Transcript No Slide Title

Two Years Safety and Efficacy of
Tenofovir Disoproxil Fumarate (TDF) in
Patients With HBV-Induced Cirrhosis
M Buti,1 S Hadziyannis,2 P Mathurin,3 P Urbanek,4 M Sherman,5 S Strasser,6 C Wang,7
J Petersen,8 EJ Heathcote,9 P Marcellin,10 J Sorbel,11 E Mondou,11 J Anderson,11 and
F Rousseau11
1Servicio
de Medicina Interna Hepatologia, Hospital General Universitari Vall d’Hebron, Barcelona, Spain; 2Department of Medicine, Henry
Dunant Hospital, Athens, Greece; 3Service d-Hepato-Gastroenterologie, Hopital Claude Huriez, CHRU Lille, Lille, France; 4Intern Klinika
UVN Praha, Prague, Czech Republic; 5Toronto General Hospital, Toronto, Ontario, Canada; 6AW Morrow Gastroenterology & Liver Center,
Royal Prince Alfred Hospital, Camperdown, NSW, Australia; 7Digestive Disease Institute, Virginia Mason Medical Center, Seattle,
Washington, USA; 8Klinik & Poliklinik F. Innere Medizin, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany; 9Toronto Western
Hospital, University of Toronto, Ontario, Canada; 10Hopital Beaujon, Clichy, France; 11Gilead Sciences, Inc., Foster City, CA and Durham,
NC, USA
44th Annual Meeting of the European Association for the Study of the Liver
April 22-26, 2009
Copenhagen, Denmark
Oral Presentation # 21
Introduction
•
Tenofovir DF has shown maintained virologic suppression
< 400 copies/mL in treatment naïve patients with chronic
hepatitis B.
– In an ITT analysis, 78% of HBeAg+ and 91% of HBeAg– patients
maintained virologic response at week 96 in 2 pivotal studies *
– Among patients remaining on treatment 89% of HBeAg+ and 99%
of HBeAg– patients had HBV DNA < 400 c/mL*
• Both non-cirrhotic and cirrhotic patients were enrolled in
these studies allowing evaluation of the cirrhotic subset
treated with tenofovir DF for 96 weeks
*Marcellin et al., AASLD 2008; Heathcote et al., AASLD 2008
Objective
• To evaluate the efficacy and safety of tenofovir DF
among cirrhotic patients with chronic hepatitis B
participating in tenofovir DF pivotal studies
GS-174-0102 (HBeAg–) and GS-174-0103 (HBeAg+)
GS-174-0102 (HBeAg–) and
GS-174-0103 (HBeAg+) Study Design
Open-label
RANDOMIZE
2:1
Double-Blind
8 Years
TDF 300 mg once daily (n =426*)
Tenofovir DF 300 mg once daily
ADV 10 mg once daily (n = 215*)
Pre-treatment
Liver Biopsy
≥ Week 72 option for
Week 48
FTC+TDF if viremic
Liver Biopsy†
Paired biopsies in 391 TDF
(92%) and 192 ADV (89%)
Week 240
Liver Biopsy
*Combined across both pivotal studies
†Open label participation gated by Week 48 biopsy
Eligibility criteria required abnormal ALT, Knodell necroinflammatory score ≥ 3, and
viremia with HBV DNA > 105 c/mL with the Roche COBAS TaqMan assay (LLOQ=169
c/mL [29 IU/mL])
Cirrhotics (Knodell fibrosis score=4) with compensated liver disease were eligible
Methods
• Virologic response (defined as HBV DNA < 400 c/mL
[69 IU/mL]) was prospectively evaluated long term (ITT)
• HBV DNA and safety laboratory parameters were
performed every 4 weeks (Year 1) and 8 weeks
(Year 2)
• For the subset analysis, the comparison of primary
interest is tenofovir DF-treated cirrhotic patients versus
non-cirrhotic patients through Week 96
Proportion of Patients With Cirrhosis at
Study Entry in Various Subsets
• 123 cirrhotic patients were enrolled across the 2 studies
• Cirrhotic patients comprised 19% of all patients
