Adefovir Dipivoxil 10 mg for the

Treatment of Chronic Hepatitis B

NDA 21-449

August 6, 2002

Gilead Sciences, Inc.

Proposed Indication

Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease

Consultants

Jules L. Dienstag, MDProfessor of Medicine, Harvard Medical SchoolMassachusetts General Hospital (Gastrointestinal Unit)

Zachary D Goodman, MD, PhDChief, Division of Hepatic PathologyArmed Forces Institute of Pathology

Paul Klotman, MDChief, Division of Nephrology and Chairman, Department of Medicine Mt. Sinai School of Medicine

Eugene Schiff, MDProfessor of Medicine and Chief, Division of HepatologyDirector,Center For Liver Diseases University of Miami School of Medicine

Teresa Wright, MDProfessor of Medicine University of California, San Francisco

Agenda

Introduction Alan Taylor, PhDChronic Hepatitis B Vice President

Pre-clinical Regulatory Affairs

Clinical Pharmacokinetics

Clinical Efficacy & Safety Carol Brosgart, MDPivotal studies Vice President

Supportive studies Clinical Research

Further studies

1Lok AS, Gastroenterology 20012Lee W, NEJM 1997

Chronic Hepatitis BA Global Healthcare Issue

400 million with chronic hepatitis B worldwide1 — HBeAg+ — HBeAg–

25-33% develop progressive disease— Cirrhosis or hepatocellular carcinoma— 1 million deaths per year

1.25 million with chronic hepatitis B in US2

— 17,000 hospitalizations and 5,000 deaths per year— 6th leading indication for adult liver transplantation

400 million with chronic hepatitis B worldwide1 — HBeAg+ — HBeAg–

25-33% develop progressive disease— Cirrhosis or hepatocellular carcinoma— 1 million deaths per year

1.25 million with chronic hepatitis B in US2

— 17,000 hospitalizations and 5,000 deaths per year— 6th leading indication for adult liver transplantation

Current Therapies for Chronic Hepatitis B

Limited treatment options — Interferon alpha

Cytokine immunomodulator Parentally administered Safety and tolerability issues Contraindicated for decompensated liver disease

— Lamivudine Nucleoside analog Orally administered Resistance

Goals for New Antiviral Therapies for Chronic Hepatitis B

Safe and well-tolerated for long term use Effective in all patient populations

— HBeAg+ and HBeAg–— HBV genotypes (A-G)— Compensated and decompensated liver disease— Post-liver transplantation— Drug resistant virus

High threshold for the development of resistance

Adefovir Dipivoxil

Oral prodrug of adefovir Nucleotide analog of adenosine monophosphate Potent in vitro activity against hepadnaviruses,

retroviruses, and herpes viruses Competitive inhibitor of HBV DNA polymerase

— Ki = 0.1 M Long intracellular half-life (12-36 hours) Adefovir-associated resistance mutation sites

identified in HIV RT not present in HBV DNA polymerase

In vitro activity against wild-type andlamivudine-resistant HBV

HBV DNA PolymeraseFold Change in Ki

Mutation Adefovir DP Lamivudine TP

Wild-type 1.0 1.0

M552I 1.3 8.0

M552V 2.2 19.6

L528M+M552V 0.8 25.2

In Vitro Activity of AdefovirWild-type and Lamivudine-resistant HBV

Xiong et al. Hepatology, 1998, 28:1669-1673

Preclinical Pharmacology and Toxicology

Antiviral activity and safety in DHBV, WHV, and transgenic mice expressing HBV— Reduced serum viremia in all models — In DHBV model, reduced cccDNA in liver and

DHBV DNA/viral antigen in bile duct epithelial cells — No adverse effects in woodchucks

Dose proportional PK of adefovir following oral administration of adefovir dipivoxil

Eliminated as unchanged adefovir in urine Kidney principal target organ

Adefovir Dipivoxil 10 mgClinical Pharmacokinetics

Oral bioavailability 59%, T1/2 7 hours Pharmacokinetics not affected by food, chronic

hepatitis B disease, demographic characteristics No clinically relevant drug-drug interactions

— Not substrate or inhibitor of CYP450— Lamivudine, acetaminophen, ibuprofen,

trimethoprim/sulfamethoxazole Change in dosing interval required in patients

with moderate to severe renal impairment— Increased exposure with CLcr < 50 mL/min

