Transcript ICAAC - IDSA - HIV-9

The 48th Interscience Conference
on Antimicrobial Agents and Chemotherapy and
46th Infectious Disease Society of America
Meeting
Washington, DC
October 24-28, 2008
and
9th International Congress on Drug Therapy in
HIV Infection
Glasgow, Scotland
November 9-13, 2008
When to Start
NA-ACCORD: Improved Survival
When ART is Started with ≥350 CD4
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North American AIDS Cohort Collaboration on Research and
Design (NA-ACCORD)
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Study patients: All HIV-infected individuals with CD4 count
of 351-500 cells/mm3 while in active follow-up between
1996 and 2006
Outcome: All-cause mortality
Groups compared from same CD4 count level:
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Regional collaboration of 22 HIV research cohorts from
United States and Canada
Immediate treatment: Initiate ART within 1.5 yrs after 1st CD4 count
between 351-500 cells/mm3
Deferred treatment: Do not initiate ART in this time frame
Patients censored when not initiating within the 1.5 year interval
after their target CD4 count for ART initiation
Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b
NA-ACCORD:
Baseline Characteristics
Initiate HAART
(n=2,473)
Defer HAART
(n=5,901)
8,358
16,636
Males (%)
83
75
Median Age (years)
40
38
White (%)
39
38
Median CD4 count cells/mm3
421
432
Median log10 HIV RNA copies/mL
4.3
4.1
Hepatitis C virus infection (%)
27
34
History of Injection Drug Use (%)
16
21
Follow up person-years
Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b
NA-ACCORD: Results
Relative
Hazard
(RH)*
95%
Confidence
Interval
P-value
Deferral of HAART at 351-500
cells/mm3
1.7
1.4, 2.1
<0.001
Female Sex
1.1
0.9, 1.5
0.290
Older Age (per 10 years)
Baseline CD4 count
(per 100 cells/mm3)
1.6
1.5, 1.8
<0.001
0.9
0.7, 1.0
0.083
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HIV RNA was not an independent predictor of mortality
Rate of virologic suppression (<500 c/ml) similar between groups
*Stratified by Cohort and Year
Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b
What to Start
STARTMRK:
Raltegravir vs Efavirenz
Randomized (1:1), double blind, study
ART-naïve
subjects
(N=561)
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RAL (400 mg BID)
+ TDF/FTC QD
+ EFV Placebo
EFV (600 mg QHS)
+ TDF/FTC QD
+ RAL Placebo
HIV RNA >5000 c/mL
Susceptible to EFV, TDF and FTC
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
STARTMRK:
Baseline Characteristics
RAL + TDF/FTC
(n=281)
EFV + TDF/FTC
(n=282)
Age (mean, years)
38
37
% Male
81
82
% Non-White
59
56
103,205
106,215
% with vRNA >105 copies/mL
55
51
Mean CD4 count (cells/μl)
219
217
% with CD4 ≤200 cells/μl
47
48
% Hepatitis B or C
7
7
% Non-Clade B
21
17
vRNA copies/mL
(geometric mean)
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
STARTMRK: Results
100
86%
Non-inferiority
p-Value <0.001
Percent with
HIV RNA <50 c/mL
80
82%
60
40
RAL + TDF/FTC
EFV + TDF/FTC
20
CD4 change:
+189 cells/mm3
+163 cells/mm3
(95% CI: 4,47)
0
0 2 4
8
12 16
24
32
Weeks
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
40
48
STARTMRK: Results
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Time to virologic suppression faster with RAL
(P<0.001)
Virologic failures similar
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RAL 12 (4 with RAL, 3 with FTC resistance)
EFV 8 (3 with EFV, 1 with FTC resistance)
Lower incidence of drug-related adverse events with
RAL
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Overall: RAL 44% vs EFV 77% (P<0.001)
CNS at week 8: RAL 10.3% vs 17.7% (P=0.015) – persisted
through week 48
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
STARTMRK: Fasting Serum Lipid
Changes from Baseline to Week 48
P<0.001
Mean Change (mg/dL)
40
P<0.001
P<0.001
37
33
RAL+TDF/FTC
EFV+TDF/FTC
30
20
10
16
10
10
4
6
-3
0
-10
P<0.001
T CHOL
HDL-C
LDL-C
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
TG
ARTEMIS:
Phase III Study Design
689 ARV-naïve patients
VL>5,000
DRV/r 800/100mg QD
+ TDF/FTC
(n=343)
LPV/r* 400/100mg BID or
800/200mg QD
+ TDF/FTC
(n=346)
96 Week Results Presented
*Dosing was based on regulatory approval; switch was made according to local regulatory approval and drug availability.