– 81/426 (19%) on tenofovir DF (34 HBeAg+; 47 HBeAg– )
– 42/215 (20%) on ADV (17 HBeAg+; 25 HBeAg–)
• Combined study results are presented to maximize cirrhotic patient sample
size with focus on patients receiving tenofovir DF for 96 weeks
Percent with Cirrhosis at Entry
50
40
30
19%
19%
20%
19%
19%
20
10
0
Overall
TDF
ADV
HBeAg+
HBeAg-
Tenofovir DF Cirrhotics and Non-Cirrhotics
Baseline Characteristics
Characteristic
Cirrhotics
n = 81
Non-Cirrhotics
n = 341
P-valuea
Median age (yr) (IQR)
47 (40-55)
39 (29-47)
<0.001
Median weight (kg) (IQR)
76 (68-88)
71 (62-81)
0.003
Male n (%)
64 (79%)
246 (72%)
0.26
Caucasian n (%)
Asian n (%)
Black n (%)
Pacific Islander n (%)
49 (60%)
21 (26%)
5 (6%)
5 (6%)
201 (59%)
105 (31%)
16 (5%)
5 (1%)
0.1
Genotype A
B
C
D
18 (23%)
4 (5%)
15 (19%)
40 (51%)
50 (15%)
43 (13%)
56 (17%)
169 (51%)
0.17
IQR, interquartilie range
a. P-values for categorical endpoints from a Fisher's exact test. For certain endpoints the extension to Rx2 tables was used;
p-values for all continuous variables calculated using a two-sided Wilcoxon Rank Sum test.
Tenofovir DF Cirrhotics and Non-Cirrhotics
Baseline Characteristics (cont’d)
Cirrhotics
n = 81
Non-Cirrhotics
n = 341
P-valuea
0 (0%)
0 (0%)
44 (54%)
37 (46%)
3 (1%)
27 (8%)
243 (71%)
68 (20%)
<0.001
7.58 (6.63-8.69)
6.81 (5.86, 8.04)
7.87 (6.56-8.79)
7.10 (5.80, 8.04)
0.424
ALT U/L (IQR)
92 (71-141)
108 (71-167)
0.223
HBeAg+ n (%)
34 (42%)
137 (40%)
0.802
Parameter
Knodell Necroinflammatory score
n (%)
0–1
2–4
5–9
10 – 14
HBV DNA log10 c/mL (IQR)
IU/mL (IQR)
Values are medians for continuous variables.
a. P-values for categorical endpoints from a Fisher's exact test. For certain endpoints the extension to Rx2 tables was used;
p-values for all continuous variables calculated using a two-sided Wilcoxon Rank Sum test.
TDF Produced Consistent HBV DNA Suppression Among
Cirrhotic and Non-Cirrhotic Patients Through Week 96
8
Mean (95% CI) HBV DNA (Log10 Copies/mL)
7
6
5
4
3
< 169 c/mL (< 29 IU/mL)
2
1
0
0
8
16
24
32
40
48
56
64
72
80
88
96
Weeks on Study
Cirrhotic
N=
81
75
77
73
72
Non-Cirrhotic N= 341
325
320
293
281
ITT Proportion of Patients With/Without Cirrhosis with HBV
DNA <400 c/mL (69 IU/mL) on TDF
100
90
80
90% vs. 85%
p=0.178
Percentage (%)
70
60
50
40
30
20
10
0
0
8
16
24
32
40
48
56
64
72
80
88
96
Weeks on Study
Cirrhotic
Non-Cirrhotic
N=
81
76
79
80
79
N= 341
333
335
324
317
On-Treatment Proportion of Patients With/Without
Cirrhosis With HBV DNA <400 c/mL (69 IU/mL) on TDF
100
90
97% vs. 95%
p=0.423
80
Percentage (%)
70
60
50
40
30
20
10
0
0
8
16
24
32
40
48
56
64
72
80
88
96
Weeks on Study
Cirrhotic
Non-Cirrhotic
N=
81
75
77
73
72
N= 341
325
320
293
281
On-Treatment Proportion of Patients With/Without Cirrhosis
With ALT in Normal Range on TDF
100
90
80
Percentage (%)
70
60
83% vs. 78%
p=0.381
50
40
30
Mean ALT 34.2 & 35.2 U/L
20
10
0
0
8
16
24
32
40
48
56
64
72
80
88
96
Weeks on Study
Cirrhotic
Non-Cirrhotic
N=
81
77
77
73
70
N= 341
322
319
294
282
Serology Results in Cirrhotic Patients
•
Among 47 HBeAg– cirrhotic patients : None lost HBsAg
•
Among 34 HBeAg+ patients
–
–
2/34 (6%) lost HBsAg (both genotype D) and both seroconverted to anti-HBs (at Week 24 and 96)
– one did not continue beyond year 1 (no Week 48 biopsy)
Of those with Week 96 serology results 9/29 (31%) seroconverted to anti-HBe (p=0.48 versus non-cirrhotic
patients).
