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Pathogenesis of HIV-hepatitis B co-infection
Sharon R Lewin, FRACP, PhDInfectious 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
Pathogenesis of disease progression in HIV-HBV co-infection Virological factors Immunological factors Hepatic factors Treatment
Emerging research issues
Live
r re
late
d m
orta
lity
rate
/100
py
0
2
4
6
8
10
12
14
16
HBV HIV HIV/HBV
HIV/HBV co-infection: mortality
Thio et al Lancet 2002; 360:1921;
Drug HBV HIV
3TC / FTC ++ ++
Tenofovir +++ +++
Adefovir ++ ?
Entecavir +++ +
Telbivudine +++ ?
IFN / PEG-IFN +++ +
Treatment of HIV-HBV co-infection
Immune responses in HBV mono-infection post treatment
2-5%
1-2%
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
Longitudinal Thai cohort (n=47); HBeAg-positive (n=30); median follow up = 27 monthsHBeAg loss = 46%; HBsAg loss = 13%
Avahingson et al., 5th IAS Conference, Capetown 2009, Poster # WEPEB226
0.0
00
.25
0.5
00
.75
1.0
0
0 10 20 30 40Months
ALT normal ALT abnormal
HBeAg loss by pre-HAART ALT
High rates of HBeAg seroconversion following HBV active HAART
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
Thio et al Lancet 2002
Liv
er
rela
ted
mo
rta
lity
rate
/10
0 p
y
0
5
10
15
20
25
30
35
HIV/HBV co-infection: mortality
<1996 1996-2000HBV 1996-2007
Hoffman et al., AIDS 2009
HAART
HBV-active (95%)
Increased liver mortality on HBV-active HAART
Hoffman et al., AIDS 2009
HIV-HBV pathogenesis
Virological factors
Immunological factors
Hepatic factors
Treatment
High Baseline HBV DNA Associated With Increased Risk of HCC and Cirrhosis
≥ 100,00010,000-99,999
Pat
ien
ts (
%)
Cumulative Incidence of HCC at
Year 13 Follow-up[1] (N = 3653)
50
40
30
20
10
01.3 1.4 3.6
12.214.9
Cumulative Incidence of Cirrhosis at Year 13 Follow-up[2] (N = 3582)
4.5 5.99.8
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
HBV Replication: HBV DNA Pathway
Adapted from: Diestag, N Engl J Med, 2008
HBV Replication: HBsAg (Envelope) Pathway
Adapted from: Diestag, N Engl J Med, 2008
Reverse transcriptaseinhibitors
Cumulative Risk for HCC and HBsAg in HBV mono-infection
Yuen M-F, et al. Gastroenterology 2008; 135:1192
HBV DNA and HBsAg following HBV-active HAART
HBV DNA
Baseline Week 480
2
4
6
8
10p < 0.0001
HB
V D
NA
(lo
g1
0 I
U/m
L)
qHBsAg
Baseline Week 480
2
4
6
8p = 0.007
qH
BsA
g (
log
10
IU/m
l)
Iser, Matthews, Bowden et al., unpublished; Avahingson et al, 5 th IAS, poster #WEPEB226
n=36; Thai cohort; genotype B and C
HIV-HBV pathogenesis
Virological factors
Immunological factors
Hepatic factors
Treatment
T cell immunity and HBV
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
% o
f pa
tient
s w
ith H
BV
-spe
cific
T-c
ell r
espo
nse
s
HBV (naïve)
HBV (treated)
HBV/HIV (treated)
n= 7 13 14
No change in HBV-specific T-cells following HBV-active HAART
HB
V p
eptid
es
Crane et al., submitted
Weeks following HBV-active HAART
0 4 8 24 48 0 4 8 24 480 4 8 24 48
IFN- TNF- IFN- and TNF-
n=24; Thai cohort; median CD4=60 pre-HAART
HIV-HBV pathogenesis
Virological factors
Immunological factors
Hepatic factors
Treatment
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.
Portal Vein
HSC
KC
HC
EC
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-1Fol
d in
crea
se in
S
MA
pro
tein **
**p<0.05
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)
Fol
d ch
ange
qR
T-P
CR
Tuyama et al CROI Boston 2008
Immune activation and liver disease
HIV -> GIT CD4+ T-cell depletion
Immune activation
IL-1TNF-IFN-IL-12
Hepatic fibrosisHSC activation
Microbial translocation LPS
DCs
macrophage
CirrhosisHCVAlcohol
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..
HIV-HBV pathogenesis
Virological factors
Immunological factors
Hepatic factors
Treatment
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
Hepatic flare: Case definition: ALT > 5x ULN or > 100 IU/ml increase from baseline (within 12 weeks of HAART initiation)
HBV IRD
Case n=8Control n=28
Hepatic flare following initiation of HBV-active HAART is common
n=36
Wk 12 Wk 48
Inclusion: HIV- HBV co-infected, HBV DNA > 105 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 (cases)
n=8
Non hepatic flare
(controls) n=28
P value
Baseline CD4 (/mm3) 52 32 NS
Baseline CD8 (/mm3) 603 588 NS
Baseline HIV-1 RNA (log10)
4.9 4.7 NS
Baseline ALT 79 36 0.008
Baseline HBV DNA (log10) 9.9 8.3 0.011
CD4 change to week 12 57 60 NS
Risk factors for hepatic flare
Crane et al., J Infect Dis 2009;199(7):974-81
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
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
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