No dose alteration for hepatic impairment

Adefovir Dipivoxil in Chronic Hepatitis B Dose Selection

Doses of 5-125 mg evaluated in chronic hepatitis B— 3 - 4 log10 copies/mL reduction in HBV DNA at all

doses > 5 mg at 4-12 weeks Adefovir dipivoxil 60 and 120 mg in HIV 10 and 30 mg selected for evaluation in HBV Sustained HBV DNA reduction and increased

ALT normalization up to 136 weeks— No adefovir-associated resistance mutations

identified (n=27)— Renal laboratory abnormalities at 30 mg

10 mg target dose for registration

Chronic Hepatitis BExposure to Adefovir Dipivoxil

Total 2084

ADV 10 mg1647

Other ADV doses437

Phase 2, Supportive Studies, Early Access

831

Pivotal studies and transplantation

816 48 Weeks

578 72 Weeks

420

96 Weeks 256

As of NDA Safety update

Clinical Efficacy and Safety

Carol Brosgart, MD

Vice President, Clinical Research

Gilead Sciences

Adefovir Dipivoxil Pivotal Studies

9648

Liver Histology

Study 438HBeAg–

Week 0

Liver Histology

ADV 10 mg (n=171)Study 437HBeAg+

ADV 30 mg (n=173)

Placebo (n=167)

Placebo (n=142)

ADV 10 mg (n=138)

ADV 10 mg (n=123)ADV 10 mg (n=79)Placebo (n=40)

Placebo (n=71)ADV 10 mg (n=85)

Placebo (n=61) ADV 10 mg (n=60)

Studies 437 and 438 Key Inclusion Criteria

Documented HBsAg positive for 6 months Compensated liver disease Adequate renal function HIV, HCV, and HDV seronegative Liver biopsy

HBeAg– 105 copies/mL

1.5–15

HBeAg+ 106 copies/mL

1.2–10HBV DNA

ALT x ULN

Studies 437 and 438Baseline Characteristics (ITT)

HBeAg+(n=511)

HBeAg–(n=184)

Median age (years) 33 46

Male 74% 83%

AsianCaucasianBlack

59%36%

3%

30%66%

3%

Prior IFNPrior LAM

24% 2%

41% 8%

Studies 437 and 438Baseline HBV Characteristics (ITT)

HBeAg+(n=511)

HBeAg–(n=184)

Median HBV DNA(log10 copies/mL) 8.4 7.1

Median ALT (IU/L) xULN

942.3

982.3

Median KnodellTotal Score

10 10

Cirrhosis 6% 11%

Studies 437 and 438Primary Endpoint

Improvement in liver histology at week 48, relative to baseline (ADV 10 mg vs. placebo)— Defined as 2 point reduction in the Knodell

necroinflammatory score with no worsening in fibrosis— Missing/unevaluable week 48 biopsy = no improvement

Histology assessed— One histopathologist blinded to treatment assignment

and sequence (baseline or week 48) — Knodell and Ishak scoring systems

Evaluable paired biopsies— 86% HBeAg+— 91% HBeAg–

33%

64%

25%

53%

0%

10%

20%

30%

40%

50%

60%

70%

Studies 437 and 438 (ITT) 48 WeeksPrimary Endpoint: Improvement in Liver Histology

p<0.001a

Patients(%)

PLB

ADV 10

PLB

ADV10

HBeAg+ HBeAg–

p<0.001a

Missing/unevaluable week 48 biopsy = no improvement

aCochran-Mantel-Haenszel Test

Studies 437 and 438 Integrated 48 Weeks (ITT)Histological Improvement by Demographic Characteristics

0%

10%

20%

30%

40%

50%

60%

70%PlaceboADV 10

Gender Ethnicity Age

Patients(%)

Male

Female Caucasian Asian 40 < 40(n =) (388) (119) (238) (249) (261) (246)

Studies 437 and 438 Integrated 48 Weeks (ITT)Histological Improvement by Baseline HBV Characteristics

2xULN < 2xULN< 7.6 7.6 No Prior Prior 10 < 10

0%

10%

20%

30%

40%

50%

60%

70%

80%

Patients (%)

IFN Knodell HBV DNA ALT

n = (358) (149) (177) (230) (282) (225) (322) (185)

