Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102) 1 Hopital Beaujon, Clichy, France; 2 Hospital Valle Hebron, Barcelona, Spain; 3 University Hospital “St Ivan Rilsky”, Sofia, Bulgaria; 4 University of Uludag, Bursa, Turkey; 5 Tokuda Hospital, Sofia, Bulgaria; 6 Royal Free Hospital, London U.K.; 7 University of Calgary, Calgary Alberta, Canada; 8 Toronto Western Hospital, University of Toronto, Toronto Ontario, Canada; 9 Gilead Sciences, Durham NC Patrick Marcellin 1, Maria Buti 2, Zahary Krastev 3, Selim Gurel 4, Rozalina Balabanska 5, Geoff Dusheiko 6, Robert Myers 7, E Jenny Heathcote 8, Jeff Sorbel 9, Jane Anderson 9, Elsa Mondou 9 and Franck Rousseau 9 59 th Annual Meeting of the American Association for the Study of Liver Disease October 31-November 4, 2008 San Francisco, CA Oral Presentation # 146

Acknowledgements Participating Centers Australia & New Zealand W.Cheng D. Crawford P. Desmond E. Gane J. George P. Gow I.Kronborg C. Moyes M. Ngu S. Roberts J. Sasadeusz W. Sievert N.Stace S. Strasser F. Weilert US & Canada N. Afdahl F. Anderson M. Bennett N. Bzowej S. Chan A. DiBisceglie P. Gaglio N. Gitlin S. Gordon J. Heathcote US & Canada K. Hu I.Jacobson L. Jeffers K. Kaita A. Lok P. Martin T. Min R. Myers T. Nguyen P. Pockros N.Ravendhran R. Rubin V.Rustgi M. Sherman M. Shiffman M. Tong H. Trinh N. Tsai C. Wang Z. Younossi Bulgaria, Czech Republic & Poland R. Balabanska M. Beniowski R. Flisiak A.Gladysz W. Halota A. Horban P. Husa I. Kotzev Z.Krastev W. Kryczka T. Mach J. Sperl K. Tchernev P. Urbanek M. Volfova Spain, Germany & France K. Barange Y. Benhamou T. Berg J. Bronowicki W. Boecher P. Buggisch M. Buti J. Calleja Spain, Germany & France T. Casanovas J. Enriquez G. Gerken F. Habersetzer T. Heintges C. Hezode H. Hinrichsen D. Huppe S. Kaiser M. Manns P. Mathurin S. Mauss B. Moller J. Peterson M. Prieto G. Teuber C. Trepo R. Zachoval J. Zarski S. Zeuzem UK & Netherlands R. DeMan G. Dusheiko D. Mutimer R. Williams Greece, Turkey & Italy U. Akarka P. Andreone G. Dalekos G. Germanidis S. Gurel S. Hadziyannis G. Kitis O. Kurdas S. Ozenirler M. Rizzetto H. Senturk O. Ozdogan Gilead Sciences J. Dinsdale A. Foster E. Montgomery ICON Quintiles

Patrick Marcellin, MD Hospital Beaujon, University of Paris I have financial relationships within the last 12 months relevant to my presentation with: Hoffman La Roche, Schering Plough, Gilead Sciences, Bristol Myers Squibb and Idenix-Novartis,Vertex, Human Genome Sciences, Cytheris, Intermune, Pharmasset and Tibotec. AND My presentation does include discussion of off-label use of emtricitabine for the treatment of chronic hepatitis B

Background Tenofovir DF (TDF) is a nucleotide analog and obligate chain terminator Approved for HIV-1 in 2001: ~ 2 million patient-years of experience Approved for chronic hepatitis B (CHB) in 2008 Week 48 Phase 3 data showed TDF superior to ADV: –93% of HBeAg-negative TDF-treated patients had HBV DNA <400 copies/mL

Aim To evaluate the safety and efficacy of: 2 years of TDF therapy Switch from ADV to TDF

RANDOMIZATION 2:1 Tenofovir 300 mg Adefovir 10 mg Open-label Week 48 Liver Biopsy Pre-treatment Liver Biopsy Double Blind Week 96 Tenofovir 300 mg HBeAg Negative Study 102 Design * Week 72 HBV DNA ≥ 400 copies/mL option to add emtricitabine (FTC) to TDF in a fixed dose tablet Year 2 Year 1 Week 72* TDF TDF-TDF: N= TDF FTC/TDF: N= (2)* ADV ADV-TDF: N= Patients (on study drug) Week 384 Year 8

HBeAg- patients Age years Compensated liver disease Lamivudine experienced or naive HBV DNA > 10 5 copies/mL ALT > ULN and <10 x ULN Knodell necroinflammatory score ≥ 3 HIV-1, HDV, HCV seronegative Key Eligibility Criteria

Methods HBV DNA and laboratory analyses every 8 weeks HBsAg every 16 weeks Resistance surveillance: patients with HBV DNA ≥ 400 copies/mL (69 IU/mL) Assessments During Year 2 (after week 48 through week 96)

