Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in...
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Transcript of Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in...
Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV)
Switch Data in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102)
1Hopital Beaujon, Clichy, France; 2Hospital Valle Hebron, Barcelona, Spain; 3University Hospital “St Ivan Rilsky”, Sofia, Bulgaria; 4University of Uludag, Bursa, Turkey; 5Tokuda Hospital, Sofia, Bulgaria; 6Royal
Free Hospital, London U.K.; 7University of Calgary, Calgary Alberta, Canada; 8Toronto Western Hospital, University of Toronto, Toronto Ontario, Canada; 9Gilead Sciences, Durham NC
Patrick Marcellin1, Maria Buti2, Zahary Krastev3, Selim Gurel4, Rozalina Balabanska5, Geoff Dusheiko6, Robert Myers7, E Jenny Heathcote8, Jeff Sorbel9, Jane Anderson9, Elsa Mondou9 and Franck Rousseau9
59th Annual Meeting of the American Association for the Study of Liver DiseaseOctober 31-November 4, 2008
San Francisco, CAOral Presentation # 146
Acknowledgements Participating Centers
Australia &New Zealand
W.ChengD. CrawfordP. DesmondE. GaneJ. GeorgeP. GowI.KronborgC. MoyesM. NguS. RobertsJ. SasadeuszW. SievertN.StaceS. StrasserF. Weilert
US & CanadaN. AfdahlF. AndersonM. BennettN. BzowejS. ChanA. DiBisceglieP. GaglioN. GitlinS. GordonJ. Heathcote
US & CanadaK. HuI.JacobsonL. JeffersK. KaitaA. LokP. Martin T. MinR. MyersT. NguyenP. PockrosN.RavendhranR. RubinV.RustgiM. ShermanM. ShiffmanM. TongH. TrinhN. TsaiC. WangZ. Younossi
Bulgaria, Czech Republic & PolandR. BalabanskaM. Beniowski R. FlisiakA.GladyszW. HalotaA. HorbanP. HusaI. KotzevZ.KrastevW. KryczkaT. MachJ. SperlK. TchernevP. UrbanekM. Volfova
Spain, Germany & FranceK. BarangeY. BenhamouT. BergJ. BronowickiW. BoecherP. BuggischM. ButiJ. Calleja
Spain, Germany & France T. CasanovasJ. EnriquezG. GerkenF. HabersetzerT. HeintgesC. HezodeH. HinrichsenD. HuppeS. KaiserM. MannsP. MathurinS. MaussB. MollerJ. PetersonM. PrietoG. TeuberC. TrepoR. ZachovalJ. ZarskiS. Zeuzem
UK & NetherlandsR. DeManG. DusheikoD. MutimerR. Williams
Greece, Turkey & ItalyU. AkarkaP. AndreoneG. DalekosG. GermanidisS. GurelS. HadziyannisG. KitisO. KurdasS. OzenirlerM. RizzettoH. SenturkO. Ozdogan
Gilead SciencesJ. DinsdaleA. FosterE. Montgomery
ICONQuintiles
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
RA
ND
OM
IZA
TIO
N
2:1
Tenofovir 300 mg
Adefovir 10 mg
Open-label
Week 48
Liver BiopsyPre-treatment Liver Biopsy
Double Blind
Week 96
Tenofovir 300 mg
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 2Year 1
Week 72*
TDF TDF-TDF: N= 250 235 225 TDF FTC/TDF: N= (2)* ADV ADV-TDF: N= 125 112 110
Patients (on study drug)
Week 384
Year 8
• HBeAg- patients• Age 18-69 years • Compensated liver disease• Lamivudine experienced or naive• HBV DNA > 105 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 andDemographic Characteristics
CHARACTERISTICTDF
(N=250)ADV
(N=125)
Mean Age (years) 44 43
Race Caucasian Asian
64%25%
65%24%
Male 77% 78%
Prior lamivudine experience 17% 18%
Mean HBV DNA (log10 copies/mL) 6.86 6.98
Mean ALT (U/L) 128 164
Mean Knodell necroinflammatory score Mean Knodell fibrosis score
7.82.3
7.82.4
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)
Pe
rce
nta
ge
(%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
89%
91% P=0.672
Randomized Double Blind Open Label
18% LAM Exp: 93%
96%
250TDF-TDF N= 250250 245245245 243243243 248248248 247247247 242242242 243243243 234234234
