Virologic Determinants of 24-Week Virologic Determinants of 24-Week Efficacy of Atazanavir With or Without Efficacy of Atazanavir With or Without

Ritonavir in Patients with Prior Failure on Ritonavir in Patients with Prior Failure on a Protease Inhibitora Protease Inhibitor

C. ZalaC. Zala, A. Lazzarin, A. Casiro, B. Grinsztejn, , A. Lazzarin, A. Casiro, B. Grinsztejn, L. Nieto, R. Salazar, E. Ledesma, T. Kelleher, L. Nieto, R. Salazar, E. Ledesma, T. Kelleher,

R. McGovern, A. Rightmire, C. McLaren.R. McGovern, A. Rightmire, C. McLaren.

Mea

n P

lasm

a C

on

cen

trat

ion

(S

D)

at S

tead

y S

tate

(n

g/m

L)

Time (h)0 4 8 12 16 20 24

400 mg ATV

300 mg ATV/100 mg RTV

1

10

100

1000

10,000

75th percentile

25th percentile

Median 22.6 ng/mL

4.8–3132.3 ng/mL

Rationale for ATV 300 mg Boosted with RTV 100 mg

in vitro Estimated ProteinAdjusted EC90 Range

To determine the extent to which Baseline viral mutations correlate to antiviral effects of:

• Unboosted atazanavir (ATV 400mg QD)• Boosted atazanavir (ATV 300mg QD plus RTV 100mg QD)

In patients with prior treatment failure:

ObjectivesObjectives

Study Designs: BMS-043 and BMS-045Study Designs: BMS-043 and BMS-045

LPV400mg BID

N=150 N=150

Currently failing PI-based regimen

BMS-043

+2 NRTIs +2 NRTIs

RTV

ATV400mg QD

N=120 N=123 N=115

Failed at least two regimens including:

1 PI

1 NRTI

1 NNRTI

BMS-045

+ TDF

+1 NRTI

ATV300mg QD

RTV

LPV400mg BID

RTV

+ TDF

+1 NRTI

ATV400mg QD

SQV

+ TDF

+1 NRTI

Physician choiceNRTI use:

RTV

100mg per dose

Patient Characteristics: BaselinePatient Characteristics: Baseline

BMS-043

Age (median), yr 36 38

Female 23% 18%

Race

Hispanic/Latino 51% 52%

White 43% 41%

Black 6% 7%

AIDS 23% 27%

CD4 (median), cells/mm3 288 261

Randomized, N 150 150

LPV400mg BID

RTV

ATV400mg QD

BMS-045

39 39

20% 22%

23% 22%

63% 58%

15% 17%

28% 29%

317 283

120 123

ATV300mg QD

RTV

LPV400mg BID

RTV

Virologic Characteristics: BaselineVirologic Characteristics: Baseline

BMS-043

HIV RNA (median), log10 c/mL 4.18 4.14

69% 59%<30,000 c/mL

30,000 to <100,000 c/mL 16% 23%

Baseline susceptibility *

ATV, n (%) 108 (72)

LPV 129 (86)

>4 mutations at Baseline

PI 39 (26) 35 (23)

NRTI 24 (16) 24 (16)

100,000 c/mL 15% 17%

LPV400mg BID

RTV

ATV400mg QD

BMS-045

4.44 4.47

53% 50%

23% 27%

88 (74)

91 (77)

39 (33) 45 (37)

47 (39) 53 (43)

23% 23%

ATV300mg QD

RTV

LPV400mg BID

RTV

* Baseline phenotypic susceptibility determined as <2.5 Fold Change (ViroLogic Phenosense)

NRTI and PI Substitutions EvaluatedNRTI and PI Substitutions Evaluated

10 20 24 32 33 36 46 48 50 54 63 71 73 82 84 90PI genotype

L K L V L M M G I I L A G V I LWild Type

SubstitutionsF I I I F I V M A P I A A V MIV

M RTV

R

IV

LV

IL L

VACFGH QST

TV

ST

FILT

41 65 67 70 74 151 184 210 215 219RT genotype

M K D K L Q M L T KWild Type

SubstitutionsL R A R M F E EV I

V GQ

GNT

SW

FINSVYCHR

RAN

Source: Stanford HIV RT and Protease Sequence Database

Treatment HistoryTreatment History

BMS-045

133 (0.1-321) 136 (0.1-346)