Baseline Disease and Demographic Characteristics CHARACTERISTIC TDF (N=250) ADV (N=125) Mean Age (years)4443 Race Caucasian Asian 64% 25% 65% 24% Male77%78% Prior lamivudine experience17%18% Mean HBV DNA (log 10 copies/mL) Mean ALT (U/L) Mean Knodell necroinflammatory score Mean Knodell fibrosis score Knodell fibrosis score = 4 (cirrhosis)19%20% Viral Genotype A B C D 12% 9% 12% 64% 11% 14% 10% 63%

% Patients with HBV DNA <400 copies/mL (95% CI) (ITT)

% Patients with HBV DNA <400 copies/mL (95% CI) (On-Treatment Analysis)

Mean HBV DNA (log 10 copies/mL) (95% CI)

ADV Switch Patients Viral suppression on ADV is maintained after switching to TDF –100% of patients (76/76) were responders at Week 96 Viral suppression of viremic patients on ADV is rapidly obtained with TDF –At week 64: 94% –At week 96: 100% HBV DNA response (below 400 copies/mL) at Week 96 for ADV patients who switched to TDF at Week 48:

Mean ALT (U/L) (95% CI) ULN for females=34 U/L ULN for males=43 U/L

Patients with Virologic Breakthrough During Year 2 Definition of Virologic Breakthrough: confirmed ≥400 copies/mL after being <400 copies/mL OR confirmed 1 log increase from nadir

Patients with Virologic Breakthrough Pt 7957 TDF FTC+TDF Non-adherent (TDF levels BQL) HBV DNA (Log 10 Copies/mL) Weeks on Study LLOQ TDF non-adherent (TDF levels BQL) Pt 6852

Patients with Virologic Breakthrough Pt 1674 Pt 1669 Patient off drug between weeks 80 and 96 TDF

Resistance Surveillance All patients : – at baseline – yearly if ≥ 400 copies/mL ( ≥ 69 IU/mL – at discontinuation of TDF mono-therapy if ≥ 400 copies/mL Any patient post-baseline with: –conserved site changes in pol/RT –virologic breakthrough –polymorphic site changes (> 1 patient)

Resistance Surveillance Results No resistance up to 2 years of TDF mono-therapy No HBV pol/RT amino acid substitutions associated with TDF resistance were detected through 96 weeks of TDF monotherapy Week 96 TDF Resistance Surveillance; A Snow-Lampart et al. Poster # 977

Summary of Safety Data during Open Label TDF Week 96 TDF-TDF (N=250) ADV-TDF (N=125) Study Drug-Related SAE 1 (<1%)0 Deaths Metastatic liver carcinoma1 (<1%) 0 G3 or G4 Laboratory23 (10%)11 (10%) Discontinue due to an AE hepatic neoplasm dizziness, fatigue, lack of concentration 2 (1%) Confirmed ↓ phosphorus < 2mg/dL 2 (<1%) 1 (<1%) Confirmed 0.5 mg/dL  in creatinine 00 Confirmed creatinine clearance <50 mL/min 00

Conclusions Week 96 TDF demonstrated durable, potent antiviral activity through Week 96: –99% of patients on therapy had HBV DNA <400 copies/mL No resistance to TDF monotherapy detected up to 2 years Patients can safely and effectively switch from ADV to TDF treatment: –100% of patients had HBV DNA <400 copies/mL TDF was well tolerated through Week 96

Patient Disposition N= 375 Randomized and Treated TDF  TDF n = 225 Completed Week 96 N = 125 Adefovir Dipivoxil (ADV) Entered Open-Label TDF Period TDF  TDF = 235 ADV  TDF = 112 Discontinued Treatment Prior to Week 48 TDF = 6 ADV = 4 N= 250 Tenofovir DF (TDF) ADV  TDF n = 110 Completed Week 96 Discontinued Treatment Between Weeks 48 and 96 TDF  TDF n = 10 ADV  TDF n = 2 Permanently Initiated FTC/TDF prior to Week 96 TDF  TDF n = 2 ADV  TDF n = 0

Patient Disposition N= 375 Randomized and Treated TDF  TDF N = 225 TDF-TDF – FTC/TDF* N= 2 (of 225) Completed Week 96 N = 125 Adefovir Dipivoxil (ADV) Entered Open-Label TDF Period TDF  TDF = 235 ADV  TDF = 112 Discontinued Treatment Prior to Week 48 TDF N = 6 ADV N = 4 N= 250 Tenofovir DF (TDF) ADV  TDF N = 110 ADV-TDF – FTC/TDF* N= 0 (of 110) Completed Week 96 Discontinued Treatment Between Weeks 48 and 96 TDF  TDF N = 10 ADV  TDF N = 2 Marcellin P, et al., AASLD 2008; Oral #146 ~ 89% Retention *Permanently Initiated FTC/TDF Combination therapy  Week 72 TDF  TDF N = 2 ADV  TDF N = 0