Transcript ARV-trials Switch 2011

Switch to RAL-containing regimen
- Canadian Study
- CHEER
- Montreal Study
- EASIER
- SWITCHMRK
- SPIRAL
EASIER Study: Switch ENF to RAL
 Design
Randomisation
1:1
Open-label
193 HIV+ adults
History of triple class (NRTI, NNRTI, PI)
failure or intolerance
HIV-1 RNA < 400 c/mL > 3 months
on an ENF-based regimen
Integrase inhibitor-naïve
W24
N = 85 Continue ENF regimen
+ other ARVs
N = 85 Switch to RAL 400 mg bid
+ continue other ARVs
 Objective


EASIER
Non inferiority in the proportion of patients with virologic failure at W24
(Intent-to-treat analysis) ; upper limit of the 95% CI for the difference =
10%, 80% power
Virologic failure : confirmed HIV-1 RNA ≥ 400 c/mL, or a single
HIV-1 RNA ≥ 400 c/mL followed by treatment modification or last
HIV-1 RNA ≥ 400 c/mL without confirmation
De Castro N, CID 2009;49:1259-67
EASIER Study: Switch ENF to RAL
Baseline characteristics and patient disposition
ENF, N = 85
RAL, N = 84
Median age, years
48.4
47.6
Female
14%
17%
History of CDC class C diagnosis
55%
50%
Hepatitis B or C co-infection
5%
8%
374 ; 56
410 ; 39
88%
85%
2.2
2.5
Number of ARV drugs in baseline regimen
(including ENF), median
4
4
ARV drugs in regimen: PI* ; NNRTI ; NRTI
(TDF)
100% ; 6% ; 95%
(54%)
99% ; 10% ; 94%
(60%)
3
2
For adverse event
0
0
For virologic failure
1
1
CD4 cell count at baseline ; at nadir, /mm3
HIV-1 RNA < 50 c/mL at baseline
Duration of prior ENF therapy, median years
Discontinuation before W24, N (%)
* TPV/r in 34% vs 44% and DRV/r in 40% vs 36%, in ENF vs RAL groups, respectively
EASIER
De Castro N, CID 2009;49:1259-67
EASIER Study: Switch ENF to RAL
Outcome at week 24
Virologic failure
%
ENF
100
RAL
Other endpoints
HIV-1 RNA
< 50 c/mL
88

89
80
–
–


60
40

20
1.2
1.2
0
1.2

0
EASIER
ITT analysis
On-treatment
analysis
95% CI
for the difference
= -6.7 ; 6.8
95% CI
for the difference
= -5.6 ; 8.1
ITT analysis
Median CD4 increase
ENF: +15/mm3
RAL: +11/mm3
No AIDS events
No difference in the overall
incidence of adverse reactions
between both groups
Higher incidence of grade 1 to
4 laboratory abnormalities in
the RAL arm (p = 0.001)
Median increases in
triglycerides and total
cholesterol were significantly
higher in the RAL group
De Castro N, CID 2009;49:1259-67
EASIER Study: Switch ENF to RAL
Grade 3 or 4 emerging adverse events or laboratory abnormalities
Adverse events occurred in 7 patients on ENF
and 11 patients on RAL, with a total of 8 and
13 events, respectively
Laboratory abnormalities occurred in 6
patients on ENF and 12 patients on RAL,
with a total of 8 and 14 abnormalities,
respectively
EASIER
ENF
RAL
Coronary events
2
2
Gastrointestinal
1
1
Infection
0
3
Nervous system
0
1
Psychiatric
1
1
Respiratory
2
1
Other
2
4
Aminotransferase > 5 ULN
1
2
Gamma GT > 5 ULN
2
6
Alkaline phosphatase > 5 ULN
0
2
CPK > 5 ULN
3
2
Triglyceride > 8.6 mmol/L
0
2
Lipase > 3 ULN
1
0
Potassium < 2.7 mmol/L
1
0
De Castro N, CID 2009;49:1259-67
EASIER Study: Switch ENF to RAL
 Conclusions from W24 data
– In patients infected with multidrug-resistant HIV-1 receiving
suppressive enfuvirtide-containing antiretroviral therapy, a
switch from enfuvirtide to RAL is:
• Safe
• Well-tolerated
• And virologically non-inferior to the maintenance of ENF
EASIER
De Castro N, CID 2009;49:1259-67
EASIER Study: Switch ENF to RAL
 At week 24
– ENF arm switched to RAL (deferred RAL), n = 84
– RAL arm continued on RAL (immediate RAL), n = 84
 Week 48 analyses
– Primary : cumulative proportion of patients with confirmed
HIV RNA ≥ 400 c/mL, or last HIV RNA ≥ 400 c/mL or treatment change after a single HIV
RNA ≥ 400 c/mL (on-treatment and intent-to-treat analyses)
– Secondary
•
•
•
•
•
Proportion of patients with HIV RNA < 50 c/mL
Emergence of resistance in patients with virologic failure
Changes from baseline in CD4 cell counts
Proportion of patients with permanent discontinuation of RAL
Safety
 Baseline GSS assessed on cumulative historical genotypes
– GSS ≥ 1 : 86% ; 0.5 : 11% ; 0 : 3% (n = 5)
EASIER
Gallien S, JAC 2011;66:2099-2106
EASIER Study: Switch ENF to RAL
Proportion of patients
with HIV RNA < 50 copies/ml
100%
88%
90%
89%
90%
90%
88%
80%
85%
70%
Deferred switch
Immediate switch
10%
0%
N patients