LPV/r BID 75%; Capsule/tablet switch 86%
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
ARTEMIS:
Baseline Characteristics
DRV/r +
TDF/FTC QD
(n=343)
LPV/r +
TDF/FTC QD
(n=267)
104 (30)
105 (30)
40%
44%
Median HIV-1 RNA (c/mL)
70,800
62,100
Median CD4 (cells/mm3)
228
218
HBV/HCV co-infected
13%
14%
CD4 count <200 cells/mm3
41%
43%
Plasma HIV-1 RNA ≥100,000 c/mL
34%
35%
Baseline demographics
Female, N (%)
Caucasian
Baseline disease characteristics
Stratification factors at screening
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
Percent HIV RNA <50 c/mL
ARTEMIS: HIV RNA <50 c/mL
to Week 96 (TLOVR)
100
80
60
DRV/r + TDF/FTC
LPV/r + TDF/FTC
P=0.024
93
79
87
71
40
20
0
ITT*
VF Only
*Estimated difference in response vs LPV/r for non-inferiority: PP = 8.4% (95% CI 1.9;14.8, P<0.001)
*Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012)
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
ARTEMIS: Response by VL and
CD4 Strata and Adverse Events
% HIV RNA <50 copies/mL (ITT-TLOVR)
DRV/r + TDF/FTC
100
80
P=0.174
81
75
P=0.023
100
63
60
20
20
≥100,000
0
Baseline viral load (copies/mL)
n=
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226
226
117
120
75
65
40
<100,000
P=0.345
79
79
40
0
P=0.009
80
76
60
LPV/r + TDF/FTC
<200
≥200
Baseline CD4 cell count (cells/mm3)
n=
141
148
202
198
Higher rate of GI adverse events in LPV/r arm (Diarrhea 4% vs. 11% , P<0.001)
Grade 2-4 increases in total cholesterol (18% vs. 28%, P=0.0016) and
triglycerides (4% vs. 13%, P<0.0001) higher in LPV/r arm
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
ARTEMIS: Median Increase in
Lipid Levels at Week 96
Median increase in
concentration (mg/dL)
60
DRV/r + TDF/FTC
LPV/r + TDF/FTC
56
50
40
30
35
26
20
17
18
15
10
0.0
5
Total
cholesterol
LDLc
cholesterol
8
HDL
cholesterol
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
Triglycerides
CASTLE: Study Design
International, multicenter, open-label, randomized, 96-week study
to determine the comparative clinical efficacy and safety of
ATV/r and LPV/r in treatment-naïve HIV-1 infected subjects
HIV RNA 5000 c/mL, no CD4 cell count restriction
Stratified by HIV RNA <100,000 c/mL vs 100,000 c/mL and geographic region
(1:1)
ATV/r 300/100 mg QD
+ TDF/FTC QD
(n=440)
LPV/r 400/100 mg BID
+ TDF/FTC QD
(n=443)
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
CASTLE:
Baseline Characteristics
ATV/r +
TDF/FTC
(n=440)
LPV/r +
TDF/FTC
(n=443)
Median Age (years)
34
36
Female (%)
31
31
4
5
HIV RNA median (log10 c/mL)
5.01
4.96
HIV RNA ≥100,000 c/mL (%)
51
47
205
204
CD4 <50 cells/mm3 (%)
13
11
HBV or HCV +ve (%)
14
12
HIV subtype B (%)
67
66
CDC Class C (%)
CD4 median (cells/mm3)
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
CASTLE:
HIV RNA <50 c/mL (CVR, NC = F)
Percent HIV RNA <50 c/mL
100
ATV/r + TDF/FTC (n=440)
LPV/r + TDF/FTC (n=443)
80
60
40
HIV RNA <50 c/mL: 74% ATV/RTV vs 68% LPV/RTV
20
Difference estimate: 6.1 (95% CI, 0.3%–12.0%, P<0.05)
0
B/L
12
24
36
48
60
Weeks
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
72
84
96
CASTLE: Response by Baseline
HIV RNA and CD4
Responder (%) <50 copies/mL
