Transcript Slide 1

Elvitegravir Once Daily is Non-Inferior to
Raltegravir Twice Daily in TreatmentExperienced Patients: 48 Week Results
From a Phase 3 Multicenter, Randomized
Double-Blind Study
J-M Molina1*, A LaMarca2, J Andrade-Villaneuva3, B Clotet4,
N Clumeck5, Y-P Liu6, L Zhong6, N Margot6, A Cheng6,
J Szwarcberg6 and SL Chuck6
1Hopital Saint
3Hospital Civil de
Louis and Univ. Paris 7 Diderot, Paris, France; 2Therafirst Medical Center, Ft Lauderdale, FL;
Guadalajara, CUCS, U de G, Guadalajara, Mexico; 4Hospital Universitario Germans Trias i Pujol,
Barcelona, Spain; 5C.H.U. St. Pierre, Brussels, Belgium; 6Gilead Sciences, Foster City, CA, USA
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention
20 July 2011
Paper # WELBB05
Study Design 183-0145
•
96-week randomized (1:1), double-blind,
double-dummy
•
Treatment-experienced patients
EVG 150 or 85 mg QD
•
Background regimen (BR) based on
resistance testing:
Protease Inhibitor/r
2nd Agent: fully active PI/r
3rd Agent
(n = 702)
RAL Placebo BID
3rd Agent: NRTI, ETR, MVC, T-20
If M184V/I, may add 3TC or FTC
•
•
Primary Endpoint: HIV-1 RNA < 50
copies/mL through 48 weeks
(FDA
TLOVR)
RAL 400 mg BID
Protease Inhibitor/r
3rd Agent
EVG Placebo QD
Non Inferiority Study
with lower limit 95% CI at -10%
2
Baseline Characteristics
EVG
(n = 351)
RAL
(n = 351)
44
45
Female
17%
19%
Non White
40%
36%
5%/13%
3%/16%
HIV RNA (log10 copies mL), Median
4.35
4.42
HIV RNA VL ≥ 100,000
26%
26%
CD4 count (cells/mm3), Mean
259
264
44%
45%
NRTI
69%
68%
NNRTI
63%
60%
Primary PI
31%
34%
Two or more classes
64%
60%
Characteristic
Age (years), Mean
Coinfection with HBV/HCV
CD4 count < 200 cells/mm3
Baseline Resistance Mutations
3
Subject Disposition through Week 48
Screened (n=1335)
Screen Failure (n=603)
Not Randomized (n=8)
Randomized (n=724)
Not Treated (n=7)
Not Treated (n=5)
EVG (n=354)
RAL (n=358)
GCP violation (n=3)
GCP violation (n=7)
EVG (n=351)
76% on EVG
at W48 (n=266)
RAL (n=351)
24% not on EVG
at W48 (n=85)
24% not on RAL
at W48 (n=83)
76% on RAL
at W48 (n=268)
Reason for Discontinuing Study
Drug
Reason for Discontinuing
Drug
Study
Subject Non-compliance
21
Subject Non-compliance
17
Lost to Follow-up
22
Lost to Follow-up
21
Withdrew Consent
15
Withdrew Consent
9
Protocol Violation
7
Protocol Violation
6
Lack of Efficacy
9
Lack of Efficacy
9
Adverse Event
8
Adverse Event
12
Death
0
Death
7
1
Investigator Discretion
2
2
Pregnancy
0
Investigator Discretion
Pregnancy
4
Selected Background Regimens
3rd Agent
PI/r
NRTI 3rd Agent
Etravirine
13%
Maraviroc
6%
Other*
1%
Lopinavir
19%
FTC/TDF
27%
Atazanavir
16%
Darunavir
58%
Lamivudine
4%
Abacavir
3%
Tenfovir DF
59%
Fosamprenavir
5%
Tipranavir
2%
Other^
7%
NRTI only
80%
NRTI only
Etravirine
Maraviroc
Other
Tenofovir DF
Truvada
Lam ivudine
Abacavir
Other
*Other: T-20, T-20+TDF, ETR+NRTI
^Other: 3TC/ABC, 3TC/ZDV, Zidovudine, Didanosine, Emtricitabine
Darunavir
Lopinavir
Atazanavir
Fosamprenavir
Tipranavir
Patients on 3 or more drugs were allowed if M184VI mutation present.
