chicago, illinois | september 17-20, 2007
DESCRIPTION
Key HIV Research From ICAAC 2007: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Faculty:. Chicago, Illinois | September 17-20, 2007. Cal Cohen, M.D., M.S. Eric Daar, M.D. This activity is supported by an educational grant from:. Faculty for This Activity. - PowerPoint PPT PresentationTRANSCRIPT
Key HIV Research From ICAAC 2007: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy
Key HIV Research From ICAAC 2007: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, Illinois | September 17-20, 2007
Faculty:
Cal Cohen, M.D., M.S.
Eric Daar, M.D.This activity is supported by an educational grant from:
The Body PRO
ICAAC 2007: Key HIV Research
Cal Cohen, M.D., M.S.
Eric Daar, M.D.
Dr. Daar is the chief of HIV medicine at Harbor-UCLA Medical Center in Los Angeles, Calif., and a professor of medicine at the University of California-Los Angeles' David Geffen School of Medicine. He has been an active HIV physician and researcher since the 1980s; during the past three decades, he has led dozens of studies on a vast range of HIV-related issues, with a particular focus on coinfections and other health complications associated
with HIV and HIV treatment, including hepatitis C, metabolic complications, cardiovascular disease and psychosocial issues such as depression.
Dr. Cohen is the research director of the Community Research Initiative of New England and teaches at Harvard Medical School in Boston, Mass. In addition, he works as a HIV clinical management consultant and internist at Harvard Pilgrim Health Care, Boston, Mass., and is affiliated with Harvard Vanguard Medical Associates. Dr. Cohen was co-chair of the Scientific Advisory Committee of amfAR community-based clinical trials network, and served as co-principal investigator of the Harvard/BCH AIDS Clinical Trials Unit, AIDS Clinical Trials Group. He holds appointments at Brigham and Women's Hospital and Beth Israel Hospital, both in Boston, Mass.
Faculty for This ActivityFaculty for This Activity
The Body PRO
ICAAC 2007: Key HIV Research
ICAAC 2007: Key HIV ResearchICAAC 2007: Key HIV Research
About this slide presentation
• This presentation was created to accompany The Body PRO's podcast summary of key research presented at ICAAC 2007, featuring interviews with Cal Cohen, M.D., M.S., and Eric Daar, M.D. For more information about this program, please visit us on the Web at:
TheBodyPRO.com/ICAAC2007
• Please feel free to use this slide presentation for personal reference or for your own presentations; however, we ask that you not modify any aspects of the slides contained within this presentation, so proper attribution can be retained. If you would like to publish all or part of this presentation, or repost any of these slides online, permission must first be obtained from Body Health Resources Corporation.
• Our gratitude goes out to all who granted permission for their slides to be adapted for this presentation.
DisclaimerKnowledge about HIV changes rapidly. Note the date of this presentation's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this presentation.
The Body PRO
ICAAC 2007: Key HIV Research
First-Line Antiretroviral TherapyFirst-Line Antiretroviral Therapy
The Body PRO
ICAAC 2007: Key HIV Research
ARTEMIS: Phase III Study DesignARTEMIS: Phase III Study Design
Dosing was based on regulatory approval; switch was made according to local regulatory approval and drug availability
DRV/r 800/100mg qd + TDF 300 mg and FTC 200 mg (N=343)
LPV/r 400/100mg bid or 800/200mg qd+ TDF 300 mg and FTC 200 mg (N=346)
LPV dosing LPV formulation
qd = 15% Capsule only = 15%
bid = 77% Tablet only = 2%
bid/qd = 7% Capsule/tablet switch = 83%
689 ARV-naïve patients
VL>5,000; no CD4 entry
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
62,100(667–4,580,000)
218 (2–714)
48 (14)
70,800
(835–5,580,000)
228 (4–750)
43 (13)
Baseline disease characteristics
Median HIV-1 RNA (cpm)
(range)
Median CD4 (cells/mm3 [range])
HBV/HCV co-infected, n (%)
41%
36%
105 (30)
35 (9)
44/21/22
LPV/r qd or bid
(N=346)
DRV/r qd
(N=343)
40%
36%
104 (30)
36 (9)
40/23/23
Stratification factors at screening
CD4 count <200 cells/mm3
Plasma HIV-1 RNA ≥100,000 cpm
Baseline demographics
Female, N (%)
Mean (±SD) age (yrs)
