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.
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Faculty for This Activity
The Body PRO
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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The Body PRO
Case Studies
CCR5 Antagonists and Tropism Testing in Clinical Practice
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The Body PRO
Case 1
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Patient History
The Body PRO
• 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
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Patient History Continued
The Body PRO
• 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)
• After eight weeks, VL 734,000 copies/mL (from 1,162,500 copies/mL), CD4+
75 cells/mm3 (7.8%)
– < 0.5 log10 decrease, thus considered a virologic failure
• Switched to open-label MVC 150 mg BID, IDV/RTV, TDF/FTC, ddI
– 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
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Would You Consider Changing the
Patient’s Regimen at This Time?
The Body PRO
A. No
B. Not Sure
C. Yes
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Case Progression
The Body PRO
• 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
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Case 1: Results of a Tropism Assay
The Body PRO
Tropism
Result
Copyright © Monogram Biosciences. Reprinted with permission.
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Results of Patient’s Resistance Test
The Body PRO
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Should a Boosted PI Be Included in
the Patient’s New Regimen?
The Body PRO
A. Yes
B. No
C. Not sure
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: If You Included a PI, Which Would
You Use?
The Body PRO
A. Atazanavir + ritonavir
B. Darunavir + ritonavir
C. Fosamprenavir + ritonavir
D. Lopinavir/ritonavir
E. Saquinavir + ritonavir
F. Tipranavir + ritonavir
G. No PIs
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Would You Switch the NRTI
Component of the Patient’s Regimen?
The Body PRO
A. No
B. Yes, I would drop ddI
C. Yes, I would drop tenofovir/FTC
D. Yes, I would not use NRTIs in his new regimen
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Would You Include Raltegravir in the
Patient’s New Regimen?
The Body PRO
A. Yes
B. No
C. Not sure
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Would You Include Etravirine in the
Patient’s New Regimen?
The Body PRO
A. Yes
B. No
C. Not sure
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Case 1: Etravirine Resistance Information
The Body PRO
2008 Update
• Clinical cut offs (CCOs) determined for
phenotypic sensitivity
• Four additional etravirine RAMS identified
(17 total)
• Weighted scoring system developed
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Case 1: Response According to Phenotypic
Etravirine CCOs
The Body PRO
Proportion of Patients With Viral Load
< 50 Copies/mL (DUET Week 24),
% (n)
Decrease in log10 Viral Load From
Baseline (DUET Week 24),
Mean (SE)
71 (190/269)
–2.67 (1.03)
3–13
50 (37/74)
–2.39 (1.21)
> 13
37 (22/60)
–1.79 (1.42)
36 (149/414)
–1.51 (1.42)
Etravirine
CCO
<3
Overall
Placebo
The highest responses occurred in patients with a fold change < 3
Virological responses were greater than placebo in patients with a fold change < 13
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Effect of the Etravirine RAMs 2008
(17) on Virological Response
The Body PRO
Patients with confirmed VL
<50 HIV-1 RNA copies/mL (%)
80
New
New
New
70
New
60
50
40
30
20
10
52
34
115
22
12
8
4
59
110
53
9
26
5
24
8
6
14
7
n=
0
*no detectable baseline NNRTI RAM from the list of 44;
Dashed line indicates 75% of response in patients without NNRTI RAMs
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The Body PRO
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Case 1: Weighting of 2008 Etravirine RAMs
The Body PRO
Weight for
Individual Mutations
Y181I
Y181V
K101P
L100I
Y181C
M230L
E138A
V106I
G190S
V179F §
V90I
V179D
K101E
K101H
A98G
V179T
G190A
3
3
2.5
2.5
2.5
2.5
1.5
1.5
1.5
1.5
1
1
1
1
1
1
1
Add Together
§V179F
Total
Weighted
Score
was never present as single Etravirine RAM (always with Y181C)
CCR5 Antagonists and Tropism Testing in Clinical Practice
The Body PRO
Case 1: Relation Between the 2008 Etravirine
Genotypic Score and the Virological
Response (< 50 Copies/mL At Week 24)
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Case 1: Would You Continue Maraviroc in the
Patient’s New Regimen?
