Switch to RAL-containing regimen
Canadian Study CHEER Montreal Study EASIER SWITCHMRK SPIRAL Switch ER
EASIER Study: Switch ENF to RAL
Design
Objective 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 singleHIV-1 RNA ≥ 400 c/mL followed by treatment modification or last HIV-1 RNA ≥ 400 c/mL without confirmation
Switch to RAL 400 mg bid+ continue other ARVs
Continue ENF regimen+ other ARVs
Randomisation1 : 1
Open-label
Randomisation1 : 1
Open-label
193 HIV+ adultsHistory of triple class (NRTI, NNRTI, PI)
failure or intoleranceHIV-1 RNA < 400 c/mL > 3 months
on an ENF-based regimenIntegrase inhibitor-naïve
193 HIV+ adultsHistory of triple class (NRTI, NNRTI, PI)
failure or intoleranceHIV-1 RNA < 400 c/mL > 3 months
on an ENF-based regimenIntegrase inhibitor-naïve
N = 85
N = 85
W24W24
De Castro N, CID 2009;49:1259-67EASIEREASIER
EASIER Study: Switch ENF to RAL
ENF, N = 85 RAL, N = 84Median 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%
CD4 cell count at baseline ; at nadir, /mm3 374 ; 56 410 ; 39
HIV-1 RNA < 50 c/mL at baseline 88% 85%
Duration of prior ENF therapy, median years 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%)
Discontinuation before W24, N (%) 3 2
For adverse event 0 0
For virologic failure 1 1
Baseline characteristics and patient disposition
* TPV/r in 34% vs 44% and DRV/r in 40% vs 36%, in ENF vs RAL groups, respectively
De Castro N, CID 2009;49:1259-67EASIEREASIER
EASIER Study: Switch ENF to RAL
Outcome at week 24Other endpoints
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
Virologic failure
De Castro N, CID 2009;49:1259-67EASIEREASIER
1.2
88
1.2
89
ITT analysis
ENF RAL%
0
20
40
60
80
100
95% CI for the difference
= -6.7 ; 6.8
HIV-1 RNA < 50 c/mL
0 1.2
On-treatment analysis
95% CI for the difference
= -5.6 ; 8.1
ITT analysis
EASIER Study: Switch ENF to RAL
ENF RAL
Adverse events occurred in 7 patients on ENF and 11 patients on RAL, with a total of 8 and 13 events, respectively
Coronary events 2 2
Gastrointestinal 1 1
Infection 0 3
Nervous system 0 1
Psychiatric 1 1
Respiratory 2 1
Other 2 4
Laboratory abnormalities occurred in 6 patients on ENF and 12 patients on RAL,with a total of 8 and 14 abnormalities, respectively
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;49:1259-67EASIEREASIER
Grade 3 or 4 emerging adverse events or laboratory abnormalities
EASIER Study: Switch ENF to RAL
Conclusions from W24 data– In patients infected with multidrug-resistant HIV-1 receiving
suppressive enfuvirtide-containing antiretroviral therapy, aswitch from enfuvirtide to RAL is:
• Safe
• Well-tolerated
• And virologically non-inferior to the maintenance of ENF
De Castro N, CID 2009;49:1259-67EASIEREASIER
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)
Gallien S, JAC 2011;66:2099-2106EASIEREASIER
Gallien S, JAC 2011;66:2099-2106
EASIER Study: Switch ENF to RAL
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
EASIEREASIER
Deferred switch Immediate switch
0%
10%
70%
80%
90%
100%
Pro
po
rtio
n o
f p
ati
en
tsw
ith
HIV
RN
A <
50
co
pie
s/m
l
W08584
W48584
W88584
W248484
W288479
W328484
W168584
W408284
W488383
DefImmN patients
88%89% 90%
90%88%
85%
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
Grade 3-4 laboratory abnormalities occurred in 20 patients (12%)
Aminotransferase > 5 ULN 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
Grade 3 or 4 emerging adverse events or laboratory abnormalitiesIn both arms between weeks 24 and 48 (N = 168)
Gallien S, JAC 2011;66:2099-2106
EASIER Study: Switch ENF to RAL
EASIEREASIER
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
Silva EF, JID 2013;208:892-7EASIEREASIER
EASIER substudy: Inflammatory and coagulation biomarkers
Silva EF, JID 2013;208:892-7
D-dimer (g/ml)Deferred SwitchImmediate Switch
EASIEREASIER
IL-6 (log10 pg/ml) hsCRP (log10 g/ml)
0.198
Values are median (IQR)
0.0
-0.4
-0.8
0.4
0.8
1.2
1.6
2.0
W08183
W247879
W487571
0.63 0.74
0.20
p=0.0003
0.66 0.32
0.20
ENF
RAL
RAL
RAL
0.0
0.4
0.8
1.2
1.6
2.0
W08183
W247879
W487572
0.56 0.61
0.28
p<0.001
0.540.23 0.18RAL
RAL
RAL
ENF
0.5
0.4
0.3
0.2
0.1
0.0
W08183
W247879
W487572
0.369 0.3870.189
p<0.00010.369
0.189 RAL
RALRAL
ENF
EASIER substudy: Inflammatory and coagulation biomarkers