) 50 40 36.2 30 23.5 Patients (%) 20 14.9 12.2 9.8 10 5.9 4.5 3.6 1.4 1.3 0 100,000- 999,999 ≥ 1 million 300- 999 1000- 9999 10,000- 99,999 300- 9999 < 300 ≥ 100,000 < 300 10,000- 99,999 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.

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

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

  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 n=36; Thai cohort; genotype B and C Iser, Matthews, Bowden et al., unpublished; Avahingson et al, 5th IAS, poster #WEPEB226

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

  18. T cell immunity and HBV

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

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

  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 ** 4 3.5 3 2.5 Fold increase in aSMA protein 2 1.5 1 0.5 0 control SDF-1 **p<0.05 Hong et al, Hepatology 2009;49:2055-2067

  24. HIV infection increases stellate cell activation 2.5 2 1.5 Fold change qRT-PCR 1 0.5 0 mock HIV IIIB gp120 mock HIV IIIB Collagen I a-SMA (smooth muscle actin) Tuyama et al CROI Boston 2008

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

  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. HBV IRD Hepatic flare:Case definition: ALT > 5x ULN or > 100 IU/ml increase from baseline (within 12 weeks of HAART initiation) Hepatic flare following initiation of HBV-active HAART is common Inclusion: HIV- HBV co-infected, HBV DNA > 105 IU/ml, ARV naïve, HBV Rx naive AZT / LAM / EFV n=36 AZT / TDF / EFV LAM / TDF / EFV Wk 8 Wk 12 Wk 48 Wk 0 Wk 4 Case n=8 Control n=28 Matthews et al., Hepatology2008; 48(4):1062-9

  29. 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 CXCL-10 Gradient CXCR3 T-cell Crane et al., J Infect Dis 2009;199(7):974-81; Oliver et al., 5th IAS, poster #TUPEB160

  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. 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 Acknowledgements

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