269 (40-782) 265 (0.1-679)

78 (0.1-227) 69 (0.1-304)

120 123

ATV300mg QD

RTV

LPV400mg BID

RTV

PI36%

PI37%NNRTI

61%NNRTI58%

BMS-043

Prior ARV use (median)

133 (0.1-338) 136 (0.1-536)Prior PI use, weeks (range)

159 (0.1-645) 167 (26.1-630)Prior NRTI use, weeks (range)

Prior NNRTI use, weeks (range) 133 (1.6-210) 85 (1.6-158)

150 150Randomized, N

LPV400mg BID

RTV

ATV400mg QD

Preceding regimen (PI or NNRTI) PI

100%PI

100%

-2

-1

B/L 4 8 12 16 24

unboosted ATVboosted LPV

-1.67

-2.11

Time Averaged Difference Estimate: ATV - LPV/r: 0.30 log10 c/mL. [97.5% CI: 0.09, 0.51]

Study week

0

Me

an

HIV

-1 R

NA

Ch

an

ge

fro

m B

as

eli

ne

Primary Endpoint: Virologic Efficacy Primary Endpoint: Virologic Efficacy Through 24 WeeksThrough 24 Weeks

BMS-043: ATV vs LPV/r

Time Averaged Difference Estimate: ATV/r - LPV/r: 0.14 log10 c/mL. [97.5% CI: -0.09, 0.37]

ATV/SQV - LPV/r: 0.31 log10 c/mL. [97.5% CI: 0.07, 0.55]

B/L 4 8 12 16 24

-2

-1

-1.86-1.89

-1.52

Study week

0

Me

an

HIV

-1 R

NA

Ch

an

ge

fro

m B

as

eli

ne

ATV/rLPV/rATV/SQV

BMS-045: ATV/r vs LPV/r

Effect of NRTI and PI Substitutions on Viral Load Reduction

•BMS-043: ATV (unboosted) vs LPV/r•BMS-045: ATV/r vs LPV/r

-3

-2

-1

0none 1 2 3 4 5

Mea

n C

han

ge

in V

iral

Lo

ad a

t W

eek

24 (

log

10 c

/mL

)

none 1 2 3 4 5

BMS-043: Baseline Genotypic Determinants BMS-043: Baseline Genotypic Determinants of Viral Load Reduction at Week 24of Viral Load Reduction at Week 24

ATV, n

LPV/r, n

26

20

33

43

8

13

15

11

8

9

5

6

15

8

22

22

18

27

20

22

9

7

11

16

Number of Baseline NRTI Mutations Number of Baseline PI Mutations

ATV (unboosted)

LPV/r

-3

-2

-1

0none 1 2 3 4 5

Mea

n C

han

ge

in V

iral

Lo

ad a

t W

eek

24 (

log

10 c

/mL

)

ATV/r, n

LPV/r, n

16

13

22

15

9

18

21

19

18

13

26

32

none 1 2 3 4 5

17

10

28

24

22

26

11

10

10

15

24

25

BMS-045: Baseline Genotypic Determinants BMS-045: Baseline Genotypic Determinants of Viral Load Reduction at Week 24of Viral Load Reduction at Week 24

Number of Baseline NRTI Mutations Number of Baseline PI Mutations

ATV/r

LPV/r

Effect of NRTI and PI Substitutions on Proportion of Subjects

<400 copies/mL

•BMS-043: ATV (unboosted) vs LPV/r•BMS-045: ATV/r vs LPV/r

0

20

40

60

80

100

none 1 2 3 4 5

Pro

po

rtio

n <

400

cop

ies/

mL

, %

Number of Baseline NRTI Mutations

ATV, n

LPV/r, n

32

26

37

46

13

14

16

13

10

9

6

7

none 1 2 3 4 5

16

9

28

27

20

29

22

23

10

8

18

19

BMS-043: Baseline Genotypic Determinants of BMS-043: Baseline Genotypic Determinants of Virologic Response (<400 c/mL) at Week 24Virologic Response (<400 c/mL) at Week 24

