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  Pathogenesis of disease progression in HIV-HBV co- infection  Virological factors  Immunological factors  Hepatic factors  Treatment  Emerging research issues

Liver related mortality rate/100 py HBVHIVHIV/HBV HIV/HBV co-infection: mortality Thio et al Lancet 2002; 360:1921;

DrugHBVHIV 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., 5 th IAS Conference, poster # WEPEB226

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 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., 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

Thio et al Lancet 2002 Liver related mortality rate/100 py HIV/HBV co-infection: mortality < HBV 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 ≥ 100,000 10, ,999 Patients (%) Cumulative Incidence of HCC at Year 13 Follow-up [1] (N = 3653) Cumulative Incidence of Cirrhosis at Year 13 Follow-up [2] (N = 3582) < < , , , ,999 ≥ 1 million Baseline HBV DNA (copies/mL) 1. Chen CJ, et al. JAMA. 2006;295: Iloeje UH, et al. Gastroenterology. 2006;130: 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 transcriptase inhibitors

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 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

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

No change in HBV-specific T-cells following HBV-active HAART HBV peptides Crane et al., submitted Weeks following HBV-active HAART 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.

Hepatic Stellate Cells express high levels of CXCR4 Hong et al, Hepatology 2009;49: controlSDF-1 Fold increase in  SMA protein ** ** p<0.05

HIV infection increases stellate cell activation mockHIV IIIBgp120mockHIV IIIB Collagen I  -SMA (smooth muscle actin) Fold change qRT-PCR Tuyama et al CROI Boston 2008

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

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=8 Control n=28 Hepatic flare following initiation of HBV- active HAART is common n=36 Wk 12Wk 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 (cases) n=8 Non hepatic flare (controls) n=28 P value Baseline CD4 (/mm 3 )5232NS Baseline CD8 (/mm 3 )603588NS Baseline HIV-1 RNA (log 10 ) NS Baseline ALT Baseline HBV DNA (log 10 ) CD4 change to week 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