PlaceboADV 10

Studies 437 and 438 Secondary Endpoints

Ranked assessment of liver histology Change in serum HBV DNA

— Roche Amplicor PCR, LLQ = 400 copies/mL

Change in ALT HBeAg loss and seroconversion (Study 437) Resistance

Studies 437 and 438 (ITT) 48 WeeksNecroinflammation – Ranked Assessment

p<0.001a p<0.001a

HBeAg+ HBeAg–

Improved

Worsened

Patients(%)

42%

80%

51%

3%

ADV10

PLB PLB

ADV10

41%

71%

34%

13%

40%

20%

0%

20%

40%

60%

80%

60%

aCochran-Mantel-Haenszel Test

p<0.001a p<0.001a

Studies 437 and 438 (ITT) 48 WeeksFibrosis – Ranked Assessment

24%

41%

26%

14%

30%

20%

10%

0%

10%

20%

30%

40%

50%

PLB

ADV10

Improved

Worsened

25%

48%

38%

4%

PLB

ADV10

Patients(%)

40%

aCochran-Mantel-Haenszel Test

HBeAg+ HBeAg–

Studies 437 and 438 Median Change from Baseline in HBV DNA

aWilcoxon Rank-Sum Test

p<0.001a

HBeAg-

p<0.001a

HBeAg+

PLB

ADV 10-4

-3

-2

-1

0

PLB

ADV 10

Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48

-4

-3

-2

-1

0

0 4 8 12 16 20 24 28 32 36 40 44 48

log10 copies/mL

Studies 437 and 438 (ITT) 48 WeeksSerum HBV DNA < 400 copies/mL

p<0.001a p<0.001a

0% 0%

21%

51%

0%

10%

20%

30%

40%

50%

60%

PLB

ADV10

PLB

ADV10

HBeAg+ HBeAg–

Patients(%)

aCochran-Mantel-Haenszel Test

Missing = Failure

Studies 437 and 438 (ITT) 48 Weeks ALT Normalization

29%

16%

72%

48%

0%

10%

20%

30%

40%

50%

60%

70%

80%

PLB

ADV10

PLB

ADV10

HBeAg+ HBeAg–

p<0.001a p<0.001a

Patients(%)

aCochran-Mantel-Haenszel Test

Missing = Failure

Study 437 (ITT) 48 WeeksHBeAg Loss and Seroconversion

11%

6%

24%

12%

0%

5%

10%

15%

20%

25%

30%

HBeAg Loss HBeAg Seroconversion

PLB

ADV10

PLB

ADV10

p=0.001a p<0.05a

Patients(%)

aCochran-Mantel-Haenszel Test

Missing = Failure

Study 437 and 438 Efficacy Beyond 48 Weeks

Study 437 and 438 All ADV 10 mg (n=492)Efficacy Beyond 48 weeks

HBeAg+(n=309)

HBeAg-(n=183)

Week48

Week72

Week48

Week72

HBV DNA < 400 copies/mLa 26% 46% 66% 80%

ALT normalizationa 67% 78% 76% 81%

HBeAg lossa 23% 44% NA NA

HBeAg seroconversiona 14% 23% NA NA

aK-M estimates

Studies 437 and 438 ADV 10 mgEfficacy Summary

Statistically significant improvement in— Liver histology— HBV DNA— ALT— HBeAg loss and seroconversion (Study 437)

Histological improvement appears similar across all baseline demographics and disease characteristics

Continued improvement in efficacy beyond 48 weeks

Studies 437 and 438 Safety of Adefovir Dipivoxil 10 mg

Studies 437 and 438 0-48 WeeksAdverse Events and Discontinuations

HBeAg+ HBeAg–

PLB ADV 10 PLB ADV 10 (n=167) (n=171) (n=61) (n=123)

Adverse events (AEs) 89% 87% 74% 76%

Treatment-related AEs 56% 53% 36% 33%

Serious AEs 5% 5% 7% 3%

Deaths 0 0 0 0

Discontinuation rate 8% 7% 2% 2%

Discontinuations due to AEs

<1% 2% 0% <1%

Studies 437 and 438 Integrated 0-48 WeeksGrade 1-4 Treatment-Related Adverse Eventsa

PLB ADV 10(n=228) (n=294)

Asthenia 14% 13%

Abdominal pain 11% 9%

Headache 10% 9%

Nausea 8% 5%

Flatulence 4% 4%

Diarrhea 4% 3%

Dyspepsia 2% 3%

aObserved in 3% of ADV treated patients

Studies 437 and 438 Integrated 0-48 Weeks Grade 3-4 Laboratory Abnormalitiesa

PLB ADV 10

(n=228) (n=294)