ITT-Confirmed Virologic Response (NC =F)
by Qualifying HIV Viral Load
100
90
80
70
<100,000 c/mL
75%
70%
≥100,000 c/mL
74%
66%
60
50
40
30
20
10
0
N=
217 218
223 225
LPV/r + TDF/FTC
ITT-Confirmed Virologic Response (NC =F)
by Baseline CD4 Cell Count
Responder (%) <50 copies/mL
ATV/r + TDF/FTC
100
P=NS
90
80
70
P=NS
78%
76%
71% 71%
69% 70% 69%
58%
60
50
40
30
20
10
0
N=
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
ATV/r
222
106 45
LPV/r
58
228 134
29
48
≥200 cells/mm3
50 - <100 cells/mm3
100 - <200 cells/mm3
< 50 cells/mm3
CASTLE: Adverse Events
at 96 Weeks
ATV/r + TDF/FTC
(n=441)
LPV/r + TDF/FTC
(n=437)
Death
1%
1%
SAE
14%
11%
AE leading to
discontinuation
3%
5%
Jaundice/
hyperbilirubinemia
<1%
0
0
2%
<1%
<1%
Diarrhea
Renal
*Lipid Changes are Mean Percent Increase From Baseline
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
CASTLE: Mean Fasting Lipids
at Baseline and Week 96
ATV/r + TDF/FTC Baseline
200
Lipid Values mg/dl
180
160
ATV/r + TDF/FTC Wk 96
186
LPV/r + TDF/FTC Baseline
168
149
184
LPV/r + TDF/FTC Wk 96
150
140
140
126
125
120
100
92
112
110
105
140
129
114
93
80
60
37
40
44
46
36
20
0
TC
LDL-c
HDL-c
Non-HDL-c
TG
Difference Estimate
-8.9%*
-1.7%
-5.5%
-9.7%*
-24.5%*
(95% CI) ATV/r-LPV/r
(-11.6%, -6.1%)
(-5.9%, 2.6%)
(-10.0%, -0.8%)
(-13.0%, -6.3%)
(-29.9%, -18.8%)
* P<0.0001
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
Meta-Analysis of TDF/FTC vs
ABC/3TC in Boosted PI Trials
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12 clinical trials (N=4896)
Aggregate results favor TDF/FTC
DRV/r
TDF (n=343)
ATV/r
TDF (n=493)
ABC (n=112)
FPV/r
TDF (n=53)
ABC (n=722)
LPV/r
TDF (n=2285)
ABC (n=722)
SQV/r
TDF (n=166)
50%
60%
70%
80%
90%
100%
% HIV RNA <50 copies (ITT TLOVR) at Week 48
Hill A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1254
Convergence of First-line
Regimens
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Number Started on a Unique Regimen/
Number of Patients Started on ARVs
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Treatment-naïve patients at U of Alabama not participating in a clinical trial
Over time, significant decline in first-line regimen variability
In 2007, 95% started one of two regimens: TDF/FTC/EFV or TDF/FTC + ATV/r
Fewer changes of therapy with TDF/FTC/EFV (10%) vs. ZDV/3TV + EFV (43%)
Annual Treatment Share for All Regimens Utilized as Initial Therapy
100
90
80
70
60
50
40
30
20
10
0
2003 (n=67)
FTC/TDF/EFV
3TC/ZDV/LPV/r
3TC/ddI/EFV
2004 (n=75)
2005 (n=68)
2006 (n=66)
3TC/ZDV/EFV
3TC/ZDV/NFV
FTC/TDF/ATV/r
McKinnell J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1260
2007 (n=65)
3TC/ABC/ZDV
3TC/ZDV/NVP
Other – (<5% Treatment Share)
Issues Regarding ARV Therapy
in Treatment-Experienced
Patients
TITAN: Study Design
Screening phase
(4 weeks)
• LPV-naïve,
treatmentexperienced
Treatment phase
(96 weeks)
DRV/r 600/100mg bid
+ OBR (n=298)
• VL >1,000
copies/mL
• Stable HAART
for ≥12 weeks
(STI allowed)
LPV/r 400/100mg bid
+ OBR (n=297)
595 patients
randomised
and treated
STI = structured treatment interruption; OBR = optimized background regimen
Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.
