Influence of Baseline Factors on Virologic Response to Darunavir/Ritonavir (DRV/r) vs Lopinavir/r (LPV/r): Week 48 Outcome in TITAN

1
Influence of Baseline Factors on Virologic
Response to Darunavir/Ritonavir (DRV/r) vs
Lopinavir/r (LPV/r) Week 48 Outcome in TITAN

•  W. David Hardy, MD1 Daniel Berger, MD2 Els De
  Paepe, MSc3 Sandra De Meyer, PhD3 David
  Moriarty, PhD4 Joseph Mrus, MD5 Sabrina
  Spinosa-Guzman, MD3
• 1Cedars-Sinai Medical Center, Los Angeles, CA,
  USA 2Northstar Medical Center, Chicago, IL, USA
  3Tibotec BVBA, Mechelen, Belgium 4Tibotec Inc.,
  Yardley, PA, USA and 5Tibotec Therapeutics,
  Bridgewater, NJ, USA

TITAN TMC114/r In Treatment-experienced
pAtients Naïve to lopinavir
2
TITAN (TMC114-C214) Study Design

• Phase III randomized, controlled trial with
  primary analysis at Week 48

Treatment phase (96 weeks)
Screening phase (4 weeks)
DRV/r 600/100mg bid OBR

• Treatment-experienced, LPV-naïve
• VL 1,000 copies/mL
• Stable HAART (12 wks) or STI (4 wks)

LPV/r 400/100mg bid OBR
785 patients screened, 595 randomized and treated

• All patients received optimized background
  therapy (OBR)
• Two to three ARVs from approved NRTI and/or NNRTI
  classes
• Enfuvirtide disallowed
• Stratification factors Baseline VL and use of
  NNRTI in OBR

LPV/r patients were allowed to switch to new
formulation upon its approval by the regulatory
authorities VL viral load DRV/r darunavir
with low-dose ritonavir, LPV/r lopinavir with
low-dose ritonavir
3
Summary of Previous Findings from TITAN
Overall, in treatment-experienced, LPV-naïve
patients

• DRV/r was virologically non-inferior and superior
  to LPV/r (VL lt400 and VLlt50 copies/mL)
• Twice as many patients receiving LPV/r
  experienced virologic failure (VF) compared with
  patients receiving DRV/r
• Following VF and compared with LPV/r, DRV/r-based
  therapy was associated with lower rates of
  development of
• Primary PI mutations or NRTI RAMs
• Phenotypic resistance to the PI or NRTI(s) in the
  study regimen
• DRV/r was safe and well tolerated, with a lower
  rate of diarrhea and lower increases in
  triglycerides than LPV/r, and a higher rate of
  rash

VL, viral load RAM, resistance-associated
mutation
4
TITAN Virologic Response through Week 48
(ITT-TLOVR) All Patients
VL lt400 copies/mL
VL lt50 copies/mL
100
100
P .008
90
90
P .005
77
80
80
71
70
70
67
60
60
60
Patients with VL lt400 and lt50 copies/mL ( 95
CI)
50
50
DRV/r (n298)
40
40
DRV/r (n298)
LPV/r (n297)
LPV/r (n297)
30
30
20
20
10
10
0
BAS
4
8
12
16
24
36
48
Time (weeks)

