Transcript VIREAD™ (tenofovir disoproxil fumarate)

VIREAD (Tenofovir DF)
Update
Viread Update
 Pharmacokinetics
 Safety & Tolerability
 Efficacy
 Virology
Pharmacokinetics
Tenofovir DF Pharmacology
 Once-daily dosing
– Long intracellular half-life (tenofovir-DP)
• Activated cells: 10 hours; Resting cells: 50 hours
– Serum t1/2 17 hours
 Renally cleared
– interval adjustment for CrCl < 50 mL/min
 Bioavailability
– Can be given without regard to food*
* US package insert August 2003
Tenofovir DF Pharmacology (cont’d)
 Not a substrate or inhibitor of human CYP450 enzymes
 No significant plasma drug interactions with:
– FTC
– 3TC
– ABC
– EFV
– LPV/r
– IDV
– FOS-APV
– TPV
 Clinically significant drug interactions with:
– ddI (plasma levels increased 44-60%)
– ATV (AUC  25%)
Study 984
Tenofovir DF and Didanosine EC
Interaction: Background & Objectives
Background:
 Previous PK studies with ddI EC 400 mg have
demonstrated increased ddI exposures when
co-administered with TDF1
Objectives:
To evaluate PK of ddI EC 250mg dosed:
 Separated dosing
– on an empty stomach two hours prior to TDF and a light meal
 In a simplified dosing regimen
– together with TDF and a light meal
– together with TDF on an empty stomach
1 Viread
Prescribing Information
Kearney B, et al. 10th Conference on Retroviruses and Opportunistic Infection, Feb. 2003, Abstract 533
Study 984
Tenofovir DF and Didanosine EC
Interaction: Results
ddI AUC
(ghr/mL)
ddI Cmax
(g/mL)
2.75
1.18
2.74 (0%)
1.06 ( 11%)
- together with a light meal
(simplified dosing)
2.44 ( 11%)
0.84 ( 29%)
- together on an empty stomach
(simplified dosing)
3.14 ( 14%)
1.09 ( 8%)
Regimen
ddI EC 400 mg Alone
ddI EC 250 mg + TDF
- separated by 2 hours
(per current regulatory labeling)
Kearney B, et al. 10th Conference on Retroviruses and Opportunistic Infection, Feb. 2003, Abstract 533
Viread Prescribing Information
Study 984
Tenofovir DF and Didanosine EC
Interaction: Results
 ddI EC 250 mg dosed with TDF, in the presence
or absence of food, results in drug exposures
similar to ddI EC 400 mg dosed alone
 When TDF and ddI is given, dose of ddI should be
decreased to 250 mg in patients 60 kg*
Kearney B, et al. 10th Conference on Retroviruses and Opportunistic Infection, Feb. 2003, Abstract 533
Viread Prescribing Information
* US package insert August 2003
TDF and FTC
Concentration (ng/mL)
3000
No Interaction Observed
1000
emtricitabine alone
emtricitabine + TDF
100
TDF alone
TDF + emtricitabine
10
0
6
mean  95%CI
Blum et al. ICAAC 2003, poster A-1621
12
Time (hr)
18
24
TDF and LPV/r
Steady-State LPV and RTV Concentrations
Concentration (ng/mL)
10000
LPV alone
LPV + TDF
1000
100
RTV alone
RTV+TDF
10
LPV IC50(wt)
1
0
mean  95%CI
Kearney et al. ICAAC 2003, poster A-1617
6
Time (hr)
12
Tenofovir Concentration (ng/mL)
TDF and LPV/r
Steady-State TDF Concentration
1000
TDF alone
TDF + LPV/r
100
TDF AUC 32%
10
0
6
mean  95%CI
12
Time (hr)
Kearney et al. ICAAC 2003, poster A-1617
18
24
TDF+LPV/r-Containing Regimens:
Long-Term Safety Assessment (Study 908)
 LPV/r was used in 271/296 (94%) of patients
– mean duration of concomitant use: 63 weeks
(maxiumum: 96 weeks)
 The incidence of confirmed changes in serum creatinine to
> 2.0 mg/dL or serum phosphorus < 1.5 mg/dL was < 1%
 TDF discontinuation due to changes in serum creatinine
occurred in 5 of 271 TDF+LPV/r-treated patients with