Rollover and
follow-up
phase after
1 and 4
weeks
TITAN: Results at 96 Weeks
Patients <50 copies/mL (%)
DRV/r
100
90
80
70
60
50
40
30
20
10
0
LPV/r
P<0.001*
60
55
P=0.154
56
63
P<0.0001
P=0.078
69
68
56
P=0.007
62
49
38
0
≥1
0
≥1
Overall
Primary PI Mutations**
*Non-inferiority; **at baseline
Previously Used PIs**
CD4 Cell Change: DRV/r 93 cells/mm3 vs. LPV/r 81 cells/mm3
Virologic Failures: DRV/r 14% vs. LPV/r 26% (p<0.001)
Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.
TITAN: Adverse Events and Median
% Change in Lipids at Week 96
• Notable Grade 2-4 AEs
• Diarrhea: DRV/r 8% vs. LPV/r 15% (p=0.007)
• Rash: DRV/r 3% vs. LPV/r 1% (p=0.09)
• No notable differences regarding laboratory abnormalities
DRV/r
Median change from
baseline (%)
60
LPV/r
44%
40
31%*
18%
20
12%**
10%
13%
10%
4%**
0
Triglycerides
Total
cholesterol
LDL
calculated
HDL
*p<0.05 vs LPV/r
**p<0.01 vs LPV/r
Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.
BENCHMRK:
Resistance Analysis
Changes from Baseline Genotype
Genotyping of BENCHMRK
virologic failures (VF)
○
○
Population sequencing
GT at Baseline, VF (HIV
RNA >400), and time point(s)
post VF
○
○
○
○
●
1
2
>2
60
105 VFs (out of 462 on RAL)
94 VFs with BL and VF data
30 VFs with no changes at
VF
64 VF included in this
analysis
Patients who fail RAL
develop mutational patterns
associated with high level
resistance
Number of Mutations
70
Number of Genotypes
●
50
40
30
20
10
0
First Failure Genotype Post-failure Genotype
•
First failure: 27% at position 148
•
Subsequent: 53% at position 148
Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898
BENCHMRK: Pharmacokinetics
and Pharmacodynamics
RAL “Post-Antibiotic” Effect (in vitro)
RAL Effective Across Range of Trough Levels
% patients with HIV RNA <400 c/mL
100
GM Observed C12hr <33 nM
P24 at
48h
Infect
90
remove 6, 8, 10 or 12h post infection
No drug
80
80
RAL
70
60
60
50
40
40
30
20
20
10
0
0
8 - 125
128 - 254 254 - 545 547 - 9151
No Wash
6h
8h
10 h
12 h
GM Observed C12hr (nM)
• Trough concentrations do not predict RAL effectiveness
• Prolonged pre-integration complex binding may explain the lack of correlation with trough
concentration
Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898
ACTG 5211: Analysis Using Enhanced
Sensitivity Tropism Testing
Screening: R5 tropism by
the original Trofile assay
VCV 5*, 10 or 15 mg QD or Placebo
Failing ART regimen
Study
Screen
Study
Entry
Optimized ART regimen
Day
14
Week
24
Original Trofile
Week
48
Trofile ES
Screen
Entry
At Failure
DM at Screen (n, %)
R5
DM
DM/X4
7/12, 58%
R5
R5
DM/X4
9/18, 50%
R5
R5
R5
9/84, 11%
Trofile ES reclassified 25/114 individuals with R5 virus
at screen using original Trofile
*Stopped early
Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895
ACTG 5211:
Response Based on Trofile ES
Week 24
Day 14
Trofile ES
D/M Screen
R5 Screen
D/M Entry
R5 Screen
R5 Entry
N
15
5
64
Mean HIV RNA Change*
-0.09
-0.66
-1.15
Adjusted p value**
<0.0001
0.37
Reference
N
14
5
58
Mean HIV RNA Change*
-0.57
-1.20
-1.95
Adjusted p value**
0.0001
0.10
Reference
* log10 c/mL ** From regression model adjusted for baseline HIV-1 RNA and study stratification factors
Enhanced sensitivity tropism (Trofile ES) testing:
● Detects greater numbers of D/M and X4 virus and improves response
