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Perspectivas del Maraviroc en el Tratamiento del VIH. Hernán Valdez, MD Director Médico Global, Virología Pfizer, Inc. Tópicos. Tropismo Efectos extra-antivirales de Maraviroc, alguna evidencia? Se puede usar el Maraviroc una vez al dia?. Tropismo. Trofile Patient Population. - PowerPoint PPT Presentation
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Hernán Valdez, MD
Director Médico Global, Virología
Pfizer, Inc.
Perspectivas del Maraviroc en el Tratamiento del VIH
Tópicos
● Tropismo
● Efectos extra-antivirales de Maraviroc, alguna evidencia?
● Se puede usar el Maraviroc una vez al dia?
Tropismo
Trofile Patient Population
1216 Randomized
Patients (47%)
Screening Population 1434 R5 patients
(56%)
and
1126 DM or X4 patients (44%)
Virologic benefit with MVC
R5MOTIVATE
1 and 2
N = 1049
NON-R5A4001029
n = 167
No net virologic benefit with MVC
Harrigan, IAS 2009
Genotype Patient Population
1216 Randomized
Patients
R5MOTIVATE
1 and 2
N = 999
NON-R5A4001029
n = 165
96% of clinical validation set
Harrigan, IAS 2009
Methods
● Triplicate PCR with fully automated sequence analysis
● Tropism prediction using “Geno2pheno” algorithm (g2P - 5% FPR) without knowledge of clinical outcome
● Initial endpoint of 8 week change in viral load; 24 weeks endpoint also analyzed
Harrigan, IAS 2009
Median Viral Load Reduction in the MVC BID Arm is Predicted by Trofile
Weeks From Start of Treatment
Trofile R5 (n = 406)
Trofile X4 (n = 57)
Lo
g10
Ch
ang
e in
Vir
al L
oad
(co
pie
s/m
L)
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
P < 0.001
0 4 8 12
X
X
X
X
X Harrigan, IAS 2009
X
Median Viral Load Reduction in the MVC BID Arm is Predicted by Trofile and Genotype
Weeks From Start of Treatment
Trofile R5 (n = 406)
Trofile X4 (n = 57)
g2p R5 (n = 394)
g2p X4 (n = 69)
Lo
g10
Ch
ang
e in
Vir
al L
oad
(co
pie
s/m
L)
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
P < 0.001
P = 0.002
0 4 8 12
X X
X XX
X X
X
Harrigan, IAS 2009
Trofile and Genotype Have Similar Sensitivity and Specificity to Predict Antiviral Activity to MVC at Week 8: MVC BID
* A response at week 8 was defined as a viral load < 50 or a viral load reduction of 2 log.
Assay Tropism VL response*, n+ - R5 Success Sens. Spec.
TrofileR5 272 108
72% 92% 20%X4 25 27
g2PR5 263 103
72% 89% 24%X4 34 32
Harrigan, IAS 2009
Concordant and Discordant Results in Combined MVC Arms: Similar Virologic Responses Regardless of the Direction of Discordance
Concordant Results Discordant Results
Concordant R5 n = 735
Concordant X4 n = 80
Trofile X4/g2p R5 n = 31
Trofile R5/g2p X4 n = 60
Weeks From Start of Treatment
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0 4 8 12
Lo
g10
Ch
ang
e in
Vir
al L
oad
(co
pie
s/m
L)
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0 4 8 12
Harrigan, IAS 2009
Genotype is Comparable to Trofile in Predicting the Percent of R5 Patients Viral
Load <50 copies (Week 24; MVC BID)
Pat
ien
ts A
chie
vin
g H
IV R
NA
< 5
0 c/
mL
(%
)46.4%
95%CI 41.6- 51.3
0
20
40
60
80
100
Trofile g2P
n = 188/405 181/393
46.1%
95%CI 41.2, 51.0
MOTIVATE+1029 studies enrolled triple class experienced and/or resistant patients.
The use of raltegravir, darunavir, or etravirine was not allowed
Harrigan, IAS 2009
Conclusiones
● El genotipo es un método viable para identificar pacientes con experiencia previa que responderán al Maraviroc
● Las características del genotipo son muy similares a las de la prueba de Trofile original
● La genotipificación ofrece un método más viable para identificar a candidatos para el maraviroc
Efectos extra-antivirales del Maraviroc, hay alguna evidencia?