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Primary Endpoint ITT
TLOVR Week 48 HIV-1 RNA <50 copies/mL
EVG
(n=351)
RAL
(n=351)
Prop Diff (95% CI)
59
58
1.1% (-6.0 – 8.2)*
75
73
20
22
Rebound
11
16
Never suppressed
8
5
Switched background regimen
1
1
<1
2
2
3
19
15
Treatment Outcome, %
Responder1
Per Protocol Analysis
Virologic failure
Deaths
Drug discontinuation due to AE
Drug discontinuation due to Other2
1.4% (-5.9 – 8.6)
*p=0.001 for non-inferiority
1
Responder: achieved and maintained confirmed HIV-1 RNA <50 copies/mL through Week 48
2
Drug DC due to Other: Lack of Efficacy, Lost to Follow-up, Non-compliance, Investigator Discretion,
Pregnancy, Protocol Violation, Withdrew Consent
6
Mean Change from Baseline in CD4 (cells/mm3)
Change from Baseline in CD4 (cells/mm3)
200
EVG
RAL
150
147
138
100
50
0
Weeks on Study
BL
EVG
RAL
2
4
8
12
16
20
24
32
40
48
340
321
313
317
309
301
293
293
284
273
341
311
322
322
313
314
300
302
259
290
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Resistance Development by Week 48
In Subjects with Virologic Failure*
Subjects with
Virologic Failure
EVG
(n=61)
RAL
(n=75)
Any NRTI-R
7/59 (12%)
10/75 (13%)
Any PI-R
4/59 (7%)
3/75 (4%)
16/60 (27%)
15/72 (21%)
T66I/A
7 (12%)
0
E92Q
5 (8%)
1 (1%)
T97A
3 (5%)
3 (4%)
0
1 (1%)
S147G
3 (5%)
0
Q148R/H
3 (5%)
4 (6%)
N155H
3 (5%)
9 (13%)
Any Integrase-R1
Y143R/H/C
• Virologic Failure: subjects who experience either suboptimal virologic response (two consecutive visits
with HIV-1 RNA ≥50 c/mL and <1 log10 below baseline at week 8), virologic rebound (two consecutive
visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir),
or had HIV-1 RNA ≥400 c/mL at their last visit.
• 1 Integrase inhibitor resistance mutations: T66I/A/K, E92Q/G, T97A, Y143R/H/C, S147G, Q148H/K/R,
and N155H/S in integrase.
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Adverse Events
EVG
(n = 354)
RAL
(n = 358)
Any
88%
87%
Lead to Study Drug Discontinuation
3%
4%
Grade 3 or 4
19%
22%
Serious Adverse Events (SAE)
16%
21%
1
8
Adverse Events (Treatment Emergent)
Deaths (n)
9
Adverse Events Grades 2-4*
EVG
(n=354)
RAL
(n=358)
Diarrhea^
12%
7%
Upper Respiratory Tract Infection
6%
5%
Bronchitis
5%
5%
Back Pain
5%
4%
Depression
5%
4%
Sinusitis
4%
4%
Arthralgia
4%
2%
Nausea
4%
2%
Urinary Tract Infection
3%
4%
Adverse Event (Treatment Emergent)
*≥ 3% of subjects in either group
^p-value=0.023
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Laboratory Abnormalities – Grade 3-4*
EVG
(n = 354)
RAL
(n = 358)
Amylase
21 (6%)
18 (5%)
Total Bilirubin
18 (5%)
27 (8%)
Cholesterol
12 (4%)
13 (4%)
Triglycerides
11 (4%)
11 (4%)
Hyperglycemia
15 (4%)
12 (3%)
GGT^
9 (3%)
21 (6%)
Neutrophils
11 (3%)
11 (3%)
CK
12 (3%)
11 (3%)
ALT†
6 (2%)
18 (5%)
AST#
5 (1%)
18 (5%)
Grade 3-4 Labs, n (%)
*>5 subjects in any treatment group
