Transcript CCR5 Antagonists and Tropism Testing in Clinical Practice

The Body PRO Presents:
CCR5 Antagonists and Tropism
Testing in
Clinical Practice
Faculty: W. David Hardy, M.D.
Director, Division of Infectious Diseases
Cedars-Sinai Medical Center; Los Angeles, California
W. David Hardy, M.D.
This activity is supported by educational grants from
This activity is jointly sponsored by Postgraduate
Institute for Medicine and The Body PRO.
Copyright © 2008 Body Health Resources Corporation. All rights reserved.
1
Faculty for This Activity
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W. David Hardy, M.D.
W. David Hardy, M.D., is an associate professor of medicine-in-residence at the David
Geffen School of Medicine, University of California, Los Angeles (UCLA). He gained his
medical degree from the Baylor College of Medicine in Houston, Texas, in 1981,
completed a residency in internal medicine at Harbor-UCLA Medical Center in Torrance,
California in 1984 and a clinical fellowship in infectious diseases and immunology in 1986
at UCLA School of Medicine. Later in his career he also completed a postdoctoral
fellowship in basic retrovirology in 2002, also at the UCLA School of Medicine.
Dr. Hardy has conducted clinical trials with several antiretroviral agents beginning in
1986. He is a member of numerous professional societies including the American
Academy of HIV Medicine, for whom he serves as a member of the National Board of
Directors and Chairman of the California/Hawaii Chapter.
Disclosures
Dr. Hardy has received grants or research support from Boehringer Ingelheim, Gilead
Sciences, GlaxoSmithKline, Pfizer and Tibotec. He has served as a consultant for
Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Monogram, Pfizer
and Tibotec. He has received fees for non-CME services from Gilead Sciences, Pfizer
and Tibotec. He owns stock in Merck.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Retrovirus Life Cycle
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Coreceptor, CD4
Binding Inhibitors
maraviroc
vicriviroc
TNX 355
Fusion Inhibitors
enfuvirtide
Reverse Transcriptase
Inhibitors
zidovudine
nevirapine
didanosine
delavirdine
zalcitabine
efavirenz
stavudine
lamivudine
emtricitabine
abacavir
tenofovir
etravirine
Maturation Inhibitor
bevirimat
Protease Inhibitors
saquinavir
indinavir
ritonavir
nelfinavir
fosamprenavir
lopinavir
atazanavir
tipranavir
darunavir
Integrase Inhibitors
raltegravir
elvitegravir
rilpivirine
CCR5 Antagonists and Tropism Testing in Clinical Practice
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HIV Entry Inhibitors
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Adapted from Moore JP, PNAS 2003;100:10598-10602.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Targets Involved in HIV Entry
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Structure of the HIV-1 Envelope Glycoprotein
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Binding of the gp120 Subunit to CD4
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Conformational Change
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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gp120 Binds to the Coreceptor, CCR5
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Conformational Changes in the gp41 Subunit
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
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Fusion of the Viral and Cell Membranes
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Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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HIV Natural History and Tropism Expression
CCR5 Antagonists and Tropism Testing in Clinical Practice
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CCR5 Function and Genetics
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• CCR5 is a receptor for C-C chemokines (chemo-attractive cytokines)
– Expressed on immune effector cells and antigen presenting cells
– Molecules that bind to CCR5 include MIP-1, MIP-1, and RANTES
• Activation of CCR5 on T cells by chemokines leads to:
– T-cell migration to the site of inflammation
– Immune response to various antigens
• CCR5, together with CD4, are the primary receptors utilized by HIV for
viral entry
Galvani AP et al. Proc Natl Acad Sci U S A. 2003;100:15276-15279. McNicholl JM et al. Emerg Infect Dis. 1997;3:261-271.
Stephens JC et al. Am J Hum Genet. 1998;62:1507-1515.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Mixed or Dual-Tropic Viruses Use
CCR5 and/or CXCR4 (in vitro)
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Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Coreceptor Usage of HIV-1 Variants
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X4
R5
CD4
CD4
CCR5
CXCR4
T-cell lines
Primary lymphocytes
CD4 Naive
Monocyte/macrophages
CD4 memory
Copyright © 2002-2008 Pfizer Inc. All rights reserved.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Global Prevalence of CCR5 D32 Allele
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~14%
~10%
10%15%
~6%
Rare
Rare
Rare
Rare
~10%
•
5%-14% of Caucasians of European descent carry CCR5 D32
(1% are CCR5 D32 homozygous)
•
The origin of the CCR5 D32 allele has been traced to European geography ~1,000 years ago
Possible selection by pandemic pathogen, likely smallpox or bubonic plague
Galvani AP et al. PNAS. 2003;100:15276-15279. McNicholl JM et al. Emerg Infect Dis. 1997;3:261-271.
