Efficacy and Safety of Darunavirritonavir versus Lopinavirritonavir in ARV TreatmentNave HIV1Infecte

1
Efficacy and Safety of Darunavir/ritonavir versus
Lopinavir/ritonavir in ARV Treatment-NaïveHIV-1-I
nfected Patients at Week 48ARTEMIS
(TMC114-C211)

• DeJesus E, Ortiz R, Khanlou H, Voronin E,
• Van Lunzen J, Andrade-Villanueva J, Fourie J,
• De Meyer S, Haley M, Lefebvre E,
• Vanden Abeele C, Spinosa-Guzman S

2
ARTEMIS Phase III study design
DRV/r 800/100mg qd TDF 300 mg and FTC 200 mg
(N343)
689 ARV-naïve patients VLgt5,000 no CD4 entry
LPV/r 400/100mg bid or 800/200mg qd TDF 300 mg
and FTC 200 mg (N346)
Dosing was based on regulatory approval switch
was made according to local regulatory approval
and drug availability
3
ARTEMIS Study objectives

• Primary end point
• Proportion of patients with an HIV RNA lt50
  copies/ml at Week 48
• Primary objective
• demonstrate non-inferiority of DRV/r qd vs LPV/r
  based on that primary end point
• Secondary objectives
• evaluate long-term safety, tolerability and
  durability of virologic responses
• compare immunologic responses
• conduct pharmacokinetic evaluations

4
ARTEMIS Baseline characteristics
LPV/r qd or bid (N346)
DRV/r qd (N343)
105 (30) 35 (9) 44/21/22
104 (30) 36 (9) 40/23/23
Baseline demographics Female, N () Mean
(SD) age (yrs) Caucasian/Black/Hispanic,
62,100(6674,580,000) 218 (2714) 48 (14)
70,800 (8355,580,000) 228 (4750) 43 (13)
Baseline disease characteristics Median HIV-1
RNA (cpm) (range) Median CD4 (cells/mm3
range) HBV/HCV co-infected, n ()
Stratification factors at screening CD4 count
lt200 cells/mm3 Plasma HIV-1 RNA 100,000 cpm
41 36
40 36
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ARTEMIS Patient disposition
LPV/r qd or bid (N346)
DRV/r qd (N343)
Incidence ()
56 (16)
41 (12)
Discontinuation
24 (7)
12 (3)
AE
Four deaths (1 in DRV/r group 3 in LPV/r group)
Table includes all data up to the point when the
last patient reached week 48 Mean exposure was 56
weeks (range 083 weeks)
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ARTEMIS Viral load lt50 copies/mLto Week 48
(ITT-TLOVR)
100
DRV/r qd (N343)
LPV/r qd or bid (N346)
90
84
80
78
70
60
Patients with VL lt50 copies/mL ( SE)
50
40
Estimated difference in response vs LPV/r for
non-inferiority PP 5.6 (95 CI 0.111.3)
plt0.001
Estimated difference in response vs LPV/r for
non-inferiority PP 5.6 (95 CI 0.111.3)
plt0.001 Estimated difference in response vs LPV/r
for superiority ITT 5.5 (95 CI 0.311.2)
p0.062
30
20
10
0
4
8
12
16
24
36
48
2
Time (weeks)
7
ARTEMIS Confirmed response by baseline VL or
CD4 at Week 48 (ITT-TLOVR)
100
plt0.05 vs LPV/r
86
85
n194
79
n191
n28
80
67
60
Patients with VL lt50 copies/mL ()
40
20
0
100,000
lt100,000
Baseline viral load (copies/mL)
N 226 226 117 120
Chi square analysis
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ARTEMIS Responses by LPV/r dosing schedule
100
78
80
60
Patients with VL lt50 copies/mL ()
40
20
0
LPV/r
346
N
9
ARTEMIS Median change in absoluteCD4 cell count
to Week 48 (ITT-NCF)
150
141 cells/mm3
137 cells/mm3
120
90
Median change in CD4 cell count from baseline
(cells/mm3)
60
30
0
4
8
12
16
24
36
48
2
Time (weeks)
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ARTEMIS Virologic failure (VF) and emergence of
mutations
LPV/r qd or bid
DRV/r qd
(N346)
(N343)
49 (14)
34 (10)
VF (gt 50 cpm)
18 (5)
11 (3)
VF (gt 400 cpm)
18
10
Paired baseline and VF genotype available
0
IAS-USA PI RAMS
1
IAS-USA NRTI mutations
1
2
A71T, V77I
184V
VF by TLOVR
IAS-USA mutations, Fall 2006 Johnson et al.
Topics in HIV Medicine. 2006 14125-130
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ARTEMIS Grade 24 adverse events
plt0.01
plt0.05
At least possibly related to study drug,
excluding laboratory-related events

