The 48th Interscience Conference on Antimicrobial Agents and Chemotherapy and 46th
Infectious Disease Society of America MeetingWashington, DC
October 24-28, 2008
and
9th International Congress on Drug Therapy in HIV Infection
Glasgow, ScotlandNovember 9-13, 2008
When to Start
NA-ACCORD: Improved Survival When ART is Started with ≥350 CD4
● North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)○ Regional collaboration of 22 HIV research cohorts from
United States and Canada
● 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:
○ 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-896bKitahata 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)
Follow up person-years 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
Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896bKitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b
NA-ACCORD: Results
Relative Hazard (RH)*
95% Confidence
IntervalP-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) 1.6 1.5, 1.8 <0.001
Baseline CD4 count (per 100 cells/mm3) 0.9 0.7, 1.0 0.083
● HIV RNA was not an independent predictor of mortality● Rate of virologic suppression (<500 c/ml) similar between groups
Kitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896bKitahata M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896b
*Stratified by Cohort and Year
What to Start
STARTMRK: Raltegravir vs Efavirenz
● HIV RNA >5000 c/mL● Susceptible to EFV, TDF and FTC
Randomized (1:1), double blind, study
ART-naïve subjects(N=561)
RAL (400 mg BID)+ TDF/FTC QD+ EFV Placebo
EFV (600 mg QHS)+ TDF/FTC QD
+ RAL Placebo
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896aLennox 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
vRNA copies/mL (geometric mean) 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
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896aLennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
STARTMRK: Results
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
Perc
en
t w
ith
HIV
RN
A <
50 c
/mL
0 2 4 8 12 16 24 32 40 48
0
20
40
60
80
100
82%
Non-inferiorityp-Value <0.001
86%
RAL + TDF/FTC
EFV + TDF/FTC
Weeks
CD4 change:+189 cells/mm3
+163 cells/mm3
(95% CI: 4,47)
STARTMRK: Results
● Time to virologic suppression faster with RAL (P<0.001)
● Virologic failures similar○ 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
○ 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
-3
10
4 610
33
16
37
-10
0
10
20
30
40
T CHOL HDL-C LDL-C TG
RAL+TDF/FTCEFV+TDF/FTC
Mea
n C
han
ge
(mg
/dL
)
P<0.001P<0.001P<0.001P<0.001
Lennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896aLennox J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-896a
ARTEMIS: Phase III Study Design
96 Week Results Presented
DRV/r 800/100mg QD + TDF/FTC
(n=343)
LPV/r* 400/100mg BID or 800/200mg QD
+ TDF/FTC (n=346)
689 ARV-naïve patientsVL>5,000
*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%*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-1250cMills 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)
Baseline demographics
Female, N (%) 104 (30) 105 (30)
Caucasian 40% 44%
Baseline disease characteristics
Median HIV-1 RNA (c/mL) 70,800 62,100
Median CD4 (cells/mm3) 228 218
HBV/HCV co-infected 13% 14%
Stratification factors at screening
CD4 count <200 cells/mm3 41% 43%
Plasma HIV-1 RNA ≥100,000 c/mL 34% 35%
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250cMills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
ARTEMIS: HIV RNA <50 c/mL to Week 96 (TLOVR)
79
93
71
87
0
20
40
60
80
100
ITT* VF Only
DRV/r + TDF/FTC LPV/r + TDF/FTC P=0.024
Perc
en
t H
IV R
NA
<50 c
/mL
*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-1250cMills 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
● 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
DRV/r + TDF/FTC LPV/r + TDF/FTC
8176
≥100,000
75
<100,000Baseline viral load (copies/mL)
0
20
40
60
80
100
% H
IV R
NA
<5
0 c
opie
s/m
L (I
TT-T
LOV
R)
63
P=0.023
n = 226 226 117 120
P=0.174
79
65
≥2000
20
40
60
80
100
7975
<200
Baseline CD4 cell count (cells/mm3)202 198n=
P=0.009 P=0.345
141 148
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250cMills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
ARTEMIS: Median Increase in Lipid Levels at Week 96
18
LPV/r + TDF/FTCDRV/r + TDF/FTC
0.0
10
20
40
Total cholesterol
LDLc cholesterol
HDL cholesterol Triglycerides
Media
n incr
ease