Stephens JC et al. Am J Hum Genet. 1998;62:1507-1515.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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CCR5 Wild Type and CCR5 D32
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CCR5 wild type 
 CCR5 D32
Normal
Heterozygotes
Homozygotes
wt/wt
wt/D32
D32/D32
• Normal CCR5 exp
• Progression of HIV
• Normal immune fx*
• Decreased CCR5 exp
• Delayed prog. to AIDS/death
• Normal immune fx*
• No CCR5 exp
• Rare infection with X4
• Normal immune fx*
*fx = function
Click on slide for animation.
Liu R et al. Cell. 1996;86:367-377. Huang Y et al. Nat Med. 1996;2:1240-1243. Samson M et al. Nature. 1996;382:722-725.
Michael NL et al. Nat Med. 1997;3:1160-1162. Dean M et al. Science. 1996;273:1856-1862. Eugen-Olsen J et al. AIDS. 1997;11:305-310.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Patients Heterozygous for CCR5 D32 Have
Slower Progression to AIDS and Death
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Adapted from de Roda Husman A-M, et al. Ann Intern Med. 1997;127:882-890.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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The Tropism Assay
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Why is a Tropism Test Required?
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•
CCR5 antagonists block entry of HIV that uses CCR5 only, no effect on HIV that uses CXCR4
•
Presence of X4 HIV has been associated with more rapid CD4 decline and disease progression
•
The effect a CCR5 antagonist will have in patients with R5/X4 HIV is unknown
•
Regulatory agencies likely to require tropism assay prior to use of a CCR5 antagonist
Copyright © 2002-2008 Pfizer Inc. All rights reserved. Reprinted with permission.
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The Monogram Tropism Assay
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Envelope Expression Vector (pHIVenv)
HIV envelope
gp120
P
a/b
gp41
A+
c/d
HIV-1 Expression Vector (pHIVlucDU3)
gag
P
R U5
D env
pol
P
Luciferas
e
Indicator Gene
Copyright © Monogram Biosciences. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
R
A+
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HIV Entry Cell Assay
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Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:920-928.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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HIV Entry Cell Assay: R5 HIV Only
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Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:920-928.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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HIV Entry Cell Assay: X4 HIV Only
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Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:920-928.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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HIV Entry Cell Assay: R5/X4 Tropic HIV
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Adapted from Petropoulos CJ et al. Antimicrob Agents Chemother. 2000;44:920-928.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Demonstration of R5 Virus
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Light Generated
CCR5 Use
Virus
R5 Virus
No Light Generated
No CXCR4 Use
Virus
Not an
X4 Virus
Virus
CXCR4
CCR5
Click on slide for animation.
Copyright © Monogram Biosciences. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Demonstration of Dual Virus
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Light is generated on both CCR5 and CXCR4 cell lines.
Virus
Virus
This is a DUAL virus.
Virus
Virus
CCR5
CXCR4
Click on slide for animation.
Copyright © Monogram Biosciences. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Demonstration of Mixed Virus Population
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This population shows CCR5 AND CXCR4 co-receptor use.
This is a mixed population.
CCR5
CXCR4
Click on slide for animation.
Copyright © Monogram Biosciences. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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What Is This Population?
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Most of these viruses are R5:
Strong luciferase activity
Some are X4:
Lower level luciferase activity
CCR5
CXCR4
Click on slide for animation.
Copyright © Monogram Biosciences. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Comparison of Original Tropism to Enhanced
Sensitivity Tropism Test
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Sensitivity
Standard
Tropism Assay
Enhanced
Tropism Assay
(August 2007 – June 2008)
(June 2008 – Present)
• 100% if X4-using HIV
> 10% of viral population
• 83% if X4-using HIV
> 5% of viral population
• 100% if X4-using HIV
> 0.3% of viral population
Plasma Volume Required
3 mL
3 mL
Shipping Requirement
Dry ice
Dry ice
Viral Load Requirement
> 1,000 copies/mL
> 1,000 copies/mL
Turnaround Time
~ 2 weeks
~ 2 weeks
Copyright © Monogram Biosciences. Reprinted with permission.