advanced disease
 Changes in serum creatinine and phosphorus similar to
background incidence reported in advanced patient
population1
Kearney et al. ICAAC 2003, poster A-1617
1Fisher
et al. AIDS 2001, 15: 1695-1700
TDF and ABC
No Interaction Observed
Concentration (  g/mL)
10
ABC was measurable in plasma
for 6 to 8 hours following dosing
1
0.1
ABC alone
ABC + TDF
0.01
0
mean  95%CI
Kearney et al. ICAAC 2003; poster A-1615
6
12
Time (hr)
18
24
Puzzle-2 Study
Steady State ATV and RTV PK with TDF (N=11)
ATV/r 300/100 mg + TDF provides
an IQ higher than ATV 400 mg alone
and similar to historical data for ATV/r
Concentration (ng/mL)
10000
Historical data
for boosted ATV
1000
100
ATV alone
ATV + TDF
Historical data for
unboosted ATV
RTV alone
RTV + TDF
ATV IC50(wt)
10
0
6
mean  95%CI
12
Time (hr)
Taburet AM, et al. 10th CROI, Boston 2003, #537
Data on file, BMS Co., 2003
18
24
ATV and TDF + RTV
CMAX
ATV 400
ATV 400
TDF 300
%
change
ATV 300
RTV 100
ATV 300
RTV 100
TDF 300
%
change
5785
4579
( 21)
4422
3190
( 28)
118
70
( 40)
636
491
( 23)
29196
21,866
( 25)
46,073
34,459
( 25)
(ng/ml)
CMIN
(ng/ml)
AUC
(ng*hr/ml)
Data on file with BMS and Gilead
Taburet AM et al. 10CROI Feb 2003. Abstract # 537
BMS 045
Virologic Response (ITT)* at Week 24
Regimens (all with TDF+NRTI)
Percent Responders
100
ATV 300/RTV (N = 120)
ATV 400/SQV (N = 115)
80
 400 c/mL
LPV/RTV (N = 123)
64
62
60
44
42
39
40
23
20
 50 c/mL
0
B/L
2
4
8
12
Weeks
16
For LOQ = 400 c/mL:
ATV 300/RTV – LPV/RTV Difference Estimate (95% Cl) = 2.4 (-9.8, 14.5)
*Time to Loss of Virologic Response
24
Other PK Studies
 No Interaction Observed:
– Methadone1
– Oral Contraceptive2, 3
– Ribavirin4
1Smith
P et al. 2nd IAS, July 2003, Poster 869; 2 Viread Prescribing Information;
3Kearney
4Margot
et al. 43rd ICAAC, September 2003, Poster A-1618
and Miller. 2nd IAS, July 2003, Poster 980
Summary of Tenofovir Drug
Interaction Data
Agent Studied
FTC
3TC
d4T
ABC
ddl
FosAPV/r
IDV
LPV
RTV
ATV
EFV
Methadone
Oral contraceptives
No Systemic PK
Interaction




Dose Change w/ TDF
ddl 250 mg







Consider ATV/r
300/100
Renal Safety
Study 903
Study Design
ART-naive
patients
TDF
EFV
3TC
d4T placebo
QD
QD
BID
BID
Stratification by:
• plasma HIV RNA >/ 100,000 c/ml
(N = 600)
randomized
1:1
144 wks
• CD4 count /< 200 cells/mm³
d4T
EFV
3TC
TDF placebo
BID
QD
BID
QD
Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b
144 wks
Study 903
Serum Creatinine through Week 96
Maximum Toxicity Grade
0-96 Weeks in mg/dL
TDF + 3TC + EFV
(n=296)
d4T + 3TC + EFV
(n=296)
10 ( 3%)
7 ( 2%)
2 (2.1-3.0)
2 (1%)
0 (0%)
3 (3.1-6.0)
0 (0%)
2 (1%)
4 (>6.0)
0 (0%)
0 (0%)
1 (0.5 from baseline)
Gallant et al. ICAAC. 2003. Abstract H840.
Study 903
Consecutive Visits with Graded Creatinine
15
TDF+3TC+EFV
d4T+3TC+EFV
Number of Patients
12
9
10
5
4
1
1
0
0
1
2
Consecutive Visits
Gallant et al. ICAAC. 2003. Abstract H840.
3
Study 903
Serum Phosphorus through Week 96
Maximum Toxicity Grade
0-96 Weeks in mg/dL
TDF + 3TC + EFV
(n=296)
d4T + 3TC + EFV
(n=296)
1 (2.0-2.2)
9 (3%)
9 (3%)
2 (1.5-1.9)
8 (3%)
7 (2%)
3 (1.0-1.4)
1 (1%)
1 (1%)
4 (1.0)
0 (0%)
0 (0%)
Gallant et al. ICAAC. 2003. Abstract H840.
Study 903
Consecutive Visits with Graded Serum
Phosphorus through Week 96
20
Number of Patients
18
TDF+3TC+EFV
d4T+3TC+EFV
17
15
10
5
3
1
0
1
2
Consecutive Visits
Gallant et al. ICAAC. 2003. Abstract H840.