rate with CCR5 antagonist regimen
● Excludes only a small number of patients who would respond to CCR5
antagonist
● Role of repeat tropism testing not yet clarified
Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895
MERIT: Efavirenz vs. Maraviroc
in ARV-Naïve Patients
Randomization 1:1
Patient eligibility criteria:
- Treatment naive
- R5 HIV-1 infection with HIV RNA ≥2000 c/mL
- No resistance to EFV, 3TC or ZDV
Patients stratified by:
- HIV-1 RNA < and ≥100,000 copies/mL at screening
- Geographic location: No. and So. Hemispheres
EFV
+ ZDV/3TC**
MVC (300 mg BID)*
+ ZDV/3TC**
Week 48
Primary Analysis
Week 96
*MVC QD arm discontinued at week 16 for failure to meet protocol-defined criteria to continue
**In event of toxicity, ZDV or 3TC switch to alternative NRTI allowed
Saag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a
MERIT ES: Re-analysis of CCR5
Screening
Screened as R5 by
Standard Trofile
Rescreened as D/M
by Trofile ES
EFV +
ZDV/3TC
n/N (%)
MVC +
ZDV/3TC
n/N (%)
Total
n/N (%)
N
BL
D/M on
study
23
D/M
-
4/10
(40.0)
7/13
(53.8)
11/23
(47.8)
29
R5
YES
6/9
(66.7)
10/20
(50.0)
16/29
(55.2)
615
R5
NO
46/314
(14.6)
29/301
(9.6)
75/615
(12.2)
Saag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a
MERIT ES: Viral Suppression Using
Enhanced Tropism Testing
EFV + ZDV/3TC
<400 copies/mL
100
90
Patients (%)
80
–3.0 (–9.5*)
MERIT ES
0.6 (–6.4*)
73.1
72.3
MERIT
70
70.6
MVC + ZDV/3TC
73.3
90
50
50
40
40
30
30
20
20
10
10
360
303
311
*Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10%
Saag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a
MERIT ES
–4.2 (–10.9*)
–0.2 (–7.4*)
69.3
70
60
n= 361
MERIT
80
60
0
<50 copies/mL
100
0
n=
361
65.3
360
68.3 68.5
303
311
MERIT ES: Summary of
Discontinuations through 48 Weeks
Only patients with an R5 screening result by enhanced Trofile assay are
included in MERIT ES
Reason for discontinuation
EFV + ZDV/3TC
MVC + ZDV/3TC
MERIT
(N=361)
MERIT ES
(N=303)
MERIT
(N=360)
MERIT ES
(N=311)
91 (25.2)
78 (25.7)
97 (26.9)
76 (24.4)
Adverse event*, n (%)
49 (13.6)
43 (14.2)
15 (4.2)
13 (4.2)
Lack of efficacy, n (%)
15 (4.2)
12 (4.0)
43 (11.9)
29 (9.3)
Other reason, n (%)
9 (2.5)
9 (3.0)
13 (3.6)
11 (3.5)
Withdrew consent or lost to
follow-up, n (%)
18 (5.0)
14 (4.6)
25 (6.9)
22 (7.1)
All, n (%)
*All cause events
Saag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a
MOTIVATE 1 & 2
MOTIVATE 1 & 2:
Trial Design
2 identical ongoing Phase IIb/III studies
Randomized (1:2:2), double-blind, placebo controlled
1076 ARV-experienced patients
R5 HIV-1 infection (44% screen failures)
HIV-1-RNA ≥ 5,000 copies/mL
Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks
Resistance to and/or ≥ 6 months’ experience with ≥ 1 ARV from 3 classes (≥ 2 for PIs)
All received OBT*
Stratified by ENF use and HIV-1 RNA < and ≥ 100,000 copies/mL
Placebo
(n=209)
MVC 150mg† QD
(n=414)
MVC 150mg† BID
(n=426)
Week 96 Data: Includes all patients who reached Week 48 with HIV-1 RNA <50 c/mL and
continued on blinded therapy or open-label MVC BID
*OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)
†Pts receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg of MVC, all others received 300 mg of MVC
Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.
