48-week results of once-daily maraviroc (MVC) 150 mg in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve patients infected with R5 HIV-1 (Study A4001078)
Simon Portsmouth,1 Charles Craig,2 Anthony Mills,3 Donna Mildvan,4 Daniel Podzamczer,5 Gerd Fätkenheuer,6 Manuel Leal,7 Hernan Valdez,1 Srinivas Rao Valluri,1 Jayvant Heera1
1Pfizer Inc., New York, NY, USA; 2Pfizer, Sandwich, Kent, UK; 3Anthony Mills MD, Los Angeles, CA, USA; 4Beth Israel Medical Center Division of Infectious Diseases, New York, NY, USA; 5HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain; 6University Hospital of Cologne Köln, Germany; 7Laboratory of Immunovirology, Biomedicine Institute of Seville (IBIS), Infectious Disease Service, Virgen del Rocio University Hospital, Seville, Spain
Rationale for MVC + boosted PI regimen
• Potential for early use: prevalence of CCR5 tropic virus is greatest in treatment-naïve individuals1
• Nucleoside-sparing regimen• Good penetration of MVC in CSF and genital
secretions2-4
• MOTIVATE and PK studies support use of MVC 150 mg QD with selected ritonavir-boosted PIs
1. Hoffmann, Eur J Med Res, 2007. 2. Tiraboschi et al, J Acquir Immune Defic Syndr, 20103. Dumond et al, J Acquir Immune Defic Syndr, 2009. 4. Brown et al, J Infect Dis, 2011
Study A4001078: an exploratory pilot study of a low pill burden QD dual-therapy regimen, MVC + ATV/r
Study designOpen-label, 48-week Phase 2b pilot study
• Patient eligibility criteria – R5 HIV (ESTA) at screening– ≥16 years of age– HIV-1 RNA ≥1000 copies/mL– CD4 ≥100 cells/mm3
– No evidence of resistance to ATV/r, TDF, or FTC
– Study has iDMC– Ongoing study: USA, Spain,
Germany– Extended to 96 weeks– Study is not powered to show a
treatment difference and no formal comparative statistics will be performed
Randomization 1:1
N=121 MVC (150 mg QD) + ATV/r (300/100 mg QD)
FTC/TDF + ATV/r (300/100 mg QD)
0 24 wk 48 wkScreening(6
weeks)
16 wk
Week 2First 15 US patients
Serial PK of MVC
Interim analyses Primary analysis
*Sparse PK sampling on all patients at Weeks 2 (non-PK substudy), 12 and 24 (Vourvahis. Abstract 37 IWCPHIV, 2010)
VL, HIV-1 RNA, viral load
Study disposition
MVC + ATV/rn=60
FTC/TDF + ATV/rn=61Discontinued
n=7• 2 AE (vomiting,
jaundice)• 3 lost to follow-
up• 1 withdrew
consent• 1 insufficient
clinical response (VL 934 copies/mL)
Enrolled into study n=121
Screening n=220
Discontinued n=7
• 2 lost to follow-up
• 1 withdrew consent
• 2 protocol violations
• 1 pregnancy• 1 other:
possible TDF-related kidney failure
Continuing in study n=53
Continuing in study n=54
• Two patients in each arm experienced protocol defined treatment failure
Summary of baseline characteristics
MVC + ATV/r n=60
FTC/TDF + ATV/r n=61
Mean age, years (range) 38.3 (21–61) 35.3 (18–68)Male, n (%) 56 (93.3) 52 (85.2)Race, n (%) White Black Asian Other
