The%2048th%20Interscience%20Conference%20on%20Antimicrobial%20Agents%20and%20Chemotherapy%20and%2046th%20Infectious%20Disease%20Society%20of%20America%20Meeting%20Washington,%20DC%20October%2024-28,%202008%20and%209th%20International%20Congress%20on%20Drug%20Therapy%20in%20HIV%20Infection%20Glasgow,

1
The 48th Interscience Conference on
Antimicrobial Agents and Chemotherapy and 46th
Infectious Disease Society of America
MeetingWashington, DCOctober 24-28,
2008and9th International Congress on Drug
Therapy in HIV InfectionGlasgow,
ScotlandNovember 9-13, 2008
2
When to Start
3
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-896b
4
NA-ACCORD Baseline Characteristics
Initiate HAART (n2,473) Defer HAART (n5,901)
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-896b
5
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 lt0.001
Female Sex 1.1 0.9, 1.5 0.290
Older Age (per 10 years) 1.6 1.5, 1.8 lt0.001
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 (lt500 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
6
What to Start
7
STARTMRK Raltegravir vs Efavirenz
Randomized (11), double blind, study

• HIV RNA gt5000 c/mL
• Susceptible to EFV, TDF and FTC

Lennox J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-896a
8
STARTMRKBaseline Characteristics
RAL TDF/FTC (n281) EFV TDF/FTC (n282)
Age (mean, years) 38 37
Male 81 82
Non-White 59 56
vRNA copies/mL (geometric mean) 103,205 106,215
with vRNA gt105 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-896a
9
STARTMRK Results
Lennox J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-896a
10
STARTMRK Results

• Time to virologic suppression faster with RAL
  (Plt0.001)
• 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 (Plt0.001)
• CNS at week 8 RAL 10.3 vs 17.7 (P0.015)
  persisted through week 48

Lennox J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-896a
11
STARTMRK Fasting Serum Lipid Changes from
Baseline to Week 48
Lennox J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-896a
12
ARTEMIS Phase III Study Design
689 ARV-naïve patients VLgt5,000
DRV/r 800/100mg QD TDF/FTC (n343)
LPV/r 400/100mg BID or 800/200mg QD TDF/FTC
(n346)

• 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
13
ARTEMIS Baseline Characteristics
DRV/r TDF/FTC QD(n343) LPV/r TDF/FTC QD (n267)
Baseline demographics Baseline demographics Baseline demographics
Female, N () 104 (30) 105 (30)
Caucasian 40 44
Baseline disease characteristics Baseline disease characteristics 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 Stratification factors at screening Stratification factors at screening
CD4 count lt200 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-1250c
14
ARTEMIS HIV RNA lt50 c/mL to Week 96 (TLOVR)
P0.024
Percent HIV RNA lt50 c/mL
Estimated difference in response vs LPV/r for
non-inferiority PP 8.4 (95 CI 1.914.8,
Plt0.001) Estimated difference in response vs
LPV/r for superiority ITT 8.3 (95 CI
1.814.7, P0.012)
Mills A, et al. 48th ICAAC/46th IDSA Washington,
DC October 25-28. Abst. H-1250c
15
ARTEMIS Response by VL and CD4 Strata and
Adverse Events
100
100
P0.023
P0.174
P0.009
P0.345
81
79
79
80
80
76
75
75
65
63
60
60
HIV RNA lt50 copies/mL (ITT-TLOVR)
40
40
20
20
0
0
200
lt200
100,000
lt100,000
Baseline viral load (copies/mL)
Baseline CD4 cell count (cells/mm3)
n 226 226 117 120
202
198
n
141
148

• Higher rate of GI adverse events in LPV/r arm
  (Diarrhea 4 vs. 11 , Plt0.001)
• Grade 2-4 increases in total cholesterol (18 vs.
  28, P0.0016) and triglycerides (4 vs. 13,
  Plt0.0001) higher in LPV/r arm