Caucasian/Black/Hispanic, %
ARTEMIS: Baseline CharacteristicsARTEMIS: Baseline Characteristics
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Estimated difference in response vs LPV/r for non-inferiority:
PP = 5.6% (95% CI –0.1;11.3) p<0.001
Estimated difference in response vs LPV/r for non-inferiority:
PP = 5.6% (95% CI –0.1;11.3) p<0.001
Estimated difference in response vs LPV/r for superiority:
ITT = 5.5% (95% CI –0.3;11.2) p=0.062
ARTEMIS: Viral Load <50 copies/mL to Week 48 (ITT-TLOVR)ARTEMIS: Viral Load <50 copies/mL to Week 48 (ITT-TLOVR)
50
40
30
20
10
0
100
90
80
70
60
84%78%
4 8 12 16 24 36 48Time (weeks)
Pat
ien
ts w
ith
VL
<50
co
pie
s/m
L (
% [
±SE
])
LPV/r qd or bid (N=346)
DRV/r qd (N=343)
2
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
86
79†
≥100,000
85
<100,000
Baseline viral load (copies/mL)
ARTEMIS: Confirmed Response by Baseline Viral Load or CD4 at Week 48 (ITT-TLOVR)
ARTEMIS: Confirmed Response by Baseline Viral Load or CD4 at Week 48 (ITT-TLOVR)
LPV/r qd or bidDRV/r qd
n=194 n=191 n=28
0
20
40
60
80
100
Pat
ien
ts w
ith
VL
<50
co
pie
s/m
L (
%)
67
†p<0.05 vs LPV/r
N = 226 226 117 120†Chi square analysis
87
6771
77
0
<50 >2000
20
40
60
80
100
8084
50–200
Baseline CD4 cell count (cells/mm3)
Pat
ien
ts w
ith
VL
<50
co
pie
s/m
L (
%)
N = 30 30 111 118 202 198
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
ARTEMIS: Virologic Failure (VF)and Emergence of MutationsARTEMIS: Virologic Failure (VF)and Emergence of Mutations
49 (14%) 34 (10%)VF (> 50 cpm)
18 10 Paired baseline and VF genotype available
18 (5%)11 (3%)VF (> 400 cpm)
1* 0IAS-USA PI RAMS
(N=346)
LPV/r qd or bid
(N=343)
DRV/r qd
*IAS-USA mutations, Fall 2006; Johnson et al. Topics in HIV Medicine. 2006; 14:125-130
IAS-USA NRTI mutations 1† 2†
*A71T, V77IVF by TLOVR †184V
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
ARTEMIS: Grade 2–4 Adverse Events (AEs)ARTEMIS: Grade 2–4 Adverse Events (AEs)
Gr 2–4 AEs† ≥2% Incidence, n (%)
DRV/r qd LPV/r qd or BID
(N=343) (N=346)
GI (all AEs) 23 (7) 47 (14)
Diarrhea 14 (4) 34 (10)
Nausea 6 (2) 10 (3)
Rash (all types) 9 (3) 4 (1)
†At least possibly related to study drug, excluding laboratory-related events
• No renal SAEs and no treatment discontinuations due to renal AEs
p<0.01
p<0.05
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
ARTEMIS: ConclusionsARTEMIS: Conclusions
• The use of once-daily DRV/r 800/100mg + TDF/FTC in treatment-naïve patients:
– resulted in excellent virologic and immunologic responses
– provided suitable exposure in all patients
– was well tolerated, with a favorable safety profile
• In comparison to the LPV/r arm* in treatment-naïve patients:
– For efficacy, DRV/r 800/100mg qd was non-inferior in the overall population, and superior in patients with high VL
– DRV/r had lower incidence of common GI toxicities and triglyceride elevations
*LPV/r arm included: LPV/r 400/100mg bid or 800/200mg qd, capsule and tablet formulations
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Antiretrovirals in Development for Antiretrovirals in Development for Treatment-Experienced PatientsTreatment-Experienced Patients
The Body PRO
ICAAC 2007: Key HIV Research
Antiretrovirals in Advanced DevelopmentAntiretrovirals in Advanced Development
Drug Name Class Development Stage
Notes
elvitegravir (GS-9137, JTK-303)
Integrase inhibitor
Phase II • Regimens including boosted PIs could have greater antiviral activity.• No clinically relevant drug interaction with etravirine.• When boosted, increases maraviroc exposure.• Showed synergistic interactions with enfuvirtide (T-20, Fuzeon), darunavir (TMC114, Prezista) and efavirenz (Sustiva, Stocrin) in vitro.
etravirine (TMC125)
NNRTI Phase III • No clinically relevant drug interaction with elvitegravir.
maraviroc (Selzentry)
CCR5 inhibitor Phase III • Patients failing regimen had higher mean CD4 increases even with D/M or X4-tropic virus.• Exposure increases when used with boosted elvitegravir; use reduced dose of 150mg twice daily.
raltegravir (MK-0518)
Integrase inhibitor
Phase III • In patients with limited treatment options, all doses had potent and durable effects.
vicriviroc (SCH 417690,
SCH-D)
CCR5 inhibitor Phase II • No adverse effect on white blood cell counts.• Not associated with an increased risk of infections.