ALT (> 5 x ULN) 41% 20%

AST (> 5 x ULN) 23% 8%

Hematuria ( 3+) 10% 11%

CK (> 4 x ULN) 7% 7%

Amylase (> 2 x ULN) 4% 4%

Glycosuria ( 3+) 3% 1%

aObserved in 1% of ADV treated patients

Studies 437 and 438 Integrated 0-48 Weeks Grade 1-4 Renal Laboratory Parameters

PLB(n=228)

ADV 10(n=294)

Hematuria 31% 30%

Proteinuria 16% 19%

Serum phosphorus decrease 8% 7%

Glycosuria 7% 3%

Serum bicarbonate decrease <1% 2%

Serum creatinine increase 0% 1%

BUN increase <1% <1%

Studies 437 and 438 Integrated 0-48 WeeksRenal Laboratory Abnormalities

PLB ADV 10 (n=228) (n=294)

Serum creatinine

Increase 0.5 mg/dLa 0% 0%

Median change (mg/dL) 0.0 0.0

Serum phosphorus

<1.5 mg/dLa 0% 0%

Median change (mg/dL) 0.1 0.1

aConfirmed (two consecutive laboratory abnormalities)

Studies 437 and 438 0-48 Weeks Renal Laboratory Abnormalities

HBeAg+ HBeAg-

PLB (n=167)

ADV 10 (n=171)

PLB (n=61)

ADV 10 (n=123)

Serum creatinine Increase 0.3 mg/dLa

1%

5%

5%

2%

Serum phosphorus < 2.0 mg/dLa

1%

0%

0%

0%

aConfirmed (two consecutive laboratory abnormalities)

Studies 437 and 438 Integrated ADV 10 mgRenal Laboratory Abnormalities 0-96 Weeks

aConfirmed (two consecutive laboratory abnormalities)

All ADV 10 (n=492)

Serum creatinine Increase 0.3 mg/dLa 0.5 mg/dLa Median change (mg/dL)

29 (6%)

2 (<1%) 0.1

Serum phosphorus < 2.0 mg/dLa Median change (mg/dL)

0

0.0

Study 437 and 438 All ADV 10 mgResolution of 0.3 mg/dL Increases in Serum Creatinine 0-96 Weeks (n=29)

Resolved ondrugn=20

Stable ondrugn=8

Resolved on discontinuation

n=1

Studies 437 and 438 Integrated 0-48 WeeksALT Elevations > 10 x ULN

PLB ADV 10 (n=228) (n=294)

ALT > 10 x ULN 17% 6%

ALT > 10 x ULN with:

Bilirubin 2.5 mg/dL and 2% 0% 1mg/dL above baseline

Albumin < 3 g/dL 1% 0%

PT prolonged 1.5 sec <1% 0% above ULN

Studies 437 and 438 Integrated ADV 10 mgALT Elevations > 10 x ULN 48-96 Weeks

ADVADV ADVPLB (n=164) (n=111)

ALT > 10 x ULN 6% 25%

ALT > 10 x ULN with:

Bilirubin 2.5 mg/dL and <1% 3% 1 mg/dL above baseline

Albumin < 3 g/dL 0% 0%

PT prolonged 1.5 sec 0% 0% above ULN

Studies 437 and 438 Integrated 0-96 WeeksAdefovir Dipivoxil 10 mg Safety Summary

Safety and tolerability of ADV 10 mg similar to placebo through 48 weeks— Increases in ALT and AST more frequent on placebo

Safety appears similar with extended dosing Incidence of increases in serum creatinine is low

— One patient discontinued

No hypophosphatemia Increases in serum ALT after stopping treatment

— Liver function should be closely monitored for at least 12 weeks after discontinuation of therapy

Adefovir Dipivoxil 30 mgEfficacy and Safety

Study 437 (ITT)Efficacy Results 48 Weeks

PLB ADV 10 ADV 30 (n=167) (n=171) (n=173)

Histological improvement 25% 53% 59%

Median change HBV DNA (log10 copies/mL)

-0.55 -3.52 -4.76

Median change ALT (IU/L)

