A Randomized Trial of HBIG Withdrawal Using Emtricitabine/Tenofovir DF in

Post-Liver Transplant Recipients – Final Results

L Teperman1, J Spivey2, F Poordad3, T Schiano4, N Bzowej5, P Martin6, D Coombs7, K Hirsch7, J Anderson7 and F Rousseau7

1The Mary Lea Johnson Richards Organ Transplantation Center, New York University Medical Center, New York, NY; 2Emory Healthcare, Atlanta, GA; 3Cedars-Sinai Medical Center, Los Angeles, CA;

4Recanati/Miller Transplantation Institute, Mount Sinai Hospital, New York, NY; 5California Pacific Medical Center, San Francisco, CA; 6Schiff Liver Institute, University of Miami, Miller School of

Medicine, Miami, FL; 7Gilead Sciences Inc., Foster City, CA

February 25, 2014GI Grand Rounds

Background

• HBIG prophylaxis is routinely prescribed to prevent HBV recurrence post-OLT

• HBIG prevents recurrence by neutralizing HBsAg

• Long-term prophylaxis with HBIG is inconvenient and expensive, but is the mainstay of post-transplant therapy.

Cost of HBIG Based on Dosing and Administration Strategy

Yearly cost of different schedules of HBIg administration in Euros. The “on demand” schedule using 2,000 IU of HBIg allows a savings of over 50% compared with fixed monthly doses of 5,000 IU.

Di Paolo et al. Transplantation 2004; 77: 1203-1208.

Primary Objectives

• Phase 2 randomized study to evaluate the safety and efficacy of FTC/TDF with/without HBIG in preventing recurrence of CHB post OLT

• Outcomes in this population measured by– Virologic outcomes (HBV recurrence)– Adverse events– Renal safety

Study Design

FTC + TDF is given as a fixed-dose combination tablet (Truvada) taken once daily

FTC/TDF+HBIG

Week 24

Year 2

Week 96

FTC/TDF

FTC/TDF+HBIGN=40

• OLT recipientfor CHB infection

• 12 weeks ofprophylactic therapyincluding HBIG

• HBV DNA negative

• HBsAg negative

Enrollment

RANDOMIZATION 1:1

Study Methods: Key Eligibility Criteria

• 18–75 years of age with CHB prior to transplant • No CHB recurrence after transplant • Stable patients with ≥ 12 weeks of prophylactic

therapy including HBIG after transplant• Creatinine clearance ≥ 40 mL/min • No prior TDF or FTC/TDF treatment after transplant • HCV, HIV-1, and HDV sero-negative• No significant renal, cardiovascular, pulmonary, or

neurological disease

Study Methods:Monitoring Parameters

• HBV DNA (Roche COBAS TaqMan assay; LLOQ=169 copies/mL) and HBsAg every 8 to 12 weeks

• Safety laboratory parameters every 8-12 weeks• Adverse Events • Resistance surveillance for any patient with HBV

DNA ≥ 400 copies/mL

Baseline Disease and Demographic Characteristics

Baseline CharacteristicOverall

Population N=40

Randomized TVD+HBIG

N=19

Randomized TVDN=18

Discontinued Prior to

RandomizationN=3

Median Age (min, max) 59 (37,73) 55 (38,73) 61 (37,71) 65 (58,70)

Race, n (%):

Asian 15 (38%) 6 (32%) 8 (44%) 1 (33)

White 13 (33) 7 (37) 5 (28) 1 (33)

Black 10 (25) 5 (26) 4 (22) 1 (33)

Other 2 (5) 1 (5) 1 (6) 0

Male, n (%) 32 (80) 15 (79%) 15 (83%) 2 (67)

Median ALT U/L (min, max) 21.0 (10,58) 19.0 (10,43) 21.0 (15,58) 25.0 (23,34)

Median years since transplant (min, max)

3.4 (0.3,17.7)

3.1 (0.3,17.7)

3.4 (0.4,9.5)

5.9(5.0,12.5)

HBeAg negative prior to transplant, n (%)

25/34 (74%) 11/17 (65%) 12/15 (80%) 2/2 (100%)

History of HCC 15 (38%) 7 (37%) 7 (39%) 1 (33%)

Patient Disposition

ScreenedN=51

EnrolledN=40

Week 24N=37

FTC/TDF+HBIN=19

FTC/TDFN=18

Completed Week 96 N=16

Discontinued N=2N=1

N=51

N=40

Randomized Week 24N=37

Discontinued N=3

GN=19 N=18

Completed Week 96 N=18

Discontinued

Patient Disposition and Exposure by Baseline Renal Function

Baseline Creatinine Clearance

Overall N <50 mL/min 50-80 mL/min >80 mL/min

Number of Patients Enrolled 40 9 24 7

# Patients Randomized to FTC/TDF+HBIG 19 3 13 3

# Patients Randomized to FTC/TDF 18 5 11 2

# Patients not randomized * 3 1 0 2

Number of Patients Randomized by Week in Study

Week 96 34 8 21 5

Summary of Safety Data

Overall N=40

Randomized FTC/TDF+HBIG

N=19

Randomized

FTC/TDF N=18

Prior to Randomization

N=40

Study Drug Discontinuation due to AE/Death

4 (10%) 1 (5%) 1 (6%) 2 (5%)

Serious AE (SAE)- considered related to FTC/TDF

13 0

80

4 0

10

Grade 2 − 4 AE- considered related to FTC/TDF

51 3

271

15 0

9 2

• FTC/TDF discontinuation due to AE/Death included increased in ALT/AST (n=2), worsening in colitis (n=1) and Stroke resulting in death (n=1)

• SAE Related to FTC/TDF included increased ALT/AST

• Grade 2-4 AE related to FTC/TDF included increased Cr/decreased CrCl (n=2) and worsening colitis

Summary of Grade 3/4 Laboratory Abnormalities

0

0.5

1

1.5

2

2.5

3

3.5

Prior to Randomization FTC/TDF + HBIG FTC/TDF

Thrombocytopenia CK Leukopenia

Hypernatremia Hyperbilirubin Transaminitis

PT Hyperglycemia Glycosuira

# of

Eve

nts

Summary of Renal Safety

Baseline Creatinine Clearance

<50 mL/min N=9

50 to 80 mL/min N=24

>80 mL/min N=7

Phosphorus <2 mg/dL 0 0 0

0.5 mg/dL increase in creatinine 0 1 0

Creatinine clearance < 50 mL/min 7 6 0

Creatinine Clearance Over Time

9<50 N= 9 9 9 9 9 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 2450-80 N= 24 24 24 24 24 24 24 24 24 24 24 22 22 22 22 22 22 22 22 21 21 7>80 N= 7 7 7 7 7 6 6 6 6 6 6 5 5 5 5 5 5 5 5 5 5

Virologic Outcomes

• All patients maintained HBV DNA below LLOQ (Roche COBAS TaqMan assay; LLOQ=169 copies/mL) during the study period

• No evidence of HBV recurrence• All subjects remained HBsAg negative• No re-initiation of HBIG• No evidence of resistance to FTC/TDF

Conclusions

• No patient on FTC/TDF who discontinued HBIG had detectable HBV DNA or HBsAg

• FTC/TDF is well tolerated in post-OLT patients• Creatinine clearance remained stable and managed

with labeled dose reductions• These data support the use of FTC/TDF without

HBIG for the prevention of post-OLT HBV