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Coreceptor Tropism: Epidemiological Data
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Percentage of HIV Coreceptor Usage
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Study/Source
Population
N
R5
X4
R5/X4
Homer cohort1
Naive
979
82%
< 1%
18%
C & W cohort2
Naive
402
81%
< 1%
19%
Demarest3
Naive
299
88%
0%
12%
Study 10264
Naïve
1428
85%
< 1%
15%
TORO 1/26
Experienced
612
62%
4%
34%
ViroLogic5
Experienced
> 2000
48%
2%
50%
ACTG 52117
Experienced
391
49%
4%
47%
MOTIVATE 1/28
Experienced
2560
56%
3%
41%
This table may not include all available reported data; majority of data are generated in the developed world (subtype B)
1Brumme
ZL et al. J Infect Dis. 2005;192:466-474. 2Moyle GJ et al. J Infect Dis. 2005;191:866-872.
J et al. ICAAC 2004; abstract H-1136. 4Waters L et al. ICAAC 2006; abstract H-1667.
5Whitcomb JM et al. CROI 2003; abstract 557. 6Paxinos EE et al. ICAAC 2002; abstract 2040.
7Wilkin T et al. CROI 2006; abstract 655. 8Coakley E et al. International Workshop on Targeting HIV Entry 2006; abstract 8.
3Demarest
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Prevalence of X4 Phenotype by Baseline
CD4+ Count
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92.8
60
• Coreceptor use was determined in
1191 patients starting HAART
• Patients with D/M virus had a poorer
clinical profile than patients with R5 virus
80
54.4
–
Median CD4+ T-cell count of 110
versus 290 cells/mm3 (P<.0001)
–
HIV RNA of 175,000 versus
120,000 copies/mL (P=.0006)
R5
45.6
• The following were associated with the
prevalence of D/M-tropic virus:
20
Baseline CD4
350-499
200-349
100-199
50-99
25-49
0
7.2
≥ 500
40
D/M
< 25
Percentage of Patients
100
–
Low baseline CD4+ T-cell count
–
High baseline HIV RNA
–
CCR5-Δ32 deletion heterozygous
patients
–
Basic mutations at gp120-V3
codons 11 or 25
Adapted from Brumme ZL et al. J Infect Dis. 2005:192;466-74
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Tropism in Naive Patients: Impact on CD4+
Decline and Response to Treatment
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• 402 treatment-naive subjects had tropism tested
– 326 R5
– 73 D/M
– 3 X4
• 340 started HAART by August 2006
– 229 R5
– 60 D/M
– 51 excluded from analysis
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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CD4+ Decline Before HAART
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DAVG analysis (time weighted differences in average. Censored at HAART; Error bars are 95% CI
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Time to Viral Suppression
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Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAART
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Tropism Does Not Affect Response to HAART
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R5 Tropic
R5/X4
Tropic
P Value
CD4+ T-Cell Count Rise at
12 Months, Cells/mm3 (95% CI)
185
(166-204)
182
(145-219)
.812
CD4+ T-Cell Count Rise at
24 Months, Cells/mm3 (95% CI)
247
(227-267)
292
(254-330)
.482
Patients With VL < 50 Copies/mL at
12 Months, n (%)
168 (73.4)
47 (78.3)
.509
Patients With VL < 50 Copies/mL at
24 Months, n (%)
166 (72.4)
41 (68.3)
.67
CI = confidence interval
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Clinical Trials
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Trial Design
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David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Demographics and
Baseline Characteristics
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David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Mean Change in HIV-1 RNA*
From Baseline to Week 48
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David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Percentage of Patients With
Undetectable HIV-1 RNA
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David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Mean Change in CD4+ Cell
Count From Baseline to Week 48
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• CD4+ cell count increases up to 48 weeks were more favorable
in both the maraviroc groups than the placebo group
• The mean change from baseline in CD4+ cell count* was:
• +61 cells/mm3 in the placebo + OBT
• +116 cells/mm3 in maraviroc QD + OBT
• +124 cells/mm3 in the maraviroc BID + OBT group
* Last observation carried forward approach used to impute missing values
David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Patients With HIV-1 RNA
< 50 Copies/mL by Screening Viral Loads and
Baseline CD4+ Cell Count (Week 48)
David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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44
MOTIVATE 1&2: Safety Analyses Unadjusted
For Duration of Exposure
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David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Maximum Liver Function
Test Values Over 48 Weeks Without Regard
To Baseline
David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MOTIVATE 1&2: Percentage of Adverse
Events Occurring in ≥ 5% of Patients in Any
Group, Unadjusted for Treatment Exposure
David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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47
VICTOR-E1: Phase IIb Trial of Vicriviroc in
Treatment-Experienced Patients
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Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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VICTOR-E1: Virologic Efficacy of Vicriviroc vs.