-17 -51 -54

ALT normalization 16% 48% 55%

HBeAg loss 11% 24% 27%

HBeAg seroconversion 6% 12% 14%

Study 437Renal Laboratory Abnormalities 48 Weeks

aConfirmed (two consecutive laboratory abnormalities)

PLB ADV 10 ADV 30(n=167) (n=171) (n=173)

Serum creatinineIncrease 0.5 mg/dLa

Median change (mg/dL)0%

00%

07%0.2

Serum phosphorus< 1.5 mg/dLa

< 2.0 mg/dLa

Median change (mg/dL)

0%1%0.1

0%0%0.1

0% 5% -0.1

Study 437 Assessment of Adefovir Dipivoxil 30 mg

Efficacy demonstrated with ADV 10 and 30 mg Renal laboratory abnormalities with ADV 30 mg Safety profile of ADV 10 mg similar to placebo

and favorable for long-term dosing

Resistance Surveillance

Studies 437 and 438Resistance Surveillance

Prospective, blinded analysis Methods

— Sequenced RT domain of HBV DNA polymerase (344 amino acids)

— Compared baseline and week 48 — Assessed phenotypic resistance in vitro for all

emerging substitutions at conserved sites

498 of 695 patients with paired samples had detectable HBV DNA > 400 copies/mL at baseline and week 48

Studies 437 and 438Resistance Surveillance Results

10 patients with substitutions at conserved sites — 6 in placebo — 4 in ADV

2 ADV 10 mg, 2 ADV 30 mg S467A, H481L, V562A, H582Q All had ~4 log10 copies/mL HBV DNA reductions

at week 48 and no rebound viremia

All susceptible to adefovir in vitro No adefovir-associated resistance mutations

identified up to 48 weeks

Supportive Studies

Lamivudine Resistance

Incidence of mutations (YMDD)1-3

— 24% at 1 year— 69% at 5 years

Resistance associated with— Loss of HBV DNA suppression— Increased ALT— Loss of histological and clinical benefit

1 Lai et al. Gastroenterol Hepatol, 20002 Leung MWY et al. J Hepatology, 19993 Guan et al. APDW, 2002

Study 435 Compassionate Access

Adefovir Dipivoxil 10 mg for the Treatment of Patients Pre- and Post-Liver Transplantation

with Lamivudine-Resistant HBV

Study 435 Mortality Rates in Advanced Liver

Disease One year survival rates prior to the availability of

therapies for chronic hepatitis B— Post-liver transplantation: 73%1

— Decompensated cirrhosis: 65%2

Survival improved with therapies for hepatitis B Lamivudine resistance is associated with

significant morbidity and mortality in high-risk patients

1 Weissberg et al. Ann Intern Med.,1984 2 Perillo et al. Hepatology 2001

Study 435Baseline Characteristics

Post-transplant(n=196)

Pre-transplant(n=128)

Age years (range)a 54 (12–75) 51 (18–72)

Weeks on lamivudine postloss of treatment responsea 56 69

Serum creatinine 1.5 mg/dL 28% 8%

Weeks post-transplantationa 200 NA

Cyclosporine or tacrolimus 95% NA

aMedian

Study 435Baseline HBV Disease Characteristics

Post-transplant (n=196)

Pre- transplant (n=128)

Median HBV DNA (log10 copies/mL)

8.2 7.4

Median ALT x ULN 2.1 1.8

CPT Score 7 23% 63%

Serum bilirubin > ULN 30% 66%

Serum albumin < LLN 22% 59%

Prothrombin Time > ULN 16% 53%

Study 435Median Change from Baseline in HBV DNA

169Post-transplant

161 156 149 116 88 57 43 27 24 15

103Pre-transplant

98 91 84 52 28 13 2 2 2 0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

0 4 8 12 24 36 48 60 72 84 964 8 12 24 36 48 60 72 84 96

Pre-transplant Post-transplant

log10 copies/mL

Post-transplant

(n=196)

Pre-transplant

(n=128)

HBV DNA < 400 copies/mL 34% 81%

Normalization

ALT 49% 76%

Albumin 76% 81%

Bilirubin 75% 50%

Prothrombin time 20% 83%

CPT stable or improved 96% 92%

Study 435 Week 48Secondary Efficacy Endpoints

Through NDA Safety Update

Post-transplant

185 170 155 135 127 117

0.0

0.2

0.4

0.6

0.8

1.0

0 8 16 24 32 40 48 56 64 72 80 88 96

Week

109 94 84 69 55 42 28

Pre-transplant

96 69 50 37 24 11 5 3 2

Study 435Survival

Post-transplant

Pre-transplant

Post-transplant

(n=196)

