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  • You just need to add ADV to the treatments
  • This is great. Could you perhaps modify so the DNA pathway and HBsAg pathway don’t overlap. Also, can you “fade” the HBsAg path on this slide and “fade” the HBV DNA path on the other slide. Also, I think the font needs to be a little larger as it is still difficult to read. Finally I would keep the RNA as before ie the 2.4 and 3.5 kb RNA
  • See previous slide. It would be better if the 2 pathways don’t cross. Can you animate these at all? Best I can do- I COULD animate but it would probably take me another week!
  • We initially examined HBV-specific T cells in a small cross-sectional study published in 2005 7 HBV chronically infected therapy naïve individuals, 13 on treatment and 14 HBV HIV coinfected on treatment individuals were examined We found individuals who are on HBV treatment have significantly higher frequency of CD4 T cell responses than those who are therapy naïve However this reconsitution of HBV-specific CD4 T-cell responses was not observed in HIV infected individuals even though these individuals were on therapy and had a relatively normal CD4 count Analysis of HBV viral load showed that detection of a responses to HBV was associated with a loss of HBV VL regardless of treatment or co-infection Analysis of HBV viral load showed that detection of a responses to HBV was associated with a loss of HBV VL
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Transcript

  • 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 Liver related mortality rate/100 py 0 2 4 6 8 10 12 14 16 HBV HIV HIV/HBV Thio et al Lancet 2002; 360:1921;
  • 4. Treatment of HIV-HBV co-infection + +++ IFN / PEG-IFN ? +++ Telbivudine + +++ Entecavir ? ++ Adefovir +++ +++ Tenofovir ++ ++ 3TC / FTC HIV HBV Drug
  • 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. 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., 5 th 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., 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. HIV/HBV co-infection: mortality Thio et al Lancet 2002 Liver related mortality rate/100 py 0 5 10 15 20 25 30 35 <1996 1996-2000 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. Reduced HBV-specific CD4+ T-cells in HIV-HBV co-infected patients on HAART 7 13 14 Chang et al., J Virol 2005;79:3038-3051; Chang, Sirivichayakul et al., J Virol 2009; 83(15):7649-58 % 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 0 4 8 24 48 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 control SDF-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 mock HIV IIIB gp120 mock HIV 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 translocation LPS 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 following initiation of HBV-active HAART is common Case n=8 Control n=28 n=36 Wk 12 Wk 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 Hepatic flare: Case definition: ALT > 5x ULN or > 100 IU/ml increase from baseline (within 12 weeks of HAART initiation) HBV IRD
  • 29. Risk factors for hepatic flare Crane et al., J Infect Dis 2009;199(7):974-81 NS 60 57 CD4 change to week 12 NS 588 603 Baseline CD8 (/mm 3 ) 8.3 36 4.7 32 Non hepatic flare (controls) n=28 0.011 9.9 Baseline HBV DNA (log 10 ) NS 4.9 Baseline HIV-1 RNA (log 10 ) 79 52 Hepatic flare (cases) n=8 0.008 Baseline ALT NS Baseline CD4 (/mm 3 ) P value
  • 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