Transcript Key HIV Research From ICAAC 2007: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy Faculty: Chicago, Illinois | September 17-20, 2007 This activity is.

Key HIV Research From ICAAC 2007:
The 47th Interscience Conference on
Antimicrobial Agents and Chemotherapy
Faculty:
Chicago, Illinois | September 17-20, 2007
This activity is supported by an educational grant from:
Cal Cohen,
M.D., M.S.
Eric Daar,
M.D.
Faculty for This Activity
The Body PRO
Cal Cohen,
M.D., M.S.
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.
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 CaliforniaLos 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.
ICAAC 2007: Key HIV Research
Eric Daar,
M.D.
ICAAC 2007: Key HIV Research
The Body PRO
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
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Disclaimer
Knowledge 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.
ICAAC 2007: Key HIV Research
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First-Line Antiretroviral Therapy
ICAAC 2007: Key HIV Research
ARTEMIS: Phase III Study Design
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DRV/r 800/100mg qd
689 ARV-naïve
patients
+ TDF 300 mg and FTC 200 mg (N=343)
VL>5,000;
no CD4 entry
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 =
bid =
77%
Tablet only =
bid/qd =
7%
15%
2%
Capsule/tablet switch = 83%
Dosing was based on regulatory approval; switch was made
according to local regulatory approval and drug availability
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
ICAAC 2007: Key HIV Research
ARTEMIS: Baseline Characteristics
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DRV/r qd
LPV/r qd or bid
(N=343)
(N=346)
104 (30)
105 (30)
36 (9)
35 (9)
40/23/23
44/21/22
Baseline demographics
Female, N (%)
Mean (±SD) age (yrs)
Caucasian/Black/Hispanic, %
Baseline disease characteristics
Median HIV-1 RNA (cpm)
(range)
Median CD4 (cells/mm3 [range])
HBV/HCV co-infected, n (%)
70,800
(835–5,580,000)
62,100
(667–4,580,000)
228 (4–750)
218 (2–714)
43 (13)
48 (14)
Stratification factors at screening
CD4 count <200 cells/mm3
40%
41%
Plasma HIV-1 RNA ≥100,000 cpm
36%
36%
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
ICAAC 2007: Key HIV Research
Patients with VL <50 copies/mL (% [±SE])
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ARTEMIS: Viral Load <50
copies/mL to Week 48 (ITT-TLOVR)
100
DRV/r qd (N=343)
LPV/r qd or bid (N=346)
90
84%
78%
80
70
60
50
40
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
30
20
10
0
2 4
8
12
16
24
Time (weeks)
36
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
ICAAC 2007: Key HIV Research
48
Patients with VL <50 copies/mL (%)
100
86
80
DRV/r qd
100
†p<0.05
vs LPV/r
85
n=194 n=191
n=28
79†
67
60
40
20
Patients with VL <50 copies/mL (%)
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ARTEMIS: Confirmed Response by
Baseline Viral Load or CD4 at Week
48 (ITT-TLOVR)
LPV/r qd or bid
87
80
84
80
77
71
67
60
40
20
0
0
<100,000
≥100,000
0
N=
square analysis
226
226
117
120
50–200
>200
Baseline CD4 cell count (cells/mm3)
Baseline viral load (copies/mL)
†Chi
<50
N=
30
30
111
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
ICAAC 2007: Key HIV Research
118
202 198
ARTEMIS: Virologic Failure (VF)
and Emergence of Mutations
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DRV/r qd
LPV/r qd or bid
(N=343)
(N=346)
VF (> 50 cpm)
34 (10%)
49 (14%)
VF (> 400 cpm)
11 (3%)
18 (5%)
Paired baseline and VF
genotype available
10
18
IAS-USA PI RAMS
IAS-USA NRTI mutations
0
1*
1†
2†
†
184V
VF by TLOVR
*A71T, V77I
*IAS-USA mutations, Fall 2006; Johnson et al. Topics in HIV Medicine. 2006; 14:125-130
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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)
23 (7)
47 (14)
p<0.01
Diarrhea
14 (4)
34 (10)
p<0.05
Nausea
6 (2)
10 (3)
Rash (all types)
9 (3)
4 (1)
GI (all AEs)
†At
least possibly related to study drug, excluding laboratory-related events
• No renal SAEs and no treatment discontinuations due to renal AEs
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
ICAAC 2007: Key HIV Research
ARTEMIS: Conclusions
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• 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.
ICAAC 2007: Key HIV Research
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Antiretrovirals in Development for
Treatment-Experienced Patients
ICAAC 2007: Key HIV Research
Antiretrovirals in Advanced
Development
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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 (T20, 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 (MK0518)
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.
ICAAC 2007: Key HIV Research
DUET: Study Design
and Major Inclusion Criteria
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Screening
6 weeks
48-week treatment period
with optional 48-week extension
Follow up
4 weeks
24-week primary analysis
TMC125 + BR*
600 patients
target per trial
Placebo + BR*
*BR = darunavir/ritonavir with optimised NRTIs and optional enfuvirtide
• 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
BR = background regimen; RAM = resistance-associated mutation
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
ICAAC 2007: Key HIV Research
DUET: Viral Load Reduction From
Baseline (ITT NC=F)
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Mean change in viral load from
baseline (log10 copies/mL) ± SE
0.0
TMC125 + BR (n=599)
Placebo + BR (n=604)
–0.5
–1.0
p<0.0001
–1.5
–1.7
–2.0
–2.4
–2.5
–3.0
–3.5
0
4
8
12
16
20
24
Time (weeks)
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
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
ICAAC 2007: Key HIV Research
DUET: Change in CD4 Cell Count
From Baseline (ITT NC=F)
Mean change in CD4 cell count
from baseline (cells/mm3) ± SE
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100
+86
75
+67
p<0.0001
50
25
TMC125 + BR (n=599)
Placebo + BR (n=604)
0
0
4
8
12
Time (weeks)
16
20
24
BR = background regimen; SE = standard error;
ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
ICAAC 2007: Key HIV Research
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DUET: Response (<50 copies/mL)
According to Enfuvirtide (ENF)
Use (Primary Analysis)
Patients with viral load
<50 copies/mL at Week 24 (%)
TMC125 + BR (n=599)
p<0.0001
p=0.427
Placebo + BR (n=604)
p<0.05
73%
80
67%
62%
62%
56%
60
Using de novo ENF
DRV FC category,
%
34%
40
20
0
Adjusted for
differences in
baseline DRV
FC between
groups
Unadjusted
response
rates
Re-using or not
using ENF
Using de novo
ENF
TMC125 +
BR
Placebo + BR
<2
20
27
2–10
40
39
10–40
26
26
>40
15
8
Using de novo
ENF
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
ICAAC 2007: Key HIV Research
DRV = darunavir
FC = baseline fold change
DUET: Response (<50 copies/mL)
According to Number of Active
Background Antiretrovirals
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Number of fully active
background ARVs (PSS)
TMC125 + BR (n=545)
45%
40/88
0
7/91
Placebo + BR (n=559)
8%a
60%
120/199
1
30%
63/211
74%
67%
191/258
≥2
171/257
0
20
40
60
80
100
Patients with viral load <50 copies/mL at Week 24 (%)
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
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
ICAAC 2007: Key HIV Research
DUET: Conclusions
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• 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.
ICAAC 2007: Key HIV Research
Protocol 004: Study Design
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Interim Analysis of Part I Before Initiating Part II
Part I
Part II
Integrase Monotherapy for 10 Days
~ 8 pts
Raltegravir 600 mg BID
~ 8 pts
Raltegravir 400 mg BID
~ 8 pts
Raltegravir 200 mg BID
~ 8 pts
Raltegravir 100 mg BID
~ 8 pts
Placebo BID
Part I cohort: Rx-naive
patients stratified and
randomized to integrase
monotherapy or placebo
for 10 days
Total
Combination Therapy
~ 30 pts
~ 30 pts
~ 30 pts
~ 30 pts
~ 30 pts
Raltegravir 600 mg BID + TDF/3TC
~ 38 pts
Raltegravir 400 mg BID + TDF/3TC
~ 38 pts
Raltegravir 200 mg BID + TDF/3TC
~ 38 pts
Raltegravir 100 mg BID + TDF/3TC
~ 38 pts
Efavirenz 600 mg QD + TDF/3TC
~ 38 pts
Part II cohort: Rx-naive
patients stratified and
randomized to
combination therapy for
48 weeks
Adapted from Martin Markowitz et al. IAS 2007; abstract TUAB104.
ICAAC 2007: Key HIV Research
Protocol 005: Study Design
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Weeks 1-24
Weeks 25-48
Raltegravir 200 mg BID* (43)
Raltegravir 400 mg BID* (45)
Raltegravir 400 mg BID*
(178)
Raltegravir 600 mg BID* (45)
Placebo BID* (45)
All 178 HIV-infected participants had an
HIV 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.
ICAAC 2007: Key HIV Research
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Protocol 005: Patient and
Optimized Background Therapy
(OBT) Characteristics
Raltegravir (MK-0518) + OBT
Placebo + OBT
200 mg
400 mg
600 mg
N = 43
N = 45
N = 45
N = 45
Percentage Male
84
89
91
89
Median Age in Years
43
43
44
43
Median Years of Prior Antiretrovirals
10
11
9
10
Mean CD4 Count in mm3
245
221
220
274
Mean HIV RNA in log10copies/mL
4.6
4.8
4.7
4.7
4
4
4
4
Phenotypic Sensitivity Score*: 0 to Protease Inhibitors
42 (98%)
42 (93%)
40 (89%)
38 (84%)
Phenotypic Sensitivity Score*: 0 to All Antiretrovirals
20 (47%)
26 (58%)
22 (49%)
18 (40%)
Genotypic Sensitivity Score*: 0 to All Antiretrovirals
27 (63%)
38 (84%)
35 (78%)
28 (62%)
Number of Patients With Enfuvirtide (T-20, Fuzeon)
as New OBT
13 (30%)
8 (18%)
13 (29%)
10 (22%)
OBT: Median Number of Antiretrovirals
*By Phenosense GT
Note: Enfuvirtide is not included in the phenotypic sensitivity score since there is no clinical cut-off.
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
ICAAC 2007: Key HIV Research
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Protocol 005: Time to Loss of Virologic
Response to Week 72: Raltegravir (MK0518) All Doses Combined vs. Placebo
% of Patients Remaining
HIV RNA <400 copies/mL
100
80
Raltegravir All Doses Combined
60
40
20
Placebo
Placebo
0
02 4 8 12 16
24
32
40
Week
48
56
64
72
100
8
95
6
86
5
69
4
43
3
12
1
# of Patients at Risk
Raltegravir All Doses Combined* 133122 122 122 120 113
Placebo* 45 11 11 11 9
9
92
5
* Plus optimized background therapy.
Patients who never achieved HIV RNA <400 copies/mL were considered failures. Non-responders assigned failure at time 0.
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
ICAAC 2007: Key HIV Research
Protocol 005: Analysis of
Raltegravir (MK-0518) Resistance
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 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
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
ICAAC 2007: Key HIV Research
Protocol 005: Safety During
Double-Blind Study Period
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 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)
Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.
ICAAC 2007: Key HIV Research
Elvitegravir (EVG) Phase 2
Study Schema
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Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
MOTIVATE 1 and 2: Summary of
Week 24 Efficacy Results
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Includes all patients who received at least one dose of study medication
P<0.001*
Difference: +51
(95% CI: 33, 69)
MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
100
90
80
70
60
50
40
30
20
10
0
P<0.0001*
44
P<0.0001*
45
23
HIV-1 RNA
<50 copies/mL†
†
Mean change from
baseline in CD4 count (cells/mm3)
Patients (%)
OBT alone (N=209)
120
109
P<0.001*
Difference: +49
(95% CI: 31, 67)
106
100
80
60
57
40
20
0
Mean Change from
Baseline in CD4 Count‡
* versus OBT alone
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks
‡ Last observation carried forward
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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)
Tropism determined for all patients at screening,
baseline, and all visits where VL>500 c/mL (Trofile™
assay, Monogram Biosciences)
R5*
Only CCR5-tropic
virus detected
X4†
Only CXCR4-tropic
virus detected
D/M*†
Dual/mixed tropic
virus population
NR/NP
Non-reportable/
non-phenotypable
Assessment of CD4 count at failure, time of
failure, and occurrence of Category C events
by tropism result
* CCR5-using virus; †CXCR4-using virus
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
ICAAC 2007: Key HIV Research
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MOTIVATE 1 and 2: Viral
Populations That May Exist Within
a Patient
A) Pure
R5
X4
X
X
X
X
X
X
X
X
XX
X
X
X
X X X
X X
D D
D
D D D D D
D
D D D D
D D
D D D D
D
B) Mixed
R
R
R R R R
R R R R R
R
RR R R RR
R R R
Dual/mixed (D/M) tropism
X R
X X X X X
X XX R X X
R X X X XX
X X X
D D R
X R X X
X D X R
R X DX
X X R
XD
X
X
R
D
R R R
R R XR R
R RR R X
X R R R RR
R R R
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
ICAAC 2007: Key HIV Research
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MOTIVATE 1 and 2: CXCR4-Using
Clones Were Detected at Low
Frequency in the Baseline Sample
Patient T6
R5
DM DM
DM DM
DM
DM
R5
HIV-1 RNA (log10 copies/mL)
6
-100
R5
500
5
400
4
3
2
• CXCR4-using clones
detected at baseline
(7%)
• No CCR5-tropic
clones on treatment
1
Time Since First Administration (Day)
0
100
200
300
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.
ICAAC 2007: Key HIV Research
300
200
100
0
CD4 Count (cells/mm3)
R5
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MOTIVATE 1 and 2: Selective Inhibition
of R5 Viruses Can Lead to a Change in
Tropism Result to D/M or X4

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
R RR R R RR R R RR R R RR R
R RR R RRR R R RR R RRR R
RRR D R RR D RRR D R RR D
R RR R R RR R R RR R R RR R
R RR R R RR R R RR R R RR R
RRR R R RR R RRR R R RR R
R RR X RRR D R RR D RRR D
R RR R R RR R R RR R R RR R
R5
D
D
D
D
X
D
D
D
MVC
D/M
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
ICAAC 2007: Key HIV Research
The Body PRO
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.
ICAAC 2007: Key HIV Research
MOTIVATE 1: Trial Design
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OBT* + placebo
Randomization
1:2:2
N=601
OBT* + maraviroc (150 mg† QD)
OBT* + maraviroc (150 mg† BID)
Screening
(6 weeks)
Patient eligibility criteria:
• R5 HIV-1 infection
• HIV-1 RNA ≥5,000 copies/mL
0
24w
• 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)
Patients stratified by:
• Enfuvirtide use in OBT
• HIV-1 RNA < and ≥100,000 copies/mL at screening
* 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
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
ICAAC 2007: Key HIV Research
48w
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MOTIVATE 1 – Week 48:
Mean Change From Baseline in
HIV-1 RNA
OBT alone (N=118)
Mean change in HIV-1 RNA
from baseline (log10 copies/mL)
Includes all patients who received at least one dose of study medication
24
0.0
Study week
48
MVC QD + OBT (N=232)
MVC BID + OBT (N=235)
-0.5
-1.0
-0.80
-1.03
-1.5
-2.0
-2.5
-1.82
Difference: -0.79*
(97.5% CI: -1.14, -0.44)
-1.66
-1.95
Difference: -0.85*
(97.5% CI: -1.22, -0.49)
-1.82
Difference: -1.02*
(97.5% CI: -1.39, -0.66)
Difference: -0.92*
(97.5% CI: -1.28, -0.57)
HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks
*Treatment difference vs OBT alone
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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MOTIVATE 1 and 2: Proportion of Patients
Receiving ENF With Undetectable HIV-1
RNA at Week 48 According to ENF First Use
Patients (%)
OBT alone
N=
100
90
80
70
60
50
40
30
20
10
0
Maraviroc QD + OBT
Maraviroc BID + OBT
<400 copies/mL
71
<50 copies/mL
71
64
61
43
36
35
32
27
3
25
3
59 91 108
30 75 72
ENF first use ENF experienced/
resistance
59 91 108
30 75 72
ENF first use ENF experienced/
resistance
Last observation carried forward
Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.
ICAAC 2007: Key HIV Research
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MOTIVATE 1 and 2 – Week 48: Change in
CD4+ Cell Count From Baseline by
Tropism Result at Time of Failure
Mean change from baseline in CD4+ count in patients with
treatment failure (cells/mm3 )
OBT alone
N=271
MVC QD + OBT
N=477
MVC BID + OBT
N=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)
Tropism result, Baseline→ Treatment Failure
* 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.
ICAAC 2007: Key HIV Research
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HIV Drug Resistance and the
Complications of HIV/HAART
ICAAC 2007: Key HIV Research
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TITAN: Development of Primary Protease
Inhibitor Mutations and NRTI ResistanceAssociated Mutations Upon Virologic Failure
Simon F. De Meyer et al. ICAAC 2007; abstract H-1020. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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Genotypic Results and Virological
Response After Interruption of
NNRTI-Based Treatment
Forty-three participants taking NNRTI-based antiretroviral
therapy.
Study Design
Characteristics
Upon Reinitiation
of Antiretroviral
Therapy
Characteristics
After Three and
Six Months of
Antiretroviral
Therapy
Dual NRTIs were continued for 7 or 10 days after
participants stopped taking nevirapine and efavirenz,
respectively.
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.
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.
ICAAC 2007: Key HIV Research
Change in cGFR: Abacavir (ABC)
vs Tenofovir (TDF)
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Christopher Polk et al. ICAAC 2007; abstract H-383. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
ACTG 5102: Lipid Metabolism
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Pablo Tebas et al. ICAAC 2007; abstract H-378. Reprinted with permission.
ICAAC 2007: Key HIV Research
ACTG 5102: Changes in Immune
Activation
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Pablo Tebas et al. ICAAC 2007; abstract H-378. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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Comparison of Luciferase Activity
(RLUs) Between Standard and
Enhanced Trofile Assays
Jacqueline D. Reeves et al. ICAAC 2007; abstract H-1026. Reprinted with permission.
ICAAC 2007: Key HIV Research
Sensitivity to Detect Minor CXCR4Using Subpopulations
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Jacqueline D. Reeves et al. ICAAC 2007; abstract H-1026. Reprinted with permission.
ICAAC 2007: Key HIV Research
V3 Loop Sequence-Based CRT
Prediction Results
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Eric W. Stawiski et al. ICAAC 2007; abstract H-1028. Reprinted with permission.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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Incidence Rate Ratios (IRR) of Non-AIDSDefining Malignancies (non-ADM) in HIVInfected vs. Non-Infected Veterans in the
HAART Era
IRR in
Confidence
HIV+ Veterans
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.
ICAAC 2007: Key HIV Research
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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.
ICAAC 2007: Key HIV Research
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Three-Year Survival Data of
Liver Transplant Recipients in
Spain
Years After Transplant
Hepatitis C
Monoinfected
Patients*
HIV/Hepatitis C
Coinfected
Patients*
1
2
3
81%
74%
69%
(78%-83%)
(70%-76%)
(65%-72%)
88%
75%
64%
(74%-94%)
(58%-86%)
(43%-79%)
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.
ICAAC 2007: Key HIV Research
PROVE1: Study Design
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Additional Weeks and Doses
Weeks 1-12
Group 1
Telaprevir (TVR, VX-950) 750 mg q8h
20
patients
Peginterferon alfa-2A 180 µg/week
Group 2
Telaprevir 750 mg q8h
80
patients
Peginterferon alfa-2A 180 µg/week
Group 3
Telaprevir 750 mg q8h
82
patients
Peginterferon alfa-2A 180 µg/week
Group 4
(control)
81
patients
Ribavirin (RBV) 1,000-1,200 mg/day
Ribavirin 1,000-1,200 mg/day
Ribavirin 1,000-1,200 mg/day
0 Weeks
Peginterferon alfa-2A
with Ribavirin
12 Weeks
Peginterferon alfa-2A
with Ribavirin
36 Weeks
Peginterferon alfa-2A
with Ribavirin
36 Weeks
Peginterferon alfa-2A/Ribavirin
Peginterferon alfa-2A
with Ribavirin
Adapted from Mark Sulkowski et al. ICAAC 2007; abstract V-1383.
ICAAC 2007: Key HIV Research
Analysis
performed
when all
patients
completed 12
weeks.
Samples were
collected for
sequencing at
baseline and
at each
HCV RNA
assessment.
PROVE1 Study Results:
Undetectable HCV RNA
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All Group Results, Weeks 4 and 12
Week 4
Week 12
Groups 1-3*
Undetectable HCV RNA
(LOD 10 IU/mL)
79%
Group 4 (Control)
Undetectable HCV RNA
(LOD 10 IU/mL)
11%
Groups 1-3*
Undetectable HCV RNA
(LOD 10 IU/mL)
70%
Group 4 (Control)
Undetectable HCV RNA
(LOD 10 IU/mL)
39%
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).
Adapted from Mark Sulkowski et al. ICAAC 2007; abstract V-1383.
ICAAC 2007: Key HIV Research
ICAAC 2007: Key HIV Research
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ICAAC 2007: Key HIV Research