Transcript Efficacy and Safety of Atazanavir (ATV) Based HAART in

4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia, July 22-26, 2007
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WEPEB117LB
Efficacy and safety of switching from boosted
Lopinavir (LPV/r) to boosted Atazanavir
(ATV/r) in patients with virologic suppression
receiving a LPV/r containing HAART: The
ATAZIP study
Mallolas J.1, Podzamczer D.2, Domingo P.3, Clotet B.4, Ribera E.5, Gutierrez
F.6, Knobel H.7, Cosin J.8, Ferrer E.2, Arranz J.A.9, Roca V.10, Vidal F.13,
Murillas J.14, Pedrol E.15, Llibre J.M.16, Dalmau D.17, Garcia I.18, Aranda M.19,
Pich J.11, de Lazzari E.12, Gatell J.M.1, for the ATAZIP study group
1Hospital Clinic Universitari, Infectious Diseases, Barcelona, Spain, 2Bellvitge, Infectious Diseases, Barcelona, Spain, 3Hospital Sant Pau,
Medicina Interna, Barcelona, Spain, 4Fundacio IrsiCaixa, HIV, Barcelona, Spain, 5Hospital Vall d´Hebron, Infectious Diseases, Barcelona,
Spain, 6Hospital de Elche, Medicine, Elche, Spain, 7Hospital del Mar, Infectious Diseases, Barcelona, Spain, 8Gregorio Marañon, Medicina,
Madrid, Spain, 9Hospital Principe de Asturias, Medicina, Madrid, Spain, 10Clinico San Carlos, Medicina, Madrid, Spain, 11Hospital Clinic
Universitari, Pharmacology, Barcelona, Spain, 12Hospital Clinic Universitari, Biostatistics, Barcelona, Spain 13 Hospital Joan XXIII,
Tarragona 14 Hospital Son Dureta. Palma de Mallorca. 15 Hospital de Granollers. 16 Hospital de Calella.17 Mutua de Tarrasa. 18 Hospital de
Hospitalet. 19 Consorci Sanitari de Tarrasa.
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Background
 ATV is a potent, well-tolerated, once-daily (QD) protease
inhibitor (PI) extensively studied in treatment-naive and experienced patients
 The SWAN study (BMS 097)1 demonstrated that switching
from PI ± RTV-containing regimens to an unboosted ATVcontaining regimen maintained virologic suppression with
improvement in plasma lipids through 48 weeks in patients
without previous failures to PI contaning regimens
 However, there are limited data available on the utility of
switching virologically suppressed patients from LPV/rbased regimens to a different boosted PI such as ATV/r
including those with previous failures to PI containing
regimens or PI associated mutations
1Gatell
et al. Clin Infect Dis 2007
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Objective
 To assess the safety and efficacy of ATV/r
based HAART in virologically suppressed
patients receiving a LPV/r contaning regimen
including patients with previous failures (< 3)
to PI regimens or history of having PI
associated mutations (< 5) prior to starting the
LPV/r-based regimen.
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Study Design
Study Population (N = 265)
 Stable LPV/r-based Regimen for > 6 months (VL < 200)
 < 3 Previous Virologic Failures While on PI-based HAART
and < 5 PI-associated mutations
 The study was conducted in Spain
1:1 Randomization
Switch to ATV/r QD†
(N = 121)
Baseline
Continue LPV/r BID*
(N = 127)
Primary Analysis, Week 48
Final Analysis, Week 96
* LPV/r 400/100 mg BID capsules then tablets when available + unchanged NRTI backbone.
† ATV/r 300/100 mg QD + unchanged NRTI backbone.
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Primary end-point
–
The proportion of patients with treatment
failure for any reason through Week 48
• Includes virologic rebound (> 200 cp/mL),
discontinuation of study therapy or lost to followup, progression to a new CDC event or death.
• Non-inferiority study. Upper limit of 95% CI of
estimated difference < 12.5%.
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Secondary end-points
–
The proportion of patients with virologic
rebound at or prior to Week 48
• Confirmed on-study HIV RNA ≥ 200 copies/mL or
last on-study HIV RNA ≥ 200 copies/mL followed by
discontinuation
–
Time to treatment failure and to virologic
failure
–
Safety
–
Evolution of fasting plasma lipids
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Baseline Characteristics
ATV/r
LPV/r
N = 121
42
N = 127
43
97 (80)
100 (79)
45(37)
27(22)
39 (32)
10 (8)
48 (40)
40(31)
41 (32)
37 (29)
9 (7)
74 (57)
CD4 < 200, cell/ mm3
9(8)
12 (10)
Median CD4, cells/mm3
472
435
General
Median Age, y
Gender, N (%)
Male
Risk group, N (%)
Heterosexual trans.