Number of Baseline PI Mutations

ATV (unboosted)

LPV/r

ITT: Time to Loss Of Virologic Response

0

20

40

60

80

100

none 1 2 3 4 5

Pro

po

rtio

n <

400

cop

ies/

mL

, %

ATV/r, n

LPV/r, n

none 1 2 3 4 5

BMS-045: Baseline Genotypic Determinants of BMS-045: Baseline Genotypic Determinants of Virologic Response (<400 c/mL) at Week 24Virologic Response (<400 c/mL) at Week 24

18

17

23

15

9

18

23

20

18

16

29

37

18

13

28

27

23

27

12

11

10

15

29

30

Number of Baseline NRTI Mutations Number of Baseline PI Mutations

ATV/r

LPV/r

ITT: Time to Loss Of Virologic Response

Effect of NRTI and PI Substitutions on Proportion of Subjects

<50 copies/mL

•BMS-043: ATV (unboosted) vs LPV/r•BMS-045: ATV/r vs LPV/r

0

20

40

60

80

100

none 1 2 3 4 5

Pro

po

rtio

n <

50 c

op

ies/

mL

, %

ATV, n

LPV/r, n

32

26

37

46

13

14

16

13

10

9

6

7

none 1 2 3 4 5

18

17

23

15

9

18

23

20

18

16

29

37

BMS-043: Baseline Genotypic Determinants BMS-043: Baseline Genotypic Determinants of Virologic Response (<50 c/mL) at Week 24of Virologic Response (<50 c/mL) at Week 24

Number of Baseline NRTI Mutations Number of Baseline PI Mutations

ATV (unboosted)

LPV/r

ITT: Time to Loss Of Virologic Response

0

20

40

60

80

100

none 1 2 3 4 5

Pro

po

rtio

n <

50 c

op

ies/

mL

, %

ATV/r, n

LPV/r, n

none 1 2 3 4 5

BMS-045: Baseline Genotypic Determinants BMS-045: Baseline Genotypic Determinants of Virologic Response (<50 c/mL) at Week 24of Virologic Response (<50 c/mL) at Week 24

18

17

23

15

9

18

23

20

18

16

29

37

18

13

28

27

23

27

12

11

10

15

29

30

Number of Baseline NRTI Mutations Number of Baseline PI Mutations

ATV/r

LPV/r

ITT: Time to Loss Of Virologic Response

• The efficacy of ATV- and LPV-containing regimens decreased with increasing numbers of PI and NRTI mutations

• The relative magnitude of this effect was greatest in non-boosted ATV regimens

• The effect of PI and NRTI mutations was similar in ATV/r and LPV/r regimens

• These results indicate that RTV-boosted ATV may be a more appropriate regimen than unboosted ATV for patients with multiple PI and NRTI mutations

ConclusionsConclusions

C. ZalaC. Zala 1 1, A. Lazzarin, A. Lazzarin 2 2, A. Casiro, A. Casiro 3 3, B. Grinsztejn, B. Grinsztejn 4 4, , L. NietoL. Nieto 5 5, R. Salazar, R. Salazar 6 6, E. Ledesma, E. Ledesma 7 7, T. Kelleher, T. Kelleher 7 7, ,

R. McGovernR. McGovern 7 7, A. Rightmire, A. Rightmire 7 7, C. McLaren, C. McLaren 7 7..

11 Fundacion Huesped, Buenos Aires, Argentina. Fundacion Huesped, Buenos Aires, Argentina. 22 Instituto di Ricovero e Cura a Carattere Scientifico S. Raffaele, Milan, Italy. Instituto di Ricovero e Cura a Carattere Scientifico S. Raffaele, Milan, Italy. 33 Hospital Teodoro Alvarez, Buenos Aires, Argentina. Hospital Teodoro Alvarez, Buenos Aires, Argentina. 44 Instituto de Pesquisa Clínica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil. Instituto de Pesquisa Clínica Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil.