in
conce
ntr
ati
on (
mg/d
L)
26
17
5
35
15
8
56
30
Mills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250cMills A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250c
50
60
ATV/r 300/100 mg QD+ TDF/FTC QD
(n=440)
CASTLE: Study Design
(1:1)
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 restrictionStratified by HIV RNA <100,000 c/mL vs 100,000 c/mL and geographic region
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-1250dMolina 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
CDC Class C (%) 4 5
HIV RNA median (log10 c/mL) 5.01 4.96
HIV RNA ≥100,000 c/mL (%) 51 47
CD4 median (cells/mm3) 205 204
CD4 <50 cells/mm3 (%) 13 11
HBV or HCV +ve (%) 14 12
HIV subtype B (%) 67 66
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250dMolina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
CASTLE: HIV RNA <50 c/mL (CVR, NC = F)
Perc
ent
HIV
RN
A <
50
c/m
L
Weeks
B/L 12 24 36 480
20
40
60
80
100
60 72 84 96
ATV/r + TDF/FTC (n=440)LPV/r + TDF/FTC (n=443)
HIV RNA <50 c/mL: 74% ATV/RTV vs 68% LPV/RTV
Difference estimate: 6.1 (95% CI, 0.3%–12.0%, P<0.05)
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250dMolina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
CASTLE: Response by Baseline HIV RNA and CD4
N=
0
20
40
60
80
100
30
50
70
90
10Resp
onder
(%)
<5
0 c
opie
s/m
L
217 218 223 225
75%70%
74%
66%
<100,000 c/mL ≥100,000 c/mL
ITT-Confirmed Virologic Response (NC =F) by Qualifying HIV Viral Load
ATV/r + TDF/FTC LPV/r + TDF/FTC
≥200 cells/mm3
100 - <200 cells/mm3
N=
0
20
40
60
80
100
30
50
70
90
10Resp
onder
(%)
<5
0 c
opie
s/m
L P=NS
ITT-Confirmed Virologic Response (NC =F) by Baseline CD4 Cell Count
222
76%71%
78%
71% 69% 70%
58%
69%
ATV/r LPV/r106 45 58 228 134 29 48
P=NS
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250dMolina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
50 - <100 cells/mm3
< 50 cells/mm3
CASTLE: Adverse Eventsat 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
Diarrhea 0 2%
Renal <1% <1%
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250dMolina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250d
*Lipid Changes are Mean Percent Increase From Baseline
CASTLE: Mean Fasting Lipids at Baseline and Week 96
149
92
37
112
126
168
105
44
125
140
150
93
36
114
129
186
110
46
140
184
0
20
40
60
80
100
120
140
160
180
200
TC LDL-c HDL-c Non-HDL-c TG
Lip
id V
alu
es m
g/d
l
ATV/r + TDF/FTC Baseline
ATV/r + TDF/FTC Wk 96
LPV/r + TDF/FTC Baseline
LPV/r + TDF/FTC Wk 96
Difference Estimate
(95% CI) ATV/r-LPV/r
Difference Estimate
(95% CI) ATV/r-LPV/r
-8.9%*
(-11.6%, -6.1%)
-8.9%*
(-11.6%, -6.1%)
-1.7%
(-5.9%, 2.6%)
-1.7%
(-5.9%, 2.6%)
-5.5%
(-10.0%, -0.8%)
-5.5%
(-10.0%, -0.8%)
-9.7%*
(-13.0%, -6.3%)
-9.7%*
(-13.0%, -6.3%)
-24.5%*
(-29.9%, -18.8%)
-24.5%*
(-29.9%, -18.8%)
* P<0.0001* P<0.0001
Molina J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1250dMolina 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
● 12 clinical trials (N=4896)● Aggregate results favor TDF/FTC
50% 60% 70% 80% 90% 100%
% HIV RNA <50 copies (ITT TLOVR) at Week 48
SQV/r
DRV/r
FPV/r
LPV/r
TDF (n=53)
ABC (n=722)
TDF (n=2285)ABC (n=722)
TDF (n=166)
TDF (n=343)
TDF (n=493)ATV/r ABC (n=112)
Hill A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1254Hill A, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1254
Convergence of First-line Regimens
● 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%)
Nu
mb
er
Sta
rte
d o
n a
Un
iqu
e R
eg
ime
n/
Nu
mb
er
of
Pa
tien
ts S
tart
ed
on
AR
Vs
Annual Treatment Share for All Regimens Utilized as Initial Therapy
FTC/TDF/EFV3TC/ZDV/LPV/r3TC/ddI/EFV
2003 (n=67) 2004 (n=75) 2005 (n=68) 2006 (n=66) 2007 (n=65)
3TC/ZDV/EFV3TC/ZDV/NFVFTC/TDF/ATV/r
3TC/ABC/ZDV3TC/ZDV/NVPOther – (<5% Treatment Share)
0
20
40
60
80
100
30
50
70
90
10
McKinnell J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1260McKinnell J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1260
Issues Regarding ARV Therapy in Treatment-Experienced Patients
TITAN: Study Design
• LPV-naïve, treatment-experienced
• VL >1,000 copies/mL
• Stable HAART for ≥12 weeks (STI allowed)
DRV/r 600/100mg bid + OBR (n=298)
LPV/r 400/100mg bid + OBR (n=297)
Rollover and follow-up
phase after 1 and 4 weeks
Screening phase (4 weeks)
Treatment phase (96 weeks)
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.Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.
