XVII International AIDS ConferenceAugust 3-8, 2008

Mexico City, MexicoPoster # THPE0186

Renal Safety Profile of Tenofovir DF (TDF)-containing vs. Thymidine Analog-

containing Regimens Through 144 Weeks in Antiretroviral-naïve Patients

JE Gallant,1 AL Pozniak,2 E DeJesus,3 SS Chen,4 AK Cheng,4 and J Enejosa4

1Johns Hopkins Univ School of Medicine, Baltimore, MD; 2Chelsea & Westminster Hosp, London, UK; 3Orlando Immunology Center, Orlando, FL; 4Gilead Sciences, Inc., Foster City, CA

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Background

• In clinical trials, TDF has not been associated with nephrotoxicity; nevertheless, several spontaneous cases of renal dysfunction associated with use of TDF have been reported, mostly in patients with underlying renal impairment, pre-existing systemic conditions, or in patients taking nephrotoxic agents.

• We investigated the renal safety profile of TDF in two large, long-term, randomized, prospective clinical studies

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Study 903 Study Design

ART-naivepatients

(N = 600)

randomized1:1

TDF QDEFV QD3TC BIDd4T placebo BID

d4T BID

EFV QD

3TC BID

TDF placebo QD

144 wks

144 wks

Any CD4 cell countHIV RNA > 5,000 copies/mLScreening GFR 60 mL/minSerum creatinine < 1.5 mg/dLSerum phosphorus 2.2 mg/dL

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Study 934 Study Design

ART-naïvepatients

(n = 511)

randomized1:1

144 wks

144 wks

Any CD4 cell countHIV RNA > 10,000 copies/mLScreening GFR 50 mL/minSerum creatinine < 1.5 mg/dLSerum phosphorus 2.2 mg/dL

TDF QD

FTC QD

EFV QD

AZT/3TC BID

EFV QD

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Methods

• We evaluated the renal parameters in antiretroviral-naive patients who initiated a TDF-containing vs a thymidine analog-containing regimen (Control) through 144 weeks in Studies 903 and 934

• We explored changes from baseline in renal laboratory parameters in the following sub-populations:

– Black patients

– Patients ≥50 yrs old at baseline

– Patients with mild renal impairment at baseline

– Defined as an estimated glomerular filtration rate (GFR) by Cockcroft-Gault (CG) of 50-80 mL/min

– Patients taking concomitant anti-hypertensive and/or anti-diabetic medications

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Baseline Characteristics

TDF(n=556)

Control(n=555)

p-valuea

Mean Age in yrs [Range] 36 [18 to 80] 37 [18 to 67] 0.54

Male 79% 80% 0.65

Race Caucasian Black Hispanic Other

60%23%11%6%

63%19%11%7%

0.40

Median HIV-1 RNA (log10 c/mL) 5.0 4.9 0.39

Median CD4 cell count (cells/mm3) 239 255 0.52

a. Wilcoxon rank sum test for continuous variables and Fisher’s Exact test for categorical variables

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Renal Parameters at Baseline

a. Median (IQR) valuesb. Modification of Diet in Renal Disease formula for estimated GFR

Renal Parametersa TDF[n=556]

Control[n=555]

Serum creatinine in mg/dL 0.8 (0.7, 0.9) 0.8 (0.7, 0.9)

Serum phosphorus in mg/dL 3.5 (3.1, 3.9) 3.5 (3.1, 3.9)

Estimated GFR Cockcroft-Gault (CG) in mL/min MDRDb in mL/min/1.73m2

120 (102, 142)110 (96, 123)

121 (103, 142)109 (95, 126)

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Change in Renal Parameters at Week 144

a. Median (IQR) values

Change from Baselineat Week 144a

TDF[n]

Control[n]

p-valuea

Serum creatinine in mg/dL0 (-0.1, 0.1)

[378]0 (-0.1, 0)

[336]<0.001

Serum phosphorus in mg/dL-0.1 (-0.5, 0.3)

[378]0 (-0.4, 0.4)

[336]0.08

Estimated GFR CG in mL/min MDRD in mL/min/1.73m2

-2 (-15, 10)[373]

-2 (-17, 8)[378]

3 (-10, 15)[334]

-1 (-4, 18)[336]

0.001<0.001

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Renal Parameters Through 144 Weeks

a. Confirmed toxicity: 2 consecutive valuesb. UnconfirmedP=NS for comparison between groups