On-Treatment Percentage with HBeAg Seroconversion
35
30
25
20
15
10
5
0
31
26
24
20
9/29
8/31
24/120
Week 48
25/103
Week 96
Cirrhotic
Non-cirrhotic
Cumulative Safety of Tenofovir DF was Not Significantly Different
Among Cirrhotic and Non-Cirrhotic Patients Through Week 96
Cirrhotic
n = 81
Non-cirrhotic
n = 341
P-valuea
9 (11%)
46 (13%)
0.71
12 (15%)
1 (1%)
30 (9%)
3 (1%)
0.15
---
25 (31%)
5/2 (6%/2%)
3 (4%)
6 (7%)
4 (5%)
3 (4%)
5 (6%)
4 (5%)
78 (23%)
17/5 (5%/1%)
8 (2%)
39 (11%)
18 (5%)
1 (0.3%)
13 (4%)
5 (1%)
0.15
Phosphorus < 2 mg/dl
3 (4%)
4 (1%)
---
Creatinine 0.5 mg/dl increase or CrCl
< 50 mL/min
0 (0%)
0 (0%)
---
Parameter
Grade 3 or 4 AE
Serious AE
Hepatocellular carcinoma
Grade 3 / 4 Labs (any)
Amylase/Lipase
Creatine Kinase
ALT (> 5 × ULN)
AST
Total bilirubin (> 2.5 × ULN)
Urine glucose
Prothrombin time
Specific Grade 3 / 4 laboratory analytes included if present in > 1 cirrhotic patient.
a. P-values from a two-sided Fisher’s exact test included for combined Grade 3/ 4 AEs and labs, and SAEs.
Summary of Safety
• Tenofovir DF was well tolerated in cirrhotic and
non-cirrhotic patients
• No patient developed decompensated liver disease
or clinical evidence of impaired hepatic function while
taking tenofovir DF; no cirrhotic patient died
No Resistance After 96 Weeks of TDF Monotherapy
• No HBV polymerase/reverse transcriptase (pol/RT) amino acid
substitutions associated with resistance to tenofovir were identified
through 96 weeks of TDF monotherapy
• Across both studies 24 patients had HBV DNA ≥ 400 c/mL (69
IU/mL) through 96 weeks of TDF monotherapy
– 4 cirrhotic and 20 non-cirrhotic
– No cirrhotic patient had virologic breakthrough
– 2 cirrhotic patients had virus with no HBV pol/RT changes, one
could not be genotyped, and one had polymorphic site changes
Conclusions
• Tenofovir DF demonstrated potent HBV DNA
suppression and good tolerability with no safety
concerns in patients with compensated cirrhosis
due to chronic hepatitis B
• Consistent efficacy responses were observed
among cirrhotic and non-cirrhotic patients treated
with tenofovir DF
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. Akarca
P. Andreone
G. Dalekos
G. Germanidis
S. Gurel
S. Hadziyannis
G. Kitis
O. Kurdas
S. Ozenirler
M. Rizzetto
H. Senturk
N. Tozun
Gilead Sciences
J. Dinsdale
A. Foster
E. Montgomery
S. Nonaka-Wong
J. Quinn
A. Snow-Lampart
C. Welborn
K. Washington
ICON
Quintiles