Greater CD4 Cell Increases on MVC in Non-responders (> 50 c/mL) at Week 48 Were Related to a Lower Incidence of Category C Events
21
2
9
0
2
4
6
8
10
12
14
16
Viral Load at Week 48
Pat
ien
ts (
%)
N= 256 285 104 75
< 50 copies/mL > 50 copies m/L
Lazzarin, ICAAC 2008
Med
ian
CD
4+ c
han
ge
fro
m b
asel
ine
to w
eek
48
Non-responders (> 50 c/mL) at Week 48
-200
-100
0
100
200
300
400
500
131
77
MaravirocN=96
EfavirenzN=63
Maraviroc
Efavirenz
15
Background and Objectives• Untreated HIV-infection is associated with chronic immune activation (IA) and evidence of
inflammation
• Decreases in immune activation and inflammation during HAART have been associated with decreased expression of adhesion molecules and a redistribution of CD4+ cells from lymphoid tissues to blood1 – This redistribution may account for the rise in peripheral blood CD4+ cells that occurs early after HAART
initiation
• MVC treatment has been associated with larger increases in CD4+ cell counts than is attributable to its antiviral activity2-5
– Differences in CD4+ rises between MVC and control occur early in therapy2,4
• It is unknown whether these CD4+ cell rises are related to MVC’s potential effect on markers of immune activation or inflammation
• We analyzed a subset of patients from the MERIT study to explore whether MVC for HIV‑infected treatment-naive patients has different effects than EFV on clinically relevant markers of immune activation and inflammation
• Secondary objectives included:– Explaining differences in clinical or laboratory outcomes in the MERIT study
– Exploring whether MVC has early immunologic effects beyond those expected after antiviral activity
– Identifying potential clinical markers to be studied prospectively
Change in plasma HIV-1 RNA levels: ACTG 315
100
1000
10000
100000
0 2 4 6 8 10 12 14
Weeks
Cop
ies/
mL
• After treatment with HAART there is a 99.9% decrease in HIV-RNA in the first 3 months
• Most of that decrease (99%) occurs in the first 4 weeks
Lederman, JID 1998
ACTG 315: Effects of HAART on co-expression of activation antigens - CD38, HLA-DR
0
20
40
60
0 10 20 30 40 50 60 70 80 90
Day
Per
cen
tag
e o
f cel
ls c
o-e
xpre
ssin
g
CD
38/H
LA
-DR
*
*
59
29
25
13
CD8+
CD4+
• Whereas decrease in activation occurs more slowly
• Less than half of the decrease in activated CD8 occurs in the first month of HAART
• Similar kinetics are observed in decreases in TNF-alpha
Lederman, JID 1998
18
Randomization 1:1
MERIT Study: Phase 3 Trial Design
Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)*
Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*
Primary analysis
0 48 wk 96 wkScreening(6 weeks)
Patients stratified by:• HIV-1 RNA < and ≥100,000 copies/mL at screening• Geographic location: Northern Hemisphere and Southern Hemisphere
Patient eligibility criteria: • ≥ 16 years of age• Treatment naive• R5 HIV-1 infection
First patient visit
Nov 2004
• HIV-1 RNA ≥ 2,000 copies/mL• No evidence of resistance to EFV, ZDV, or 3TC
MVC QD arm discontinued at end of Phase 2b (Week 16) for failure to meet protocol-defined criteria to continue (205 patients completed 16 weeks)
* Patients experiencing toxicity to zidovudine (ZDV) or lamivudine (3TC) were permitted to substitute an alternative NRTI
19
Marker Sample Rationale
CD38 expression on CD4+ cells PBMC Marker of immune activation, associated with early rises in CD4+ cells after HAART
CD38 expression on CD8+ cells PBMC Marker of immune activation; better prognostic indicator than viral load; remains elevated despite HAART
High sensitivity C-reactive protein (hsCRP) Plasma Elevated despite HAART in some patients. High levels