Def
Imm
W0
85
84
W4
85
84
W8
85
84
W16
85
84
W24
84
84
W28
84
79
W32
84
84
W40
82
84
W48
83
83
On-treatment analysis : 1 virologic failure (W8) in immediate arm ; baseline GSS = 0,
no emergence of RAL-associated resistance mutations
No significant changes in the median CD4 cell counts following RAL switch in either arm
No significant changes between baseline and W48 in glucose levels or fasting lipids
in either arm
EASIER
Gallien S, JAC 2011;66:2099-2106
EASIER Study: Switch ENF to RAL
Grade 3 or 4 emerging adverse events or laboratory abnormalities
In both arms between weeks 24 and 48 (N = 168)
n
Grade 3-4 adverse events
occurred in 12 patients (7%)
Coronary events
1
Gastrointestinal
2
Infection
8
Nervous system
1
Psychiatric
0
Respiratory
0
Other
10
Aminotransferase > 5 ULN
Grade 3-4 laboratory abnormalities
occurred in 20 patients (12%)
EASIER
7 (all patients on TPV/r)
Gamma GT > 5 ULN
7
Alkaline phosphatase > 5 ULN
1
CPK > 5 ULN
7 (all asymptomatic)
Hyperbilirubinemia > 5 ULN
1
Lipase > 3 ULN
1
Hypoglycemia < 2.2 mmol/L
1
Gallien S, JAC 2011;66:2099-2106
EASIER substudy: Inflammatory and coagulation
biomarkers
 164 patients, Immediate switch (n = 83) ; deferred switch (n = 81)
 Biomarkers
– IL-6
– hsCRP
– D-dimer
 Primary objective : changes in IL-6, hsCRP and D-dimer plasma levels from
baseline to W24 between the immediate and deferred arms
– Log10 transformation of levels
– Median changes from baseline assessed by 1-sample t tests
– Comparison between arms used 2-sample t tests with no adjustment for
baseline factors
 Similar analyses to compare changes from baseline to W48
EASIER
Silva EF, JID 2013;208:892-7
EASIER substudy: Inflammatory and coagulation
biomarkers
hsCRP (log10 mg/ml)
IL-6 (log10 pg/ml)
2.0
2.0
1.6
1.2
0.8
0.4
0.0
-0.4
-0.8
1.6
p<0.001
1.2
0.8
0.4
0.0
W0
81
83
0.56
0.54
ENF
RAL
0.61
RAL
0.23
Deferred Switch
Immediate Switch
0.28
0.18
RAL
W24
78
79
W48
75
72
ENF
0.63
RAL
0.74
0.32
0.66
RAL
0.20
RAL
p=0.0003
W0
81
83
0.20
W24
78
79
W48
75
71
D-dimer (mg/ml)
0.5
Values are median (IQR)
0.4
0.3
0.2
0.369
0.1
0.369
0.0
W0
81
83
EASIER
ENF
RAL
0.387
p<0.0001
W24
78
79
0.189
RAL
RAL
0.189
0.198
W48
75
72
Silva EF, JID 2013;208:892-7