R Campo 1 , E DeJesus 2 , H Khanlou 3 , H Wang 4 , K White 4 ,
description
Transcript of R Campo 1 , E DeJesus 2 , H Khanlou 3 , H Wang 4 , K White 4 ,
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SWIFT Study: Switching From Lamivudine/Abacavir (3TC/ABC)
to Emtricitabine/Tenofovir DF (FTC/TDF)
R Campo1, E DeJesus2, H Khanlou3, H Wang4, K White4, L Dau4, J Flaherty4, and T Fralich4
1Univ of Miami Sch of Med, Miami, FL, USA;2Orlando Immunology Ctr, Orlando, FL, USA;
3AIDS Healthcare Foundation, Los Angeles, CA, USA;4Gilead Sciences, Inc., Foster City, CA, USA
6th IAS Conference on HIV Pathogenesis, Treatment and PreventionJuly 17-20, 2011, Rome, ItalyOral Presentation WELBB03
Study GS-164-0216
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1. DHHS Guidelines, January 10, 2011, pp 51-522. Arribas, JR, ACTG 5202, JAIDS, 20083. Post FA, ASSERT, JAIDS, 2010 4. Mallal, S, HLA-B*5702, NEJM, 2008
Background
5. D:A:D Study Group, Lancet, 20086. Saxs, 5202, NEJM, 20097. Martinez E, et al. BICOMBO, IAS 20078. Moyle G, et al. ROCKET I, HIV10 2010
• DHHS and IAS-USA Guidelines1 list FTC/TDF as the “preferred” NRTI backbone and 3TC/ABC as an alternative backbone– The DHHS Committee based its recommendations on ACTG 52022, ASSERT3,
hypersensitivity reactions (HSR) to 3TC/ABC4, D:A:D Cohort5
• EACS Guidelines list both FTC/TDF and 3TC/ABC as recommended and when using ABC, states the need for HLA-B*5701 testing and caution in persons with higher risk of CV disease and baseline high viral load6
• BICOMBO showed less virologic failures7 at week 48 and ROCKET I demonstrated lipid benefits8 in subjects on FTC/TDF compared to 3TC/ABC
• These Guidelines and published studies may prompt clinicians to consider switching virologically stable patients from 3TC/ABC to FTC/TDF
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Prospective, open-label, multicenter, randomized, Phase 4, 48-week study conducted in Canada, Puerto Rico, and the United States
FTC/TDF + PI/rn=155
3TC/ABC + PI/rn=156
48 weeks
Ran
dom
ized
1:13TC/ABC +PI/r
for ≥3 monthsHIV RNA < 200c/mL ≥ 3 months
N = 311 randomized and treated
SWIFTStudy Design
No prior history of resistance to study drugs No CD4 restrictionStratified by PI: 32% LPV/r vs. 68% Non-LPV/r
LPV/r ATV+RTV FPV+RTV 100mg FPV+RTV 200mg DRV+RTV
FTC/TDF 48/311 (15%) 62/311 (20%) 22/311 (7%) 12/311 (4%) 9/311 (3%)
3TC/ABC 53/311 (17%) 60/311 (19%) 12/311 (4%) 19/311 (6%) 11/311 (4%)
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Primary Endpoint• Proportion of subjects with HIV‑1 RNA 200 copies/mL through Week 48
based on TLOVR (virologic failure*, premature discontinuation for any reason, ARV modifications = TLOVR failure)
• The FTC/TDF arm would be declared non-inferior to the 3TC/ABC arm if the lower bound of the 95% CI was greater than −12%
Secondary Endpoints• Proportion who experienced virologic failure through Week 48• Safety and tolerability through 48 weeks • Change from baseline in GFR by Cockcroft Gault and MDRD• Change from baseline in fasting lipid parameters (TC, LDL, HDL, TG,
and TC/HDL ratio) through 48 weeks
Study Endpoints
*Virologic failure pre-defined as confirmed HIV RNA > threshold, or last on-study > threshold, with the thresholds of HIV‑1 RNA at 200 copies/mL
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Characteristic FTC/TDFn=155
3TC/ABCn=156
Age, median (IQR), years 46 (40, 52) 46 (41, 53)Male gender, n (%) 129 (83) 134 (86)Race, n (%) White 96 (62) 106 (68) African American 43 (28) 44 (28)HIV RNA c/mL, n (%) <50 139 (90) 145 (93) 50 to < 200 13 (8) 10 (6) 200 to < 400 2 (1) 1 (1) > 400 1 (1) 0Time since first ARV therapy, median (IQR), years 4 (2.5, 6.9) 3.7 (2.5, 6.7)CD4 cell count, median (IQR), cells/mm3 532 (354, 725) 532 (382, 728)Lipid modifying agent, n (%) 67 (43) 80 (51)
Baseline Characteristics
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Subject Disposition through Week 48
Subject Randomized N=312*
Subject Treated N=311†
FTC/TDFn=155n (%)
3TC/ABC n=156 n (%)
Completed 48 weeks of study 138 (89%) 139 (89%)
Discontinued study prematurely 17 (11%) 17 (11%)
Adverse events 7 3 Pregnancy 0 1 Lack of efficacy 0 1 Withdrew consent 5 4 Lost to follow-up 4 5 Investigator discretion 0 3 Protocol violation 1 0
*1 subject randomized to FTC/TDF and not treated† As treated (n=311) for safety analysis; ITT (n=310) for efficacy analysis (as 1subject in the FTC/TDF had major protocol