TITAN: Results at 96 Weeks
60 5668
5662
5563
38
69
49
0102030405060708090
100
0 ≥1 0 ≥1
Pat
ien
ts <
50 c
op
ies/
mL
(%
)DRV/r LPV/r
Previously Used PIs**Primary PI Mutations**Overall
P=0.154 P<0.0001 P=0.078 P=0.007P<0.001*
*Non-inferiority; **at baseline
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.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
*p<0.05 vs LPV/r**p<0.01 vs LPV/r
• 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
LPV/r
Me
dia
n c
ha
ng
e f
rom
ba
se
lin
e (
%)
31%*
12%**10%
4%**
44%
18%13%
0
20
40
60
Triglycerides Totalcholesterol
LDLcalculated
HDL
10%
Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.Bánhegyi D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. P022.
BENCHMRK: Resistance Analysis
● Genotyping of BENCHMRK virologic failures (VF)○ Population sequencing○ GT at Baseline, VF (HIV
RNA >400), and time point(s) post VF○ 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
0
10
20
30
40
50
60
70
First Failure Genotype Post-failure Genotype
1 2 >2
• 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-898Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898
Number of Mutations
Changes from Baseline Genotype
Nu
mb
er
of
Ge
no
typ
es
BENCHMRK: Pharmacokinetics and Pharmacodynamics
• 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-898Miller M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-898
P24 at 48h
remove 6, 8, 10 or 12h post infection Infect
0
10
20
30
40
50
60
70
80
90
No Wash 6 h 8 h 10 h 12 h
No drug RAL
RAL “Post-Antibiotic” Effect (in vitro)
% p
atie
nts
wit
h H
IV R
NA
<40
0 c/
mL
GM Observed C12hr (nM)
GM Observed C12hr <33 nM
8 - 125 128 - 254 254 - 545 547 - 9151
0
20
40
60
80
100
RAL Effective Across Range of Trough Levels
ACTG 5211: Analysis Using Enhanced Sensitivity Tropism Testing
Trofile ES reclassified 25/114 individuals with R5 virusat screen using original Trofile
Original Trofile 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%
Screening: R5 tropism by the original Trofile assay VCV 5*, 10 or 15 mg QD or Placebo
Optimized ART regimenFailing ART regimen
StudyScreen
StudyEntry
Day14
Week24
Week48
Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895*Stopped early
ACTG 5211: Response Based on Trofile ES
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
Day 1
4W
eek 2
4
Trofile ES
D/M Screen R5 ScreenD/M Entry
R5 ScreenR5 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
Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895Su Z, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-895
* log10 c/mL** From regression model adjusted for baseline HIV-1 RNA and study stratification factors
Randomization 1:1Patient 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
MVC (300 mg BID)* + ZDV/3TC**
MERIT: Efavirenz vs. Maraviroc in ARV-Naïve Patients
EFV+ ZDV/3TC**
Week 48Primary 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*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/Mby Trofile ES
N BL D/M on study
EFV + ZDV/3TCn/N (%)
MVC + ZDV/3TCn/N (%)
Totaln/N (%)
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
*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
MVC + ZDV/3TCEFV + ZDV/3TC
<400 copies/mL
0
10
20
30
40
50
60
70
80
90
100
361 360
303 311
73.1 70.6
Pati
ents
(%
)
n=
–3.0 (–9.5*) 0.6 (–6.4*)
72.3 73.3
MERIT MERIT ES
<50 copies/mL
–0.2 (–7.4*)
361 360 303 311n=
68.3 68.5
0
10
20
30
40
50
60
70
80
90
100
69.365.3
–4.2 (–10.9*)
MERIT MERIT ES
MERIT ES: Summary of Discontinuations through 48 Weeks
Reason for discontinuation EFV + ZDV/3TC MVC + ZDV/3TC
MERIT (N=361)
MERIT ES (N=303)
MERIT(N=360)
MERIT ES (N=311)
All, n (%) 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 tofollow-up, n (%) 18 (5.0) 14 (4.6) 25 (6.9) 22 (7.1)