• DRV/r was non-inferior and superior to LPV/r

P value for superiority derived from logistic
regression model including treatment and
stratification factors baseline log10 VL and use
of NNRTI in the optimized background regimen
5
TITAN Baseline Characteristics
DRV/r (n298) LPV/r (n297)
Demographics Male, n () Mean (SD) age (years) 229 (77) 41 ? 9.0 241 (81) 41 ? 8.6
Disease characteristics Mean ( SD) baseline log10 VL Median CD4 (cells/mm3 range) 4.33 ?0.79 235 (3831) 4.28 ?0.81 230 (21,096)
History of ARV treatment Structured treatment interruption, n () Previous ARV experience, n () NRTIs 4 NNRTIs 1 PIs 0 PIs 1 PIs 2 64 (21) 156 (52) 225 (76) 94 (32) 108 (36) 96 (32) 71 (24) 151 (51) 229 (77) 93 (31) 115 (39) 89 (30)
Optimized background therapy Number of active NRTIs used, n () 0 1 2 Active NNRTI used, n () 30 (10) 70 (24) 188 (65) 31 (10) 42 (15) 75 (26) 171 (59) 21 (7)
Baseline fold change in EC50 (FC) to PI DRV FC 10 LPV FC 10 287 (98) 263 (90) 286 (99) 261 (90)
Activity of ARVs assessed by baseline phenotype
(Antivirogram) 576 of 582 patients with
phenotype data used 1 NRTI in the OBR 54
patients used an NNRTI, irrespective of activity
582 (DRV/r292 LPV/r290) patients had baseline
phenotype available
6
TITAN Baseline Characteristics
DRV/r (n298) LPV/r (n297)
Demographics Male, n () Mean (SD) age (years) 229 (77) 41 ? 9.0 241 (81) 41 ? 8.6
Disease characteristics Mean ( SD) baseline log10 VL Median CD4 (cells/mm3 range) 4.33 ?0.79 235 (3831) 4.28 ?0.81 230 (21,096)
History of ARV treatment Structured treatment interruption, n () Previous ARV experience, n () NRTIs 4 NNRTIs 1 PIs 0 PIs 1 PIs 2 64 (21) 156 (52) 225 (76) 94 (32) 108 (36) 96 (32) 71 (24) 151 (51) 229 (77) 93 (31) 115 (39) 89 (30)
Optimized background therapy Number of active NRTIs used, n () 0 1 2 Active NNRTI used, n () 30 (10) 70 (24) 188 (65) 31 (10) 42 (15) 75 (26) 171 (59) 21 (7)
Baseline fold change in EC50 (FC) to PI DRV FC 10 LPV FC 10 287 (98) 263 (90) 286 (99) 261 (90)
Activity of ARVs assessed by baseline phenotype
(Antivirogram) 576 of 582 patients with
phenotype data used 1 NRTI in the OBR 54
patients used an NNRTI, irrespective of activity
582 (DRV/r292 LPV/r290) patients had baseline
phenotype available
7
TITAN Difference in Virologic Response (VL lt50
copies/mL) at Week 48 Univariate Analysis
n
DRV/r -LPV/r ()
Overall (ITT) 595
11 Gender Male
470 11 Female
125 10 Baseline CD4 (cells/mm3) lt100
109 1 100 lt200
126 6 200 lt350
185 11 ³350
169 20 Baseline VL (copies/mL)
lt100,000 489 12
³100,000 106 7
Active ARVs in OBR 0 56
11 1 130 23 2 390 8
Active NRTIs in OBR 0 72 19
1 145 16 2 359 8
Active NNRTI in OBR Yes 52 25 No
524 10
-50
-40
-30
-20
-10
0
10
20
30
40
50
Activity assessed by BL phenotype
(Antivirogram) 522 patients did not use an
NNRTI and 2 patients used an inactive NNRTI ITT,
intent-to-treat VL, viral load OBR, optimized
background regimen
8
TITAN NRTIs and NNRTIs Used in the OBR
LPV/r arm (N297) NRTI/NNRTI sensitive
NRTI/NNRTI resistant
DRV/r arm (N298) NRTI/NNRTI sensitive
NRTI/NNRTI resistant
80
58
60
54
Patients ()
47
44
41
38
40
28
26
26
22
18
20
15
13
12
9
5
3
2
0
TDF
3TC
ZDV
ddI
ABC
FTC
d4T
EFV
NVP
NRTIs
NNRTIs

• NRTI use was generally well-balanced between
  treatment groups and consistent with current
  practice