% of Patientswith Maximum Toxicity

TDF[n]

Control[n]

Serum creatininea ≥ 2.1 mg/dL0

[543]<1%[542]

Serum phosphorusa < 2.0 mg/dL<1%[543]

<1%[542]

Proteinuriab ≥100 mg/dL5%

[547]6%

[545]

• No patients in TDF group discontinued due to renal adverse events or laboratory abnormalities

– 1 patient in Control group (Study 903) discontinued due to acute renal failure

• No patient developed Fanconi syndrome or proximal tubular dysfunction

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Median Estimated GFR

Weeks

Es

tim

ate

d G

FR

TDF N= 549 503 452 423 402 388 378Control N= 550 486 438 403 369 348 336

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD Control

Weeks

Es

tim

ate

d G

FR

TDF N= 549 503 452 423 402 388 378Control N= 550 486 438 403 369 348 336

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDFCG TDF CG ControlCG ControlMDRD TDFMDRD TDF MDRD ControlMDRD Control

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Individual Plots of GFR by Cockcroft-Gault in Patients Whose Baseline GFR are in the Lowest

Quartile (25th Percentile)

TDF ControlGFR by CG

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Individual Plots of GFR by MDRD in Patients Whose Baseline GFR are in the Lowest Quartile

(25th Percentile)

TDF ControlGFR by MDRD

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Black Sub-population: Median Estimated GFRE

sti

ma

ted

GF

R

Weeks

TDF N= 129 114 94 91 85 78 74Control N= 102 86 66 60 58 49 47

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD Control

Es

tim

ate

d G

FR

Weeks

TDF N= 129 114 94 91 85 78 74Control N= 102 86 66 60 58 49 47

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD ControlCG TDFCG TDF CG ControlCG ControlMDRD TDFMDRD TDF MDRD ControlMDRD Control

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Patients ≥ 50 yrs old at Baseline:Median Estimated GFR

Es

tim

ate

d G

FR

Weeks

TDF N= 54 50 46 45 43 41 41Control N= 53 43 38 36 30 30 28

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD Control

Es

tim

ate

d G

FR

Weeks

TDF N= 54 50 46 45 43 41 41Control N= 53 43 38 36 30 30 28

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD ControlCG TDFCG TDF CG ControlCG ControlMDRD TDFMDRD TDF MDRD ControlMDRD Control

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Patients with Mild Renal Impairment at Baseline (GFR 50-80 mL/min): Median Estimated GFR

CG TDF CG ControlMDRD TDF MDRD Control

Es

tim

ate

d G

FR

WeeksTDF N= 28 26 20 20 19 18 19Control N= 29 24 22 20 18 17 16

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD ControlCG TDFCG TDF CG ControlCG ControlMDRD TDFMDRD TDF MDRD ControlMDRD Control

Es

tim

ate

d G

FR

WeeksTDF N= 28 26 20 20 19 18 19Control N= 29 24 22 20 18 17 16

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Patients Taking Concomitant Anti-hypertensive and/or Anti-diabetic Medications:

Median Estimated GFR

CG TDF CG ControlMDRD TDF MDRD ControlE

sti

ma

ted

GF

R

Weeks

TDF N= 62 60 56 53 48 47 46Control N= 73 70 63 57 51 51 48

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

CG TDF CG ControlMDRD TDF MDRD ControlCG TDFCG TDF CG ControlCG ControlMDRD TDFMDRD TDF MDRD ControlMDRD ControlE

sti

ma

ted

GF

R

Weeks

TDF N= 62 60 56 53 48 47 46Control N= 73 70 63 57 51 51 48

0

20

40

60

80

100

120

140

0 24 48 72 96 120 144

Gallant JE, et al., WAIDS 2008; Poster #THPE0186

Conclusions

• This comparison of TDF-containing vs. thymidine analog-containing regimens in treatment-naïve patients did not demonstrate an increased incidence of renal dysfunction associated with TDF through 144 weeks

– No significant changes in estimated GFR by either CG or MDRD were observed in TDF arm

– No patient in TDF group discontinued due to renal adverse events or laboratory abnormalities

– No patient developed Fanconi syndrome or proximal tubular dysfunction

• Through 144 weeks, no clinically relevant changes in renal function were seen in black patients, patients ≥ 50 yrs old, patients with mild renal impairment or in patients taking anti-hypertensive and/or anti-diabetic medications