The Body PRO
ICAAC 2007: Key HIV Research
24-week primary analysis
• DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified
• Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks
• ≥1 NNRTI RAM, at screening or in documented historical genotype
• ≥3 primary PI mutations at screening
• Patients recruited from Thailand, Australia, Europe and the Americas
Screening6 weeks
600 patients target per trial
48-week treatment period with optional 48-week extension
*BR = darunavir/ritonavir with optimised NRTIs and optional enfuvirtide
TMC125 + BR*
Placebo + BR*
Follow up4 weeks
DUET: Study Design and Major Inclusion CriteriaDUET: Study Design and Major Inclusion Criteria
BR = background regimen; RAM = resistance-associated mutation
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
DUET: Viral Load Reduction From Baseline (ITT NC=F)DUET: Viral Load Reduction From Baseline (ITT NC=F)
BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm;
changes below the detection limit (<50 copies/mL) were imputed as 49 copies/mL
–1.7
–2.4
Mea
n c
han
ge
in v
iral
load
fro
m
bas
elin
e (l
og
10 c
op
ies/
mL
) ±
SE
0.0
–0.5
–1.0
–1.5
–2.0
–2.5
–3.0
–3.5
Time (weeks)
0 4 8 12 16 20 24
p<0.0001
TMC125 + BR (n=599)Placebo + BR (n=604)
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
DUET: Change in CD4 Cell Count From Baseline (ITT NC=F)DUET: Change in CD4 Cell Count From Baseline (ITT NC=F)
+86
+67
Mea
n c
han
ge
in C
D4
cell
cou
nt
fro
m b
asel
ine
(cel
ls/m
m3 )
± S
E
Time (weeks)
p<0.0001
BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm
100
75
50
25
00 4 8 12 16 20 24
TMC125 + BR (n=599)Placebo + BR (n=604)
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
DUET: Response (<50 copies/mL) According to Enfuvirtide (ENF) Use (Primary Analysis)
DUET: Response (<50 copies/mL) According to Enfuvirtide (ENF) Use (Primary Analysis)
Pat
ien
ts w
ith
vir
al lo
ad
<50
co
pie
s/m
L a
t W
eek
24 (
%)
p<0.0001
Using de novo ENF
DRV FC category, %
TMC125 + BR Placebo + BR
<2 20 27
2–10 40 39
10–40 26 26
>40 15 8
Placebo + BR (n=604)TMC125 + BR (n=599)
67%
Using de novo ENF
p=0.427
34%
56%
Unadjusted response
rates
0
20
40
60
80
Re-using or not using ENF
62%
DRV = darunavir FC = baseline fold change
Using de novo ENF
p<0.05
62%
73%
Adjusted for differences in baseline DRV FC between
groups
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
DUET: Response (<50 copies/mL) According to Number of Active Background Antiretrovirals
DUET: Response (<50 copies/mL) According to Number of Active Background Antiretrovirals
0 20 40 60 80 100
2
1
0
Patients with viral load <50 copies/mL at Week 24 (%)
Nu
mb
er o
f fu
lly a
ctiv
e b
ackg
rou
nd
AR
Vs
(PS
S) 45%
60%
8%a
≥
30%
67%74%
Analysis excludes patients who discontinued except for virological failure; PSS = phenotypic sensitivity score; darunavir and enfuvirtide are counted as fully active if FC<10 or used de novo, respectively
7/91
40/88
63/211
120/199
171/257
191/258
Placebo + BR (n=559)TMC125 + BR (n=545)
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
DUET: ConclusionsDUET: Conclusions
• In treatment-experienced patients, including those with NNRTI resistant virus, TMC125 consistently demonstrated superiority over placebo– 59% of patients achieved confirmed undetectable VL (<50 copies/mL) with TMC125
plus BR at Week 24
• Even in the absence of any other fully active background agents, with TMC125, 45% of patients achieved undetectable (<50 copies/mL)viral load– response rates increased as more active agents were used in the background regimen
• 13 TMC125 resistance-associated mutations (TMC125 RAMs) were identified– the greatest added benefit in the TMC125 versus placebo group was seen in patients
with <3 TMC125 RAMs– 86% patients had <3 TMC125 RAMs
• Except for rash, incidence and severity of AEs with TMC125 were similar to placebo
• TMC125 has the ability to extend and enhance the NNRTI class and provide a new treatment option for patients with resistance to other NNRTIs
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Protocol 004: Study DesignProtocol 004: Study Design
Interim Analysis of Part I Before Initiating Part IIInterim Analysis of Part I Before Initiating Part II
Raltegravir 600 mg BIDRaltegravir 600 mg BID
Raltegravir 400 mg BIDRaltegravir 400 mg BID
Raltegravir 200 mg BIDRaltegravir 200 mg BID
Raltegravir 100 mg BIDRaltegravir 100 mg BID
Placebo BIDPlacebo BID
Part I cohort: Rx-naive patients stratified and randomized to integrase monotherapy or placebo for 10 days
Part I cohort: Rx-naive patients stratified and randomized to integrase monotherapy or placebo for 10 days
Integrase Monotherapy for 10 Days
Part II cohort: Rx-naive patients stratified and randomized to combination therapy for 48 weeks
Part II cohort: Rx-naive patients stratified and randomized to combination therapy for 48 weeks
~ 30 pts
~ 30 pts
~ 30 pts
~ 30 pts
~ 30 pts
Combination TherapyTotal
~ 38 pts
~ 38 pts
~ 38 pts
~ 38 pts
~ 38 pts
Part I Part II
~ 8 pts
~ 8 pts
~ 8 pts
~ 8 pts
~ 8 pts
Raltegravir 600 mg BID + TDF/3TCRaltegravir 600 mg BID + TDF/3TC
Raltegravir 400 mg BID + TDF/3TCRaltegravir 400 mg BID + TDF/3TC
Raltegravir 200 mg BID + TDF/3TCRaltegravir 200 mg BID + TDF/3TC
Raltegravir 100 mg BID + TDF/3TCRaltegravir 100 mg BID + TDF/3TC
Efavirenz 600 mg QD + TDF/3TCEfavirenz 600 mg QD + TDF/3TC
Adapted from Martin Markowitz et al. IAS 2007; abstract TUAB104.