Study 903
Proteinuria through Week 96
Maximum Toxicity Grade
0-96 Weeks in mg/dL
TDF + 3TC + EFV d4T + 3TC + EFV
(n = 296)
(n = 296)
1 (30-99)
35 (12%)
46 (16%)
2 (100-300)
18 (6%)
17 (6%)
3 (>300)
0 (0%)
0 (0%)
4 Nephrotic Syndrome
0 (0%)
0 (0%)
Gallant et al. ICAAC. 2003. Abstract H840.
Study 903
Glucosuria through Week 96
Maximum Toxicity Grade
0-96 Weeks in mg/dL
TDF + 3TC + EFV d4T + 3TC + EFV
(n = 296)
(n = 296)

1 ( 250)
2 (1%)
3 (1%)
2 (250-500)
2 (1%)
1 (1%)
3 (500-1000)
2 (1%)
3 (1%)
>
4 ( 1000)
0 (0%)
0 (0%)
Gallant et al. ICAAC. 2003. Abstract H840.
Study 903
Mean Increase from Baseline in Calculated
Creatinine Clearance (Calc Cr Cl): Week 96
mL/min
TDF + 3TC + EFV d4T + 3TC + EFV
(n = 296)
(n = 296)
Baseline
122
125
Week 48
2
8
Week 96
1
4
Gallant et al. ICAAC. 2003. Abstract H840.
Study 903
Summary of Results:
Parameters Through Week 96
TDF+3TC+EFV
(n = 296)
d4T+3TC+EFV
(n = 296)
Graded Serum Creatinine
12 ( 4%)
9 ( 3%)
Graded Serum Phosphorus
18 ( 6%)
17 ( 6%)
Graded Proteinuria
53 (18%)
63 (21%)
Graded Glucosuria
6 ( 2%)
7 ( 2%)
Baseline Calc Cr Cl* (mL/min)
122
125
Mean Change from Baseline in
Calc Cr Cl* (mL/min)
+1
+4
Patients with Fanconi’s Syndrome
0
0
Parameters through 96 weeks
*Using Cockcroft-Gault Equation
Gallant et al. ICAAC. 2003. Abstract H840.
Recent Retrospective Analysis
Harris Analysis1 - Canada Expanded Access
 Population
– Patient population not well-matched
– TDF patients older and longer time on previous ARVs
 Increases in serum creatinine
– At 6 months, increases in serum creatinine (1.5x baseline) observed
in 8% TDF vs 4% ABC patients (p<0.001)
– Consecutive (confirmed) increases were observed in 4% TDF vs
9% ABC patients (p=0.004)
 Discontinuations
– At least 1-2% discontinued TDF during first year
– Patients more likely to discontinue TDF than ABC due to increased
creatinine
1Harris
M, et al. 2nd IAS. Abstract 55.
Recent Reports
 3 cases of Fanconi’s syndrome among 81 ART-experienced patients
initiated on a TDF-containing regimen1
– Glycosuria, hypophosphatemia, proteinuria, decrease in CrCl
– Initial signs appeared after 8, 9, and 11 months of TDF exposure
– 2/3 cases had low Cr clearance at baseline
 3 patients developed hypophosphatemia on TDF2
– Phosphate levels remain stable in two patients who continued TDF
with phosphate supplementation
– 3/3 patients previously on ADV 60 or 120mg and diagnosed
with renal tubular acidosis with hypophosphatemia
1Reynes
2Blick
J, et al. 10th CROI. February 10-14, 2003. Abstract 717
G, et al. 10th CROI. February 10-14, 2003. Abstract 718
CPCRA 039
Background Incidence of Renal
Abnormalities in HIV+ Patients
 A placebo-controlled study of Adefovir 120 mg in
HIV-infected patients with CD4 <50
– 1:1 randomization, 505 patients
– at study termination ~ 11 months follow-up
 Renal abnormalities observed in placebo arm
–
–
–
–
8% hypophosphatemia
6% serum creatinine increase 0.5 mg/dL
0.8% Fanconi Syndrome
4 patients with renal-related serious adverse events
Fisher et al. AIDS 2001, 15: 1695-1700
Viread in Patients with Renal Impairment
 Dosing interval adjustment is recommended in all patients with
creatinine clearance < 50 mL/min
 The majority of reported cases of renal impairment in patients
taking VIREAD occurred in patients with underlying systemic or
renal disease, or in patients taking nephrotoxic agents
 VIREAD should be avoided with concurrent or recent use of a
nephrotoxic agent
 Patients at risk for, or with a history of, renal dysfunction and
patients receiving concomitant nephrotoxic agents should be
carefully monitored
Viread Package Insert August 2003
Dosing Interval Recommendations for
Viread in Patients with Renal Impairment
Creatinine Clearance (mL/min)*
> 50
30-49
10-29
Every 24 h
Every 48 h
Twice/wk
Hemodialysis
Patients
Every 7 days or after a
total of approximately
12 hours of dialysis **
*Calculated using ideal (lean) body weight
** Generally once weekly assuming three hemodialysis sessions a week of approximately
4 hours duration. VIREAD should be administered following completion of dialysis.