125ADV-TDF N= 125125 125125125 124124124 120120120 123123123 123123123 122122122 122122122
% Patients with HBV DNA <400 copies/mL (95% CI)(On-Treatment Analysis)
Pe
rce
nta
ge
(%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
250TDF-TDF N= 250250 242242242 239239239 242242242 241241241 226226226 224224224 214214214125ADV-TDF N= 125125 123123123 121121121 117117117 117117117 110110110 109109109 109109109
99%100%
P=0.166
~ 89% Retention
Randomized Double Blind Open LabelRandomized Double Blind
18% LAM Exp: 97% 100%
Mean HBV DNA (log10copies/mL) (95% CI)
P=0.181
Randomized Double Blind Open Label
P<0.001
Mea
n (9
5% C
I) H
BV
DN
A (
Log 1
0 C
opie
s/m
L)
0
1
2
3
4
5
6
7
8
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
250TDF-TDF N=250250 242242242 239239239 242242242 241241241 226226226 224224224 214214214125ADV-TDF N=125125 123123123 121121121 117117117 117117117 110110110 109109109 109109109
LLOQ
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)M
ean
(95%
CI)
ALT
(U
/L)
0
25
50
75
100
125
150
175
200
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
250TDF-TDF N= 250250 244244244 238238238 242242242 240240240 223223223 223223223 215215215125ADV-TDF N= 125 123123 122122 118118 117117 107107 108108 108108
P=0.82735 U/L34 U/L
Randomized Double Blind Open Label
ULN for females=34 U/LULN 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
HB
V D
NA
(Log
10 C
opie
s/m
L)
1
2
3
4
5
6
7
8
9
10
11
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
LLOQ
TDF TDF
FTC+TDF
Non-adherent (TDF levels BQL)
HB
V D
NA
(Lo
g 10
Cop
ies/
mL)
1
2
3
4
5
6
7
8
9
10
11
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
LLOQ
TDFTDF
non-adherent (TDF levels BQL)
Pt 6852
Patients with Virologic Breakthrough
Pt 1674
HBV
DN
A (L
og10
Cop
ies/
mL)
1
2
3
4
5
6
7
8
9
10
11
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
LLOQ
Pt 1669
Patient off drug between weeks 80 and 96 Patient off drug between weeks 80 and 96
TDF TDF TDF TDF
HB
V D
NA
(Lo
g10
Cop
ies/
mL)
1
2
3
4
5
6
7
8
9
10
11
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
LLOQ
TDF 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)
Genotyping(HBV pol / RT)
Phenotyping(HBV pol / RT)
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 carcinoma 1 (<1%) 0
G3 or G4 Laboratory 23 (10%) 11 (10%)
Discontinue due to an AE hepatic neoplasm dizziness, fatigue, lack of concentration
2 (1%)11
000
Confirmed ↓ phosphorus < 2mg/dL 2 (<1%) 1 (<1%)
Confirmed 0.5 mg/dL in creatinine 0 0
Confirmed creatinine clearance <50 mL/min 0 0
ConclusionsWeek 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= 375Randomized and Treated
TDFTDFn = 225
Completed Week 96
N = 125Adefovir Dipivoxil (ADV)
Entered Open-Label TDF Period TDFTDF = 235 ADVTDF = 112
Discontinued Treatment Prior to Week 48
TDF = 6ADV = 4
N= 250Tenofovir DF (TDF)
ADVTDFn = 110
Completed Week 96
Discontinued Treatment Between Weeks 48 and 96 TDFTDF n = 10ADVTDF n = 2
Permanently Initiated FTC/TDF prior to Week 96TDFTDF n = 2ADVTDF n = 0
Patient Disposition
N= 375Randomized and Treated
TDFTDFN = 225
TDF-TDF – FTC/TDF*N= 2 (of 225)
Completed Week 96
N = 125Adefovir Dipivoxil (ADV)
Entered Open-Label TDF Period TDFTDF = 235 ADVTDF = 112
Discontinued Treatment Prior to Week 48
TDF N = 6ADV N = 4
N= 250Tenofovir DF (TDF)
ADVTDFN = 110
ADV-TDF – FTC/TDF*N= 0 (of 110)
Completed Week 96
Discontinued Treatment Between Weeks 48 and 96
TDFTDF N = 10ADVTDF N = 2
Marcellin P, et al., AASLD 2008; Oral #146
~ 89% Retention
*Permanently Initiated FTC/TDF Combination
therapy Week 72TDFTDF N = 2ADVTDF N = 0