MSM
IDUs
Other
AIDS, N (%)
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Baseline Characteristics
ATV/r
LPV/r
N = 121
N = 127
28 (23%)
26 (20%)
4 (3%)
13 (10%)*
LDL-c > 130 mg/dl, N (%)
24 (20%)
25 (20%)
HDL-c < 40 mg/dl, N (%)
19 (16%)
27 (21%)
ALT > 40, N (%)
28 (24%)
22 (18%)
AST > 40, N (%)
20 (21%)
24 (23%)
ALT or AST > 40, N (%)
34 (28%)
33 (26%)
Laboratory
Total chol > 240 mg/dl, N (%)
TG > 500 mg/dl, N (%)
* P=0.023
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Baseline Characteristics
ATV/r
LPV/r
N = 121
N = 127
ARV exposure, yr.
1st. ARV regimen, N (%)
1st. ARV regimen with PI, N (%)
Previous mono/bi therapy, N (%)
5.1
17 (14)
36 (30)
47 (39)
5.4
19 (15)
42 (33)
48 (38)
Current ZDV+3TC, N (%)
Current TDF+3TC, N (%)
Current TDF+ddI, N (%)
Current ddI+3TC, N (%)
12 (10)
24 (20)
21 (17)
8 (7)
20 (16)
22 (17)
12 (9)
9 (7)
Previous PI failures (>=1), N (%)
25 (21)
25 (20)
History of Previous PI mutations
>=1, N (%)
43 (36)
41 (32)
>=1 major, N (%)
17 (14)
13 (10)
3 (1)
9 (7)
75 (63)
77 (61)
ARV Therapy
None, N (%)
Not tested, N (%)
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Patient Disposition at month 12
Pacientes enrolled
(n=265)
Assigned to switch to
ATV/r (n=121) #
Continuing assigned therapy
Discontinued
Adverse events
Death
Virological failure
Lost to follow-up
Patient decission
Other
†5
105† (86%)
17 (14%)
6
0
1
7
0
2
subjects with virological failure
# 11 additional patients not eligible
Assigned to continue with
LPV/r (n=127) #
Continuing assigned therapy
Discontinued
Adverse events
Death
Virological failure
Lost to follow-up
Patient decission
Other
†7
109† (86%)
18 (14%)
6
1*
1
6
2
2
subjects with virological failure
* Hepatic encephalopaty
# 6 additional patients not eligible
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Treatment Failure and Virologic Failure
(≥ 200 c/mL) through month 12
Virologic Failure (≥ 200 c/mL)
Treatment Failure
ATV/r
LPV/r
30
30
25
25
20
20%
Proportion of patients
Proportion of patients
p = NS
17%
15
10
5
0
21/121
25/127
Difference Estimate (95% CI) -2.3% (–12%, 8%)
20
p = NS
15
10
5%
6%
5
0
6/121
8/127
–1.3% (–7.7%, 4.8%)
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Time to treatment failure
14
Time to virological failure
P=0.5
P=0.5
p=0.609, long rank test
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Virological failures through month 12
ATV/r (n=121)
LPV/r (127)
N
6
8
Previous PI failures
Previous PI mutations
Previous PI major mutations
High baseline risk (*)
2
6
2
5
4
1
1
5
Reported lack of adherence
Continue with same cART
Virological response at 12 mo.
0
5
3
4
7
4
* Previous >= 1 PI failure or >= 3 PI mutations or >= 1 major PI mutation
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CD4 Changes
 Median changes from baseline in CD4 cell count were
similar beteween groups: +26 cells/mm3 (ATV/r) and
+51 cells/mm3 (LPV/r) at month 12 (p=0.2)
CD4 count (cells/mL)
600
550
541
500
495
472
450
435
LPV/r
ATV/r
400
BL
m1
m4
m8
m12
17
Adverse Events through month 12.