violation with baseline resistance to study drug)
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Primary Endpoint: TLOVR Responders with HIV-1 RNA <200 c/mL through Week 48
86% 83%
0%
20%
40%
60%
80%
100%
FTC/TDF 3TC/ABC
% T
LOVR
Res
pond
ers
HIV
-1 R
NA
< 20
0c/m
L
-5.1 3.0 11.2
-12 0 12
95% CI for difference (FTC/TDF- 3TC/ABC)
% Difference TLOVR Responder Rate
Favors FTC/TDF ◄ Favors 3TC/ABC
3
11
0
5
10
15
FTC/TDF 3TC/ABC
# Su
bjec
ts w
ith V
irolo
gic
Failu
re
*VF is estimated by Kaplan Meier product limit method and log-Rank test is used for detecting treatment differences through Week 48
Virologic Failure* (HIV-1 RNA 200 c/mL) through Week 48
p=0.034 • 3TC/ABC VFs (n=11)– 8 No genotypes performed (VL<1,000 c/mL)– 3 Genotypes (no resistance to study drug)
• #1: Wk 48 PI: L63T, A71V, V77I• #2: WK 48 PI: L33V, L63P, L89M• #3: WK 24 NNRTI: V90I, K103N, V179V/I
• FTC/TDF VFs (n=3)– 3 No genotypes performed (VL<1,000 c/mL)
• BLIPS (n=5)– 3 3TC/ABC– 2 FTC/TDF
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Adverse Events (AE) Summary
FTC/TDFn=155n (%)
3TC/ABC n=156 n (%)
Number of subjects with any treatment-emergent AE 112 (72) 120 (77)All Grades of Treatment-emergent AEsReported for ≥ 5% of Patients
Diarrhea 13 (8) 11 (7)
Headache 8 (5) 5 (3)Cough 8 (5) 8 (5)
Grade 3 or 4 Adverse Events 13 (8) 16 (10)Grade 3 or 4 AE related to Study Drug 1 (1) 0Serious AE 12 (8) 11 (7)AE Leading to Study Drug Discontinuation 7 (5) 3 (2) Renal events* 1 1 Death† 1 2 Other‡ 5 0
*Renal events: One subject discontinued FTC/TDF due to mild elevation in Cr from 1.0 to 1.3mg/dl; One subject discontinued 3TC/ABC due to renal failure/dehydration†Deaths: FTC/TDF arm 1 suicide; 3TC/ABC arm 1 homicide, 1 lymphoma‡Other: Multiple CNS symptoms and rash; malaise and lower back pain; decreased weight; cellulitis and streptococcal sepsis; and rash
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0 4 12 24 36 480
20
40
60
80
100
120
0 4 12 24 36 480
20
40
60
80
100
120
eGFR through 48 WeeksEs
timat
ed G
FR b
y M
DR
D
(mL/
min
/1.7
3m2 )
155 153 147 144 139 137156 153 150 146 142 139
FTC/TDF3TC/ABC
FTC/TDF3TC/ABC
p=0.008
- 9.2
Week155 153 147 144 139 137156 153 150 146 142 139
Estim
ated
GFR
by
IBW
CG
(m
L/m
in)
p=0.012
FTC/TDF3TC/ABC
- 4.5
FTC/TDF3TC/ABC
Week
MDRD Cockcroft-Gault
Plotted median at each visit; p-values for comparison between treatment groups on change from baseline to Week 48 are from Wilcoxon Rank-Sum test
- 8.3- 4.2
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Fasting Lipids Change from Baseline Values at Week 48
-25
-20
-15
-10
-5
0
5
FTC/TDF3TC/ABC
Med
ium
Cha
nge
From
BL
at W
eek
48
(mg/
dL [m
mol
/L])
P =<0.001*
P =0.007*
P =0.26* P =0.074*
*p values for between arm differences from Wilcoxon rank-sum testTC = Total Cholesterol, LDL = Low-Density Lipoprotein, HDL = High-Density Lipoprotein, TG = Triglycerides
TC
LDL
HDL
TG-21[-0.54]
-3 [-0.08]
-7 [-0.18]
2 [0.05]
-1 [-0.03]-0 [0.00]
-18 [-0.20]
-9 [-0.10]
No significant difference between groups in total cholesterol/HDL ratio at Week 48
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Conclusions
• Through 48 weeks, switching to FTC/TDF was non-inferior to remaining on 3TC/ABC
• Significantly fewer subjects who switched to FTC/TDF experienced virologic failure compared to those who remained on 3TC/ABC through Week 48
• Switching to FTC/TDF resulted in significant improvement in fasting LDL and TC
• Declines in eGFR of unclear clinical significance were seen in both arms and were higher in the FTC/TDF arm
• Switching to FTC/TDF was safe and well tolerated with similar AEs observed between arms
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Acknowledgements
• All of the subjects
• All investigators who participated in the SWIFT study
• Thank you to the study team for their dedication David Piontkowsky, JD, MD Ramin Ebrahimi, MS
Todd Fralich, MD Maggie Wang, MSJohn Flaherty, PharmD Janet Ecker, BSN, MBALauren Dau, PharmD Naz Barlow, MSKirsten White, PhD Betsy Leung, BS
Back-up
Forthcoming analysis to be presented at future conferences in 2011
• Analysis of secondary endpoints– Proportion of subjects with HIV‑1 RNA < 50 copies/mL– KM analysis proportion with VFs
• Responses by stratified by:– Protease inhibitor used– Baseline comorbidities– CV/Framingham– Lipid analysis based NCEP thresholds and lipid lowering agents
• Resistance in subject with detectable viremia15