ARTEMIS: Efficacy and safety of lopinavir (BID vs QD) and darunavir (QD) in antiretroviral-na

1
ARTEMIS Efficacy and safety of lopinavir (BID vs
QD) and darunavir (QD) in antiretroviral-naïve
patients

• N Clumeck, J Van Lunzen, P Chiliade, B Clotet, C
  Vanden Abeele, E Lefebvre, T Vangeneugden, R
  DeMasi, S Spinosa-Guzman

2
ARTEMIS Phase III study design

• Multinational study, conducted across 26 countries

DRV/r 800/100mg QD TDF 300mg and FTC 200mg QD
(N343)
689 ARV-naïve patients VLgt5,000 no CD4 entry
restrictions
LPV/r 400/100mg BID or 800/200mg QD TDF 300mg
and FTC 200mg QD (N346)
DRV/r darunavir/ritonavir TDF tenofovir FTC
emtricitabine LPV/r lopinavir/ritonavir
DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
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ARTEMIS study objectives

• Primary end point
• proportion of patients with an HIV RNA lt50
  copies/mL at Week 48 (ITT-TLOVR)
• Primary objective
• demonstrate non-inferiority of DRV/r QD vs LPV/r
  (BID or QD) based on the primary endpoint
• Secondary objective
• evaluate efficacy, safety and tolerability over
  192 weeks

DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
4
ARTEMIS baseline characteristics
LPV/r overall (N346)
DRV/r QD (N343)
241 (70) 35 (9) 153 (44)
239 (70) 36 (9) 137 (40)
Baseline demographics Male, n () Mean
age, years (SD) Caucasian, n ()
70,800 (8355,580,000) 228 (4750) 43 (13) 26 (8)
Baseline disease characteristics Median HIV-1
RNA, copies/mL (range) Median CD4,
cells/mm3 (range) HBV/HCV co-infected, n ()
CDC class C, n ()
62,100(6674,580,000) 218 (2714) 48 (14) 34 (10)
Stratification factors at screening CD4 count
lt200 cells/mm3 Plasma HIV-1 RNA 100,000
copies/mL
41 36
40 36
Includes all patients receiving LPV/r,
regardless of BID or QD dosing schedule
DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
5
ARTEMIS primary endpoint viral load lt50
copies/mL at Week 48 (ITT-TLOVR)
100
DRV/r QD (N343)
LPV/r overall (N346)
90
84
80
78
70
60
Patients with viral load 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 Per-protocol 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)
Includes all patients receiving LPV/r,
regardless of BID or QD dosing schedule
DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
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Analysis background and rationale

• Previous findings in treatment-naïve patients
  suggest that the efficacy of LPV/r is similar
  between the QD and BID dosing regimens1
• Recent data from study ACTG 5073 showed
  LPV/r BID was more effective than LPV/r QD in
  treatment-naïve patients with high baseline viral
  loads (100,000 copies/mL)2
• The present analysis evaluated virological
  response rates for LPV/r QD and BID and DRV/r QD
  in treatment-naïve patients in the ARTEMIS trial3

1. Gathe J, et al. 11th CROI 2004. Abstract
5702. Mildvan D, et al. 14th CROI 2007. Abstract
1383. DeJesus E, et al. 47th ICAAC 2007.
Abstract H-718b
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Objective of exploratory analysis

• Compare the efficacy and safety of DRV/r QD with
  LPV/r QD and BID
• LPV/r dosing schedules were
• not randomised
• based on local regulatory approval and
  investigator or patient preference