Bone Safety
Study 903
Baseline Incidence of Osteopenia in
HIV+ Patients
 HIV disease associated with osteopenia
 At baseline
– 24% patients were osteopenic at the lumbar spine
(p=0.007)
– 23% patients were osteopenic at the femoral neck
(p=0.011)
 Analyses done WHO Definitions by T Score:
Normal > -1 SD, Osteopenia -1 SD to -2.5 SD,
Osteoporosis < -2.5 SD
McGowan et al. 8th CROI, 2001, Abstract #628
Study 903
Median (IQ) % Change in Spine BMD
Study 903
Median (IQ) % Change in Hip BMD
Study 903
Bone Fractures Summary
(0-96 Weeks)
TDF+3TC+EFV
(n=299)
d4T+3TC+EFV
(n=301)
Fractures
1
7
*All fractures involved significant trauma
Data on file. Gilead Sciences, Inc. Feb 2003
Possible contributing factors to decreased
BMD in HIV-infected Patients
M. Glesby, CID supplement, Sept. 2003
Lipid Safety
Study 903
Change from Pre-Baseline (mg/dL)
Mean (95% CI) Change in Fasting
Cholesterol
Wk 96, p < 0.001
– TDF+3TC+EFV
– d4T+3TC+EFV
70
51 mg/dL
60
50
40
30
20
30 mg/dL
10
0
0
4
12
24
36
48
72
96
199
208
183
182
177
179
Weeks
234 214
250 219
206
221
207
214
205
205
Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b
Study 903
Change from Pre-Baseline (mg/dL)
Mean (95% CI) Change in Fasting
Triglycerides
120
110
100
90
80
70
60
50
40
30
20
10
0
-10
-20
Wk 96, p < 0.001
– TDF+3TC+EFV
– d4T+3TC+EFV
103 mg/dL
5 mg/dL
0
4
12
24
36
48
72
96
199
208
183
182
177
179
Weeks
234 214 206
250 219 221
207
214
205
205
Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b
Study 903
Time to First Lipid Lowering Drug
– TDF+3TC+EFV
– d4T+3TC+EFV
*p < 0.001
% Taking Lipid Drug
25
20
15
10%
10
5
2%
0
BL
4
8
12 16 20 24 28 32 36 40 44 48
56
64
72
80
88
96
231
234
229
228
227
225
224
215
224
209
195
173
Weeks
TDF+3TC+EFV: 294 288 282 276 273 269 267 263 257 250 248 243 241
d4T+3TC+EFV: 301 297 293 286 284 281 275 270 264 256 252 245 242
Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b
Study 907
Study Design
Doubleblind
Openlabel
24 wks
48 wks
Tenofovir DF 300 mg
Stable ART
8 weeks
randomized
2:1
24 wks
Placebo
Tenofovir DF 300 mg
n=550
HIV RNA 400 to 10,000 copies/mL; no CD4 criteria
Squires K et al (2003) Annals of Internal Medicine In Press
48 wks
Study 907
Change from Baseline in Cholesterol (mg/dL)
Mean (95% CI) Change from Baseline
in Cholesterol through Week 48
– Placebo
– Tenofovir DF
– Placebo to Tenofovir DF
*p<0.0001
10
0
*
-10
*
-20
-30
BL 2
4
8
12
16
20
24
32
36
40
44
48
336
334
333
334
326
313
167
164
158
155
158
153
28
Weeks on Study
TDF
PLB
PLB->TDF
368 343 358
182 174 181
353
173
350
174
348
172
Data on file. Gilead Sciences, Inc. February 2003.
344
169
335
164
170
Recover Study
Dyslipidemia Improvement in Patients
Switching from d4T to TDF
 1350 heavily pretreated patients switched single NRTI to
TDF
– d4T (65%), ddI (13%), AZT (13%), ABC (6%),
3TC (2%), ddC (1%)
 Reason for switch
– Peripheral neuropathy (13%), lipodystrophy (50%)
 d4T most frequently switched (n=886, 65%)
– Hypertriglyceridemia (n=271)
– Hypercholestrolemia (n=193)
 No virologic rebound
 No significant changes in CD4
Moreno S. 43rd ICAAC, Chicago 2003, #H-855b.