Only patients with an R5 screening result by enhanced Trofile assay are included in MERIT ES
*All cause eventsSaag M, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1232a
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
MOTIVATE 1 & 2: Trial Design
1076 ARV-experienced patients
MVC 150mg† BID(n=426)
MVC 150mg† QD (n=414)
Placebo(n=209)
R5 HIV-1 infection (44% screen failures)HIV-1-RNA ≥ 5,000 copies/mL
Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeksResistance to and/or ≥ 6 months’ experience with ≥ 1 ARV from 3 classes (≥ 2 for PIs)
MOTIVATE 1 & 2
2 identical ongoing Phase IIb/III studiesRandomized (1:2:2), double-blind, placebo controlled
All received OBT*Stratified by ENF use and HIV-1 RNA < and ≥ 100,000 copies/mL
*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.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)
Placebo + OBT (N=209)MVC QD + OBT (N=414)MVC BID + OBT (N=426)
Patie
nts
(%)
Option to switch to open-label MVC BID
43.7%
45.1%
23.0%
43.5%
46.5%
16.7%
38.9%41.3%
7.2%
Time (weeks)
0
10
20
30
40
50
60
70
80
90
100
0 8 16 24 32 40 48 56 64 72 80 88 96
Blinded Phase
Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.Hardy D, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O425.
Weighted OBT Sensitivity Score (wOBTSS)
MOTIVATE: Using a Weighted Score for the OBT to Predict Response
Any drug in continuous use, score = 0
IC50FC
S* R**
PI 1 0
NRTI 0.5 0
NNRTI 1 0
Genotype
S R
ENF 1 0
Full analysis set(N=1,049)
On-study at Week 48 or virologic failure (n=904)
Virologic Outcomes(VO) population (n=634)
Population included in regression modeling (n=628)
Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221
*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
Non-virologic failures excluded (n=145)
Missing / incomplete information (n=6)
Exclusions for protocol violations and other reasons (n=270)
MOTIVATE: Results of Using Weighted Score for 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
Proportion of subjects with HIV RNA <50 copies/mL at Week 48 by wOBTSS
Subjects ≥50 CD4+ cells/mm3 at baseline
n=
<5
0 c
op
ies/
mL
at
Week
48
(%
)
41 76 81 47 87 113 35 77 78
All subjects
Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221Valdez H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1221
PBO + OBT MVC QD + OBT MVC BID + OBT
wOBTSS <1 1-<2 ≥2 <1 1-<2 ≥2
n= 31 60 61 35 67 94 32 63 64
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 DemographicsGender, 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 (%) 6 (11%)
de novo use 4 (8%)
Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263Kerrigan H, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1263
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 response35/37 (94.6%) 28/30 (93.3%)
2.5 – 3.5
Intermediate Predicted response
9/10 (90.0%) 10/10 (100%)
>3.5
Reduced Predicted response6/6 (100%) 12/13 (92.3%)
• 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-1263Kerrigan 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
○ 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
-0.16-0.24
-0.32
-1.08
-1.26-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
369 370 371 No 369-371 No PM & Cmin>20
Lalezari J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-891Lalezari J, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-891
Effect of GAG Polymorphisms on BVM Activity
Vir
al S
up
pre
ssio
n (
log
10 c
/mL
)
Elvucitabine: 48 Week Results in ARV-Naïve Patients
Novel L-cytosine NRTI: ● 80-100 hour half-life● In-vitro activity with M184V/I mutationStudy Design: ● Randomized to ELV (10mg) or
3TC (300mg) QD○ 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: ○ ELV showed similar activity to
