IntroductionCompared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) results in a 91% reduction in plasma tenofovir exposure1,2 TAF has demonstrated less impact on surrogate markers of renal and bone healthin multiple populations2-5

The clinical impact of these differences has not been characterized

ObjectiveTo determine whether biomarkers of renal function and clinically significant renal eventsdiffered between patients with HIV-1 receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) and TDF (E/C/F/TDF) in 2 randomized Phase 3 trials through 96 weeks

Methods

Two Phase 3 randomized, double-blind, double-dummy, active-controlled studies– Study 104 (North America, European Union, Asia; NCT01780506)– Study 111 (North America, European Union, Latin America; NCT01797445)– Patients stratified by HIV-1 RNA, CD4 cell count, and geographic region

Treatment-naïve HIV-1–infected adults with eGFR ≥50 mL/min/1.73 m2 were randomized 1:1 to a single-tablet regimen of E/C/F/TAF or E/C/F/TDFRenal function assessments included serum creatinine (SCr) and eGFR by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Measures of proteinuria were assessed at baseline and throughout the study

Results

Presented at the Conference on Retroviruses and Opportunistic Infections, February 22–25, 2016, Boston, MA © 2016 Gilead Sciences, Inc. All rights reserved.

References1. Ruane P, et al. J Acquir Immune Defic Syndr 2013;63:449-5; 2. Sax P, et al. Lancet 2015;385:2606-15; 3. Kizito H, et al. CROI 2015, abstr 953; 4. Mills A, et al. Lancet Infect Dis 2016;16:43-52; 5. Pozniak A, et al. J Acquir Immune Defic Syndr 2015 [Epub ahead of print].

AcknowledgmentsWe extend our thanks to the patients, their families, and all participating investigators. These studies were funded by Gilead Sciences, Inc.

Through 96 weeks, biomarker analysis indicated that renal tubular function was less affected by E/C/F/TAF than by E/C/F/TDFClinically significant renal events were less frequent in patients receiving E/C/F/TAF vs E/C/F/TDF, with 0 vs 6 discontinuationsdue to renal dysfunction (p=0.03)These data provide further support for the improved renal safety profile of TAF compared with TDF

Conclusions

AKI CKD by GFR

Renal D/C

Patient on E/C/F/TAFPatient on E/C/F/TDF

Patients With Renal Events

AKI, acute kidney injury; CKD, chronic kidney disease; D/C, discontinuation.

E/C/F/TAF QD Treatment-naïve adultsHIV-1 RNA ≥1000 copies/mLeGFR ≥50 mL/min/1.73 m2

1:1

E/C/F/TDF QD

n=866

n=867

Primary Endpoint

44184 960Week

Current AnalysisStudy Design

Studies 104 and 111

eGFR, estimated glomerular filtration rate.

Quantitative ProteinuriaUrine albumin:creatinine ratio (UACR)Urine protein:creatinine ratio (UPCR)

Tubular ProteinuriaUrine retinol-binding protein:creatinine ratio (RBP:Cr)Urine β2-microglobulin:creatinine ratio (β2m:Cr)

E/C/F/TAFn=866

E/C/F/TDFn=867

)44 ,82( 53)24 ,62( 33)3Q ,1Q( y ,ega naideM)51( 721)51( 331)%( n ,elameF

Race and ethnicity, n (%))75( 894)65( 584etihW)52( 312)62( 322egatireh nacirfA ro kcalB)01( 98)11( 19naisA)91( 761)91( 761onitaL ro cinapsiH

Median HIV-1 RNA, log10 copies/mL (Q1, Q3) 4.6 (4.1, 5.0) 4.6 (4.1, 5.0))022( 924)612( 624)DS( Lµ/ ,tnuoc llec 4DC naeM

HIV disease status, n (%))39( 008)09( 977citamotpmysA

)4( 43)6( 35noitcefni VIH citamotpmyS)3( 92)4( 13SDIA)1<( 4)1<( 3nwonknU

Median eGFR by CKD-EPI, mL/min/1.73 m2 (Q1, Q3) 106.5 (94.8, 118.0) 104.8 (93.2, 115.4)Proteinuria grade by urinalysis, n (%)

)09( 087)09( 8770)8( 76)9( 081)2( 81)1<( 82

3 )1<( 10)1<( 10gnissiM)5( 04)3( 52)%( n ,sutillem setebaiD)71( 741)41( 911)%( n ,noisnetrepyH

)2( 41)1( 01)%( n ,esaesid ralucsavoidraC)21( 401)11( 19)%( n ,aimedipilrepyH

Baseline Demographics and Renal Parameters

Q, quartile; SD, standard deviation.