45 (75.0)13 (21.7)
02 (3.3)
46 (75.4)11 (18.0)
3 (4.9)1 (1.6)
Median CD4+ count, cells/mm3 (range)
344 (160–744)
358(110–902)
Mean HIV-1 RNA, log10 copies/mL (range) 4.6 (3.4–5.9) 4.7 (3.3–5.9)
HIV-1 RNA ≥100,000 copies/mL, n (%) 16 (27) 22 (36)
HIV-1 RNA <400 copies/mL at Week 48
0102030405060708090
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Pati
ents
wit
h H
IV-1
RN
A <
400
copi
es/m
L (%
)
MVC + ATV/r (N=59)FTC/TDF + ATV/r (N=61)
89.8%86.9%
Intent-to-treat. Missing=failure
Study week
HIV-1 RNA <50 copies/mL at Week 48
0102030405060708090
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48Study week
83.6%74.6%
MVC + ATV/r (N=59)FTC/TDF + ATV/r (N=61)
Intent-to-treat. Missing=failure
Pati
ents
wit
h H
IV-1
RN
A <
50 c
opie
s/m
L (%
)
<100,000 copies/mL ≥100,000 copies/mLWeek 24 Week 48 Week 24 Week 48
Baseline HIV-1 RNA
Patie
nts
with
HIV
-1 R
NA
<50
copi
es/m
L (%
)
0
10
60
70
80
90
100
50
40
30
20
HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load
37/39
35/43 13/1617/22
81.4
94.9
81.377.3
Intent-to-treat. Missing=failure
MVC + ATV/rFTC/TDF + ATV/r
HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load
Week 24 Week 48 Week 24 Week 48Patie
nts
with
HIV
-1 R
NA
<50
copi
es/m
L (%
)
0
10
60
70
80
90
100
50
40
30
20
<100,000 copies/mL ≥100,000 copies/mLBaseline HIV-1 RNA
34/39
33/43 17/22
11/16
76.7
87.2
68.8
77.3
37/39
35/43 13/1617/22
81.4
94.9
81.377.3
Intent-to-treat. Missing=failure
MVC + ATV/rFTC/TDF + ATV/r
HIV-1 RNA <400 copies/mL at Week 24 and Week 48 according to baseline viral load
Week 24 Week 48 Week 24 Week 48Patie
nts
with
HIV
-1 R
NA
<400
cop
ies/
mL
(%)
0
10
60
70
80
90
100
50
40
30
20
<100,000 copies/mL ≥100,000 copies/mLBaseline HIV-1 RNA
37/3939/43
15/1620/22
90.794.9 93.8
90.9
Intent-to-treat. Missing=failure
MVC + ATV/rFTC/TDF + ATV/r
HIV-1 RNA <400 copies/mL at Week 24 and Week 48 according to baseline viral load
Week 24 Week 48 Week 24 Week 48Patie
nts
with
HIV
-1 R
NA
<400
cop
ies/
mL
(%)
0
10
60
70
80
90
100
50
40
30
20
<100,000 copies/mL ≥100,000 copies/mLBaseline HIV-1 RNA
34/39
38/43 19/22
15/1688.4 87.293.8
86.4
MVC + ATV/rFTC/TDF + ATV/r37/3
939/4315/16
20/2290.7
94.9 93.890.9
Intent-to-treat. Missing=failure
Outcomes for all patients with VL >50 copies/mL at Week 48
aPatient discontinued at Week 84 due to insufficient clinical responsebPatient discontinued at Week 96
MVC+ATV/rAa
BCDEFb
GHI
FTC/TDF+ATV/rJKL
691445781
16787615158
5278055
HIV-1 RNA, copies/mLWeek 48
497 (W84)<50
(W96)<50
(W72)<50
(W84)<50
(W96)274 (W96)
<50 (W72)<50
(W84)<50
(W84)
<50 (W84)<50
(W96)<50
(W84)
Post Week 48
Change in median CD4+ cell count over time (LOCF)
0
50
100
150
200
250
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48Med
ian
chan
ge fr
om b
asel
ine
in C
D4
cell
coun
t (c
ells
/μL)
Study week
187173
