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 45

Female 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

ha

ng

e f

rom

Ba

se

lin

e i

n C

D4

(c

ell

s/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