CCR5 Antagonists and Tropism Testing in Clinical Practice This activity is supported by educational grants from Faculty: W. David Hardy, M.D. Director,
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
CCR5 Antagonists and Tropism Testing inClinical Practice
This activity is supported by educational grants from
Faculty: W. David Hardy, M.D.Director, Division of Infectious Diseases Cedars-Sinai Medical Center; Los Angeles, California
This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
2
Faculty for This ActivityFaculty for This Activity
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.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
3
Retrovirus Life CycleRetrovirus Life Cycle
Coreceptor, CD4 Binding Inhibitors
maravirocvicrivirocTNX 355
Reverse Transcriptase Inhibitors
Protease Inhibitors
Maturation Inhibitorbevirimat
Integrase Inhibitorsraltegravirelvitegravir
Fusion Inhibitorsenfuvirtide
zidovudine nevirapine
didanosine delavirdine
zalcitabine efavirenz
stavudine lamivudine
emtricitabine abacavir
tenofovir etravirine
rilpivirine
saquinavir indinavir
ritonavir nelfinavir
fosamprenavir lopinavir
atazanavir tipranavir
darunavir
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
4
HIV Entry InhibitorsHIV Entry Inhibitors
Adapted from Moore JP, PNAS 2003;100:10598-10602.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
5
Targets Involved in HIV EntryTargets Involved in HIV Entry
CCR5 Antagonists and Tropism Testing in Clinical Practice
12
HIV Natural History and Tropism Expression
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
13
CCR5 Function and GeneticsCCR5 Function and Genetics
• 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.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
14
Mixed or Dual-Tropic Viruses Use CCR5 and/or CXCR4 (in vitro)Mixed or Dual-Tropic Viruses Use CCR5 and/or CXCR4 (in vitro)
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
15
Coreceptor Usage of HIV-1 VariantsCoreceptor Usage of HIV-1 Variants
CCR5 Antagonists and Tropism Testing in Clinical Practice
16
Global Prevalence of CCR5 32 AlleleGlobal Prevalence of CCR5 32 Allele
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.
~14%
~6%Rare
10%-15%
Rare
Rare
~10%
~10%
Rare
• 5%-14% of Caucasians of European descent carry CCR5 32 (1% are CCR5 32 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
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
17
CCR5 Wild Type and CCR5 32CCR5 Wild Type and CCR5 32
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.
• 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
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
18
Patients Heterozygous for CCR5 32 Have Slower Progression to AIDS and DeathPatients Heterozygous for CCR5 32 Have Slower Progression to AIDS and Death
Adapted from de Roda Husman A-M, et al. Ann Intern Med. 1997;127:882-890.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
19
The Tropism Assay
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
20
Why is a Tropism Test Required?Why is a Tropism Test Required?
• 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
CCR5 Antagonists and Tropism Testing in Clinical Practice
31
Coreceptor Tropism: Epidemiological Data
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
32
Percentage of HIV Coreceptor UsagePercentage of HIV Coreceptor Usage
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%
1Brumme ZL et al. J Infect Dis. 2005;192:466-474. 2Moyle GJ et al. J Infect Dis. 2005;191:866-872. 3Demarest 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.
This table may not include all available reported data; majority of data are generated in the developed world (subtype B)
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
33
Prevalence of X4 Phenotype by Baseline CD4+ CountPrevalence of X4 Phenotype by Baseline CD4+ Count
Adapted from Brumme ZL et al. J Infect Dis. 2005:192;466-74
Baseline CD4
• Coreceptor use was determined in 1191 patients starting HAART
• Patients with D/M virus had a poorer clinical profile than patients with R5 virus
– 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)
• The following were associated with the prevalence of D/M-tropic virus:
– Low baseline CD4+ T-cell count
– High baseline HIV RNA
– CCR5-Δ32 deletion heterozygous patients
– Basic mutations at gp120-V3 codons 11 or 25
92.8
45.6
7.2
54.4
0
20
40
60
80
100<
25
25-4
9
50-9
9
100-
199
200-
349
350-
499
≥ 50
0
Per
cen
tag
e o
f P
atie
nts
R5
D/M
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
34
Tropism in Naive Patients: Impact on CD4+ Decline and Response to TreatmentTropism in Naive Patients: Impact on CD4+ Decline and Response to Treatment
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
• 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
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
35
CD4+ Decline Before HAARTCD4+ Decline Before HAART
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
DAVG analysis (time weighted differences in average. Censored at HAART; Error bars are 95% CI
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
36
Time to Viral SuppressionTime to Viral Suppression
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
Survival analysis; Cox’s proportional hazards regression to adjust for baseline HIV RNA and HAART
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
37
Tropism Does Not Affect Response to HAARTTropism Does Not Affect Response to HAART
Graeme Moyle et al. ICAAC 2006; abstract H-1667. Reprinted with permission.