MOTIVATE 1 & 2: HIV-1 RNA <50
Copies/mL at Week 96 (ITT, NC=F)
MVC BID + OBT (N=426)
MVC QD + OBT (N=414)
Placebo + OBT (N=209)
100
90
Blinded Phase
Option to switch
to open-label MVC BID
80
Patients (%)
70
60
50
45.1%
46.5%
40
43.7%
43.5%
41.3%
38.9%
30
20
23.0%
16.7%
10
0
0
8
16
24
32
40
48
56
Time (weeks)
Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.
7.2%
64
72
80
88
96
MOTIVATE: Using a Weighted Score
for the OBT to Predict Response
Full analysis set
(N=1,049)
Non-virologic failures excluded
(n=145)
On-study at Week 48 or virologic
failure (n=904)
Exclusions for protocol violations
and other reasons (n=270)
Weighted OBT Sensitivity Score (wOBTSS)
Any drug in continuous
use, score = 0
PI
NRTI
NNRTI
S*
R**
1
0
0.5
0
1
0
Genotype
Virologic Outcomes
(VO) population (n=634)
Missing / incomplete information
(n=6)
IC50FC
ENF
Population included in regression
modeling (n=628)
*IC50 fold-change is less than or equal to the lower clinical cut-off
**IC50 fold-change is greater than the lower clinical cut-off
Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221
S
R
1
0
MOTIVATE: Results of Using
Weighted Score for OBT
Proportion of subjects with HIV RNA <50 copies/mL at Week 48 by wOBTSS
Subjects ≥50 CD4+
cells/mm3 at baseline
<50 copies/mL
at Week 48 (%)
All subjects
100
80
20
33 33
0
51
100
80
66
60
37
40
17
81 78
59
43
53
20
20
0
n=
wOBTSS
56 51
60
40
70 72
0
0
41 76 81
47 87 113
35 77 78
<1
<1
1-<2
1-<2
≥2
≥2
PBO + OBT
n=
31 60 61
<1
<1
MVC QD + OBT
35 67 94
1-<2
1-<2
32 63 64
≥2
≥2
MVC BID + OBT
Conclusions: Using a modified score of the optimized background regimen, and limiting the population
to patients with a CD4 count >50, MVC was associated with an ~80% response rate at Wk 48
Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221
Etravirine + Raltegravir + OBT:
Data from the Expanded Access Programs
●
Cohort Kaiser Permanente cohort starting ETR + RAL + OBT (n=53)
○
○
Three class experienced and HIV viremia
Resistance (or intolerance) within each class (NRTI, NNRTI, PI)
Baseline Demographics
Gender, male, n (%)
50 (94%)
Mean age, years
49
Median baseline CD4 count, cells\mm3 (IQR)
171 (74-290)
Received boosted protease inhibitor (PI) as part of OBT, n (%)
47 (89%)
DRV/r
44 (83%)
de novo use
43 (81%)
not de novo use
1 (2%)
LPV/r
3 (6%)
de novo use
1 (2%)
not de novo use
2 (4%)
ATV/r
1 (2%)
de novo use
0 (0%)
not de novo use
1 (2%)
Received enfuvirtide as part of OBT, n (%)
de novo use
Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263
6 (11%)
4 (8%)
Etravirine + Raltegravir + OBT:
Outcomes at Week 24
Virologic and Immunologic Outcomes at Week 24 ( ITT)
HIV-1 RNA <75 c/mL, n (%)
50 (94%)
Mean CD4 cell count change
+86 cells\mm3
Virologic Outcomes at Week 24 based on Baseline and Cumulative Resistance
ETR Weighted
Mutation Score
Number of Patients with HIV-1 RNA <75 c/mL at Week 24, Based on:
Baseline Resistance Assessment,
n (%)