ATV/r
N = 121
N (%)
LPV/r
N = 127
N (%)
Total
GI-related
CNS
Liver
Metabolic-related
Hyperbilirubin/Jaundice
6 (5)
1 (1)
1 (1)
1 (1) #
1 (1)
2 (2)
6 (5)
2 (2)
0 (0)
0 (0)
4 (4)
0 (0)
Death
Any AE
0 (0)
74 (58)
1 (1) *
63 (52)
Adverse Events leading to discontinuation
* Hepatic encephalopaty; # ALT 113, AST 90
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LAB Abnormalities
Liver Function Abnormalities
(ALT/AST > 200; bilirrubin > 5)
ATV/r
N = 121
LPV/r
N = 127
ALT
2%
1%
AST
2%
ALT or AST
Total bilirubin
Liver Function Abnormalities
(ALT/AST > 200 ) when ALT or AST
were > 40 at baseline
ATV/r
N = 34
LPV/r
N = 33
ALT
9%
6%
2%
AST
9%
6%
4%
2%
ALT or AST
12%
6%
5%
2%
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Fasting LIPIDS. Median values and Changes
From Baseline in Lipid Parameters at month 12
ATV/r
LPV/r
P
value
BL
m12
Change
 mg/dL
BL
m12
Change
 mg/dL
TG, mg/dL
181
145
-51 (-29%)
191
202
-3 (-1%)
<0.0001
Total Chol, mg/dL
202
193
-19 (-9%)
205
207
-4 (-2%)
<0.0001
LDL-c, mg/dL
107
111
-8 (-7%)
111
111
-2 (-3%)
0.163
HDL-c, mg/dL
50
46
-3 (-6%)
49
46
-2 (-3%)
0.375
Fasting Lipids
20
CHANGE IN MEDIAN FASTING PLASMA LIPIDS
20
mg/dl (Mo. 12 - Mo. 0)
P<0.0001
P<0.0001
0
-20
-40
-60
Lop/r Ata/r
TG
Lop/r Ata/r
Cholest
Lop/r Ata/r
LDL
Lop/r Ata/r
HDL
21
LIPIDS. Percentage above NCEP treatment
recommendations at baseline and through
month 12.
ATV/r
LPV/r
N=121
N=127
BL
Mo 12
3%
4%
+1%
Total Chol > 240 mg/dL
23%
20%
LDL > 130 mg/dL
20%
HDL < 40 mg/dL
16%
TG m12 > 500 mg/dL
Change BL
Mo 12
Change
10%
17%
+7%
-3%
20%
26%
+6%
25%
+5%
20%
30%
+10%
32%
+16%
21%
29%
+8%
No significant changes were obseved in Lipid Lowering Agents (LLA) usage during
the follow-up in both arms.
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Conclusions
 Switching to ATV/r in virologically suppressed
patients who were receiving a LPV/r containing
HAART provided comparable efficacy and
safety profile with improved lipid parameters.
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ATAZIP Study Group
HOSPITAL CLINIC
BARCELONA
J. Mallolas
J.M. Gatell
J. Pich
E. de Lazzari
E. Martínez
A. Milinkovic
A. Cruceta
H. Agell
J.A. Arnaiz
HOSPITAL GREGORIO
MARAÑÓN MADRID
J. Cosín
M. Sánchez
M. Ramírez
I. Gutiérrez
HOSPITAL BELLVITGE
HOSPITALET
D. Podzamczer
E. Ferrer
G. Leibenger
HOSPITAL SANT PAU
BARCELONA
P. Domingo
M. Gutiérrezerrer
G. Mateo
HOSPITAL VALL D’HEBRÓN
BARCELONA
E. Ribera
S. Villar
HOSPITAL ELCHE
ALICANTE
F. Gutiérrez
M. Masiá
E. Bernal
HOSPITAL CLÍNICO
SAN CARLOS
MADRID
V. Roca
J. Vergas
M.J. Téllez
HOSPITAL SON DURETA
PALMA MALLORCA
M. Peñaranda
J. Murillas
HOSPITAL GRANOLLERS
GRANOLLERS
E. Pedrol
E. Deig
HOSPITAL PRINCIPE
ASTURIAS MADRID
J.A. Arranz
J. Sanz
E. Casas
HOSPITAL L’HOSPITALET HOSPITAL TERRASSA
HOSPITALET
TERRASSA
I. García
M. Aranda
HOSPITAL GERMANS
TRIAS I PUJOL
BADALONA
B. Clotet
P. Echeverria
C. Alcalde
HOSPITAL MAR
BARCELONA
H. Knobel
A. González
G. Mestre
HOSPITAL JOAN XXIII
TARRAGONA
F. Vidal
J. Peraire
M. Saumoy
HOSPITAL CALELLA HOSPITAL MUTUA
CALELLA
TERRASSA
J.M. Llibre
TERRASSA
S. Valero
D. Dalmau
M. Cairó