The Body PRO
ICAAC 2007: Key HIV Research
Protocol 005: Study DesignProtocol 005: Study Design
Raltegravir 200 mg BID* (43)Raltegravir 200 mg BID* (43)
Raltegravir 400 mg BID* (45)Raltegravir 400 mg BID* (45)
Raltegravir 600 mg BID* (45)Raltegravir 600 mg BID* (45)
Placebo BID* (45)Placebo BID* (45)
Raltegravir 400 mg BID* (178)
Raltegravir 400 mg BID* (178)
Weeks 1-24 Weeks 25-48
All 178 HIV-infected participants had anHIV RNA > 5,000 copies/mL and documented
resistance to three classes of oral ARTs at baseline.
*All patients received optimized background therapy.
All 178 HIV-infected participants had anHIV RNA > 5,000 copies/mL and documented
resistance to three classes of oral ARTs at baseline.
*All patients received optimized background therapy.
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
The Body PRO
ICAAC 2007: Key HIV Research
Protocol 005: Patient and Optimized Background Therapy (OBT) Characteristics
Protocol 005: Patient and Optimized Background Therapy (OBT) Characteristics
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
Raltegravir (MK-0518) + OBT Placebo + OBT
200 mg
N = 43
400 mg
N = 45
600 mg
N = 45 N = 45
Percentage Male
Median Age in Years
Median Years of Prior Antiretrovirals
Mean CD4 Count in mm3
Mean HIV RNA in log10copies/mL
84
43
10
245
4.6
89
43
11
221
4.8
91
44
9
220
4.7
89
43
10
274
4.7
OBT: Median Number of Antiretrovirals
Phenotypic Sensitivity Score*: 0 to Protease Inhibitors
Phenotypic Sensitivity Score*: 0 to All Antiretrovirals
Genotypic Sensitivity Score*: 0 to All Antiretrovirals
Number of Patients With Enfuvirtide (T-20, Fuzeon) as New OBT
4
42 (98%)
20 (47%)
27 (63%)
13 (30%)
4
42 (93%)
26 (58%)
38 (84%)
8 (18%)
4
40 (89%)
22 (49%)
35 (78%)
13 (29%)
4
38 (84%)
18 (40%)
28 (62%)
10 (22%)
*By Phenosense GTNote: Enfuvirtide is not included in the phenotypic sensitivity score since there is no clinical cut-off.
The Body PRO
ICAAC 2007: Key HIV Research
Protocol 005: Time to Loss of Virologic Response to Week 72: Raltegravir (MK-0518) All Doses Combined vs. Placebo
Protocol 005: Time to Loss of Virologic Response to Week 72: Raltegravir (MK-0518) All Doses Combined vs. Placebo
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
Placebo
45 11 11 11 9 9 8 6 5 5 4 3 1
133122122 122 120 113 100 95 92 86 69 43 12
02 4 8 12 16 24 32 40 48 56 64 72
Week
0
20
40
60
80
100 %
of
Pat
ien
ts R
emai
nin
g
HIV
RN
A <
400
cop
ies/
mL
# of Patients at Risk
Raltegravir All Doses Combined
Placebo
Raltegravir All Doses Combined*
Placebo*
* Plus optimized background therapy.Patients who never achieved HIV RNA <400 copies/mL were considered failures. Non-responders assigned failure at time 0.
The Body PRO
ICAAC 2007: Key HIV Research
Protocol 005: Analysis of Raltegravir (MK-0518) ResistanceProtocol 005: Analysis of Raltegravir (MK-0518) Resistance
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
Study found no association between dose and/or drug concentration and resistance.
The factors decreasing likelihood of developing mutations at amino acids 148 alone, 155 alone, and either 148 or 155 were found to be:
• Phenotypic sensitivity score > 0.
• Lower viral load (≤ 100,000 copies/mL vs. > 100,000 copies/mL).
• New use of enfuvirtide (T-20, Fuzeon) in optimized background therapy.