Placebo at Week 48
0
VCV 30 mg VCV 20 mg
n = 39
n = 40
Placebo
n = 35
90
-0.2
-0.4
-0.6
-0.8
-0.79
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
100
-1.77
-1.75
Difference:
Difference:
-0.96
-0.98
P = .0028
P = .0017
Patients With HIV-RNA-1
< 50 copies/mL (%)
Mean Change in HIV-1 RNA From BL
(log10 copies/mL)
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80
70
60
56
53
50
40
30
20
14
10
0
VCV 30 mg VCV 20 mg
n = 22
n = 21
No clinically significant differences in adverse events between VCV arms and placebo
Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
Placebo
n=5
49
MERIT: Maraviroc vs. Efavirenz in
Treatment-Naive Patients
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Stratified by HIV-1 RNA < or  100,000
copies/mL and by Northern or Southern
Hemisphere
Antiretroviral-naive patients
infected with CCR5-tropic
HIV-1 and HIV-1 RNA
 2000 copies/mL
(N = 740)
Week 48 primary endpoint
Week 96
MVC 300 mg twice daily + ZDV/3TC
(n = 360)
EFV 600 mg once daily + ZDV/3TC
(n = 361)
MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at
end of phase IIB (Week 16)

Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MERIT: Patients With Viral Load < 400 and
< 50 Copies/mL by Week 48 (ITT)
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EFV (n = 361)
100
VL < 400 copies/mL
80
73.1%
60
70.6%
40
Patients, %
Patients, %
100
MVC (n = 360)
80
69.3%
60
65.3%
40
20
20
0
0
0 24 8
16
24
32
Time (weeks)
40
48
VL < 50 copies/mL
024 8
16
24
32
Time (weeks)
40
48

MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)

CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MERIT: Patients With Viral Load
< 50 Copies/mL by Baseline Viral Load
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 EFV patients more likely
to discontinue due to AE
90
80
– Overall : 25.2%
– Efficacy: 4.2%
 MVC patients more likely
to discontinue due to lack
of efficacy
– AE: 4.2%
– Efficacy: 11.9%
Patients, %
– AE: 13.6%
– Overall: 26.9%
EFV
100
71.6
70
69.6
MVC
66.6
59.6
60
50
40
30
20
10
0
n=
211
204
BL VL < 100,000
Copies/mL
150
156
BL VL ≥ 100,000
Copies/mL
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
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MERIT: Week 48 Safety Analyses
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All Causalities and Severities
EFV + CBV
N=361
MVC + CBV
N=360
Patients With Adverse Events
340 (94.2)
331 (91.9)
Patients With Grade 3 AEs, n (%)
66 (18.3)
51 (14.2)
Patients With Grade 4 AEs, n (%)
24 (6.6)
22 (6.1)
Patients With SAEs, n (%)†
46 (12.7)
41 (11.3)
Patients With Category C events, n (%)
12 (3.3)
6 (1.7)
Malignancies
16 (4.4)
10 (2.8)
1
1
Deaths†*, n (%)
AEs = adverse events; SAEs = serious adverse events †Based on all data through 21 June 2007
*Deaths reported up to 28 days after stopping study drug; one additional death on EFV
within 28 days, date of death not captured in database
Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.
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MERIT: Viral Suppression at Week 48 by
Baseline Tropism
Patients With VL < 50 c/mL at Week 48 (%)
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100
EFV
MVC
90
80
70
69.3
69.3 68.0
65.3
60
54.6
50
40
30
20
7.1
10
0
n = 361 360
Tropism at
Screening
(Overall)
339 331
Tropism at
Baseline
(R5)
11
14
Tropism at
Baseline
(D/M)
• Change in detected HIV-1 tropism from R5 at
screening to D/M at BL and potentially
adherence may explain some treatment failures
on MVC
– 3.5% of patients experienced change in
detected tropism between screening and
BL
– 50.0% of patients with R5 virus at BL and
without confirmed X4 at failure had
plasma MVC concentrations below limit of
detection
• Tropism changes more common in patients with
lower mean CD4+ cell count at screening as well
as with clade B or other/undetermined
HIV-1 subtype vs clade C
Jayvany Heera et al. CROI 2008; abstract 40LB. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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MERIT: Fewer Lipid Effects With Maraviroc vs.
Efavirenz at Week 48
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Edwin DeJesus et al. CROI 2008; abstract 929. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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The Body PRO
Questions
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Main Discussion Questions
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• Does the use of CCR5 antagonists prevent the immune system from
mounting an effective defense against West Nile virus infection and its
complications?
• Is the new enhanced tropism test sensitive enough to more accurately
identify patients who may have some X4-tropic virus?
• Is there going to be a second clinical trial of maraviroc in treatmentnaive patients that uses the more sensitive assay?
• Who is the best patient to use a CCR5 antagonist?
CCR5 Antagonists and Tropism Testing in Clinical Practice