MVC + ATV/r (N=59)FTC/TDF + ATV/r (N=61)
Intent-to-treat. LOCF, last observation carried forward
No genotypic or phenotypic resistance observed through Week 48
• 3 patients in the MVC arm and 3 patients in the FTC/TDF arm were identified for virologic analysesa
aPatients who discontinued from the study early with sufficient VL (≥500 copies/mL). Assays (ESTA, Monogram GenoSeq and/or PhenoSenseGT) performed at screening/baseline and at the last on-treatment time point were available
Change in tropism
0
Development of resistance mutations
MVC ATV TDF FTC0 0 0 0
Susceptibility to drug retained
MVC FTC/TDF
3 3
Safety
MVC + ATV/r n=60
FTC/TDF + ATV/r n=61
Any AE, n (%) 58 (96.7) 60 (98.7)Serious AE, n (%) 10 (16.7) 12 (19.7)Grade 3 or 4 AE, n (%) 29 (48.3) 18 (29.5)Discontinued due to AE, n (%) 2 (3.3) 0
Hyperbilirubinemia, n (%)AE relatedGrade 3 or 4 AE relatedGrade 3 or 4 laboratory*
27 (45.0)22 (36.7)39 (65.0)
21 (34.4)12 (19.7)32 (52.5)
*DAIDS grading
• 7 patients in the MVC + ATV/r group and 3 patients in the FTC/TDF group switched off of ATV/r therapy per protocol due to either tolerability or unconjugated hyperbilirubinemia
0 10 20 30 40 50 60 70 80 90 100
Modern dual-therapy studies: 48-week results No. of patients with
post-BL resistance mutations/no. of virologic failuresa22/46
39/5616/78
0/03/3
HIV-1 RNA <50 copies/mL
COOL2
N=143 EFV +TDFEFV + TDF/3TC
EFV + 2 NRTIEFV + LPV/r
ACTG 51421
N=500LPV/r + 2 NRTI
1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009.
% of patientsafrom evaluable samplesBL, baseline
0 10 20 30 40 50 60 70 80 90 100
Modern dual-therapy studies: 48-week results
% of patients
No. of patients with post-BL resistance mutations/no. of virologic failuresa22/46
39/5616/78
0/03/3
HIV-1 RNA <50 copies/mL
COOL2
N=143 EFV +TDFEFV + TDF/3TC
EFV + 2 NRTIEFV + LPV/r
ACTG 51421
N=500LPV/r + 2 NRTI
LPV/r BID + FTC/TDFLPV/r BID + RAL BID
SPARTAN3
N=94 (2:1)
ACTG 52625
N=112
PROGRESS4
N=206
ATV BID + RAL BID
DRV/r QD + RALDRV/r QD + RAL BID
ATV/r QD + FTC/TDF 0/84/11
1/3 1/4
5/28
afrom evaluable samplesBL, baseline
1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010.
4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011.
0 10 20 30 40 50 60 70 80 90 100
Modern dual-therapy studies: 48-week results No. of patients with
post-BL resistance mutations/no. of virologic failuresa22/46
39/5616/78
0/03/3
HIV-1 RNA <50 copies/mL
COOL2
N=143 EFV +TDFEFV + TDF/3TC
EFV + 2 NRTIEFV + LPV/r
ACTG 51421
N=500LPV/r + 2 NRTI
LPV/r BID + FTC/TDFLPV/r BID + RAL BID
SPARTAN3
N=94 (2:1)
ACTG 52625
N=112
PROGRESS4
N=206
ATV BID + RAL BID
DRV/r QD + RALDRV/r QD + RAL BID
ATV/r QD + FTC/TDF 0/8 4/11
1/3 1/4
5/28
0/0 0/0
0/2 0/2
LPV/r BID + MVC QDLPV/r BID + FTC/TDF
ATV/r QD + MVC QDATV/r QD + FTC/TDF
VEMAN6
N=37
1078N=121
1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010.
