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Elvitegravir Once Daily is Non-Inferior to Raltegravir Twice Daily in Treatment- Experienced Patients: 48 Week Results From a Phase 3 Multicenter, Randomized Double-Blind Study. J-M Molina 1 *, A LaMarca 2 , J Andrade-Villaneuva 3 , B Clotet 4 , - PowerPoint PPT Presentation
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Elvitegravir Once Daily is Non-Inferior to Raltegravir Twice Daily in Treatment-
Experienced 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 Louis and Univ. Paris 7 Diderot, Paris, France; 2Therafirst Medical Center, Ft Lauderdale, FL;
3Hospital Civil de 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 Prevention20 July 2011
Paper # WELBB05
2
Study Design 183-0145
(n = 702)
• 96-week randomized (1:1), double-blind, double-dummy
• Treatment-experienced patients• Background regimen (BR) based on
resistance testing:
2nd Agent: fully active PI/r
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)
• Non Inferiority Study with lower limit 95% CI at -10%
EVG 150 or 85 mg QD
Protease Inhibitor/r
3rd Agent
RAL Placebo BID
RAL 400 mg BID
Protease Inhibitor/r
3rd Agent
EVG Placebo QD
3
Baseline Characteristics
Characteristic EVG(n = 351)
RAL(n = 351)
Age (years), Mean 44 45Female 17% 19%Non White 40% 36%Coinfection with HBV/HCV 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
CD4 count < 200 cells/mm3 44% 45%Baseline Resistance Mutations
NRTI 69% 68%NNRTI 63% 60%Primary PI 31% 34%Two or more classes 64% 60%
4
Subject Disposition through Week 48
Reason for Discontinuing Study Drug
Subject Non-compliance 21
Lost to Follow-up 22
Withdrew Consent 15
Protocol Violation 7
Lack of Efficacy 9
Adverse Event 8
Death 0
Investigator Discretion 1
Pregnancy 2
Screened (n=1335) Screen Failure (n=603)
Randomized (n=724)
RAL (n=358)EVG (n=354)
76% on EVG at W48 (n=266)
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
Subject Non-compliance 17
Lost to Follow-up 21
Withdrew Consent 9
Protocol Violation 6
Lack of Efficacy 9
Adverse Event 12
Death 7
Investigator Discretion 2
Pregnancy 0
EVG (n=351) RAL (n=351)
GCP violation (n=3)
Not Randomized (n=8)
GCP violation (n=7)
Not Treated (n=7) Not Treated (n=5)
5
Selected Background Regimens
Patients on 3 or more drugs were allowed if M184VI mutation present.
Darunavir58%
Atazanavir16%
Tipranavir2%
Lopinavir19%
Fosamprenavir5%
Darunavir Lopinavir Atazanavir Fosamprenavir Tipranavir
PI/r
*Other: T-20, T-20+TDF, ETR+NRTI^Other: 3TC/ABC, 3TC/ZDV, Zidovudine, Didanosine, Emtricitabine
3rd Agent
Tenofovir DF Truvada Lamivudine Abacavir Other
FTC/TDF27%
Abacavir3%
Other^7%
NRTI 3rd Agent
NRTI only Etravirine Maraviroc Other
NRTI only80%
Etravirine13%
Maraviroc6%Other*
1%
Tenfovir DF59%
Lamivudine4%
6
Primary Endpoint ITT TLOVR Week 48 HIV-1 RNA <50 copies/mL
Treatment Outcome, % EVG(n=351)
RAL(n=351) Prop Diff (95% CI)
Responder1
Per Protocol Analysis
59
75
58
73
1.1% (-6.0 – 8.2)*
1.4% (-5.9 – 8.6)
Virologic failure 20 22
Rebound 11 16
Never suppressed 8 5
Switched background regimen 1 1
Deaths <1 2
Drug discontinuation due to AE 2 3
Drug discontinuation due to Other2 19 15
1 Responder: achieved and maintained confirmed HIV-1 RNA <50 copies/mL through Week 482 Drug DC due to Other: Lack of Efficacy, Lost to Follow-up, Non-compliance, Investigator Discretion, Pregnancy, Protocol Violation, Withdrew Consent
*p=0.001 for non-inferiority
7
Mean Change from Baseline in CD4 (cells/mm3)C
hang
e fr
om B
asel
ine
in C
D4
(cel
ls/m
m3 )
200
150
100
50
0
EVGRAL
Weeks on Study BL 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
EVGRAL
138147
8
Resistance Development by Week 48In 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%)Any Integrase-R1 16/60 (27%) 15/72 (21%) T66I/A 7 (12%) 0 E92Q 5 (8%) 1 (1%) T97A 3 (5%) 3 (4%) Y143R/H/C 0 1 (1%) S147G 3 (5%) 0 Q148R/H 3 (5%) 4 (6%) N155H 3 (5%) 9 (13%)
•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.