From: Hazuda et al, XVI International HIV Drug Resistance Workshop, 2007, Barbados
The Body PRO
ICAAC 2007: Key HIV Research
Protocol 005: Safety During Double-Blind Study PeriodProtocol 005: Safety During Double-Blind Study Period
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
Raltegravir (MK-0518) safety profile for all doses similar to placebo Liver function test abnormalities were uncommon
• No grade 4 abnormalities for aspartate aminotransferase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP)
• Grade 3 AST: 2/133 patients (1.5%) in all MK-0518 groups • Grade 3 ALT: 1/133 patients (0.8%) in all MK-0518 groups
Most clinical adverse events (AEs) were mild to moderate 4 serious, drug-related clinical AEs
• Acute pancreatitis after 2 doses, considered 2º to optimized background therapy (200 mg group)
• Metabolic acidosis and renal insufficiency; sepsis; death (600 mg group)• Lacunar infarction by CT (placebo)• Worsening lipoatrophy (placebo)
2 discontinuations due to drug-related AE• Elevated AST/ALT, considered 2º to optimized background therapy (200
mg group)• Lipoatrophy (placebo)
The Body PRO
ICAAC 2007: Key HIV Research
Elvitegravir (EVG) Phase 2 Study SchemaElvitegravir (EVG) Phase 2 Study Schema
Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Elvitegravir Study: HIV RNA < 50 copies/mL at Week 16 for Patients With First Use of T-20
Elvitegravir Study: HIV RNA < 50 copies/mL at Week 16 for Patients With First Use of T-20
Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Week 16 HIV RNA < 50 copies/mL for Patients Receiving EVG/r 125 mg: Impact of Gradations in Activity of Optimized Background Therapy
Week 16 HIV RNA < 50 copies/mL for Patients Receiving EVG/r 125 mg: Impact of Gradations in Activity of Optimized Background Therapy
Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
23
44 45
0
1020
30
4050
60
70
8090
100
* versus OBT alone† HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks
‡ Last observation carried forward
MOTIVATE 1 and 2: Summary of Week 24 Efficacy ResultsMOTIVATE 1 and 2: Summary of Week 24 Efficacy Results
Includes all patients who received at least one dose of study medication
Mea
n ch
ange
from
ba
selin
e in
CD
4 co
unt (
cells
/mm
3 )MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
OBT alone (N=209)
P<0.0001* P<0.0001*57
109 106
0
20
40
60
80
100
120
Patie
nts
(%)
P<0.001* Difference: +51(95% CI: 33, 69)
P<0.001* Difference: +49(95% CI: 31, 67)
HIV-1 RNA <50 copies/mL†
Mean Change from Baseline in CD4 Count‡
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Characterization of Maraviroc Resistance in MOTIVATE 1 and 2: Study Overview
Characterization of Maraviroc Resistance in MOTIVATE 1 and 2: Study Overview
OBJECTIVE: To study changes in HIV-1 tropism in patients who experienced treatment failure in the MOTIVATE 1 and 2 studies
MOTIVATE 1 and MOTIVATE 2 Phase 3 studies in treatment-experienced patients (N=1,075)
Assessment of CD4 count at failure, time of failure, and occurrence of Category C events
by tropism result
NR/NPNon-reportable/
non-phenotypable
D/M*†
Dual/mixed tropic virus population
R5*
Only CCR5-tropic virus detected
X4†
Only CXCR4-tropic virus detected
Tropism determined for all patients at screening, baseline, and all visits where VL>500 c/mL (Trofile™
assay, Monogram Biosciences)
* CCR5-using virus; †CXCR4-using virusElna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
MOTIVATE 1 and 2: Viral Populations That May Exist Within a Patient
MOTIVATE 1 and 2: Viral Populations That May Exist Within a Patient
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
R5X4A) Pure
B) Mixed
R
X
XX
X
XX
XXX
XX
XX
XX X
XX
RR
RR
RR R
RRRR R
RR
RRR
RRR
DDDD
DDD D DD
DD
D DD D D D
DD
R
XX X X X XX X X X X
XX X XXXXX
XX
X X X
X XX
X X
X X X
XX
R R RRR R
R R RRRR R
RR
RR R
RR
RR R
R
R
RR
D D
DD
DD
Dual/mixed (D/M) tropism
The Body PRO
ICAAC 2007: Key HIV Research
-100 0 100 200 300
0
100
200
300
400
500
MOTIVATE 1 and 2: CXCR4-Using Clones Were Detected at Low Frequency in the Baseline Sample
MOTIVATE 1 and 2: CXCR4-Using Clones Were Detected at Low Frequency in the Baseline Sample
Time Since First Administration (Day)
• CXCR4-using clones detected at baseline (7%)
• No CCR5-tropic clones on treatment
R5 R5 DM DM DM DM DM DM R5 R5
1
2
3
4
5
6
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
CD
4 C
ou
nt
(ce
lls/m
m3 )
Patient T6
Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56 Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
MOTIVATE 1 and 2: Selective Inhibition of R5 Viruses Can Lead to a Change in Tropism Result to D/M or X4
MOTIVATE 1 and 2: Selective Inhibition of R5 Viruses Can Lead to a Change in Tropism Result to D/M or X4
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
R R RRR R RR
R R RRR R DR
R R RRR R RR
R R RRR R DR
R R RRR R RR
R R RRR R DR
R R RRR R RR
R R RRR R DR
R R RRR R RR
R R RRR R DR
R R RRR R RR
R R RRR R XR
R R RRR R RR
R R RRR R DR
R R RRR R RR
R R RRR R DR
D
X
D
D
D
D
D
D
R5 D/M
Trofile™ (like all resistance tests) measures relative proportions (not absolute amounts) of different viruses (Panel A)