The Body PRO
A. Yes
B. No
C. Not sure
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 1: Case Progression
The Body PRO
• On his new regimen of MVC, DRV/r, ETV, RAL and
TDF/FTC his HIV-1 RNA remains < 50 copies/mL and CD4+
cells slowly rise to 280 cells/mm3 (28%) over the next
eight months
• His left hip pain and MRI of it stabilize showing no further
progression
• He continues to tolerate his ART regimen well
CCR5 Antagonists and Tropism Testing in Clinical Practice
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The Body PRO
Case 2
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Case 2: Patient History
The Body PRO
• 45-year-old man
• Diagnosed with HIV-1 in 1994 when he presented
with cutaneous Kaposi’s Sarcoma
– CD4+ cell count: 360 cells/mm³
– HIV-1 RNA test not available in 1994
• PMH: mild hypertension, controlled with diuretics
• FMH: diabetes, CVD
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Case 2: Patient ARV History
The Body PRO
• 1994: ZDV monotherapy
– Discontinued six months later due to anemia and
nausea
• ddI monotherapy
– Tolerated for nine months, then developed
pancreatitis
• Discontinued ARVs: KS quiescent, CD4+ cell count
stable at 360 cells/mm³
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Case 2: Patient History on HAART Regimens
The Body PRO
• Starting in 1996, various regimens including
– d4T + 3TC + SQV
– d4T + 3TC + NFV
– ABC + 3TC + EFV
– d4T + 3TC + LPV/RTV
– TDF + 3TC + LPV/RTV + FPV
• Intolerant to ZDV (anemia), ddI (pancreatitis), d4T
(peripheral neuropathy), NFV (diarrhea), dual-boosted
PIs (GI symptoms)
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Case 2: Patient History on HAART Regimens
(Continued)
The Body PRO
• Reached HIV-1 RNA < 400 copies/mL but never < 50 copies/mL
• First genotypic assay (after d4T + 3TC + SQV)
– RT gene: M41L, L74V, M184V, T215Y
PR gene: L10I, L63P, L90M
• Second genotypic assay (after ABC + 3TC + EFV)
– RT gene: M41L, L74V, K101P, K103N, Y181C, M184V, T215Y,
K219R
– PR gene: L10I, D30D/N, L63P, G73T, V77I, L90M
• CD4+ cell counts rose and fell, nadir: 240 cells/mm³
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Case 2: Current History: 2008
The Body PRO
• Regimen: TDF + 3TC + LPV/RTV
– HIV-1 RNA: 1,500-2,500 copies/mL
– CD4+ cell count: 300-350 cells/mm³
• Hypertension poorly controlled with ACE
inhibitor/diuretic + β-blocker
• Fasting glucose > 180 mg/dL
• Serum creatinine 1.9 mg/dL (baseline 1.0-1.4 mg/dL)
• Patient wants to consider a new regimen
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Case 2: Drug Resistance Test Results
The Body PRO
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Case 2: Viral Tropism Assay
The Body PRO
Tropism
Result
Copyright © Monogram Biosciences. Reprinted with permission.
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Case 2: Would You Use Darunavir or
Tipranavir in the New Regimen?
The Body PRO
A. Yes, I would use darunavir + ritonavir
B. Yes, I would use tipranavir + ritonavir
C. Yes, I would use both
D. No, I would not use either
Darunavir Resistance Mutations
•
11I, 32I, 33F, 47V, 50V, 54L/M, 74P, 76V, 84V, 89V
Tipranavir Resistance Mutations
•
10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 2: Would You Use NRTIs in
This Regimen?
The Body PRO
A. Yes
B. No
Phenotype
•
NRTIs: susceptible to TDF, ZDV, d4T
•
NNRTIs: resistant to DLV, EFV, NVP
•
PIs: partially susceptible to DRV
CCR5 Antagonists and Tropism Testing in Clinical Practice
The Body PRO
Case 2: How Many Additional Active Agents
Does This Patient Need to Achieve HIV-1 RNA
< 50 Copies/mL?
A. 1
B. 2
C. 3
D. Individualized for patient’s viral resistance
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BENCHMRK 1&2: Response by Number of
Active Agents in OBT (24 Weeks)
Patients With VL < 50 c/mL
At Week 24 by PSS/GSS of OBT* (%)
The Body PRO
100
Raltegravir
80
79
Placebo
87
63
71
61
71
57
60
56
44
41
40
37
34
20
6
5
0
0
Overall
Efficacy Data
1
≥2
0
PSS
1
GSS
BENCHMRK-1 and -2 with virologic failures carried forward
Adapted from PN Kumar et al. EACS 2007; abstract P7.2/06.
CCR5 Antagonists and Tropism Testing in Clinical Practice
≥2
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DUET 1&2: Response by Number of Active
Agents in OBT (24 Weeks)
The Body PRO
Anthony Mills and Christine Katlama et al. IAS 2007, abstract WESS204. Reprinted with permission.
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MOTIVATE 1&2: Response by Number of
Active Agents in OBT (24 Weeks)
The Body PRO
80
58
Patients (% )
60
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.
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Case 2: Which Regimen Would You Choose?
The Body PRO
A.
tenofovir/emtricitabine, darunavir + ritonavir,
etravirine, maraviroc
B.
tenofovir/emtricitabine, darunavir + ritonavir,
maraviroc, raltegravir
C.
tenofovir/emtricitabine, darunavir + ritonavir,
etravirine, raltegravir
D.
tenofovir/emtricitabine, darunavir + ritonavir,
etravirine, maraviroc, raltegravir
E.
Something else
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 2: Evolution
The Body PRO
• New regimen: TDF/FTC + DRV/RTV + ETR + MVC + RAL
• HIV-1 RNA at 6 weeks: < 50 copies/mL
• CD4+ cell count at 10 weeks: 420 cells/mm³
• Serum creatinine ↑ to 2.7 mg/dL (from 1.9 mg/dL);
24-hour ClCr: 48 mL/min
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Case 2: What Would You Do Now With the
NRTI Portion of the Regimen?
The Body PRO
A. Continue TDF/FTC QD
B. Continue TDF/FTC but decrease the dose to QOD
C. Change TDF/FTC to ABC/3TC
D. Discontinue TDF/FTC
CCR5 Antagonists and Tropism Testing in Clinical Practice
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Case 2: Evolution
The Body PRO
• Tenofovir discontinued due to concerns about
decreased renal function
• New regimen: DRV/RTV + ETR + MVC + RAL
• HIV-1 RNA < 50 copies/mL
• CD4+ count ↑ to 550 cells/mm³ (from 420 cells/mm³)
• Serum creatinine  to 1.8 mg/dL (from 2.7 mg/dL);
24-hour ClCr: ↑ to 80 mL/min (from 24 mL/min)
CCR5 Antagonists and Tropism Testing in Clinical Practice