associated with increased cardiovascular disease
D-dimer Plasma Elevated despite HAART in some patients. High levels associated with increased mortality and cardiovascular disease
Interleukin-6 (IL-6) Plasma Elevated despite HAART in some patients. High levels associated with increased mortality and cardiovascular disease
Tumor necrosis factor receptor I Plasma Elevated despite HAART; marker of activation
Tumor necrosis factor receptor II Plasma Elevated despite HAART; marker of activation
Neopterin Plasma Elevated despite HAART; marker of activation. Lower decrease after HAART associated with worse prognosis
Markers of Activation and Inflammation
Funderburg, ICAAC 2009
20
Med
ian
perc
ent c
hang
e in
C
D38
ant
ibod
ies/
CD
4+ c
ell
Vertical lines represent interquartile ranges (IQR; 25th–75th percentile)
24 48
Weeks
0
Earlier Decreases in CD38 Expression on CD4+ T cells on MVC
–23.3
+ 0.29
–26.8
–20.1
-60
-50
-40
-30
-20
-10
0
10
20 EFV
MVC
Funderburg, ICAAC 2009
21
Weeks
Earlier Decrease in D-Dimer Concentration on MVC
Vertical lines represent interquartile ranges (IQR; 25th–75th percentile)
Med
ian
per
cen
t ch
ang
e in
D
-dim
er c
on
cen
trat
ion
-70
-50
-30
-10
10
30
0 4 8 12 16 20 24 28 32 36 40 44 48
EFVMVC
Funderburg, ICAAC 2009
EFV + CBV MVC + CBV
Although a Smaller Percentage of Patients had HsCRP > 2 on MVC at Baseline, by Week 48 Twice as many EFV Patients had hsCRP > 2
Patie
nts
with
hsC
RP
> 2
(%)
45
66
36 36
0
10
20
30
40
50
60
70
80
90
100
Baseline Week 48
Funderburg, ICAAC 2009
23
Week 96(all patients)
35 cells/mm3 (95% CI 13, 58)
0
50
100
150
200
250
171*
207*
Mea
n C
D4+
Cel
l Cha
nges
Fr
om B
asel
ine
(per
mm
3 )
< 105 copies/mL ≥ 105 copies/mL
N= 205 199 143 153
Screening HIV-1 RNA
Mea
n C
D4+
Cel
l Cha
nges
Fr
om B
asel
ine
(per
mm
3 )
0
50
100
150
200
250
167190
178
227
Week 96
MVC + CBV
EFV + CBV
MVC-Treated Patients Showed Significantly Greater Increases in Mean CD4+ Cell Count with the Difference Accentuated in those with a Higher Screening Viral Load4,5
* Mean value adjusted for randomization strataLast observation carried forward; blinded therapy values only. Includes all patients who received at least one dose of study medication
Funderburg, ICAAC 2009
24
Larger Increases in CD4+ cells are Associated with Larger Decreases in Cell-associated Immune Activation Markers
Immune marker Correlation coefficient p-value
CD4+ cell activation (CD38 antibodies/cell) -0.3 0.01
CD4+ cell activation (percent of CD38+ CD4+ cells) -0.3 0.06
CD8+ cell activation (CD38 antibodies/cell) -0.3 0.02
CD8+ cell activation (percent of CD38+ CD8+ cells) -0.3 0.03
Interleukin-6 -0.06 0.68
D-dimer -0.08 0.55
hsCRP 0.16 0.22
Funderburg, ICAAC 2009
Immune activation and HIV Replication
Untreated HIV
HIV replication
Immune activation
+
+
Treated HIV
HIV replication
HAART
Viral load decrease
Decrease in immune activation
Direct drug effect:
rapidIndirect drug effect:
Slow and variable
Early changes on activation markers would suggest direct drug effect
Other factors: CMV, HBV, HCV, microbial translocation
26
Conclusiones
• En comparación con EFV, los pacientes que reciben MVC tienen una reducción modesta y más temprana en ciertos marcadores de activación inmunológica e inflamación
• Este efecto parece ser independiente y aditivo al efecto que resulta de la actividad antiviral del MVC
• La disminución de la activación en células CD4 y CD8 está asociada a un aumento mayor en las células CD4
¿Se puede usar el Maraviroc una vez al día en pacientes con experiencia previa?
¿Maraviroc una vez al día en pacientes experimentados?