Selective inhibition of a majority virus type, increases the sensitivity to detect the minor variant (Panel B)
A B
MVC
The Body PRO
ICAAC 2007: Key HIV Research
MOTIVATE 1 and 2: Selective Inhibition of R5 Viruses Can Lead to a Change in Tropism Result to D/M or X4
MOTIVATE 1 and 2: Selective Inhibition of R5 Viruses Can Lead to a Change in Tropism Result to D/M or X4
• Maraviroc selectively inhibits R5 virus
• If maraviroc is administered as part of a sub-optimal regimen, pre-existing low (undetected) levels of D/M or X4 virus will emerge as the dominant viral population
• Since the D/M or X4 virus is pre-existing, time to failure is shorter than with R5 virus (where maraviroc resistance must be selected de novo)
• Similar to the rapid outgrowth of pre-existing (archived) drug-resistant virus when failed ARV therapy is reinitiated after treatment interruption
• After withdrawal of maraviroc, selective pressure on R5 virus is removed, allowing R5 virus to re-emerge as the dominant population
• Reversion to R5 takes approximately 16 weeks, consistent with loss of 3TC1 or enfuvirtide2 resistance after withdrawal of these ARVs
1. Deeks S, et al. J Infect Dis 2005; 192:1537-44.2. Deeks et al. J Infect Dis 2007;195:387-91.
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Randomization 1:2:2
N=601
MOTIVATE 1: Trial DesignMOTIVATE 1: Trial Design
OBT* + maraviroc (150 mg† BID)
OBT* + maraviroc (150 mg† QD)
OBT* + placebo
0 24w
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)† Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC,
all other patients received 300 mg dose of MVC
Screening(6 weeks) 48w
Patients stratified by:• Enfuvirtide use in OBT • HIV-1 RNA < and ≥100,000 copies/mL at screening
Patient eligibility criteria: • R5 HIV-1 infection• 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 ≥ one ARV from three classes (≥ two for PIs)
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
MOTIVATE 1 – Week 48:Mean Change From Baseline in HIV-1 RNA
MOTIVATE 1 – Week 48:Mean Change From Baseline in HIV-1 RNA
-1.03-0.80
-1.82-1.66
-1.95-1.82
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Includes all patients who received at least one dose of study medication
HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks*Treatment difference vs OBT alone
Mea
n ch
ange
in H
IV-1
RN
A f
rom
bas
elin
e (lo
g 10 c
opie
s/m
L)
Difference: -0.85* (97.5% CI: -1.22, -0.49) Difference: -1.02*
(97.5% CI: -1.39, -0.66)
MVC QD + OBT (N=232)
MVC BID + OBT (N=235)
OBT alone (N=118)
Study week
Difference: -0.79* (97.5% CI: -1.14, -0.44)
Difference: -0.92* (97.5% CI: -1.28, -0.57)
24 48
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
MOTIVATE 1 – Week 48:Percentage of Patients With Undetectable HIV-1 RNA
MOTIVATE 1 – Week 48:Percentage of Patients With Undetectable HIV-1 RNA
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Patie
nts
(%)
N=
Maraviroc QD + OBT Maraviroc BID + OBT OBT alone
MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use
MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use
<400 copies/mL <50 copies/mL
3
2736
3
25
6471
35 32
61
71
43
0102030405060708090
100
Last observation carried forward
ENF first use ENF experienced/resistance
91 10859 30 75 72
ENF first use ENF experienced/resistance
91 10859 30 75 72
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
MOTIVATE 1 and 2 – Week 48: Change in CD4+ Cell Count From Baseline by Tropism Result at Time of Failure
MOTIVATE 1 and 2 – Week 48: Change in CD4+ Cell Count From Baseline by Tropism Result at Time of Failure
Tropism result, Baseline→ Treatment Failure
Mean change from baseline in CD4+ count in patients with treatment failure (cells/mm3 )
OBT aloneN=271
MVC QD + OBTN=477
MVC BID + OBTN=487
All treatment failures* +24 (n=111)
+64 (n=92)
+74 (n=96)
R5→ R5 +25(n=89)
+77(n=33)
+133(n=24)
R5→ D/M or X4 +61(n=6)
+47(n=35)
+57(n=41)
* Includes patients with non-reportable/non-phenotypable tropism result at baseline and patients with non-reportable/non-phenotypable/missing tropism result at time of failure
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
HIV Drug Resistance and theHIV Drug Resistance and theComplications of HIV/HAARTComplications of HIV/HAART
The Body PRO
ICAAC 2007: Key HIV Research
TITAN: Development of Primary Protease Inhibitor Mutations and NRTI Resistance-Associated Mutations Upon Virologic Failure
TITAN: Development of Primary Protease Inhibitor Mutations and NRTI Resistance-Associated Mutations Upon Virologic Failure
Simon F. De Meyer et al. ICAAC 2007; abstract H-1020. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
TITAN: Loss of Susceptibility to Antiretrovirals in Virologic Failures (VFs) upon VF
TITAN: Loss of Susceptibility to Antiretrovirals in Virologic Failures (VFs) upon VF
Simon F. De Meyer et al. ICAAC 2007; abstract H-1020. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Genotypic Results and Virological Response After Interruption of NNRTI-Based Treatment
Genotypic Results and Virological Response After Interruption of NNRTI-Based Treatment
Study Design
Forty-three participants taking NNRTI-based antiretroviral therapy.