Mills A, et al. 48th ICAAC/46th IDSA Washington,
DC October 25-28. Abst. H-1250c
16
ARTEMIS Median Increase in Lipid Levels at Week
96
60
50
Mills A, et al. 48th ICAAC/46th IDSA Washington,
DC October 25-28. Abst. H-1250c
17
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 lt100,000 c/mL
vs ?100,000 c/mL and geographic region
(11)
ATV/r 300/100 mg QD TDF/FTC QD (n440)
LPV/r 400/100 mg BID TDF/FTC QD (n443)
Molina J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1250d
18
CASTLE Baseline Characteristics
ATV/r TDF/FTC(n440) LPV/r TDF/FTC(n443)
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 lt50 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-1250d
19
CASTLE HIV RNA lt50 c/mL (CVR, NC F)
100
80
60
Percent HIV RNA lt50 c/mL
40
HIV RNA lt50 c/mL 74 ATV/RTV vs 68
LPV/RTV Difference estimate 6.1 (95 CI,
0.312.0, Plt0.05)
20
0
B/L
36
84
12
24
48
60
72
96
Weeks
Molina J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1250d
20
CASTLE Response by Baseline HIV RNA and CD4
ATV/r TDF/FTC LPV/r TDF/FTC
ITT-Confirmed Virologic Response (NC F) by
Qualifying HIV Viral Load
100
lt100,000 c/mL
100,000 c/mL
90
80
75
74
70
70
66
60
Responder () lt50 copies/mL
50
40
30
20
10
0
N
217
218
223
225
200 cells/mm3 100 - lt200 cells/mm3
50 - lt100 cells/mm3 lt 50 cells/mm3
Molina J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1250d
21
CASTLE Adverse Eventsat 96 Weeks
ATV/r TDF/FTC(n441) LPV/r TDF/FTC (n437)
Death 1 1
SAE 14 11
AE leading to discontinuation 3 5
Jaundice/hyperbilirubinemia lt1 0
Diarrhea 0 2
Renal lt1 lt1
Lipid Changes are Mean Percent Increase From
Baseline
Molina J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1250d
22
CASTLE Mean Fasting Lipids at Baseline and Week
96
-9.7 (-13.0, -6.3)
-5.5 (-10.0, -0.8)
-1.7 (-5.9, 2.6)
-24.5 (-29.9, -18.8)
Difference Estimate (95 CI) ATV/r-LPV/r
-8.9 (-11.6, -6.1)
Plt0.0001
Molina J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1250d
23
Meta-Analysis of TDF/FTC vs ABC/3TC in Boosted PI
Trials

• 12 clinical trials (N4896)
• Aggregate results favor TDF/FTC

Hill A, et al. 48th ICAAC/46th IDSA Washington,
DC October 25-28. Abst. H-1254
24
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)

Annual Treatment Share for All Regimens Utilized
as Initial Therapy
100
90
80
70
Number Started on a Unique Regimen/Number of
Patients Started on ARVs
60
50
40
30
20
10
0
2003 (n67)
2004 (n75)
2005 (n68)
2006 (n66)
2007 (n65)
FTC/TDF/EFV3TC/ZDV/LPV/r3TC/ddI/EFV
3TC/ZDV/EFV3TC/ZDV/NFVFTC/TDF/ATV/r
3TC/ABC/ZDV3TC/ZDV/NVPOther (lt5 Treatment
Share)
McKinnell J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1260
25
Issues Regarding ARV Therapy in
Treatment-Experienced Patients
26
TITAN Study Design
Screening phase (4 weeks)
Treatment phase (96 weeks)

• LPV-naïve, treatment-experienced
• VL gt1,000 copies/mL
• Stable HAART for 12 weeks (STI allowed)

DRV/r 600/100mg bid OBR (n298)
Rollover and follow-up phase after 1 and 4 weeks
LPV/r 400/100mg bid OBR (n297)
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.
27
TITAN Results at 96 Weeks
DRV/r
LPV/r
P0.154
Plt0.0001
P0.078
P0.007
Plt0.001
Patients lt50 copies/mL ()
Overall
CD4 Cell Change DRV/r 93 cells/mm3 vs. LPV/r 81
cells/mm3
Non-inferiority at baseline
Virologic Failures DRV/r 14 vs. LPV/r 26
(plt0.001)
Bánhegyi D, et al. 9th ICDTHI Glasgow, Scotland
November 9-13, 2008. Abst. P022.
28
TITAN Adverse Events and Median Change in
Lipids at Week 96

• Notable Grade 2-4 AEs
• Diarrhea DRV/r 8 vs. LPV/r 15 (p0.007)
• Rash DRV/r 3 vs. LPV/r 1 (p0.09)
• No notable differences regarding laboratory
  abnormalities

plt0.05 vs LPV/rplt0.01 vs LPV/r
Bánhegyi D, et al. 9th ICDTHI Glasgow, Scotland
November 9-13, 2008. Abst. P022.
29
BENCHMRK Resistance Analysis
Changes from Baseline Genotype

