FLAMINGO GS2360103 ACTG A5257 WAVES ARIA Squires K Lancet HIV 2016 39e410e420 Design Objective Non inferiority of EVGCFTCTDF at W48 HIV RNA lt 50 c mL by intention to treat snapshot analysis lower margin of the 2sided 95 CI for the difference 12 ID: 621282
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Slide1
Comparison of INSTI vs PI
FLAMINGO
GS-236-0103
ACTG A5257
WAVES
ARIA Slide2
Squires K. Lancet HIV 2016; 3(9):e410-e420
Design
Objective
Non inferiority of EVG/C/FTC/TDF at W48: % HIV RNA < 50 c/
mL
by intentionto treat, snapshot analysis (lower margin of the 2-sided 95% CI for the difference = -12%)
EVG/C/FTC/TDF 150/150/200/300 mg QDATV + r + TDF/FTC placebo
ATV + r 300/100 mg + FTC/TDF QDEVG/C/FTC/TDF placebo
Randomisation*1 : 1Double-blind
WomenARV-naïveHIV RNA > 500 c/mLAny CD4 cell countSensitivity to FTC, TDF and ATVeGFR > 70 mL/min
*Randomisation was stratified by HIV RNA (< 100,000 or 100,000-400,000 or > 400,000 c/mL) at screening and race (black or non-black)
Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women
N = 286
N = 289
W48
WAVES
Open-label
extensionSlide3
EVG/C/FTC/TDF
N = 289
ATV + r + FTC/TDF
N = 286
Female
100%
100%
Median age, years
34
35White / Black / Asian
44% / 50% / 3%
42% / 47% / 6%
AIDS
4%
5%
HIV RNA (log
10
c/
mL
), median (Q1-Q3)
4.46 (4.09-4.97)
4.56 (4.02-5.00)
HIV RNA 100,000-400,000 c/mL
HIV RNA ≥ 400,000 c/mL15%9%18%8%CD4 cell count (/mm3), median344370CD4 < 200 per mm317%18%Hepatitis B / hepatitis C coinfection4% / 8%3% / 9%Discontinuation by W48, N (%)29 (10%)45 (16%)For lack of efficacyN = 0N = 1For adverse eventN = 5N = 19Lost to follow-up / Withdrew consentN = 12 / N = 6N = 12 / N = 5Non-compliance / OtherN = 4 / N = 2N = 5 / N = 3
Baseline characteristics and patient disposition
Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women
WAVES
Squires K. Lancet HIV 2016; 3(9):e410-e420Slide4
Response to treatment at week 48
Mean CD4/mm
3
increase at W48 :
+ 221
(EVG/C/FTC/TDF) vs+ 212 (ATV + r + FTC/TDF)
EVG/C/FTC/TDF (N = 289)ATV + r + FTC/TDF (N = 286)HIV RNA < 50 c/mL (ITT, snapshot)
25501007587
81
Adjusted difference(95% CI) = 6.5 % (0.4 ; 12.6)p = 0.034912
Virologic success
Virologic failure%
0
4
7
No virologic
data
Study WAVES
: EVG/C/FTC/TDF QD vs ATV + r
+ FTC/TDF QD in Women
WAVES
Squires K. Lancet HIV 2016; 3(9):e410-e420Slide5
HIV RNA < 50 c/
mL
at W48 by baseline HIV RNA and CD4 count
EVG/C/FTC/TDF
ATV + r + FTC/TDF
25
5010075
8781%8682
Overall
< 100,00008882
<
350> 350
86
79
> 100,000
HIV
RNA (copies/mL)
CD4 cell count (/mm
3
)
90
78
286
2862202146972146131143154Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 ; Squires K. Lancet HIV 2016; 3(9):e410-e420Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in WomenWAVESSlide6
Emergence of resistance
EVG/C/FTC/TDF
ATV
+
r + FTC/TDF
Resistance
analysis population1921
Final RAP*712Resistance mutations emergence
0
3NRTI-resistance1
3D67D/N
1
0
M184V/I
0
3
K65R
0
0
INSTI-resistance
0
0
Primary PI-resistance
00* Criteria :Suboptimal response (HIV RNA ≥ 50 c/mL and < 1 log10 reduction from baseline by W8, confirmed)Virologic rebound (> 400 c/mL after achieving HIV RNA < 50 c/mL, or 2 consecutive visits with > 1 log10 increase from nadir)HIV RNA > 400 c/mL at W48Exclusion of patients with HIV RNA < 50 c/mL at subsequent visitsStudy WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in WomenWAVESSquires K. Lancet HIV 2016; 3(9):e410-e420Slide7
EVG/C/FTC/TDF
ATV + r + FTC/TDF
p
DXA assessment
at baseline, spine ; hip, N
at W48, spine ; hip, N
138 ; 120
136 ; 118
150 ;128
150 ; 128
Median change from baseline in BMD
Lumbar spine
- 3.23 %
- 3.28 %
0.69
Hip
- 2.99 %
- 2.68 %
0.37
Median change from baseline in
eGFR
(
mL
/min), Cockroft-Gault formula- 6.1- 2.40.15Renal and bone mineral density (DXA) assessmentsEVG/C/FTC/TDFATV + r + FTC/TDFpTotal cholesterol+ 7+ 20.02Other lipid parameters (LDL-c, HDL-c, Triglycerides, Total cholesterol:HDL-cholesterol rationsMedian change from baseline in fasting lipids (mg/dL)Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in WomenWAVESSquires K. Lancet HIV 2016; 3(9):e410-e420Slide8
EVG/C/FTC/TDF
ATV + r + FTC/TDF
Adverse events leading to discontinuation, N
5 discontinuations
19 discontinuations
Hepatobiliary disorder
1
4
Gastro-intestinal disorder
3
4
Pulmonary tuberculosis
1
0
Renal
0
2
Skin disorder
2
9
Drug hypersensitivity
0
1
Adverse event in ≥ 10% of patients, %0Headache1615Upper respiratory tract infection1615Nausea1514Vomiting1014Jaundice / Icterus< 1 / < 111 / 12Grade 3-4 laboratory abnormalities in ≥ 2%, %
Serum amylase elevation
2
2
Neutropenia < 1000/mm
3
2
3
ALT elevation
2
2
Hyperbilirubinemia
< 1
46
Glycosuria
0
2
A
dverse events and Grade 3-4 laboratory abnormalities
Study
WAVES
: EVG/C/FTC/TDF QD
vs
ATV + r
+ FTC/TDF QD in Women
WAVES
Squires K. Lancet HIV 2016; 3(9):e410-e420Slide9
Summary
EVG/C/FTC/TDF QD was
virologically
non inferior and superior to ATV + r + FTC/TDFSimilar virologic
response of the 2 regimens in different subgroups of patients, including those with high HIV RNA or CD4 < 350/mm
3 at enrolmentDevelopment of major resistance mutations occurred inNo patients on EVG/C/FTC/TDF3 patients on ATV + r + /FTC/TDF: NRTI mutations, no PI mutationsDiscontinuation because of adverse events was lower with EVG/C/FTC/TDF
Less incidence of icterus and hyperbilirubinemia with EVG/C/FTC/TDF Comparable changes in fasting lipids in both groups, except for total cholesterol which elevation was higher with EVG/C/FTC/TDF Median decreases in estimated glomerular filtration rate and in spine and hip BMD were modest and not different between the 2 groupsStudy WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in WomenWAVES
Squires K. Lancet HIV 2016; 3(9):e410-e420