Dual NRTIs were continued for 7 or 10 days after participants stopped taking nevirapine and efavirenz, respectively.
Characteristics Upon Reinitiation of Antiretroviral
Therapy
Treatment was reinitiated a median of 5.6 (2.8-7.0) months after treatment interruption.
HIV-1 genotype testing in 21 patients (49%) showed that no mutations contributed to NRTI or NNRTI resistance.
Median CD4 cell count was 178 (152-214) cells/mm3 and median HIV RNA was 5.78 (4.86-5.88) log copies/mL.
Characteristics After Three and Six Months of Antiretroviral
Therapy
At three months, 24 (56%) patients achieved undetectable HIV RNA (<50 copies/mL) and the median CD4 cell count was 386 (224-492) cells/mm3.
At six months, 43 (100%) patients achieved undetectable HIV RNA (<50 copies/mL) and the median CD4 cell count was 419 (276-589) cells/mm3.
Adapted from Somnuek Sungkanuparph et al. ICAAC 2007; abstract H-368.
The Body PRO
ICAAC 2007: Key HIV Research
Change in cGFR: Abacavir (ABC) vs Tenofovir (TDF)Change in cGFR: Abacavir (ABC) vs Tenofovir (TDF)
Christopher Polk et al. ICAAC 2007; abstract H-383. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Changes in Renal Function Among 10 Patients Categorized as Having “Current Renal Dysfunction” With Both Baseline and 12-Month Values, HIV Outpatient Study, November 2001 – September 2005
Changes in Renal Function Among 10 Patients Categorized as Having “Current Renal Dysfunction” With Both Baseline and 12-Month Values, HIV Outpatient Study, November 2001 – September 2005
Benjamin Young et al. ICAAC 2007; abstract H-382. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
ACTG 5102: Lipid MetabolismACTG 5102: Lipid Metabolism
Pablo Tebas et al. ICAAC 2007; abstract H-378. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
ACTG 5102: Changes in Immune ActivationACTG 5102: Changes in Immune Activation
Pablo Tebas et al. ICAAC 2007; abstract H-378. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
CPCRA 060: Time to CD4 < 350 cells/µL, Therapy Initiation or Death
CPCRA 060: Time to CD4 < 350 cells/µL, Therapy Initiation or Death
Matthew B. Goetz et al. ICAAC 2007; abstract H-1027. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Comparison of Luciferase Activity (RLUs) Between Standard and Enhanced Trofile Assays
Comparison of Luciferase Activity (RLUs) Between Standard and Enhanced Trofile Assays
Jacqueline D. Reeves et al. ICAAC 2007; abstract H-1026. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Sensitivity to Detect Minor CXCR4-Using SubpopulationsSensitivity to Detect Minor CXCR4-Using Subpopulations
Jacqueline D. Reeves et al. ICAAC 2007; abstract H-1026. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
V3 Loop Sequence-Based CRT Prediction ResultsV3 Loop Sequence-Based CRT Prediction Results
Eric W. Stawiski et al. ICAAC 2007; abstract H-1028. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Description of the Most Frequent Non-AIDS, Non-HAART Related (NANHR) Severe Clinical Events
Description of the Most Frequent Non-AIDS, Non-HAART Related (NANHR) Severe Clinical Events
Tristan Ferry et al. ICAAC 2007; abstract H-1722. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Factors Associated With the Occurrence of the 385 First NANHR Severe Clinical Events
Factors Associated With the Occurrence of the 385 First NANHR Severe Clinical Events
Tristan Ferry et al. ICAAC 2007; abstract H-1722. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Incidence Rate Ratios (IRR) of Non-AIDS-Defining Malignancies (non-ADM) in HIV-Infected vs. Non-Infected Veterans in the HAART Era
Incidence Rate Ratios (IRR) of Non-AIDS-Defining Malignancies (non-ADM) in HIV-Infected vs. Non-Infected Veterans in the HAART Era
IRR in
HIV+ Veterans
Confidence
Interval (95%)
Overall 1.6 1.5-1.7
Anal Cancer 14.9 10.1-22.1
Hodgkin’s Lymphoma 4.6 3.6-6.6
Liver Cancer 2.8 2.2-3.5
Lung Cancer 2.0 1.7-2.2
Total of 33,420 HIV+ and 66,840 HIV- veterans followed.Incidence rates of non-ADM per 100,000 person-years were 1,260 and 841 respectively.
