truvada randomized trial of hbig withdrawal february 7 2014
TRANSCRIPT
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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
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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.
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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.
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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
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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
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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
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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
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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%)
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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
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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
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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
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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
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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
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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
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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
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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