• Genotyping of BENCHMRK virologic failures (VF)
• Population sequencing
• GT at Baseline, VF (HIV RNA gt400), 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

Number of Mutations
Number of Genotypes

• 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
30
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-898
31
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
Optimized ART regimen
Failing ART regimen
StudyScreen
StudyEntry
Day14
Week24
Week48
Original Trofile 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

• 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
32
ACTG 5211 Response Based on Trofile ES
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 lt0.0001 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
Day 14
Week 24
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
33
MERIT Efavirenz vs. Maraviroc in ARV-Naïve
Patients

• Randomization 11
• 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 lt and 100,000 copies/mL at screening
• Geographic location No. and So. Hemispheres

MVC (300 mg BID) ZDV/3TC
EFV 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
34
MERIT ES Re-analysis of CCR5 Screening
Screened as R5 by Standard Trofile Screened as R5 by Standard Trofile Screened as R5 by Standard Trofile Rescreened as D/M by Trofile ES Rescreened as D/M by Trofile ES Rescreened as D/M by 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
35
MERIT ES Viral Suppression Using Enhanced
Tropism Testing
MVC ZDV/3TC
EFV ZDV/3TC
lt400 copies/mL
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
36
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 EFV ZDV/3TC MVC ZDV/3TC MVC ZDV/3TC
MERIT (N361) MERIT ES (N303) MERIT(N360) MERIT ES (N311)
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)
All cause events Saag M, et al. 48th ICAAC/46th
IDSA Washington, DC October 25-28. Abst. H-1232a
37
MOTIVATE 1 2 Trial Design
MOTIVATE 1 2
2 identical ongoing Phase IIb/III
studies Randomized (122), 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 lt and 100,000 copies/mL
MVC 150mg QD (n414)
Placebo (n209)
MVC 150mg BID (n426)
Week 96 Data Includes all patients who reached
Week 48 with HIV-1 RNA lt50 c/mL and continued on
blinded therapy or open-label MVC BID
OBT optimized background therapy of 36 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.
38
MOTIVATE 1 2 HIV-1 RNA lt50 Copies/mL at Week
96 (ITT, NCF)
Hardy D, et al. 9th ICDTHI Glasgow, Scotland
November 9-13, 2008. Abst. O425.
39
MOTIVATE Using a Weighted Score for the OBT to
Predict Response
Weighted OBT Sensitivity Score (wOBTSS)
Full analysis set(N1,049)
Non-virologic failures excluded (n145)
Any drug in continuous use, score 0 IC50FC IC50FC
Any drug in continuous use, score 0 S R
PI 1 0
NRTI 0.5 0
NNRTI 1 0
Genotype Genotype
S R
ENF 1 0
On-study at Week 48 or virologic failure (n904)
Exclusions for protocol violations and other
reasons (n270)
Virologic Outcomes(VO) population (n634)
Missing / incomplete information (n6)
Population included in regression modeling (n628)
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
40
MOTIVATE Results of Using Weighted Score for OBT
Proportion of subjects with HIV RNA lt50 copies/mL
at Week 48 by wOBTSS
Subjects 50 CD4 cells/mm3 at baseline
All subjects
lt50 copies/mL at Week 48 ()
n
41 76 81 47 87 113 35 77
78
n
31 60 61 35 67 94 32 63
64
wOBTSS lt1 1-lt2 2 lt1 1-lt2 2

• Conclusions Using a modified score of the
  optimized background regimen, and limiting the
  population to patients with a CD4 count gt50, 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
41
Etravirine Raltegravir OBT Data from the
Expanded Access Programs

• Cohort Kaiser Permanente cohort starting ETR
  RAL OBT (n53)
• Three class experienced and HIV viremia
• Resistance (or intolerance) within each class
  (NRTI, NNRTI, PI)

Baseline Demographics Baseline Demographics Baseline Demographics
Gender, male, n () Gender, male, n () 50 (94)
Mean age, years Mean age, years 49
Median baseline CD4 count, cells\mm3 (IQR) Median baseline CD4 count, cells\mm3 (IQR) 171 (74-290)
Received boosted protease inhibitor (PI) as part of OBT, n () 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 () 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-1263
42
Etravirine Raltegravir OBTOutcomes at Week
24
Virologic and Immunologic Outcomes at Week 24 ( ITT) Virologic and Immunologic Outcomes at Week 24 ( ITT)
HIV-1 RNA lt75 c/mL, n () 50 (94)
Mean CD4 cell count change 86 cells\mm3
Virologic Outcomes at Week 24 based on Baseline and Cumulative Resistance Virologic Outcomes at Week 24 based on Baseline and Cumulative Resistance Virologic Outcomes at Week 24 based on Baseline and Cumulative Resistance
ETR Weighted Mutation Score Number of Patients with HIV-1 RNA lt75 c/mL at Week 24, Based on Number of Patients with HIV-1 RNA lt75 c/mL at Week 24, Based on
ETR Weighted Mutation Score 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)
gt3.5 Reduced Predicted response 6/6 (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-1263
43
Bevirimat Phase II Safety and Efficacy Data