150 y White Male

241 y Black Male

337 y Black Male

453 y Hispanic Female

550 y White Male

651 y White Male

Baseline Characteristics No known contributing comorbidities or medications

HypertensionBP 126–152/70–86 mm Hg (untreated)

Hypertension, renal diseaseBP 118–168/62–96 mm Hg on losartan, nifedipine, hydrochlorothiazide, clonidine, furosemide

Hypertension, diabetes, renal diseaseBP 108–148/66–90 mm Hg on losartan/candesartan

No known contributing comorbidities or medications

Chronic treatment with ibuprofen since 2010

seYA/NseYoNoN YesNormoglycemic Glycosuria

seYseYseYseYseY YesProximal Renal Tubulopathy*

Renal Biomarkers†

Renal Function Assessments

Quantitative Proteinuria

Tubular Proteinuria

E/C/F/TDF Discontinuation

New Regimen

Reason for Discontinuation‡ eninitaerc detavelEeruliaf laneRyhtaporhpeNeruliaf laneRRFG desaerceD Fanconi syndrome

0 200 400 600 8000 100 200 300 400

eGFR

(mL/

min

/1.7

3 m

2 )m

g/g

µg/g

0 100 200 300 400 5000

100

200

300

400

0 50 100 150 200 2500

100

200

300

400

0 200 400 600 8000

100

200

18000

10000

0 200 400 600 8000

100

200

1000

2000

0 200 400 600 8000

100

200

300

400

0 200 400 600 8000

100

200

300

400

500

0 100 200 300 400 5000

100

200

300

5000

3000

2000

1000

10000

Study Day

0 50 100 150 200 2500

100

200

300

Study Day

0 200 400 600 8000

100

200

300

50000

100000

Study Day

0 200 400 600 8000

100

200

300

50000

100000

150000

Study Day

0 200 400 600 8000

100

200

300

10000

20000

30000

40000

Study Day0 200 400 600 800

0

100

200

300

10000

20000

30000

Study Day

Day 425

ABC/3TC + NVP

Day 194

ABC/3TC + DRV/r

Day 328 Day 591

ABC/3TC/DTG

Day 610

ABC/3TC/DTG

Day 72

0

20

40

60

80

100

0 200 400 600 8000

2

4

6

8

10

0

20

40

60

80

100

0

2

4

6

8

10

0

20

40

60

80

100

0 50 100 150 200 2500

2

4

6

8

10

0

20

40

60

80

100

5000

2

4

6

8

10

0

20

40

60

80

100

0 200 400 600 8000

2

4

6

8

10

0

20

40

60

80

100

0 200 400 600 8000

2

4

6

8

10

Hypertensive crisis, Day 312Cerebrovascular accident, Day 320

eGFR SCr

UPCR UACR

β2m:Cr RBP:Cr

Tubulointerstitialnephritis diagnosis,

Day 637

3TC + DDI + RAL ABC/3TC + DRV/r

β2m:Cr

RBP:Cr

UACR

UPCR

eGFR

SCr (m

g/dL)

No Patients on E/C/F/TAF Discontinued for Renal Effects; 6 Discontinued E/C/F/TDF for Renal Effects

*Clinically determined; †Dotted lines represent critical thresholds; ‡Discontinuation for renal adverse event was at discretion of investigator, not protocol defined. ABC/3TC, abacavir/lamivudine; BP, blood pressure; DDI, didanosine; DRV/r, ritonavir-boosted darunavir; DTG, dolutegravir; N/A, not available; NVP, nevirapine; RAL, raltegravir.

Longer-Term Renal Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil FumarateBart Rijnders,1 Frank Post,2 Armin Rieger,3 Eugenio Teofilo,4 David Wohl,5 Paul Sax,6 Susan Guo,7 Andrew Cheng,7 Moupali Das,7 Marshall Fordyce7

1Erasmus MC, Rotterdam, The Netherlands; 2King’s College London, UK; 3Medical University of Vienna, Austria; 4Centro Hospitalar de Lisboa Central, EPE, Lisbon, Portugal; 5The University of North Carolina at Chapel Hill, NC; 6Brigham and Women’s Hospital, Boston, MA; 7Gilead Sciences, Inc., Foster City, CA

682Gilead Sciences, Inc.

333 Lakeside Drive Foster City, CA 94404

800-445-3252

Through 96 weeks, median change from baseline in estimated creatinine clearance was significantly lower withE/C/F/TAF than E/C/F/TDF (-2.0 vs -7.5 ml/min/1.73 m2, p<0.001)

Acute kidney injury (≥50% decline in eGFR) occurred in 3 (0.3%) vs 11 (1.3%) patients receiving E/C/F/TAF vsE/C/F/TDF (p=0.06)– eGFR recovered in 2 of 3 patients treated with E/C/F/TAF

and 7 of 11 with E/C/F/TDF – Among E/C/F/TDF patients who did not recover, 2 discontinued

drug due to persistent renal dysfunction

Patie

nts,

n

High UACR Low eGFR

0

10

20

30

40

22

3

25

12

11

6

Excluding Patients With Abnormal Baseline

E/C/F/TAF

8

E/C/F/TDFE/C/F/TAFE/C/F/TDF

All Patients

New-Onset Chronic Kidney Disease*

*UACR >30 mg/g or eGFR <60 mL/min/1.73 m2 for ≥90 days.

Med

ian

% C

hang

eFr

om B

asel

ine

(Q1,

Q3)

-20

0

20

40

UPCR UACR

-20

0

20

40

E/C/F/TAF: 44 mg/gE/C/F/TDF: 44 mg/g

5 mg/g5 mg/g

-40

0

40

80

-40

0

40

80

RBP:Cr β2m:Cr

69 kW84 kWLB69 kW84 kWLB84 kWLB Wk 96 69 kW84 kWLB

64 µg/g67 µg/g

101 µg/g103 µg/g

Baseline

p <0.001p <0.001

p <0.001

p <0.001

Changes in Proteinuria Through Week 96