switch studies in virologically suppressed patients

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


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



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


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


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


Grade 3 or 4 emerging adverse events or laboratory abnormalities


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



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


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


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

switch studies in virologically suppressed patients

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