4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011. 6. Nozza CDB325, IAS, 2011
% of patientsafrom evaluable samplesBL, baseline
Conclusions
• 48-week results of this pilot study of MVC + ATV/r support the antiviral activity of this once-daily, two-drug combination in treatment-naïve patients
• No resistance nor change in phenotypic tropism was observed
• No new unexpected safety events
• A Phase III study (A4001095; NCT01345630) will start in Q3/4 2011 – MVC + DRV/r QD vs FTC/TDF + DRV/r QD– Estimated enrollment of 804
Acknowledgments
• Thanks to the patients and investigators who participated in this study
• Editorial support was provided by Clemence Hindley of Complete Medical Communications and was funded by ViiV Healthcare
Backups
Creatinine clearance
-14
-12
-10
-8
-6
-4
-2
00 4 8 12 16 20 24 28 32 36 40 44 48
Study week
Mea
n ch
ange
from
bas
elin
e in
cr
eati
nine
cle
aran
ce (
mL/
min
)
MVC + ATV/r (N=60)FTC/TDF + ATV/r (N=61)
Pharmacokinetics
Hours0 4 8 12 16 20 24
*
7.65 ng/mL (in vivo IC50)1
1
10
100
1000
10,000
MVC
con
cent
rati
on (
ng/m
L)
• All 15 patients had plasma MVC concentrations above the in vivo IC50 across the dosing Interval (150 mg QD + ATV/r)2
• There were 139 sparse PK samples with full dose and time data collected at the 2,12 and 24 week visits yielding concentrations from 13.7 to 933 ng/mL with samples taken from 0-32 hours after dose3
* One patient accidentally dosed with MVC prior to the 24-hour sample draw1. Rosario et al, J Acquir Immune Defic Syndr, 2006.
2. Vourvahis, Abstract 37 IWCPHIV, 2010. 3. Weatherley, Abstract P_05 IWCPHIV, 2011
Definition of Virologic Failure
• HIV-1 RNA <1.0 log10 decrease from Baseline at Week 4 or thereafter (confirmed by a second measurement taken no more than 14 days after the first measurement); or
• Failure to achieve HIV-1 RNA <400 copies/mL at Week 24, (confirmed by asecond measurement taken no more than 14 days after the first measurement);
• An increase in HIV-1 RNA to detectable levels (1,000 copies/mL on 2 consecutive measurements taken no more than 14 days apart) in subjects previously confirmed to have undetectable levels of <400 copies/mL on 2 consecutive visits.
Patients switching from ATV/r
• 10 patients switched from ATV/r (7 in the MVC arm and
3 in the FTC/TDF arm) due to either tolerability issues or unconjugated hyperbilirubinemia– 8 switched to DRV/r– 2 switched to LPV/r
• All 10 patients had reached HIV-1 RNA <50 copies/mL prior to switching
HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline CD4 count
5/54/5 40/48n/N 46/49
Median CD4+ cell count over time (LOCF)
200250300350400450500550600
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Med
ian
CD4
cell
coun
t (c
ells
/mm
3 )
Study week
Week 48MVC + ATV/r = 580FTC/TDF + ATV/r =
580
MVC + ATV/r (N=59)FTC/TDF + ATV/r (N=61)
Intent-to-treat. LOCF, last observation carried forward
Week 24MVC + ATV/r = 537FTC/TDF + ATV/r =
536
Responders at Week 24 but not Week 48 HIV-1 RNA, copies/mL
Week 24 Week 32 Week 40 Week 48
MVC+ATV/r
ABCD
<50<50<50<50
<5056
<50<50
<5057
<50<50
144816158
FTC/TDF+ATV/r
Ea
FGHa
<50<50<50<50
<50<50<50<50
N/A<50<50<50
N/A780b
55N/A
N/A, not available; W, weekaPatient discontinued prior to Week 48bResult of repeat test 13 days later was <50 copies/mL
Responders at Week 24 but not Week 48HIV-1 RNA, copies/mL
Week 24 Week 32 Week 40 Week 48 Post Week 48
MVC+ATV/r
ABCD
<50<50<50<50
<5056
<50<50
<5057
<50<50
144816158
<50 (W96)<50 (W84)<50 (W72)<50 (W84)
FTC/TDF+ATV/r
Ea
FGHa
<50<50<50<50
<50<50<50<50
N/A<50<50<50
N/A780b
55N/A
N/A<50 (W96)<50 (W84)
N/AN/A, not available; W, weekaPatient discontinued prior to Week 48bResult of repeat test 13 days later was <50 copies/mL• 7/9 (MVC + ATV/r) and 3/3 (FTC/TDF + ATV/r) patients with HIV-1 RNA ≥50 copies/mL at
Week 48 had HIV-1 RNA <50 copies/mL at their latest visit. HIV-1 RNA levels for the remaining 2 patients were 274 copies/mL (W96), and 497 copies/mL (W84)