NRTI/NNRTI activity assessed by baseline
phenotype (Antivirogram)
9
TITAN Baseline Characteristics
DRV/r (n298) LPV/r (n297)
Demographics Male, n () Mean (SD) age (years) 229 (77) 41 ? 9.0 241 (81) 41 ? 8.6
Disease characteristics Mean ( SD) baseline log10 VL Median CD4 (cells/mm3 range) 4.33 ?0.79 235 (3831) 4.28 ?0.81 230 (21,096)
History of ARV treatment Structured treatment interruption, n () Previous ARV experience, n () NRTIs 4 NNRTIs 1 PIs 0 PIs 1 PIs 2 64 (21) 156 (52) 225 (76) 94 (32) 108 (36) 96 (32) 71 (24) 151 (51) 229 (77) 93 (31) 115 (39) 89 (30)
Optimized background therapy Number of active NRTIs used, n () 0 1 2 Active NNRTI used, n () 30 (10) 70 (24) 188 (65) 31 (10) 42 (15) 75 (26) 171 (59) 21 (7)
Baseline fold change in EC50 (FC) to PI DRV FC 10 LPV FC 10 287 (98) 263 (90) 286 (99) 261 (90)
Activity of ARVs assessed by baseline phenotype
(Antivirogram) 576 of 582 patients with
phenotype data used 1 NRTI in the OBR 54
patients used an NNRTI, irrespective of activity
582 (DRV/r292 LPV/r290) patients had baseline
phenotype available
10
TITAN Difference in Virologic Response (VL lt50
copies/mL) at Week 48 Univariate Analysis


n DRV/r -LPV/r
() Overall (ITT) 595 11
Previous PI experience 0 187 -4 1 223 7
?2 185 30
Baseline LPV FC 10 524 7 gt10 58 45
Baseline DRV FC 10 573 11 gt10 9 10
No. of LPV RAMs1 lt6 526 6 6 59 44
No. of DRV RAMs1 0 490 7 1 56 28
2 24 41 3 23 14
Baseline IAS-USA primary PI mutations1
0 403 3 1 190 27
-50
-40
-30
-20
-10
0
10
20
30
40
50
ITT, intent-to-treat FC, fold change in EC50
RAM, resistance-associated mutation
1Johnson VA et al. Top in HIV Med 2006
14125-130
11
TITAN Impact of IAS-USA Primary PI Mutations at
Baseline on VL lt50 Copies/mL at Week 48
All Patients
DRV/r (n296) LPV/r (n297)
90
79
80
70
69
68
70
60
50
HIV RNA lt50 copies/mL (ITT-TLOVR)
40
30
20
10
0
0
1
2
3
Number of IAS-USA primary PI mutations
n 199 204 33 33 25 27 39
33
Patients with non-missing genotype data
Excludes patients with missing LPV FC at baseline
D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L,
I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M1
1Johnson VA et al. Top in HIV Med
200715119-125
12
TITAN Impact of IAS-USA Primary PI Mutations at
Baseline on VL lt50 Copies/mL at Week 48
Patients with LPV FC 10 at BL
All Patients with LPV FC 10
DRV/r (n263) LPV/r (n261)
90
78
80
69
68
70
65
60
50
HIV RNA lt50 copies/mL (ITT-TLOVR)
40
30
20
10
0
0
1
2
3
Number of IAS-USA primary PI mutations
n 195 197 32 32 19 18 17
14
Patients with non-missing genotype data
Excludes patients with missing LPV FC at
baseline
D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L,
I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M1
1Johnson VA et al. Top in HIV Med
200715119-125
13
TITAN Difference in Virologic Response
(VL lt50 copies/mL, ITT-TLOVR)
Multivariate Analyses
Factors in Multivariate Logistic Regression Model
None (Unadjusted Result)