^p-value= 0.039; †p-value = 0.020; #p-value = 0.009
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Conclusions
 In the first Phase 3 comparative integrase inhibitor study,
Elvitegravir QD is non-inferior to Raltegravir BID, when given with
a fully active boosted protease inhibitor
 In patients with virologic failure, a minority (~20%) developed
integrase resistance
 Elvitegravir was well tolerated, with a safety profile comparable to
Raltegravir
 Elvitegravir is currently being evaluated in two ongoing Phase 3
treatment-naïve studies as a component of the Quad single-tablet
regimen
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Investigators
United States/Puerto Rico
K. Abriola
B. Akil
B. Barnett
T. Barrett
N. Bellos
D. Berger
G. Blick
R. Bolan
I. Brar
F. Bredeek
C. Brinson
J. Burack
L. Bush
R. Campo
D. Chew
P. Cimoch
C. Cohen
P. Cook
R. Corales
D. Coulston
C. Creticos
G. Crofoot
F. Cruickshank
E. DeJesus
S. Diamond
R. Dretler
H. Edelstein
R. Elion
T. File
D. Fish
J. Flamm
F. Garcia
J. Gathe, Jr.
R. Greenberg
P. Greiger-Zanlungo
D. Hagins
T. Hawkins
C. Hicks
J. Horton
R. Hsu
G. Huhn
T. Jefferson
D. Kaufman
H. Khanlou
C. Kinder
R. Kuhn
A. LaMarca
H. Lampiris
M. Lee
R. Liporace
C. Lucasti
R. MacArthur
C. Martorell
C. Mayer
M. McKellar
D. Mildvan
A. Mills
J. Morales-Ramirez
K. Mounzer
R. Myers, Jr.
R. Nahass
E. Turner Overton
G. Pierone
M. Ramgopal
J. Ravishankar
K. Rawlings
G. Richmond
W. Robbins
A. Roberts
J. Rodriguez
P. Ruane
S. Saavedra
J. Santana Bagur
L. Santiago
A. Scarsella
S. Schrader
A. Scribner
M. Sension
G. Sepulveda-Arzola
D. Shamblaw
K. Stazskow
J. Stephens
C. Shikuma
J. Slim
L. Sloan
P. Tebas
M. Thompson
J. Timpone
W. Towner
L. Waldman
D. Wheeler
A. Wilkin
S. Pegram
M. Wohlfeiler
K. Workowski
B. Zingman
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Investigators
Australia
D. Baker
M. Bloch
D. Cooper
D. Dwyer
R. Garsia
P. Konecny
D. Smith
C. Workman
Belgium
N. Clumeck
E..Florence
J. Goffard
J. Legrand
M. Moutschen
Canada
B. Chang
B. Conway
L. Johnston
F. LaPlante
R. LeBlanc
K. Logue
D. Murphy
A. Rachlis
S. Walmsley
France
J. Durant
P-M Girard
C. Katlama
B. Marchou
J-M Molina
J-L Pellegrin
L. Slama
F. Raffi
P. Yeni
Germany
S. Esser
G. Fätkenheuer
H. August Horst
H. Jäger
A. Plettenberg
S. Reuter
C. Stephan
J. van Lunzen
Italy
A. Antinori
M. Galli
A. Lazzarin
F. Maggiolo
G. Rizzardini
V. Vullo
Mexico
J. Andrade Villanueva
M. Magaña
L. Mosqueda
J. Sierra
Netherlands
B. Rjinders
Portugal
F. Antunes
T. Branco
A. Diniz
R. Serrão
R. Marques
E. Teofilo
Spain
JR. Arribas
J. Berenguer
B. Clotet
P. Domingo
J. Maria Gatell
J. Luis Gómez Sirvent
F. Gutiérrez
J. Hernández Quero
M. Márquez
S. Moreno
J. Portilla
F. Pulido
P. Viciana
United Kingdom
C. Leen
E. Wilkins
I. Williams
A. Winston
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