Recover Study
Lipid Changes Following d4T to TDF
Switch
Cholesterol (N=70)*
Triglycerides (N=94)*
550
290
500
280
mg/dL
mg/dL
270
p <0.001
450
400
350
p <0.001
260
240
230
300
220
250
210
200
200
Baseline
12 weeks
* Mean + 95% CI
Moreno S. 43rd ICAAC, Chicago 2003, #H-855b.
Baseline
12 weeks
Study 903
Toxicities Potentially Associated with
Mitochondrial Dysfunction
All Grades Through Week 96
TDF+3TC+EFV d4T+3TC+EFV
(n=299)
(n=301)
Patients (%) with events
4%*
20%*
Peripheral neuritis/neuropathy
3%*
10%*
Lipodystrophy**
1%*
12%*
Lactic acidosis**
0
1%
Pancreatitis
0
0
Relative risk (95% CI) for toxicity (d4T/TDF)
5.5 (3.0, 10.3)
*p<0.001.
**Investigator defined
Staszewski S, et al. Presented at 10th Conference on Retroviruses and Opportunistic Infections;
February 10-14, 2003; Boston, Mass. Abstract 564b.
Study 903
Mean Change from Baseline in Weight
through Week 96
– TDF+3TC+EFV
– d4T+3TC+EFV
8
7
*p = 0.002
6.1*
Pounds
6
5
4
3
2
1
0.8
0
TDF+3TC+EFV:
d4T+3TC+EFV:
0
24
48
Weeks
96
299
301
272
277
259
261
231
231
Staszewski S. 2nd IAS Conference, Paris 2003, Poster # 562
Study 903
Mean (95% CI) Total Limb Fat at
Week 96
22
20
18
16
14
12
10
8
6
4
2
0
*
Total Limb Fat (DXA)
n=126, n=132
Staszewski S. 2nd IAS Conference, Paris 2003, Poster # 562
– TDF+3TC+EFV
– d4T+3TC+EFV
* p < 0.001
Study 418: Once-daily vs. twice-daily
lopinavir/r in antiretroviral-naive
patients
24-week results
D Podzamczer, J Gathe, M Johnson, R Schwartz, J Villacian,
T Marsh, C Naylor, M King, R Tressler, S Brun
Hospital de Bellvitge, Barcelona; Therapeutic Concepts, Houston, TX;
Royal Free Hospital, London; Private Practice, Ft. Myers, FL;
Tan Tock Seng Hospital, Singapore, Abbott Laboratories, Abbott Park, IL
Study 418: Study design
LPV/r 800/200 mg QD
+ TDF 300 mg/FTC 200 mg QD
(n=115)
ARV-naive
HIV RNA >1000
c/mL
Any CD4 cell count
LPV/r 400/100 mg BID
+ TDF 300 mg/FTC 200 mg QD
(n=75)
Study 418: Baseline characteristics
Gender
Male
Female
Age (years)
Mean (Range)
Race
Caucasian
Black
Hispanic
Other
HIV RNA (log10 copies/mL)
Median (IQR)
Range
CD4 count (cells/mm3)
Median (IQR)
Below 200 cells/mm3
LPV/r 800/200 QD
(n=115)
LPV/r 400/100 BID
(n=75)
81%
19%
75%
25%
39 (19-75)
38 (19-75)
56%
27%
10%
7%
51%
36%
5%
8%
4.8 (4.3-5.5)
3.5-6.4
4.6 (4.3-5.3)
2.6-6.2
214 (116-380)
44%
232 (95-339)
47%
Study 418: Disposition through week 24
LPV/r 800/200 LPV/r 400/100
mg QD
mg BID
(n=115)
(n=75)
Subjects discontinued
18 (16%)
12 (16%)
Adverse event
Death
Lost to follow-up
Withdrew consent
Nonadherence
13 (11%)
0 (0%)
1 (1%)
3 (3%)
1 (1%)
2 (3%)
1 (1%)
5 (7%)
1 (1%)
3 (4%)
Study 418: HIV RNA <50 copies/mL (ITT M=F)
100
Proportion <50 copies/mL
LPV/r QD + TDF/FTC (n=115)
LPV/r BID + TDF/FTC (n=75)
80
57%
57%
60
40
20
0
0
4
8
12
Week
16
Week 24 difference (QD minus BID) and 95% CI:
20
24
0.1% (-14.3%, 14.4%)
Study 418: HIV RNA <50 copies/mL
(observed data)
100
Proportion <50 copies/mL
LPV/r QD + TDF/FTC (n=115)
70%
LPV/r BID + TDF/FTC (n=75)
80
60
68%
40
20
0
0
Sample Size QD: 115
BID: 75
4
8
105
69
12
16
Week
103
65
20
24
97
61
28
32
Study 418: HIV RNA <50 copies/mL
(observed data)