• - Baseline VL,
• NNRTI in OBR

Model A
- Baseline VL, - Baseline CD4, - NNRTI in OBR, -
Number of prior PIs
Model B

• - Baseline VL,
• Baseline CD4,
• Number of active ARVs in OBR
• - Baseline log10 FC to DRV or LPV

Model C
- Baseline VL, - Baseline CD4, - Number of
active ARVs in OBR - Number of DRV
resistance-associated mutations
Model D

• - Baseline VL,
• Baseline CD4,
• Number of active ARVs in OBR
• - Number of LPV resistance-associated mutations

Model E

• - Baseline VL,
• Baseline CD4,
• Number of active ARVs in OBR
• - Number of IAS-USA primary PI mutations

Model F
-40
-30
-20
-10
0
10
20
30
40
50
-50
Treatment, BL VL, number of prior PIs, and BL
resistance to treatment PI were significantly
associated with response, P lt.05 Activity of
ARVs assessed by baseline phenotype
(Antivirogram) Includes interactions with
treatment
14
TITAN Conclusions

• In treatment-experienced, LPV-naïve patients
• The difference in virologic response (VL lt50
  copies/mL) favoring DRV/r was generally
  consistent across subgroups
• Multivariate analyses demonstrated that the
  difference in response favoring DRV/r
  was maintained after adjusting for baseline
  characteristics including VL and CD4, activity of
  OBR, PI resistance, and prior PI experience
• Overall, and in patients phenotypically sensitive
  to both PIs at baseline (FC 10), the presence of
  1 or more IAS-USA primary PI mutations affected
  the response to LPV/r but not DRV/r
• As the number of IAS-USA primary PI mutations
  increased, the difference in virologic response
  favoring DRV/r increased

VL, viral load OBR, optimized background
regimen PI, protease inhibitor
15
TITAN Acknowledgments

• The patients and their families for their
  participation and support during the study
• TMC114-C214 study team and the investigators and
  co-investigators
• Argentina Pedro Cahn, Arnaldo Casiró, Isabel
  Cassetti, Daniel David, Marcelo Losso and Sergio
  Lupo
• Australia David Cooper, Robert Finlayson, Jenny
  Hoy, Patricia Martinez, Marilyn McMurchie and
  Cassy Workman
• Austria Armin Rieger and Norbert Vetter
• Belgium Nathan Clumeck, Jean-Christophe Goffard
  and Lutgarde Lynen
• Brazil Clovis Da Cunha, Beatriz Grinsztejn,
  Claudio Gonsalez, Jose Valdez-Madruga, Rogerio de
  Jesus Pedro, Jose Henrique Pilotto,
• Mauro Schechter and Artur Timerman
• Canada John Gill, Norbert Gilmore, Don Kilby,
  Patrice Junod, Anita Rachlis, Benoit Trottier,
  Chris Tsoukas and Sharon Walmsley
• Chile Juan Ballesteros, Rebeca Northland and
  Carlos Pérez
• Denmark Henrik Nielsen
• France Jacques Durant, Pierre-Marie Girard,
  Christine Katlama, Christian Michelet,
  Jean-Michel Molina, Gilles Pialoux, Christophe
  Piketty, Dominique Salmon, Daniel Vittecoq and
  Patrick Yeni
• Germany Keikawus Arasteh, Gerd Fätkenheuer,
  Heribert Knechten, Antonius Mutz, Carl Knud
  Schewe, Dieter Schuster, Albrecht Stoehr
• and Andreas Trein
• Greece George Panos
• Guatemala Eduardo Arathoon and Carlos
  Mejia-Villatoro
• Hungary Denes Banhegyi
• Italy Andrea Antinori, Giampiero Carosi, Roberto
  Esposito, Adriano Lazzarin, Francesco Mazzotta,
  Anna Maria Orani, Stefano Rusconi,
• Laura Sighinolfi and Fredy Suter

• Tibotec biostatisticians

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