the 48th interscience conference on antimicrobial agents and chemotherapy and 46th infectious...
TRANSCRIPT
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