Cumulative Resistance Assessment, n
(%)
0-2
Highest Predicted response
35/37 (94.6%)
28/30 (93.3%)
2.5 – 3.5
Intermediate Predicted
response
9/10 (90.0%)
10/10 (100%)
6/6 (100%)
12/13 (92.3%)
>3.5
Reduced Predicted response
• The combination of ETR + RAL + OBT was safe and tolerable with minimal adverse events
• Most common AEs were nausea (5), diarrhea (9) and rash (10)
Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263
Bevirimat: Phase II
Safety and Efficacy Data
Maturation Inhibitor
○
●
Not metabolized through CYP3A4
Phase II study: Placebo vs. dose
ranging BVM (n=88)
○
○
PK: Target Cmin (≥20 μg/ml) achieved
with liquid dose of ≥250mg QD
Safety
○
○
○
Only grade 1 clinical AEs observed
over 2 week period
Lab AEs grade >2: 4% AST,
8% glucose elevation
BVM activity affected by GAG
polymorphism (PM) pattern at codons
369-371
○
●
Effect of GAG Polymorphisms
on BVM Activity
62% of 1034 patients are free of Gag PM
pattern that predicts poor response to
BVM
Phase 3 planned with tablet
formulation and GAG PM screening
369
370
371
No 369-371
No PM & Cmin>20
0
Viral Suppression (log10 c/mL)
●
-0.2
-0.4
-0.16
-0.24
-0.32
-0.6
-0.8
-1
-1.2
-1.4
Lalezari J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-891
-1.08
-1.26
Elvucitabine: 48 Week Results
in ARV-Naïve Patients
○
Plus TDF and EFV QD
(blinded for first 12 weeks)
Results:
● Similar virologic suppression in
ELV and 3TC arms
● More AE discontinuations with ELV
○
○
First 12 weeks - 6 more on
ELV vs. LAM (multiple reasons)
After week 12 – DC rates the same
Conclusion:
○
Percent <50 c/mL (As-Treated)
Elvucitabine (25)
Lamivudine (30)
100
Percentage (%)
Novel L-cytosine NRTI:
● 80-100 hour half-life
● In-vitro activity with M184V/I mutation
Study Design:
● Randomized to ELV (10mg) or
3TC (300mg) QD
96.7%
90
96%
80
95% CI:
-0.7 (-10.7%, 9.3%)
70
60
50
40
30
20
10
0
0
2
4
ELV showed similar activity to
3TC to week 48
DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-892
6
8 10 12 14 16 20 24 28 32 36 40 44 48
Visit Week
RDEA806:
Activity of a Novel NNRTI
○
○
○
●
in vitro activity against
K103N
No inhibition / induction of
CYP450
Half-life 9-12 hours
○
○
○
7 day treatment period using
multiple doses of RDEA806
vs. placebo
Activity demonstrated and
dependent on Ctrough
No safety concerns identified
Uric acid reduced
Phase 2b in ARV treatmentnaïve patients planned
VL reduction
Median VL reduction
Ctrough
Median Ctrough
0
-0.5
-1
0.00
400 BID
600 QD 800 QD 1000 QD
0.01
-1.5
-2
-2.5
0.10
1.00
Ctrough (µg/ml)
Proof of Concept Study
(n=48)
○
●
Viral Load Reduction and Ctrough by Cohort
New NNRTI
Viral Load Nadir (Log10 c/mL)
●
3
-3.5
Moyle G, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-893
10.00
Proportion of patients
hospitalized (%)
Proportion of patients
hospitalized by Week 48
25
20
23%
17.5%
15
10
5
0
P=0.0006
Patients with any
AIDS-defining illness or death (%)
DUET: Impact of Treatment on
Hospitalization and Clinical Illness