Pre-transplant

(n=128)

Median weeks follow-up (max) 56 (129) 19 (72)

Patients terminating study 9% 10%

Adverse events 2% 2%

Patient request 0% 1%

Death 7% 5%

Lost to follow-up 0% 1%

Other 0% 1%

Study 435Patient Disposition

Through NDA Safety Update

Study 435Renal Laboratory Abnormalities by Week 96

Post- Pre- transplant transplantb

(n=196) (n=128)

Serum creatinineIncrease 0.5 mg/dLa 26 15 Median change (mg/dL) 0.1 0.2

Serum phosphorus<1.5 mg/dLa 1 0 Median change (mg/dL) 0.0 0.3

aConfirmed (two consecutive laboratory abnormalities)b Week 72

Study 435 Post-Transplantation Patients with Confirmed Increases in

Serum Creatinine 0.5 mg/dL from Baseline (n=26)

Concomitant cyclosporine or tacrolimus (n=26) Pre-existing medical condition placing patient at risk

for renal dysfunction (n=11) Pre-existing renal impairment (CLcr< 50 mL/min) (n=8) Decompensated cirrhosis at baseline (n=4) or disease

progression during treatment (n=6) Acute intercurrent medical event prior to onset of

serum creatinine increase (n=13) Other concomitant nephrotoxic agents administered

just prior to event (n=2)

Through NDA Safety Update

Study 435 Pre-Transplantation Patients with Confirmed Increases in

Serum Creatinine 0.5 mg/dL from Baseline (n=15)

Serum creatinine increase post liver transplantation (n=11)

Decompensated cirrhosis (n=3)— Disease progression or addition of gentamicin

Non-treatment emergent (n=1)— 3 months following last dose of ADV

Through NDA Safety Update

Establish creatinine clearance at baseline to select appropriate initial dose interval

Monitor throughout therapy and adjust dose interval if required

Adefovir Dipivoxil 10 mg Dosing Recommendations in Patients with

or at risk of Renal Impairment

Calculated Creatinine Clearance (mL/min)

50 20-49 10-19 <10

RequiringHemodialysis

10 mgevery 24

hours

10 mgevery 48

hours

10 mgevery 72

hours

10 mgevery 7

days

10 mg every 7days post-

hemodialysis

Study 435Summary

Efficacy— Change in HBV DNA and ALT similar to

pivotal studies— Normalization of albumin, bilirubin, and

prothrombin time— Stabilization or improvement in CPT Score— No adefovir-associated resistance mutations

identified through 48 weeks (n=55)

Safety— Safety profile consistent with advanced liver

disease and co-morbidities— Renal function should be monitored closely

before and during therapy

Lamivudine-Resistant HBVOther Supportive Studies

Study n Population Design

460i 35 HIV Co-infection

465B 40 Decompensated Open-label ADV+LAM

465A 95 Compensated

LAM ADV+LAM

461 59 Compensated LAM ADV+LAM ADV

-5

-4

-3

-2

-1

0

1

aData through primary endpoint Week 16 reported in NDA

p<0.001 comparedto LAM

ADV+LAM(n=19)

ADV (n= 19)

LAM (n=19)

Study 461 Median Change from Baseline in HBV DNAa

Weeks

0 8 16 24 32 40 48

log10 copies/mL

Study 461ALT Normalization Week 48

53%

47%

5%

0%

10%

20%

30%

40%

50%

60%

ADV + LAM ADV LAM

Patients(%)

(n=19) (n=19) (n=19)

Further Studies

Further Studies

Long term safety and efficacy up to 5 years Durability of seroconversion up to 5 years ADV dosing guidelines in chronic hepatitis B

patients with renal impairment Safety and efficacy in pediatrics, pregnancy,

and other populations Drug-drug interaction studies Co-infection (Studies ACTG 5127, 5149) Combination therapy in treatment-naïve patients Resistance surveillance

Adefovir Dipivoxil for the Treatment of Chronic Hepatitis B

Efficacy and safety in HBeAg+ and HBeAg- compensated liver disease

Efficacy and safety in patients with lamivudine-resistant HBV

No adefovir-associated resistance mutations identified up to 48 weeks

Proposed Indication

Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease