Download An Update on New HIV Antiretroviral Agents

An Update on New HIV
Antiretroviral Agents
Faculty: Edwin DeJesus, M.D., F.A.C.P.
Medical Director of the Orlando Immunology Center in
Orlando, Fla.
Edwin DeJesus, M.D., F.A.C.P.
This activity is supported by an educational grant from
Copyright © 2008 Body Health Resources Corporation. All rights reserved.
1
Faculty For This Activity
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Edwin DeJesus, M.D., F.A.C.P.
Dr. DeJesus is Medical Director of the Orlando Immunology Center in downtown Orlando, Fla.,
and the medical director of the HUG-Me Program's adult clinic at Orlando Regional Medical
Center.
Since 1993, Dr. DeJesus has devoted most of his time to caring for HIV- and hepatitis-infected
patients. He is also deeply involved in HIV-related research: He is the principal investigator for
the Orlando Immunology Center Research Facility, where he oversees several phase 1-4
clinical trials. In this capacity, he has presented study results at major international conferences,
including the International AIDS Conference, International AIDS Society Conference,
Interscience Conference on Antimicrobial Agents and Chemotherapy, Conference on
Retroviruses and Opportunistic Infections and European AIDS Conference.
Disclosures
Dr. DeJesus has received grants and research support from Abbott Laboratories, Boehringer
Ingelheim, Bristol-Myers Squibb Company, Gilead Sciences, GlaxoSmithKline, HoffmanLaRoche Inc., Merck & Co., Inc., Pfizer, Inc., Schering-Plough Corporation and Tibotec
Therapeutics. He has been a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline, Merck, Tibotec and Vertex Pharmaceuticals, Inc., and he serves on
speakers bureaus for Gilead, GlaxoSmithKline, Merck and Tibotec.
An Update on New HIV Antiretroviral Agents
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What Drives the Search for New
Antiretroviral Agents?
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HIV Drug Resistance
Safety and Tolerability
Cost and Convenience
• Five to 15% of newly
diagnosed patients
have drug resistance1-4
• Metabolic side effects:
lipoatrophy, dyslipidemia,
insulin resistance5
• A proportion of
treatment-experienced
patients have multiclass resistance4
• Other side effects: bone,
hematologic, central
nervous system, renal,
reproductive and
gastrointestinal
• Treatment-experienced
patients may need
mega-HAART with as
much as seven agents
or more6
• Patients must take
lifelong therapy7
1. Sabine Yerly et al. Lancet. August 28, 1999;354(9180):729. 2. Bluma Brenner et al, and the Quebec Primary Infection Study Team. Int J Antimicrob
Agents. December 2000;16(4):429-434. 3. Daniel Boden et al. JAMA. September 22, 1999;282(12):1135-1141. 4. William Wheeler et al. CROI 2007;
abstract 648. 5. Katherine Samaras. Diabetes Care. January 2007;30(1):113-119. 6. Julio Montaner et al. AIDS. January 5, 2001;15(1):61-69. 7.
Strategies for Management of Antiretroviral Therapy (SMART) Study Group et al. N Engl J Med. November 30, 2006;355(22):2283-2296.
An Update on New HIV Antiretroviral Agents
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Goals of Therapy for TreatmentExperienced Patients
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IAS-USA Guidelines,
August 20061:
US DHHS Guidelines,
January 29, 20082:
“Trials with newer antiretroviral
agents have shown that
it is possible to achieve plasma
HIV-1 RNA levels below
50 copies/mL even in highly
treatment-experienced patients.”
“The goal of treatment for
patients with prior drug exposure
and drug resistance is to reestablish maximal virologic
suppression, HIV-1 RNA < 50
copies/mL.”
1. Scott M. Hammer et al. JAMA. 2006;296:827-843. 2. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1Infected Adults and Adolescents.
January 29, 2008. Available at: http://www.aidsinfo.nih.gov/guidelines. Accessed June 11, 2008.
An Update on New HIV Antiretroviral Agents
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Timeline of Antiretroviral Development
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1987
zidovudine
1999
amprenavir
1991
didanosine
2000
lopinavir/ritonavir
1992
zalcitabine
2001
tenofovir
1994
stavudine
2003
emtricitabine, atazanavir,
enfuvirtide, fosamprenavir
1995
lamivudine, saquinavir
1996
2005
tipranavir
nevirapine, ritonavir,
indinavir
2006
darunavir
1997
delavirdine, nelfinavir
2007
raltegravir, maraviroc
1998
efavirenz, abacavir
2008
etravirine
An Update on New HIV Antiretroviral Agents
Key
NRTI
NNRTI
PI
Entry
Inhibitor
Integrase
Inhibitor
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Etravirine (TMC125):
Next-Generation NNRTI
An Update on New HIV Antiretroviral Agents
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Need for Next-Generation NNRTIs
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 Tolerability and toxicity
 CNS adverse effects, rash
 Hypersensitivity reactions (HSRs)
 Limits on prescribing to the target population
 Women of childbearing potential (i.e., efavirenz)
 Individuals with higher CD4+ cell counts (i.e., nevirapine)
 HIV drug Resistance
 Broad cross-resistance among first-generation NNRTIs
 Transmitted NNRTI resistance in up to 10% of treatmentnaive individuals*
* Potential importance of minority variants that cannot be detected currently in clinical practice
An Update on New HIV Antiretroviral Agents
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Etravirine
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 In vitro characteristics


EC50 WT HIV-1: 1.4 nmol/L
< 5-fold reduction in susceptibility against
N
N
 K103N, Y181C, Y188L, and L100I
 Phase I pharmacokinetics



H3C
Elimination half-life: 30-40 hours
Steady state attained within 5 days
Metabolized by cytochrome P450 CYP3A
O
N
Br
NH2
 Phase IIa

CH3
N
NH
2.0 log10 decline in plasma HIV-1 RNA over 7 days
Adapted from Marie-Pierre de Bethune et al. ICAAC 2000; abstract 1841.
Adapted from Stephen Piscitelli et al. Pharmacology Workshop 2002; abstract 5.3.
Adapted from Boris Gruzdev et al. AIDS. 2003;17:2487-2494.
An Update on New HIV Antiretroviral Agents
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Etravirine: Proof-of-Principle Trial in
Treatment-Experienced Patients
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HIV-1 RNA (Log10 Copies/mL)
Failing NNRTI therapy
Etravirine*
New Tx
4.5
N = 16 Patients
4.0
0.86 log10
3.5
3.0
-10
-8
-6
-4
-2
0
2
Time (Days)
4
6
8
*Etravirine 900 mg BID + continued NRTIs for seven days
Adapted from Brian Gazzard et al. AIDS. 2003;17:F49-F54.
An Update on New HIV Antiretroviral Agents
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DUET: Study Design and Major
Inclusion Criteria
Screening
6 weeks
48-week treatment period
with optional 48-week extension
Follow up
4 weeks
24-week primary analysis†
Etravirine (TMC125) (200 mg BID) + BR*
600 patients
target per trial
Placebo + BR*
BR* = darunavir/ritonavir (600/100 mg/mL) 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
† Primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR)
Adapted from Pedro Cahn et al. ICAAC 2007; abstract H-717.
An Update on New HIV Antiretroviral Agents
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DUET: Patients with Viral Load < 50
Copies/mL at Week 48 (ITT-TLOVR)
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* Pooled DUET data included for comparison; ‡ Logistic regression model;
TLOVR = time to loss of virologic response imputation algorithm. CI = confidence interval
Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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DUET: Response (<50 Copies/mL) by
PSS (DRV FC < 10 and < 40)* at Week 48
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<10 FC
< 40 FC
*PSS = phenotypic sensitivity score; DRV = darunavir; FC = fold change; ETR = etravirine; BR = background regimen;
ARVs = antiretrovirals; VL = viral load ‡Analysis excludes pts who DC except for virologic failure; ENF counted as
sensitive if used de novo
Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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DUET: Overview of Adverse Events
(Regardless of Causality) at Week 48
• No consistent or clinically relevant trends in lab, vital signs or ECGs observed
• Lab abnormalities, including hepatic and lipid parameters similar between arms
‡
All deaths in the ETR group were considered not or doubtfully related to trial medication. One death in the pooled placebo
group was considered possibly related to the background regimen (BR); AE = adverse event; ETR = etravirine
Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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DUET: Response (< 50 Copies/mL)
According to Number of TMC125 RAMS
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Number of TMC125 RAMs
Present at Baseline
TMC125 + BR (n=406)
0
121/161
64/147
1
73/121
59/157
2
37/64
17/68
3
13/32
6/24
7/28
3/18
≥4
0
Placebo + BR (n=414)
75%
44%
60%
38%
58%
25%
41%
25%
25%
17%
20
40
60
Patients with Viral Load < 50 Copies/mL at Week 24 (%)
80
•
The greatest added benefit in the TMC125 versus placebo group was seen in patients with <3 TMC125 RAMs
•
86% of patients had <3 TMC125 RAMs
Analysis excludes patients who used de-novo enfuvirtide or discontinued except for virological failure
BR = background regimen; RAM = resistance-associated mutation
Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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Etravirine
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 Recommended dose of etravirine is 200mg BID with a meal
 It can be dispersed in a glass of water
 Substrate CYP3A4, CYP2C9, CYP2C19
 Rash: main AE in clinical studies
 Grade 2 - 4 (9%), discontinuation from study (2%), Stevens-Johnson
Syndrome (<.1%)
 Mutations V179F/I and Y181C/I most commonly selected on
virologic failure
 Fold change (FC) susceptibility: < 3 FC (Monogram); < 1.6 to
> 27.6 (Virco)
 Populations:
 Pregnancy Category B
 No renal dose adjustment needed
 OK for mild to moderate liver disease
An Update on New HIV Antiretroviral Agents
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ARV Drug-Drug Interactions: Etravirine
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 No dose adjustment required







Didanosine
Tenofovir
Saquinavir/r
Lopinavir + Saquinavir2
Darunavir/r
Raltegravir
Elvitegravir/r3
a AUC
Co-administer with caution1




Lopinavir/ra
Dose modification1
Maraviroc4 (modify dose)
Co-administered contraindicated with1




of ETR after co-administration with
LPV/r is anticipated to be ~85% higher
than AUC of ETR observed in DUET
trials.1
b AUC of ETR after co-administration with
ATV/r is anticipated to be ~100% higher
than AUC of etravirine observed in
DUET trials.1
c Due to a significant increase in AUC of
APV, the appropriate doses of the
combination of ETR and FPV/r have not
been established.1
1 Intelence





Tipranavir/r
Atazanavir/rb
Fosamprenavir/rc
Full dose ritonavir
Unboosted PIs
 Atazanavir
 Fosamprenavir
 Indinavir
 Nelfinavir
Delavirdine
Nevirapine
Efavirenz
[package insert]. Raritan, NJ: Tibotec, Inc.; January 2008. 2 Marianne Harris et al. CROI 2006; abstract 575b. 3Srinivasan Ramanathan et al. ICAAC
2007; abstract H-1049. 4 J. Davis et al. EACS 2007. Abstract P4.3/02.
An Update on New HIV Antiretroviral Agents
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Protease Inhibitors
An Update on New HIV Antiretroviral Agents
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Similar Efficacy of Protease Inhibitors in
Treatment-Naïve Patients at 48 Weeks
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Percent With
HIV-1 RNA < 50 Copies/mL
ARTEMIS (ITT: TLOVR)1
Intent to Treat: Time to Loss of Virologic Response
Darunavir/ritonavir (800/100) mg QD (N = 343)
84
Lopinavir/ritonavir (400/100) mg BID or (800/200) mg QD
+ tenofovir/emtricitabine* (N = 346)
78
CASTLE (ITT-CVR: NC = F)2
78
Lopinavir/ritonavir soft-gel capsule (400/100 mg) BID
+ tenofovir/emtricitabine (N = 443)
76
1.7
(95% CI:-3.8, 7.1)
Intent to Treat
Lopinavir/ritonavir soft-gel capsule (400/100 mg) BID
+ tenofovir/emtricitabine (N = 170)
65
Saquinavir/ritonavir (1000/100 mg) BID
+ tenofovir/emtricitabine (N = 167)
64
KLEAN (ITT-E: TLOVR)4
5.5
(95% CI:-0.3, 11.2)
Intent to Treat-Confirmed Virologic Response: Non-completer = Failure
Atazanavir/ritonavir (300/100 mg) QD
+ tenofovir/emtricitabine (N = 440)
GEMINI (ITT)3
Approximated
Difference, %
1.14
(96% CI:-9.6, 11.9)
Intent to Treat-Exposed: Time to Loss of Virologic Response
Fosamprenavir/ritonavir (700/100 mg) BID
+ abacavir/lamivudine (N = 434)
66
Lopinavir/ritonavir soft-gel capsule (400/100 mg) BID
+ abacavir/lamivudine (N = 444)
65
n/a
*77% of patients received BID dosing throughout study, 83% of patients switched from soft-gel capsule to tablet formulation.
1Adapted
3Adapted
from Nathan Clumeck et al. CROI 2008; abstract 37. 2Adapted from Jean-Michel Molina et al. CROI 2008; abstract 37.
from Sharon Walmsley et al. EACS 2007; abstract PS1/4. 4Adapted from Joseph Eron Jr et al. Lancet. 2006;368:476-482.
An Update on New HIV Antiretroviral Agents
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The Evolution of Darunavir/r in the
Treatment of HIV Infection
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 Patients With Heavy ARV Experience
 POWER 1 and POWER 2
 POWER 3
 DUET 1 and DUET 2
 Patients With Limited ARV Experience
 TITAN
 Patients Naïve to Therapy
 ARTEMIS
An Update on New HIV Antiretroviral Agents
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TITAN (TMC114-C214): Study Design
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Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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TITAN: Baseline Characteristics
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Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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TITAN: Viral Load < 50 Copies/mL to
Week 48 (TLOVR) — All Patients
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Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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TITAN: Viral Load < 50 Copies/mL at
Week 48 by Baseline LPV FC (TLOVR)
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* DRV/r 600/100mg bid
† Estimated from a logistic regression model including treatment and stratification factors: baseline log 10 HIV-RNA and
use of NNRTIs in the optimised background regimen
Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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TITAN: Most Common Adverse Events
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Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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ARTEMIS: Phase III Study Design
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689 ARV-naïve
patients
VL > 5,000;
no CD4 entry
DRV/r 800/100mg QD
+ TDF 300mg and FTC 200mg (N=343)
LPV/r 400/100mg bid or 800/200mg QD
+ TDF 300mg and FTC 200mg (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.
An Update on New HIV Antiretroviral Agents
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ARTEMIS: Viral Load < 50 Copies/mL
to Week 48 (ITT-TLOVR)
Patients with VL < 50 Copies/mL (% [±SE])
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100
DRV/r QD (N=343)
90
LPV/r QD or BID (N=346)
80
84%
78%
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.
An Update on New HIV Antiretroviral Agents
48
26
ARTEMIS: Week 48 Response by QD
and BID Dosing (ITT-TLOVR)
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Difference 3% (95% CI -3; 9)
Difference 13% (95% CI 1; 24; p<0.05)
Patients with VL < 50 Copies/mL (%)
100
Difference 9%* (95% CI -3; 21)
80
84
81
78
71
60
*Difference rounded
†27
patients
receiving LPV/r BID
and QD during the
study were excluded
from this analysis.
40
20
0
N=
LPV/r overall
LPV/r BID†
LPV/r QD†
DRV/r QD
346
267
52
343
Adapted from Edwin DeJesus et al. ICAAC 2007; abstract H-718b.
An Update on New HIV Antiretroviral Agents
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ARTEMIS: Grade 2–4 Adverse Events
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DRV/r QD
LPV/r QD or BID
(N=343)
(N=346)
GI (all AEs)
23 (7)
47 (14)
p < 0.01
Diarrhea
14 (4)
34 (10)
p < 0.05
Nausea
6 (2)
10 (3)
9 (3)
4 (1)
Gr 2–4 AEs† ≥ 2%
Incidence, n (%)
Rash (all types)
†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.
An Update on New HIV Antiretroviral Agents
28
ARTEMIS: Mean Fasting Lipid Levels
Over Time
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mM
ng/mL
250
3.5
Mean Triglycerides
DRV/r QD (n=343)
LPV/r QD or BID (n=346)
2.9
2.3
200
NCEP cut-off
1.7
150
1.1
100
2 4 8 12 16
24
36
Time (weeks)
DRV/r n=343
LPV/r n= 346
320
313
Total Cholesterol/HDL Ratio
Mean Total Cholesterol/HDL Ratio (± SE)
Mean Triglyceride Concentration ( ± SE)
300
5.5
DRV/r QD (n=343)
LPV/r QD or bid (n=346)
5.0
4.5
4.0
3.5
3.0
2 4 8 12 16
48
306
301
343
346
Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
24
320
313
36
48
305
301
29
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Raltegravir:
Integrase Inhibitor
An Update on New HIV Antiretroviral Agents
30
BENCHMRK-1 & -2: Study Design
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• Randomized, double-blind, placebo-controlled with Data and Safety Monitoring Board
• Primary analysis at Week 16; secondary analysis at Week 48
Primary endpoints
Week 16
HIV-1-infected
Triple-class resistant
HIV-1 RNA > 1,000 copies/mL
No CD4 cell cut-off
Protocol 018* (N=352)
Europe, Asia/Pacific and Peru
Protocol 019* (N=351)
North and South America
Planned duration
Week 156
Raltegravir 400 mg BID + OBT
P018* (n=232)
P019* (n=230)
2:1
Placebo + OBT
P018* (n=118)
P019* (n=119)
• OBT was selected by investigator based on baseline resistance testing and prior treatment history.
Selected investigational ARTs, darunavir and tipranavir, were permitted.
*Protocol 018 (P018) is BENCHMRK-1; Protocol 019 (P019) is BENCHMRK-2
David Cooper et al. CROI 2008; abstract 788. Reprinted with permission.
Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved
An Update on New HIV Antiretroviral Agents
31
BENCHMRK-1 & -2: Patients With
HIV-1 RNA < 50 Copies/mL at Week 48
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BENCHMRK-1[1]
BENCHMRK-2[2]
*+OBR; P < .001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log10), first
ENF use in OBR, first DRV use in OBR, active PI in OBR.
1David
Cooper et al. CROI 2008; abstract 788. Reprinted with permission.
Steigbigel et al. CROI 2008; abstract 789. Reprinted with permission.
Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved
2Roy
An Update on New HIV Antiretroviral Agents
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BENCHMRK-1 & -2 Combined Efficacy: Percent
of Patients With HIV RNA <50 Copies/mL at
Week 48 by Selected ARTs in OBT
David Cooper et al. CROI 2008; abstract 788. Reprinted with permission.
Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved
An Update on New HIV Antiretroviral Agents
32
33
BENCHMRK-1 and -2: Drug-Related
Adverse Events at Week 48
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BENCHMRK-11
BENCHMRK-22
Placebo + OBT
(N = 118)
RAL + OBT
(N = 232)
Placebo + OBT
(N = 119)
RAL + OBT
(N = 230)
Diarrhea
14.4%
6.9%
10.1%
13.9%
Fatigue
0%
2.2%
2.5%
5.2%
Headache
6.8%
3.0%
5.0%
8.7%
Nausea
6.8%
3.9%
9.2%
9.6%
Rates of all-cause, serious and drug-related AEs, death and laboratory abnormalities did not
differ significantly between treatment arms.
Malignancy rate: RAL 3.5/100 person-years vs. placebo 2.3/100 person-years
RR: 1.5 (95% CI: 0.5-6.3)
1Adapted
from David Cooper et al. CROI 2008; abstract 788.
from Roy Steigbigel et al. CROI 2008; abstract 789.
Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved
2Adapted
An Update on New HIV Antiretroviral Agents
34
Study Design: MK-0518 Protocol 004
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48 Week Phase II Multicenter Double-Blind, Randomized Study
198 patients treated
Mean age 36, 80% male, 69% non-white,
34% AIDS, Mean HIV RNA at baseline 4.6-4.8 log10
MK-518
2 weeks monotherapy
EFV
(TDF + 3TC)
MK-518
(100, 200, 300, 400 BID)
(TDF + 3TC)
*Virologic failure defined as early (rebound or lack of suppression by 1 log10) or late (failure to suppress to
<200 c/mL or rebound)
Adapted from Martin Markowitz et al. IAC 2006; abstract THLB0214.
An Update on New HIV Antiretroviral Agents
35
Protocol 004: Percent (95% CI) of Patients
with HIV RNA < 50 Copies/mL (NC=F)
Percent of Patients with
HIV RNA < 50 Copies/mL
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100
80
60
*
40
*
20
0
0
MK-0518 100mg
MK-0518 200mg
MK-0518 400mg
MK-0518 600mg
Efavirenz
2
4
8
12
Week
16
24
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
37
* P < 0.001 for MK-0518 at each dose vs. EFV
Martin Markowitz et al. IAC 2006; abstract THLB0214. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
36
MK-0518 vs. EFV: Adverse Events
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MK-0518 (all doses) N=160 (%)
Efavirenz* N=38 (%)
Nausea
11
13
Headache
9
24
Dizziness
8
26
Diarrhea
7
11
Insomnia
7
11
Abnormal dreams
6
18
Flatulence
6
-
Additional adverse events seen at ≥ 5% in efavirenz group:
Nightmare (11%)
Vomiting (8%)
Malaise (8%)
Fatigue (5%)
Disturbance in attention (5%)
Lethargy (5%)
Anxiety (5%)
Adapted from Martin Markowitz et al. IAC 2006; abstract THLB0214.
An Update on New HIV Antiretroviral Agents
* With TFV/3TC
37
Raltegravir vs. EFV: Serum Lipids
The Body PRO
N = number of patients with data
* p-value < 0.05 for comparison to efavirenz
** MK-0518 and EFV were given in combination
with TFV/3TC
Hedy Teppler et al. ICAAC 2006; abstract H-0256a. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
38
The Body PRO
Maraviroc:
CCR5 Entry Inhibitor
An Update on New HIV Antiretroviral Agents
39
CCR5 Inhibitors:
The Good, The Bad, The Unknown
The Body PRO
Dual
tropic
X4 (SI)
CD4
CCR5
CXCR4
T-cell lines
R5 (NSI)
Primary lymphocytes
CD4 Naïve
Monocyte/macrophages
CD4 memory
Dan Kuritzkes. Infectious Disease Grand Rounds Feb. 2008, University of Colorado. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
40
Tropism Testing
The Body PRO
Panel on Antiretroviral Guidelines for Adults and Adolescents. Washington, DC: US Dept of Health and Human Services; December 1, 2007.
An Update on New HIV Antiretroviral Agents
41
Tropism Testing
The Body PRO
Standard Trofile Assay
Enhanced Trofile Assay
The Trofile test, which was used to
establish eligibility for clinical trials of
maraviroc, has been proven an
effective test for identifying individuals
with X4-tropic virus.1
It identified D/M tropism in more
patients in ACTG 5211 than the
standard assay:2
However, the test sometimes fails to
identify X-4 tropic minority
subpopulations.
25 of the 116 patients who were
believed to have changed from
CCR5-only to D/M tropism while
taking vicriviroc, were found to have
D/M virus at study entry when the
enhanced Trofile assay was used.
1. Jeannette M. Whitcomb et al. Antimicrob Agents Chemother. February 2007;51(2):566-475. 2. Jacqueline Reeves et al. CROI 2008; abstract 869.
An Update on New HIV Antiretroviral Agents
42
MOTIVATE-1 & -2: Study Design
The Body PRO
OBT* + Placebo
Randomization
1:2:2
MOTIVATE 1 N=601
MOTIVATE 2 N=474
OBT* + Maraviroc (150 mg† QD)
OBT* + Maraviroc (150 mg† BID)
Screening
(6 weeks)
0
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)
Patients stratified by:
• Enfuvirtide use in OBT
• HIV-1 RNA < and ≥ 100,000 copies/mL at screening
24w
48w
Planned
interim analysis
* 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
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
43
MOTIVATE 1 & 2: Combined Virologic
Efficacy at Week 48
The Body PRO
Percentage of Patients with HIV-1 RNA Suppression (solid lines, HIV-1
RNA <400 copies/mL; dashed lines, HIV-1 RNA <50 copies/mL)
David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
44
80
58
60
Patients (% )
The Body PRO
MOTIVATE-1 & -2: HIV-1 RNA < 50 Copies/mL
at Week 24 by Number of Active Drugs in
OBT
MVC BID + OBT
MVC QD + OBT
Placebo + OBT
61
55
53 52
43 43
40
29
19
18
20
9
3
0
3 or More
N= 121 132 64
2
1
0
104 88 59
134 130 44
56 51 35
Number of Active Drugs in OBT
Adapted from Mark Nelson et al. CROI 2007; abstract 104aLB.
Adapted from Jacob Lalezari et al. CROI 2007; abstract 104bLB.
An Update on New HIV Antiretroviral Agents
45
MOTIVATE 1 & 2: Virologic Outcomes
Based on Tropism
The Body PRO
HIV-1 RNA <50 c/mL
OBT alone
MVC BID + OBT
MVC QD + OBT
100
90
80
Patients (%)
70
Tropism result at baseline:
D/M
R5
60
50
50
50
40
27
30
20
18
26
18
10
0
N=
17
33
33
187 362 377
Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
46
MOTIVATE 1 & 2: 48-Week Safety
Unadjusted for Duration of Exposure
The Body PRO
All casualties and severities, n (%)
Placebo + OBT
N=209
Maraviroc QD + OBT
N=414
Maraviroc BID + OBT
N=426
Total exposure to study treatment,
patient-years
111
300
309
Treatment-emergent adverse events
177 (84.7)
375 (90.6)
393 (92.3)
Discontinuation due to adverse events
11 (5.3)
24 (5.8)
21 (4.9)
Serious adverse events
35 (16.7)
62 (14.9)
72 (16.9)
Grade 3 adverse events
46 (22.0)
84 (20.3)
104 (24.4)
Grade 4 adverse events
16 (7.7)
37 (8.9)
45 (10.6)
Category C events
16 (7.7)
29 (7.0)
23 (5.4)
Category C malignancies
5 (2.4)
3 (0.7)
4 (0.9)
Non-HIV malignancies
11 (5.3)
12 (2.9)
19 (4.5)
Deaths*
2† (1.0)
6 (1.4)
9 (2.1)
Similar frequency of serious, all-grade adverse events, toxicity-driven discontinuations, laboratory
abnormalities, AIDS-defining events among MVC and placebo arms at Week 48.
*Includes all patients who received at least one dose of study medication.
†Includes deaths reported up to 28 days after stopping study drug. No deaths were related to study drug according to the
investigator.
