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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 ,

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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 Prevention

20 July 2011

Paper # WELBB05

study design 183 0145
Study Design 183-0145
  • 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%

(n = 702)

subject disposition through week 48
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)

RAL (n=351)

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)

selected background regimens
Selected Background Regimens

PI/r

3rd Agent

NRTI 3rd Agent

Etravirine

13%

Maraviroc

6%

FTC/TDF

27%

Other*

1%

Lamivudine

4%

Abacavir

3%

Tenfovir DF

59%

Other^

7%

NRTI only

80%

*Other: T-20, T-20+TDF, ETR+NRTI

^Other: 3TC/ABC, 3TC/ZDV, Zidovudine, Didanosine, Emtricitabine

Patients on 3 or more drugs were allowed if M184VI mutation present.

primary endpoint itt tlovr week 48 hiv 1 rna 50 copies ml
Primary Endpoint ITTTLOVR Week 48 HIV-1 RNA <50 copies/mL

*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

mean change from baseline in cd4 cells mm 3
Mean Change from Baseline in CD4 (cells/mm3)

200

150

100

50

0

EVGRAL

147

138

Change from Baseline in CD4 (cells/mm3)

Weeks on Study

BL 2 4 8 12 16 20 24 32 40 48

EVGRAL

340 321 313 317 309 301 293 293 284 273

341 311 322 322 313 314 300 302 259 290

resistance development by week 48 in subjects with virologic failure
Resistance Development by Week 48In Subjects with Virologic Failure*
  • 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.
adverse events grades 2 4
Adverse Events Grades 2-4*

*≥ 3% of subjects in either group

^p-value=0.023

laboratory abnormalities grade 3 4
Laboratory Abnormalities – Grade 3-4*

*>5 subjects in any treatment group

^p-value= 0.039; †p-value = 0.020;#p-value = 0.009

conclusions
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
investigators
Investigators

United States/Puerto Rico

K. Abriola

B. Akil

B. Barnett

T. Barrett

N. Bellos

D. BergerG. 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. CreticosG. Crofoot

F. Cruickshank

E. DeJesus

S. Diamond

R. Dretler

H. Edelstein

R. Elion

T. File

D. FishJ. 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. LampirisM. Lee

R. Liporace

C. Lucasti

R. MacArthur

C. Martorell

C. Mayer

M. McKellarD. 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. WaldmanD. Wheeler

A. WilkinS. Pegram

M. Wohlfeiler

K. Workowski

B. Zingman

investigators1
Investigators

Australia D. Baker

M. Bloch

D. Cooper

D. Dwyer

R. Garsia

P. Konecny

D. Smith

C. Workman

BelgiumN. Clumeck

E..Florence

J. Goffard

J. Legrand

M. Moutschen

CanadaB. Chang

B. Conway

L. Johnston

F. LaPlante

R. LeBlanc

K. Logue

D. Murphy

A. Rachlis

S. Walmsley

FranceJ. Durant

P-M Girard

C. Katlama

B. Marchou

J-M Molina

J-L Pellegrin

L. Slama

F. Raffi

P. Yeni

GermanyS. Esser

G. Fätkenheuer

H. August Horst

H. Jäger

A. Plettenberg

S. Reuter

C. Stephan

J. van Lunzen

ItalyA. Antinori

M. Galli

A. Lazzarin

F. Maggiolo

G. Rizzardini

V. Vullo

MexicoJ. Andrade Villanueva

M. Magaña

L. Mosqueda

J. Sierra

NetherlandsB. Rjinders

PortugalF. Antunes

T. Branco

A. Diniz

R. SerrãoR. Marques

E. Teofilo

SpainJR. 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 KingdomC. Leen

E. Wilkins

I. Williams

A. Winston