100
Proportion <50 copies/mL
LPV/r QD + TDF/FTC (n=115)
70%
LPV/r BID + TDF/FTC (n=75)
80
84%
80%
60
68%
40
20
0
0
Sample Size QD: 115
BID: 75
4
8
105
69
12
16
Week
103
65
20
24
97
61
28
32
93
60
Study 418: CD4 cell count
Mean (±SE) change from baseline
150
+128
+103
cells/mm
3
100
50
LPV/r QD + TDF/FTC (n=115)
LPV/r BID + TDF/FTC (n=75)
0
0
4
8
12
Week
16
20
24
Study 418: Most common adverse events
Moderate or severe LPV/rrelated adverse events
Diarrhea
Nausea
Abdominal Pain
Vomiting
LPV/r 800/200 QD
(n=115)
LPV/r 400/100 BID
(n=75)
p-value
12%
9%
3%
3%
5%
9%
3%
5%
ns
ns
ns
ns
Includes all events occurring in >3% of patients in either group
Study 418: Distribution of total cholesterol
Baseline vs. Week 24
100
99
97
93
mg/dL (mmol/L)
81
80
0-240 (0-6.22)
Percent
>240-300 (6.22-7.77)
60
>300 (>7.77)
40
18
20
1 0
6
1
3 0
2
0
Baseline
Week 24
LPV/r QD + TDF/FTC
Baseline
Week 24
LPV/r BID + TDF/FTC
Study 418: Distribution of LDL-cholesterol
Baseline vs. Week 24 by NCEP Guidelines3
100
91
82
79
80
mg/dL (mmol/L)
74
Percent
<130 (0-3.4)
60
130-<160 (3.4-4.1)
>=160 (4.1)
40
18
17
20
11
6
8
2
4
Baseline
Week 24
Baseline
Week 24
7
0
LPV/r QD + TDF/FTC
LPV/r BID + TDF/FTC
3 JAMA
2001, 285: 2486-2497
Study 418: Distribution of HDL-cholesterol
Baseline vs. Week 24 by NCEP Guidelines3
100
80
mg/dL (mmol/L)
Percent
64
<40 (0-1.04)
60
52
48
40
48
40
38
>=60 (1.55)
34
30
20
40-<60 (1.04-1.55)
18
14
8
6
0
Baseline
Week 24
LPV/r QD + TDF/FTC
Baseline
Week 24
LPV/r BID + TDF/FTC
3 JAMA
2001, 285: 2486-24971
Study 418: No change in mean LDL:HDL
cholesterol ratio from baseline to Week 24
5
Baseline
Week 24
4
Ratio
p=0.76
3
2.60
2.56
p=0.38
2.54
2.66
2
1
0
LPV/r QD + TDF/FTC
LPV/r BID + TDF/FTC
Study 418: Conclusions
 Week 24 HIV RNA <50 copies/mL was similar in patients receiving
LPV/r QD vs. BID
– ITT (M=F): 57% (QD), 57% (BID)
– Observed data: 68% (QD), 70% (BID)
 Patients continued to achieve HIV RNA <50 copies/mL after Week 24
 Gastrointestinal events were the most common AEs, with a somewhat
higher rate of diarrhea in the QD arm.
 At Week 24, over 90% of patients demonstrated LDL cholesterol
values <160 mg/dL.
 LDL:HDL cholesterol ratio was unchanged from baseline to Week 24
Efficacy
Study 903
% Patients < 50 Copies/mL through
Week 96
Intent to Treat (Missing=Failure)
100
78%
74%
80
60
40
TDF+3TC+EFV
20
d4T+3TC+EFV
0
0 4 8
16
24
32
40
48
56
Weeks
Staszewski S. 10th CROI, Boston, MA, Feb 10-14, 2003, Abstract # 564b
64
72
80
88
96
Study 903
% Patients < 50 Copies/mL through
Week 96
As-Treated
100
95%
91%
80
60
40
TDF+3TC+EFV
20
d4T+3TC+EFV
0
0 4 8 16 24 32 40 48 56 64 72 80 88 96
Weeks
Data on file. Gilead Sciences, Inc. February 2003.
Role of Triple NRTIs?
ACTG 5095: Virologic Failure
Virologic failure
Randomized, evaluable:
n=1147
(confirmed viral load 200
copies/mL week 16)
ZDV/3TC/ABC (Trizivir®)
(n=382)
Pooled EFV (+ZDV/3TC or
ZDV/3TC/ABC)
(n=765)
21%
11%
(n=82 failures)
(n=85 failures)
Time to virologic failure greater
for EFV arms than ZDV/3TC/ABC
for viral load >100K, <100K and all patients
Gulick RM 2nd IAS; 2003; Paris, France. Abstract 41.