• Maturation Inhibitor
• Not metabolized through CYP3A4
• Phase II study Placebo vs. dose ranging BVM
  (n88)
• 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 gt2 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

Effect of GAG Polymorphisms on BVM Activity
Viral Suppression (log10 c/mL)
Lalezari J, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-891
44
Elvucitabine 48 Week Results in ARV-Naïve
Patients

• 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
• 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-892
45
RDEA806Activity of a Novel NNRTI
Viral Load Reduction and Ctrough by Cohort

• New NNRTI
• in vitro activity against K103N
• No inhibition / induction of CYP450
• Half-life 9-12 hours
• Proof of Concept Study (n48)
• 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
46
DUET Impact of Treatment on Hospitalization and
Clinical Illness
Proportion of patients hospitalized by Week 48
Proportion of patients with any AIDS-defining
illness or death
12
10.1
9.8
10
8.8
8
7.2
23
Patients with any AIDS-defining illness or death
()
5.8
6
5.4
17.5
Proportion of patients hospitalized ()
4
2
0
P0.0006
P0.0408
P0.6114
P0.0086
Overall population
ENF not de novo
ENF de novo
Haubrich R, et al. 48th ICAAC/46th IDSA
Washington, DC October 25-28. Abst. H-1239
47
Management Strategies in Patients on ARV Therapy
48
FOTO Five Days On, Two Days Off Study Design
VL lt 50 c/mL on TDF / FTC /EFV
Continue daily ARV treatment (n30)
Change to Five days On Two Days Off (n30)
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 gt48 weeks
Cohen C, et al. 9th ICDTHI Glasgow, Scotland
November 9-13, 2008. Abst. O214.
49
FOTO Results Primary Outcome
Week 24 VL lt 50 c/mL
plt0.05 to reject hypothesis that FOTO is
inferior to continuous
Patient Percent
Cohen C, et al. 9th ICDTHI Glasgow, Scotland
November 9-13, 2008. Abst. O214.
50
FOTO Additional Outcomes

lt50 c/mL to week 24 (OT)

• Adverse Events
• No drug-related SAEs
• No grade gt3 AEs in either arm
• Labs No Grade gt2 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 plt0.05 for inferiority
Cohen C, et al. 9th ICDTHI Glasgow, Scotland
November 9-13, 2008. Abst. O214.
51
AI-073 Switching Suppressed Patients to
EFV/FTC/TDF
Phase IV, multicenter (55 US sites), open-label
study (N300)

• VLlt200 c/mL
• Stable ARV Regimen
• On 1st regimen or suppressed on previous PI
  regimen
• No H/O VF

STREFV/FTC/TDF QD (n203)
Switch
Randomization 21
Stratify byPI or NNRTI
Continue
SBRStayed Baseline Regimen (n97)
Primary Endpoint Non-inferiority of STR vs. SBR
for HIV-1 RNA lt200 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.
52
AI-073 Results at 48 Weeks
Virologic failure STR 3 , SBR 1
AEs all grades STR Higher incidence -Sleep disturbance 14 vs 0 -Dizziness 11 vs 1 -GI (nauseas, diarrhea) 6 vs 2
DC due to AEs STR 10 (5), SBR 1 (1)
GFR (CG, MDRD) No significant changes
Change TG (mg/dl) STR -20, SBR -3 (P0.035)
Pt preference STR 91, SBR 9 (P0.001)
with HIV RNA lt50 c/mL (TLOVR)
Treatment Difference (STR SBR) 95 CI2.6
(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.
53
The 48th Interscience Conference on
Antimicrobial Agents and Chemotherapy and 46th
Infectious Disease Society of America
MeetingWashington, DCOctober 24-28,
2008and9th International Congress on Drug
Therapy in HIV InfectionGlasgow,
ScotlandNovember 9-13, 2008