• No renal SAEs and no treatment discontinuations
  due to renal AEs

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ARTEMIS Grade 24 laboratory abnormalities
LPV/r qd or bid (N346)
DRV/r qd (N343)
Grade 24 laboratory abnormalities 2 incidence,
n ()
Alanine aminotransferase Aspartate
aminotransferase Hyperglycemia Pancreatic amylase
Pancreatic lipase Total cholesterol Low-density
lipoprotein Triglycerides
29 (8) 32 (9) 22 (6) 23 (7) 6 (2) 44
(13) 44 (13) 10 (3)
35 (10) 31 (9) 23 (7) 17 (5) 6 (2) 78
(23) 36 (11) 38 (11)
No significant changes in calculated creatinine
clearance between baseline and Week 48 visits
13
ARTEMIS Mean fasting lipid levels over time
mM
ng/mL
Mean triglycerides
Total cholesterol/HDL ratio
3.5
300 250 200 150 100
5.5
2.9
5.0
4.5
Mean total cholesterol/HDL ratio ( SE)
2.3
Mean triglyceride concentration ( SE)
4.0
1.7
3.5
3.0
1.1
2 4 8 12 16 24 36 48
Time (weeks)
DRV/r nLPV/r n
343 320 305 346 313 301
343 320 306 346 313 301
NCEP cut-off
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ARTEMIS DRV plasma concentrations for DRV/r
800mg/100mg
10,000
1,000
DRV plasma conc (ng/mL)
100
EC50 55 ng/mL for wild-type virus(adjusted for
protein binding)
10
0 4 8 12 16 20 24
Time post-dose (hours)
PK substudy week 4 data (mean SD N9)
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ARTEMIS Conclusions

• The use of once-daily DRV/r 800/100mg TDF/FTC
  in treatment-naïve patients
• resulted in excellent virologic and immunologic
  responses
• provided suitable exposure in all patients
• was well tolerated, with a favorable safety
  profile
• In comparison to the LPV/r arm in
  treatment-naïve patients
• For efficacy, DRV/r 800/100mg qd was non-inferior
  in the overall population, and superior in
  patients with high VL
• DRV/r had lower incidence of common GI toxicities
  and triglyceride elevations

LPV/r arm included LPV/r 400/100mg bid or
800/200mg qd, capsule and tablet formulations
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ARTEMIS Acknowledgments

• The patients and their families for their
  participation and support during the study
• TMC114-C211 study team and the investigators and
  co-investigators

• Argentina Waldo Belloso, Liiana Calanni, Lidia
  Cassetti, Luisa De Wouters, Marcelo Losso
• Australia Mark Bloch, David Cooper, Dominic
  Dwyer, Robert Finlayson, Julian Gold, Mark Kelly,
  Cassy Workman
• Austria Armin Rieger and Norbert Vetter
• Belgium Nathan Clumeck, Jean-Christophe Goffard,
  Beatrjs Van der Gucht, Eric Van Wijngaerden
• Canada Joss Dewet, Don Kilby, Patrice Junod,
  Chris Tsoukas, Sharon Walmsley
• Chile Juan Ballesteros, Rebeca Northland
• Costa Rica Gisela Herrera, Iris Perez
• Denmark Jan Gerstoft, Lars Mathiesen, Henrik
  Nielsen
• France Micelle Bentata, Laurent Cotte, Pierre
  Dellamonica, Pierre-Marie Girard, Christine
  Katlama, Thierry Prazuck, Dominique Salmon,
  Patrick Yeni
• Germany Keikawus Arasteh, Gerd Fätkenheuer,
  Frank-Detlef Goebel, Thomas Harrer, Hans Jaeger,
  Joerg-Andres Rump, Dieter Schuster, Albrecht
  Stoehr, Jan Van Lunzen
• Greece George Chrysos
• Guatemala Eduardo Arathoon, Carlos
  Mejia-Villatoro
• Italy Adriano Lazzarin, Anna Maria Orani
• Malaysia Christopher Lee
• Mexico Jaime Andrade-Villanueva, Gustavo
  Reyes-Teran, Juan Sierra-Madero, Angelina
  Villasis-Keever

Panama Amalio Rodriguez, Nestor Sosa Puerto
Rico Javier Morales Ramirez, Carmen
Zorrilla-Maldonado Russia Natalia Dushkina, Oleg
Kozyrev, Valeriy Kulagin, Alexander Pronin,
Vladimir Rafalsky, Oleg Romanenko, Elena
Vinogradova, Evgeniy Voronin, Alexey
Yakovlev Singapore Lian Lim Poh South Africa
Ezio Baraldi, Jan Fourie, Prudence Ive, Lerato
Mohapi, Jennifer Pitt Spain Buenaventura Clotet,
Pere Domingo Switzerland Milos Opravil Taiwan
Jen-Hsien Wang, Su Pen Yang Thailand Ploenchan
Chetchotisakd, Winai Ratanasuwan, Kiat
Ruxrungtham, Khuanchai Supparatpinyo United
Kingdom Martin Fisher, Mark Nelson, Chloe Orkin,
Jonathan Weber United States Ben Barnett, Alfred
Burnside, Thomas Campbell, Philippe Chiliade, Amy
Colson, Edwin DeJesus, Richard Elion, Walford
Fessel, Lucia Flamm, Dushyantha Jayaweera, Peter
Kadlecik, Homayoon Khanlou, Lucia Martinez, David
McDonough, Anthony Mills, Karam Mounzer, Robert
Myers, Jeffrey Nadler, Brian Onbirbak, Roberto
Ortiz, Kristen Patterson, Daniel Pearce, Gerald
Pierone, Jayashree Ravishankar, Afsoon Roberts,
Barry Rodwick, Stefan Schneider, Michael Sension,
Paul Skolnik, Aimee Wilkin, Michael Wohlfeiler,
Bienvenido Yangco
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