Adapted from Roger J. Bedimo et al. ICAAC 2007; abstract H-1721.
The Body PRO
ICAAC 2007: Key HIV Research
Re-treatment With Pegylated Interferon Plus Weight-Adjusted Ribavirin in HIV+ Patients With Chronic HCV Results
Re-treatment With Pegylated Interferon Plus Weight-Adjusted Ribavirin in HIV+ Patients With Chronic HCV Results
Eugenia Vispo et al. ICAAC 2007; abstract H-1734. Reprinted with permission.
The Body PRO
ICAAC 2007: Key HIV Research
Three-Year Survival Data of Liver Transplant Recipients in Spain
Three-Year Survival Data of Liver Transplant Recipients in Spain
Hepatitis C Monoinfected
Patients*
HIV/Hepatitis C CoinfectedPatients*
Years After Transplant
1 2
81%(78%-83%)
74%(70%-76%)
69%(65%-72%)
88%(74%-94%)
75%(58%-86%)
64%(43%-79%)
3
Twelve (24%) HIV/hepatitis C coinfected and 273 (23%) hepatitis C monoinfected patients died during a median follow-up of 1.3 (0.5-2.4) years.
*95% confidence intervals
Adapted from José M. Miró et al. ICAAC 2007; abstract H-1732.
The Body PRO
ICAAC 2007: Key HIV Research
PROVE1: Study DesignPROVE1: Study Design
Adapted from Mark Sulkowski et al. ICAAC 2007; abstract V-1383.
Group 1
20 patients
Telaprevir (TVR, VX-950) 750 mg q8h
Peginterferon alfa-2A 180 µg/week
Ribavirin (RBV) 1,000-1,200 mg/day
Group 2
80 patients
Telaprevir 750 mg q8h
Peginterferon alfa-2A 180 µg/week
Ribavirin 1,000-1,200 mg/day
Group 3
82 patients
Telaprevir 750 mg q8h
Peginterferon alfa-2A 180 µg/week
Ribavirin 1,000-1,200 mg/day
Group 4 (control)
81 patients
Peginterferon alfa-2A/Ribavirin
Weeks 1-12
0 Weeks
Peginterferon alfa-2Awith Ribavirin
12 Weeks
Peginterferon alfa-2Awith Ribavirin
36 Weeks
Peginterferon alfa-2Awith Ribavirin
36 Weeks
Peginterferon alfa-2Awith Ribavirin
Additional Weeks and Doses
Analysis performed when all patients
completed 12 weeks.
Samples were collected for
sequencing at baseline and
at each HCV RNA
assessment.
The Body PRO
ICAAC 2007: Key HIV Research
PROVE1 Study Results: Undetectable HCV RNAPROVE1 Study Results: Undetectable HCV RNA
Adapted from Mark Sulkowski et al. ICAAC 2007; abstract V-1383.
Week 4
Groups 1-3*Undetectable HCV RNA
(LOD 10 IU/mL) 79%
Group 4 (Control)Undetectable HCV RNA
(LOD 10 IU/mL)11%
Week 12
Groups 1-3*Undetectable HCV RNA
(LOD 10 IU/mL)70%
Group 4 (Control)Undetectable HCV RNA
(LOD 10 IU/mL)39%
All Group Results, Weeks 4 and 12
Note: Of those in groups 1-3* receiving 12 weeks of treatment, six of nine
subjects with rapid virological response had undetectable HCV RNA
20 weeks after termination of treatment.
* Groups 1-3 were taking telaprevir (TVR, VX-950) with peginterferon alfa-2A and ribavirin (RBV).
The Body PRO
ICAAC 2007: Key HIV Research
ICAAC 2007: Key HIV ResearchICAAC 2007: Key HIV Research
• Visit The Body PRO for Comprehensive Coverage of ICAAC 2007.This presentation was created to accompany The Body PRO's podcast summary of key research presented at ICAAC 2007, featuring interviews with Cal Cohen, M.D., M.S., and Eric Daar, M.D. Learn more at: TheBodyPRO.com/ICAAC2007
• In addition, be sure to browse through The Body PRO’s extensive coverage of ICAAC 2007, which includes:– Downloadable MP3s and full transcripts– Expert discussion of key research– Slides and in-depth data analyses
• Visit TheBodyPRO.com/ICAAC2007 today for a full listing of our conference materials!