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