● Razones para escoger la dosis de dos veces al día
● Dosis respuesta del Maraviroc y farmacología del Maraviroc con IP potenciados
● Experiencia clínica de Maraviroc una vez al día
MOTIVATE 1 and 2: Percentage of Patients with HIV-1 RNA < 50 copies/mL by Number of Active Drugs in OBT*
0
10
20
30
40
50
60
70
80
90
100
35 51
56 44
130
134
59
88
104
64 132 121
3
18
29
9
43 43
19
52 53 5561 58
0 1 2 ≥ 3Number of active drugs in OBT*
* Based on overall susceptibility score LOCF
Patie
nts
(%)
N=
MOTIVATE 1 & 2-Week 24 CROI 2007
MVC QD + OBTMVC BID + OBT
Placebo + OBTIncludes all patients who received at least one dose of study medication
Correlation of Phase 2a Monotherapy and Phase 2b/3 Clinical Data
• Phase 2a Monotherapy Dose/exposure response studies (A4001007 and 1015) • Unboosted MVC 300 mg BID achieved a reproductive ratio <1 in all subjects
• Based on exposure-response analysis from MOTIVATE, Cave required for therapeutic effect of MVC is 100 ng/mL
• Pop PK analyses in MOTIVATE:Median Cave of MVC when dosed 150 mg QD concomitantly with
•ATV/r: 109 ng/mL •LPV/r: 149 ng/mL
• This is consistent with achieving a Cave in the region of 100 ng/mL that correlates with near maximal virologic efficacy
Data on File
A4001052 - Effect of Darunavir/r on the Pharmacokinetics of Maraviroc in Healthy Subjects
Time post dose (hours)
0 2 4 6 8 10 12
Ma
ravi
roc
pla
sma
co
nce
ntr
atio
n (n
g/m
l)
0
100
200
300
400
500
600
700
maraviroc 150mg BID + darunavir/ritonavir maraviroc 150mg BID + placebo
MVC AUC increased 405% in the presence of DRV/r 600/100 mg BID
Abel S, et al. 8th Int Wkshp Clin Pharm HIV Ther 2007. Abstract 55
Mean Maraviroc Plasma Concentration vs Time
Simulated Patient with mean BL VL of 4.6 log10 c/mL with Different DRV-containing Regimens
Non-Virological Dropouts
0%
20%
40%
60%
80%
100%
0 12 24 36 48
Weeks on Treatment
Pro
po
rtio
n w
ith <
50
Co
pie
s/m
L (
ITT
)
Max. Possible Simulated ResponseDRV/r+MVC 150 mg BIDDRV/r+MVC 150 mg QDDRV/r+NRTIsDRV/r MonotherapyNRTIs Alone
Data on File
Patients with HIV-1 RNA < 50 Copies/mL by Screening Viral Loads and Baseline CD4+ Cell Count (Week 48)
n/N (%) by subgroupPlacebo +
OBTN=209
MVC QD + OBTN=414
MVC BID + OBTN=426
Screening HIV-1 RNA, copies/mL
<100,000 32/123 (26) 140/238 (59) 142/243 (58)
≥100,000 8/84 (10) 55/170 (32) 61/176 (35)
Baseline CD4+ cell count, cells/mm3
<50 1/38 (3) 13/84 (15) 14/85 (16)
50–100 3/25 (12) 19/51 (37) 20/55 (36)
101–200 12/55 (22) 39/95 (41) 59/104 (57)
201–350 13/62 (21) 79/115 (69) 67/116 (58)
>350 10/26 (38) 44/62 (71) 43/59 (73)* Patients were stratified at time of randomization by screening HIV-1 RNA (< or ≥100,000 copies/mL)
† Baseline CD4+ cell count calculated as the average of all pre-dose measurementsIncludes all treated patients with valid baseline and on-treatment measurements;
Missing values imputed using last observation carried forward
MOTIVATE 1 & 2 – Week 48, HARDY CROI 2008
Includes all patients who received at least one dose of study medication
0102030405060708090
100
41 76 81 41 87 113 35 77 78
0
33 33
17
56 51 51
70 72
<1 1–<2 ≥2
N =
MVC QD + OBTMVC BID + OBT
Placebo + OBT All Subjects
<50
copi
es/m
L at
wk
48 (%
)
0102030405060708090
100
31 60 61 35 67 94 32 63 64
3743
20
66 5953
81 78
<1 1–<2 ≥2
N =
0
Subjects ≥50 CD4+ cells/mm3 at baseline
<50
copi
es/m
L at
wk
48 (%
)
Week 48 Virologic Responses by wOBTSS
Valdez ICAAC 2008
En Resumen
● La determinación de tropismo por genotipo es tan buena como el Trofile original en predecir respuestas clínicas al Maraviroc
● Maraviroc parece tener efectos anti-inflamatorios y anti-activación independientes de su actividad antiviral
– Numerosos estudios están investigando la relevancia clínica de estos hallazgos
● En pacientes con terapia antiviral previa que reciben algunos IP potenciados (atazanavir, lopinavir, saquinavir, darunavir), Maraviroc a una dosis de 150 mg una vez al día parece ser adecuado
– Tres estudios clínicos están analizando la actividad antiviral de estas combinaciones con Maraviroc una vez al día