9
Adverse Events
Adverse Events (Treatment Emergent) 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%
Deaths (n) 1 8
10
Adverse Events Grades 2-4*
Adverse Event (Treatment Emergent) 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%
^p-value=0.023*≥ 3% of subjects in either group
11
Laboratory Abnormalities – Grade 3-4*
Grade 3-4 Labs, n (%) 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%)
*>5 subjects in any treatment group^p-value= 0.039; †p-value = 0.020; #p-value = 0.009
12
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
13
Investigators
K. AbriolaB. AkilB. BarnettT. BarrettN. BellosD. BergerG. BlickR. BolanI. BrarF. BredeekC. BrinsonJ. BurackL. BushR. CampoD. ChewP. CimochC. CohenP. CookR. CoralesD. CoulstonC. CreticosG. CrofootF. CruickshankE. DeJesusS. Diamond
R. DretlerH. EdelsteinR. ElionT. FileD. FishJ. FlammF. GarciaJ. Gathe, Jr.R. GreenbergP. Greiger-ZanlungoD. HaginsT. HawkinsC. HicksJ. HortonR. HsuG. HuhnT. JeffersonD. KaufmanH. KhanlouC. KinderR. KuhnA. LaMarcaH. LampirisM. LeeR. Liporace
C. LucastiR. MacArthurC. MartorellC. MayerM. McKellarD. MildvanA. MillsJ. Morales-Ramirez K. MounzerR. Myers, Jr.R. NahassE. Turner OvertonG. PieroneM. RamgopalJ. RavishankarK. RawlingsG. RichmondW. RobbinsA. RobertsJ. RodriguezP. RuaneS. SaavedraJ. Santana BagurL. SantiagoA. Scarsella
S. SchraderA. ScribnerM. SensionG. Sepulveda-Arzola D. ShamblawK. StazskowJ. StephensC. ShikumaJ. SlimL. SloanP. TebasM. ThompsonJ. TimponeW. TownerL. WaldmanD. WheelerA. WilkinS. PegramM. WohlfeilerK. WorkowskiB. Zingman
United States/Puerto Rico
14
Investigators
ItalyA. AntinoriM. GalliA. LazzarinF. MaggioloG. RizzardiniV. Vullo
MexicoJ. Andrade VillanuevaM. MagañaL. MosquedaJ. Sierra
NetherlandsB. Rjinders
PortugalF. AntunesT. BrancoA. DinizR. SerrãoR. MarquesE. Teofilo
FranceJ. DurantP-M GirardC. KatlamaB. MarchouJ-M MolinaJ-L PellegrinL. SlamaF. RaffiP. Yeni
GermanyS. EsserG. FätkenheuerH. August HorstH. JägerA. PlettenbergS. ReuterC. StephanJ. van Lunzen
Australia D. Baker M. Bloch D. CooperD. DwyerR. GarsiaP. KonecnyD. SmithC. Workman
BelgiumN. ClumeckE..FlorenceJ. GoffardJ. LegrandM. Moutschen
CanadaB. ChangB. ConwayL. JohnstonF. LaPlanteR. LeBlancK. LogueD. MurphyA. RachlisS. Walmsley
SpainJR. ArribasJ. BerenguerB. ClotetP. DomingoJ. Maria GatellJ. Luis Gómez SirventF. GutiérrezJ. Hernández QueroM. MárquezS. MorenoJ. PortillaF. PulidoP. Viciana
United KingdomC. LeenE. WilkinsI. WilliamsA. Winston