12
10
Proportion of patients with any
AIDS-defining illness or death
8.8%
8
6
10.1%
9.8%
7.2%
5.8%
5.4%
4
2
0
P=0.0408
P=0.6114
P=0.0086
Overall
population
ENF de novo
ENF not de novo
ETR + BR (n=599)
Placebo + BR (n=604)
Haubrich R, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1239
Management Strategies
in Patients on
ARV Therapy
FOTO: Five Days On, Two Days
Off Study Design
VL < 50 c/mL on TDF / FTC /EFV
Continue daily ARV
treatment (n=30)
Change to Five days On;
Two Days Off (n=30)
Male (%)
83%
83%
White (%)
77%
63%
Age (years)
47
42
CD4 count (cells/mm3)
679
660
Primary Outcome: 24 weeks*
*At week 24 – pts. on Continuous arm offered change to FOTO; all followed for >48 weeks
Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.
FOTO Results:
Primary Outcome
Week 24: VL < 50 c/mL
Continuous
Patient Percent
100%
FOTO
83%
80%
80%
60%
40%
20%
0%
ITT M=F*
Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.
*p<0.05 to reject
hypothesis that
FOTO is inferior to
continuous
FOTO: Additional Outcomes
%<50 c/mL to week 24 (OT*)
Continuous
97%
100%
FOTO
96%
93%
87%
90%
88%
**
100%
86%
80%
60%
40%
20%
0%
BL
●
Week 12
Adverse Events:
○
○
○
●
Week 4
No drug-related SAEs
No grade >3 AEs in either arm
Labs: No Grade >2 in either arm
Pt. Preference Questionnaire – Week 4 on FOTO arm
○
○
Scale: 0 (prefer Continuous) to 10 (prefer FOTO)
Result: Median 9.5 (range 2-10)
*Missing = Excluded; **p<0.05 for inferiority
Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.
Week 24
AI-073: Switching Suppressed
Patients to EFV/FTC/TDF
Phase IV, multicenter (55 US sites), open-label study (N=300)
•VL<200 c/mL
•Stable ARV
Regimen
•On 1st regimen
or suppressed
on previous PI
regimen
•No H/O VF
STR=EFV/FTC/TDF QD (n=203)
Randomization
2:1
Stratify by
PI or NNRTI
SBR=Stayed Baseline Regimen (n=97)
Primary Endpoint:
Non-inferiority of STR vs. SBR for HIV-1 RNA <200 c/mL through Week 48 by TLOVR analysis
DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1234;
Young B, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P061.
AI-073: Results at 48 Weeks
% with HIV RNA <50 c/mL (TLOVR)
STR
SBR
Virologic failure
STR 3 , SBR 1
100%
87% 85%
80%
AE’s all grades
STR: Higher incidence
-Sleep disturbance 14% vs 0
-Dizziness 11% vs 1%
-GI (nauseas, diarrhea) 6% vs 2%
60%
40%
DC due to AE’s
STR 10 (5%), SBR 1 (1%)
20%
GFR (CG, MDRD)
No significant changes
Change TG (mg/dl)
STR -20, SBR -3 (P=0.035)
Pt preference
STR 91%, SBR 9% (P=0.001)
0%
Treatment Difference (STR – SBR)
95% CI:2.6% (5.9%, 11.1%)
DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1234;
Young B, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P061.
The 48th Interscience Conference
on Antimicrobial Agents and Chemotherapy and
46th Infectious Disease Society of America
Meeting
Washington, DC
October 24-28, 2008
and
9th International Congress on Drug Therapy in
HIV Infection
Glasgow, Scotland
November 9-13, 2008