Pathogenesis of HIVhepatitis B coinfection

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 3601921
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 (n47) HBeAg-positive
(n30) 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
HIV/HBV co-infection mortality
35
30
25
20
Liver related mortality rate/100 py
15
10
5
0
HBV
lt1996
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 HBsAgve
individuals in Taiwan
Cumulative Incidence of HCC at Year 13
Follow-up1 (N 3653)
Cumulative Incidence of Cirrhosis at Year 13
Follow-up2 (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
10,000- 99,999
lt 300
300- 999
1000- 9999
lt 300
300- 9999
10,000- 99,999
100,000- 999,999
1 million
Baseline HBV DNA (copies/mL)
1. Chen CJ, et al. JAMA. 200629565-73. 2.
Iloeje UH, et al. Gastroenterology.
2006130678-686.
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 1351192
16
HBV DNA and HBsAg following HBV-active HAART
n36 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
7 13 14
n 7 13 14
Chang et al., J Virol 2005793038-3051 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
n24 Thai cohort median CD460 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
plt0.05
Hong et al, Hepatology 2009492055-2067
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
Immune activation and liver disease
HIV -gt 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 18623-31
Sulkowski MS, J Infect Dis 2008 197S279-93
28
Hepatic flare following initiation of HBV-active
HAART is common
Inclusion HIV- HBV co-infected, HBV DNA gt 105
IU/ml, ARV naïve, HBV Rx naive
AZT / LAM / EFV
n36
AZT / TDF / EFV
LAM / TDF / EFV
Wk 12
Wk 48
Wk 0
Wk 4
Wk 8
Case n8 Control n28
Matthews et al., Hepatology 2008 48(4)1062-9
29
Risk factors for hepatic flare
Crane et al., J Infect Dis 2009199(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 2009199(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
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