Virologic Determinants of 24-Week Efficacy of Atazanavir With or Without Ritonavir in Patients with...
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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