3TC to week 48
DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-892DeJesus E, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-892
95% CI:-0.7 (-10.7%, 9.3%)
Elvucitabine (25) Lamivudine (30)
Perc
enta
ge (
%)
0
10
20
30
40
50
60
70
80
90
100
Visit Week
0 2 4 6 8 10 12 14 16 20 24 28 32 36 40 44 48
96.7%
96%
Percent <50 c/mL (As-Treated)
RDEA806:Activity of a Novel NNRTI
● New NNRTI○ in vitro activity against K103N○ No inhibition / induction of
CYP450○ Half-life 9-12 hours
● Proof of Concept Study (n=48)
○ 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 treatment-naïve patients planned
Moyle G, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-893
Viral Load Reduction and Ctrough by Cohort
400 BID 600 QD 800 QD 1000 QD
0
-0.5
-1
-1.5
-2
-2.5
3
-3.5
0.00
10.00
1.00
0.10
0.01
Vir
al Lo
ad
Nadir
(Lo
g1
0 c
/mL)
Ctro
ug
h (µg/m
l)
VL reduction
Ctrough
Median VL reduction
Median Ctrough
DUET: Impact of Treatment on Hospitalization and Clinical Illness
0
5
10
15
20
25
ETR + BR (n=599)Placebo + BR (n=604)
Pro
port
ion o
f pati
en
ts
hosp
italiz
ed
(%
) 23%
17.5%
P=0.0006
Proportion of patients hospitalized by Week 48
Proportion of patients with any AIDS-defining illness or death
Pati
ents
wit
h a
ny
AID
S-d
efin
ing
illn
ess
or
death
(%
)
Overall population
ENF not de novoENF de novo
0
5.8%
9.8%
7.2%
8.8%
5.4%
10.1%
2
4
6
8
10
12
P=0.0408 P=0.6114 P=0.0086
Haubrich R, et al. 48th ICAAC/46th IDSA; Washington, DC; October 25-28. Abst. H-1239Haubrich 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 /EFVVL < 50 c/mL on TDF / FTC /EFV
Continue daily ARV treatment (n=30)
Change to Five days On; Two Days Off (n=30)
Change to Five days On; Two Days Off (n=30)
Primary Outcome: 24 weeks*Primary Outcome: 24 weeks*
*At week 24 – pts. on Continuous arm offered change to FOTO; all followed for >48 weeks
Male (%) 83% 83%
White (%) 77% 63%
Age (years) 47 42
CD4 count (cells/mm3) 679 660
Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.
FOTO Results: Primary Outcome
83%80%
0%
20%
40%
60%
80%
100%
ITT M=F*
Continuous FOTO
*p<0.05 to reject hypothesis that FOTO is inferior to continuous
Week 24: VL < 50 c/mLP
atie
nt P
erce
nt
Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.
FOTO: Additional Outcomes
97%
87%
96%
86%93% 90% 88%
100%
0%
20%
40%
60%
80%
100%
BL Week 4 Week 12 Week 24
Continuous FOTO
*Missing = Excluded; **p<0.05 for inferiority
****
%<
50
c/m
L t
o w
ee
k 2
4 (
OT
*)
● Adverse Events:○ 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)
Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.Cohen C, et al. 9th ICDTHI; Glasgow, Scotland; November 9-13, 2008. Abst. O214.
AI-073: Switching Suppressed Patients to EFV/FTC/TDF
STR=EFV/FTC/TDF QD (n=203)
SBR=Stayed Baseline Regimen (n=97)
Randomization2:1
Stratify byPI or NNRTI
Continue
Switch•VL<200 c/mL •Stable ARV Regimen •On 1st regimen or suppressed on previous PI regimen •No H/O VF
Phase IV, multicenter (55 US sites), open-label study (N=300)
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. 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.
87% 85%
0%
20%
40%
60%
80%
100%
STR SBR
AI-073: Results at 48 Weeks
Virologic failure STR 3 , SBR 1
AE’s all grades
STR: Higher incidence
-Sleep disturbance 14% vs 0
-Dizziness 11% vs 1%
-GI (nauseas, diarrhea) 6% vs 2%
DC due to AE’s STR 10 (5%), SBR 1 (1%)
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)
% w
ith
HIV
RN
A <
50 c
/mL
(T
LO
VR
)
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. 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 MeetingWashington, DC
October 24-28, 2008
and
9th International Congress on Drug Therapy in HIV Infection
Glasgow, ScotlandNovember 9-13, 2008