Triple-NRTI Regimen
ABC/3TC QD + TDF
Early Non-Response to Tenofovir DF (TDF) +
Abacavir (ABC) and Lamivudine (3TC) in a
Randomized Trial Compared to
Efavirenz (EFV) + ABC and 3TC:
ESS30009 Unplanned Interim Analysis
JE Gallant, AE Rodriguez, W Weinberg, B Young, D Berger,
ML Lim, Q Liao, L Ross, J Johnson, MS Shaefer for the
ESS30009 Study Team.
Joel E. Gallant, MD, MPH
Associate Professor of Medicine & Epidemiology
Johns Hopkins University School of Medicine
ESS30009
ABC/3TC+TDF vs ABC/3TC+EFV
Open-label, randomized, multicenter trial
Entry criteria
•
•
•
•
> 18 years old
ART-naïve (<14 days ART)
VL > 5000 copies/mL
No CD4+ restrictions
Screening
48 weeks
ABC/3TC FDC QD + EFV 600mg QD
n=180 planned
Randomize*
ABC/3TC FDC QD + TDF 300mg QD
n=180 planned
Primary Endpoint
• Proportion with HIV-1 RNA <50 c/mL at week 48
* Randomization (1:1) stratified by HIV-1 RNA <100K or ≥100K c/mL
Gallant JE, et al. 43rd ICAAC, Chicago 2003, #H-1722a.
ESS30009
Virologic Non-Response for Subjects
with at least 8 Weeks HIV-1 RNA Data
ABC/3TC + EFV
(N=92)
ABC/3TC + TDF
(N=102)
3/92 (3.3%)
32/102 (31.4%)
0/92 (0%)
8/102 (7.8%)
Both criteria #1 and #2 met
2/92 (2.2%)
10/102 (9.8%)
Total
5/92 (5.4%)2
50/102 (49%)2
Criteria1
#1: <2.0 log decline from
baseline by week 8
#2: ≥1.0 log rebound
from nadir
1. No subjects met virologic non-response criteria #3
2. Difference between arms p<0.001, 95% CI (-54.3%, -32.8%)
Gallant JE, et al. 43rd ICAAC, Chicago 2003, #H-1722a.
ESS30009
Week 12 NRTI Genotypic Mutations (N=36)
Mutations
Number of subjects
(%)
M184V alone
13 (36%)
M184V + K65R
17 (47%)
M184V + K65R + V118I
3 (8%)
M184V + K65R + Y118I
3 (8%)
M184V Total
Gallant JE, et al. 43rd ICAAC, Chicago 2003, #H-1722a.
36 (100%)
ESS30009
Proposed Explanations for Response
 Inadequate pharmacokinetics of once-daily
dosing of ABC and/or 3TC?
 Intracellular pharmacologic interaction?
 Overlapping resistance profiles?
– 3TC & ABC select for M184V
– TDF & ABC select for K65R
– ABC selects for both M184V and K65R
 Insufficient potency of using only one class of
ARVs (NRTIs) to attack the virus?
Triple-NRTI Regimen
ddI+3TC+TDF
 24-week, single-site, open-label pilot study (N=24)
 Safety & efficacy of triple-NRTI regimen: ddI+3TC*+TDF
 Results:
– 91% had < 2 log10 reduction in HIV RNA by Week 12
– Resistance testing in 21 patients:
• 20 patients (95%) with M184V
• 10 patients (50%) with M184V + K65R
 Action:
– Study enrollment stopped
– Dear Health Care Provider Letter (Oct 14): ddI+3TC+TDF not
recommended
* 3TC dosed once-daily in this study
Jemsek et al. Oral Communication. September 2003
Study 903
% Patients < 50 Copies/mL through
Week 96
As-Treated
100
95%
91%
80
60
40
TDF+3TC+EFV
20
d4T+3TC+EFV
0
0 4 8 16 24 32 40 48 56 64 72 80 88 96
Weeks
Data on file. Gilead Sciences, Inc. February 2003.
