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
Top Related