David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
47
MERIT: Comparison of Efavirenz and
Maraviroc in ARV-Naïve Patients
The Body PRO
Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*
Randomization
1:1
Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)*
Screening
(6 weeks)
0
48 wk
First
patient visit
Nov, 2004
Primary
analysis
Patient eligibility criteria:
• ≥ 16 years of age
• Treatment naive
• R5 HIV-1 infection
• HIV-1 RNA ≥ 2,000 copies/mL
• No evidence of resistance to EFV, ZDV, or 3TC
96 wk
MVC QD arm discontinued at end of Phase 2b (week 16)
for failure to meet protocol-defined criteria to continue (205
pts completed 16 weeks)
*Patients experiencing toxicity to ZDV or 3TC were
Patients stratified by:
permitted to substitute an alternative NRTI
• HIV-1 RNA < and ≥ 100,000 copies/mL at screening
• Geographic location: Northern Hemisphere and Southern Hemisphere
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
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MERIT: Summary of Discontinuations
Through 48 Weeks
The Body PRO
EFV + CBV
N=361
MVC + CBV
N=360
91 (25.2)
97 (26.9)
Adverse event, N (%)
49 (13.6)
15 (4.2)
Lack of efficacy, N (%)
15 (4.2)
43 (11.9)
Other reason, N (%)
9 (2.5)
14 (3.9)
Withdrew consent or lost to follow-up, N (%)
18 (5.0)
25 (6.9)
Reason for Discontinuation
All, N (%)
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
49
MERIT: Percentage of Patients with
Undetectable HIV-1 RNA at Week 48
(Primary Endpoint)
The Body PRO
100
90
80
< 400 Copies/mL
< 50 Copies/mL
–3.0* (–9.5†)
–4.2* (–10.9†)
73.1
Patients (%)
70
70.6
69.3
EFV + CBV
MVC + CBV
65.3
Mean ∆ CD4+ from baseline:
EFV +144 vs. MVC +170 cells/mm3
Difference: +26 (95% CI: +7, +46)
60
50
40
*Difference (adjusted for
randomization strata)
30
20
Intent-to-treat (ITT) analysis
10
0
N=
361
360
361
360
†Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10%
Per-protocol analysis: <400 copies/mL difference = -4.1 (-10.5†), <50 copies/mL difference = -4.4 (-11.2†)
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
50
MERIT: Percentage of Patients with HIV-1 RNA
< 50 Copies/mL by HIV-1 RNA at Screening
The Body PRO
100
< 100,000 copies/mL
90
80
71.6
Patients (%)
70
≥ 100,000 copies/mL
EFV + CBV
69.6
66.6
60
MVC + CBV
59.6
50
40
30
20
10
0
N=
211
204
150
156
Difference in < 50 noted in Southern Hemisphere (71% vs. 62%); No difference in Northern Hemisphere (67% vs. 68%)
Missing values classified as failures/non-responders
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
An Update on New HIV Antiretroviral Agents
51
Summary of Dose Modifications
with Maraviroc
The Body PRO
Concomitant Treatment
A.M. Dose
P.M. Dose
150 mg
150 mg
Includes a Potent CYP3A4 Inhibitor
PIs ± ritonavir (except tipranavir),
clarithromycin, delavirdine, elvitegravir,
itraconazole, ketoconazole,
nefazadone, telithromycin
YES
NO
Includes a CYP3A4 Inducer
efavirenz, etravirine, rifampicin
YES
300 mg
300 mg
300 mg
300 mg
300 mg
300 mg
NO
No CYP3A4 Inhibitors or Inducers
NRTIs, nevirapine, tipranavir/r
Adapted from Maraviroc [package insert]. New York, NY: Pfizer Labs; 2007.
An Update on New HIV Antiretroviral Agents
52
Take Home Message
The Body PRO
 ARV development has been very successful in the
past decade.
 The availability of new agents and new classes have
increased treatment options for our treatment
experienced patients.
 The potential use of these agents earlier in therapy
have opened the door for new treatment strategies.
 There are several other agents in development that
can further complement the enhanced activity of these
new agents.
An Update on New HIV Antiretroviral Agents