Study 903
Phenotypic Susceptibility of NRTIs in
Presence of K65R
Fold Change Phenosense Assay (ViroLogic cut-off)
AZT
d4T
ddI
ABC
3TC
TDF
(2.5)
(1.7)
(1.7)
(4.5/6.5)
(2.5)
(1.4/4.0)
1(+M184V)
0.3
0.9
3.7
6.2
>>
1.2
2(+M184V)
0.5
1.0
3.0
7.0
>>
1.3
3(+M184V)
0.3
0.8
1.9
4.6
>>
1.1
4
0.2
0.6
0.7
1.2
11
1.0
5
0.4
1.1
1.6
1.5
8.7
1.4
0.9
0.8
1.2
1.3
>>
0.9
7
0.5
1.2
1.9
4.2
13.3
2.2
8
0.5
0.9
1.6
2.4
13
1.0
Patient
6(+M184V)
Fully Susceptible
Intermediate Susceptibility
Miller MD, XII International HIV Drug Resistance Workshop, June 2003, Abstract 135
Resistant
Study 903
Outcomes of TDF-Treated Patients
with K65R
Patient
Number
Next
Regimen
Response
(copies/mL)
Follow-up
1
TDF/AZT/LPV/r
<50
W120
2
TDF/3TC/ddl/LPV/r
<50
W108
3
ddl/d4T/IDV/r
<50
W120
4
ddl/IDV
<50
W120
5
AZT/3TC/SQV/r
<50
D/C W48
6
AZT/ddl/NFV
423
D/C W68
7
AZT/3TC/APV
1905
8
AZT/3TC/LPV/r
NA
non-adherence
(M184V developed)
no additional
follow-up yet
Miller MD, XII International HIV Drug Resistance Workshop, June 2003, Abstract 135
Study 903
Outcomes of TDF-Treated Patients
with K65R (n=8)
Viral Load ( RNA*)
Before Next Regimen
RT
Resistance
Mutations
Next
Regimen
1) 229,511 (-0.2) W24 V106M; M184V; TDF/AZT/LPV/r
K65R
Response
Comments
<50, W32
<50, W96
2)
7,047 (-0.8) W24 V179I; Y188L
M184V; K65R
TDF/3TC/ddI/
LPV/r
<50, W36
<50, W72
3)
5,623 (-1.6) W48 K103N; L100I;
M184V; K65R
ddI/d4T/IDV/r
<50, W72
On study;
no additional
follow-up yet
<50, W44
<50, W80
4)
80,600 (-0.6) W24 V179G; Y181C; ddI/IDV
G190E; K65R
* Change
from baseline (log10 copies/mL)
Miller et al., 6th Int’l Congress on Drug Therapy in HIV Infection, 2002, Glasgow, UK, Abstract P205
Study 903
Outcomes of TDF-Treated Patients
with K65R (n=8) (continued)
Viral Load ( RNA*)
Before Next Regimen
RT
Resistance
Mutations
Next
Regimen
Response
Comments
5) 18,332 (-1.2) W24 G190E/Q; K65R
AZT/3TC/SQV/r <50, W48
D/C W48, lost to
follow-up
6) 40,903 (-0.5) W48 K103N; M184I;
K65R
AZT/ddI/NFV
423, W68
D/C W68; lost
to follow-up
7) 34,295 (-1.1) W24 K103N; Y188C;
K65R
AZT/3TC/APV
1905, W32 Developed
AZT/3TC/LPV/r
NA
8) 2,945 (-1.4) W96
V108I; Y181C;
G190A; K65R
M184V at W48,
non-adherence
On study;
no additional
follow-up yet
Mean Baseline Viral Load: 235,962 (median 245,727)
Mean Viral Load Before Next Regimen: 52,407 (mean -0.9 log from baseline)
* Change
from baseline (log10 copies/mL)
Study 903
Week-96 Resistance Analysis Conclusions
 EFV resistance and M184V were the most commonly
observed mutations at failure
 K65R emerged less frequently
– Observed only with EFV resistance
– Maintained mean 0.9 log10 HIV RNA decrease from baseline
 Effective second-line regimens constructed in
patients developing K65R
Miller MD. XII International HIV Drug Resistance Workshop; 2003; Los Cabos, Mexico. Abstract 135.
The Future: TDF/FTC Fixed Dose
Combination Tablet
Tenofovir and Emtricitabine fixed
dose combination
Study 934 in progress
TDF/FTC/EFV vs COM/EFV
Bioequivalence and stability studies
in progress
Study 934
Study Design
ART-naive
patients
TDF
FTC
Efavirenz
QD
QD
QD
48 wks
(N = 300)
randomized
1:1
AZT/3TC
Efavirenz
BID
QD
48 wks
Emtriva & Viread
Summary of Similar Characteristics
 Durable efficacy in clinical trials
– Both Emtriva and Viread have shown efficacy in both treatment-naïve
and treatment-experienced patients
 Tolerability and safety
 Convenience
– Both one tablet dosed once-daily
 Pharmacokinetics
– Both have long intracellular half-lives, true once-daily dosing
– Both can be taken without regard to food
 Co-infection
– Though not indicated for hepatitis B, both have demonstrated potency
against hepatitis B in co-infected patients