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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 months

HIV RNA < 200c/mL ≥ 3 monthsN = 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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CharacteristicFTC/TDF

n=1553TC/ABC

n=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) 0

Time 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

%

TL

OV

R R

es

po

nd

ers

HIV

-1 R

NA

< 2

00

c/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

# S

ub

ject

s w

ith

Vir

olo

gic

Fai

lure

*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) 0

Serious 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 WeeksE

sti

ma

ted

GF

R b

y M

DR

D

(mL

/min

/1.7

3m

2)

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

Es

tim

ate

d G

FR

by

IB

W C

G

(mL

/min

)

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/TDF

3TC/ABC

Med

ium

Ch

ang

e F

rom

BL

at

We

ek 4

8 (m

g/d

L [

mm

ol/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, MS

John Flaherty, PharmD Janet Ecker, BSN, MBA

Lauren Dau, PharmD Naz Barlow, MS

Kirsten 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 viremia

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