55 Hospital Gabriel Mancera, IMSS, Mexico, D.F. Hospital Gabriel Mancera, IMSS, Mexico, D.F. 66 Guillermo Almenara Hospital, Lima, Peru. Guillermo Almenara Hospital, Lima, Peru. 77 Bristol-Myers Squibb Company, Wallingford, CT, USA Bristol-Myers Squibb Company, Wallingford, CT, USA

TO ALL THE PATIENTS AND STUDY CENTER PARTICIPANTSTO ALL THE PATIENTS AND STUDY CENTER PARTICIPANTS

AcknowledgmentsAcknowledgments

InvestigatorsInvestigators

Juan Echevarria, MD. Lima

Raul Salazar, MD. Lima

Peru

Leopoldo Nieto, MD. Col. Del Valle

Juan Sierra, MD. Tialpan

Mexico

Javier Morales, MD. San Juan

Gladys E. Sepulveda, MD. Ponce

Gabriel A. Martinez, MD. Cotol Laurel

Puerto Rico

Christos Tsoukas, MD. Montreal, Quebec

Canada

Juan Ballesteros, MD. Santiago

Luis Noriega, MD. Santiago

Carlos Perez, MD. Santiago

Marcelo Wolff, MD. Santiago

Chile

Sergio Lupo, MD. Rosario

Arnaldo Casiro, MD. Buenos Aires

Claudia Rodriguez, MD. Buenos Aires

Carlos Zala, MD. Buenos Aires

Argentina

Gisella Herrera, MD. San Jose

Costa Rica

Clovis Arns, MD. Curitiba

Frederico Rangel, MD. Recife

Tania Reuter, MD. Vitória

Roberto Badaro, MD. Salvador

Beatirz Grinsztejn, MD. Rio de Janeiro

Erico Arruda, MD. Fortaleza

Danilo Nunes, MD. São Paulo

Breno Santos, MD. Trein

Brazil

Robert Baker, MD. Indianapolis, IN

Nicholaos Bellos, MD. Dallas, TX

David Brand, MD. Dallas, TX,

Larry Bush, MD. Atlantis, FL

Jerry Cade, MD. Las Vegas, NV

Jeffrey Coco, MD. New Orleans, LA

Calvin Cohen, MD. Boston, MA

Timothy Cooley, MD. Boston, MA

Robert Eng, MD. East Orange, NJ

Jose Fernandez, DO. Miami Beach, FL

Jeffrey Fessel, MD. San Francisco, CA

Thomas File, MD. Akron, OH

Richard Greenberg, MD. Lexington, KY

Jose Hernandez, DO. Miami Beach, FL

Ross Hewitt, MD. Buffalo, NY

Robert Houghton, MD. San Diego, CA

Susan Jacobsen, MD. Berkely, CA

Thomas Jefferson, MD. Little Rock, AR

Joseph Jemsek, MD. Huntersville, NC

Edwin deJesus, MD. Altamonte Springs, FL

Sujata Lalla-Reddy, MD. Long Beach, CA

Harry Lampiris, MD. San Francisco, CA

Kenneth Lichtenstein, MD. Denver, CO

George McKinley, MD. New York, NY

Alexander McMeeking, MD. New Yok, NY

Jane-Ellen Mobley, MD. Birmingham, AL

Mary O’Hearn, MD. Portland, OR

Samuel Pegram, MD. Winston-Salem, NC

Peter Piliero, MD. Albany, NY

Ronald Poblete, MD. Newark, NJ

Arnaldo Quinones, MD. Ft Lauderdale, FL

James Sampson, MD. Portland, OR

Stefan Schneider, MD. Long Beach, CA

Shannon Schrader, MD. Houston, TX

David Stein, MD. Bronx, NY

Charles Steinberg, MD. Denver, CO

Donna Sweet, MD. Wichita, KS

Rohit Talwani, MD. Columbia, SC

Steven Zell, MD. Reno, NV

United States