R5 TropicR5/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
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
38
Clinical Trials
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
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)
Deaths†*, n (%) 1 1
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.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
54
MERIT: Viral Suppression at Week 48 by Baseline TropismMERIT: Viral Suppression at Week 48 by Baseline Tropism
20
30
70
0
10
40
50
60
80
90
100
69.3
54.6
7.1
n = 11 14
68.0
339 331
Pa
tie
nts
Wit
h V
L <
50
c/m
L a
t W
ee
k 4
8 (
%)
EFV
MVC
69.365.3
Tropism at Screening (Overall)
361 360
Tropism at Baseline
(R5)
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.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
55
MERIT: Fewer Lipid Effects With Maraviroc vs. Efavirenz at Week 48MERIT: Fewer Lipid Effects With Maraviroc vs. Efavirenz at Week 48
Edwin DeJesus et al. CROI 2008; abstract 929. Reprinted with permission.
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
56
Questions
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
57
Main Discussion QuestionsMain Discussion Questions
• 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 treatment-naive patients that uses the more sensitive assay?
• Who is the best patient to use a CCR5 antagonist?
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
58
Case Studies
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
59
Case 1
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
60
• 37-year-old male with extensive ART history dating back to 1995
• Past ARVs included all NRTIs except ddC, all NNRTIs except DLV, and all PIs except FPV and full-dose RTV
• History of “buffalo hump” while taking IDV; removed with liposuction
• Former participant in the RESIST 1 trial (2003-2005); ART regimen—TPV/r, TDF-FTC, EFV, ddI and ENV
– HIV-1 RNA decreased from 510,000 to 5,200 copies/mL
– CD4+ increased from 75 to 120 cells/mm3
– Failed to achieve HIV-1 RNA < 50 copies/mL
• Discontinued ENF after 2.5 years due to lack of any available injection sites
Experienced low-level viremia prior to discontinuing ENF
Case 1: Patient HistoryCase 1: Patient History
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
61
• Patient also a participant in the MOTIVATE 1 trial
• Randomized to placebo with OBR* of: SQV/RTV, TDF/FTC, ddI, EFV
– IDV/RTV predicted to have full activity by resistance testing, but refused by patient due to prior history of lipodystrophy (buffalo hump)
– Patient achieved HIV-1 RNA < 50 c/mL by week 24 and CD4+ cells increase to 155/mm3 (22%); maintained for the next six months
– At this time, patient develops bilateral hip pain, is diagnosed with advanced aseptic necrosis of the right hip joint and undergoes right total hip replacement surgery
* Optimized Background Regimen
Case 1: Patient History ContinuedCase 1: Patient History Continued
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
62
A. No
B. Not Sure
C. Yes
Case 1: Would You Consider Changing the Patient’s Regimen at This Time?Case 1: Would You Consider Changing the Patient’s Regimen at This Time?
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
63
Case 1: Case ProgressionCase 1: Case Progression
• You convince the patient to remain on his current regimen to
maintain his HIV RNA < 50 copies/mL
• HIV-1 RNA increases to 580 copies/mL (repeat 1,280 copies/mL)
(You suspect that patient’s confidence in his ART regimen has
waned due to his hip surgery.)
• You determine that a change in regimen is indicated and order a
phenotype and tropism assay
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
64
Case 1: Results of a Tropism AssayCase 1: Results of a Tropism Assay