LPV/r QD is approved for treatment-naïve
patients in the USA
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Use of QD and BID dosing in ARTEMIS
DRV/r (N343)
Dosing
LPV/r (N346)
QD
52 (15)
343 (100)
BID
267 (77)
0
BID/QD
27 (8)
0
Excluded from the analysis
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ARTEMIS baseline characteristics
DRV/r QD (N343)
LPV/r QD (N52)
LPV/r BID (N267)
Baseline demographics
239 (70)
Male, n ()
171 (64)
46 (88)
36 (1870)
Mean age, y (range)
34 (1963)
40 (2068)
137 (40)
Caucasian, n ()
118 (45)
24 (46)
Baseline disease characteristics
70,800 (8355,580,000)
Median HIV-1 RNA, copies/mL (range)
61,800 (6674,580,000)
58,850 (6,400888,000)
Median CD4, cells/mm3 (range)
228 (4750)
218 (2714)
228 (16659)
Stratification factors at screening
40
CD4 lt200 cells/mm3
41
37
Plasma HIV-1 RNA 100,000 copies/mL
36
35
35
27 patients receiving LPV/r BID and QD during
the study were excluded from this analysis
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Week 48 response by QD and BID dosing (ITT-TLOVR)
Difference 3 (95 CI -3 9)
Difference 13 (95 CI 1 24 plt0.05)
100
Difference 9 (95 CI -3 21)
84
81
78
80
71
60
Patients with VL lt50 copies/mL ()
40
20
0
DRV/r QD
LPV/r overall
LPV/r BID
LPV/r QD
343
346
267
52
N
Difference rounded

27
patients receiving LPV/r BID and QD during the
study were excluded from this analysis



27 patients receiving LPV/r BID and
QD during the study were excluded from this
analysis
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Week 48 response by baseline viral load
Baseline viral load lt100,000 copies/mL
100
86
86
85
79
80
60
Patients with VL lt50 copies/mL ()
40
20
0
DRV/r QD
LPV/r overall
LPV/rBID
LPV/rQD
N 226 175 34 226
27 patients receiving LPV/r BID and QD during
the study were excluded from this analysis
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ARTEMIS virological failure (VF) and emergence
of mutations
LPV/r QD (N52)
LPV/r BID (N267)
DRV/r QD (N343)
LPV/r overall (N346)
10 (19)
31 (12)
34 (10)
VF (gt50 copies/mL)
49 (14)
Paired baseline and VF genotype available (n)
4
11
10
18
0
1
0
IAS-USA1 PI RAMS
1
1
1
1
IAS-USA1 NRTI RAMS
2
VF by TLOVR non-VF censored (at any time,
regardless of reason for discontinuation)A71T,
V77IM184V or M184I/V
1. Johnson VA, et al. Top HIV Med 200614125130
27 patients receiving LPV/r BID and QD during
the study were excluded from this analysis
13
ARTEMIS grade 24 AEs in 2 of patients
(at least possibly related to study drug,
excluding lab-related events)
LPV/r BID (N267)
Incidence, n ()
DRV/r QD (N343)
LPV/r overall (N346)
LPV/r QD (N52)
9 (17)
22 (8)
Diarrhoea
14 (4)
34 (10)
0 (0)
8 (3)
Nausea
6 (2)
10 (3)
1 (2)
3 (1)
Rash (all types)
9 (3)
4 (1)

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

plt0.05 for DRV/r QD vs all LPV/r groups
27 patients receiving LPV/r BID and QD during
the study were excluded from this analysis
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ARTEMIS grade 24 lipid abnormalities in 2 of
patients
LPV/r QD (N52)
LPV/r BID (N267)
Incidence, n ()
DRV/r QD (N343)
LPV/r overall (N346)
8 (15)
69 (26)
Total cholesterol
78 (23)
44 (13)
4 (8)
31 (12)
Low-density lipoprotein
36 (11)
44 (13)
9 (17)
27 (10)
Triglycerides
38 (11)
10 (3)
plt0.05 for DRV/r QD vs LPV/r overall and vs
LPV/r BID plt0.05 for DRV/r QD vs all LPV/r
groups
27 patients receiving LPV/r BID and QD during
the study were excluded from this analysis
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ARTEMIS conclusions

• At Week 48, 84 of DRV/r patients versus 78 of
  LPV/r patients achieved a viral load lt50
  copies/mL
• DRV/r 800/100mg QD was non-inferior to LPV/r (QD
  or BID) in treatment-naïve patients in the
  ARTEMIS primary efficacy analysis
• DRV/r QD was superior to LPV/r (overall) in
  patients with baseline viral load 100,000
  copies/mL
• In this non-randomised comparison of ARTEMIS,
  patients receiving DRV/r QD compared with those
  receiving LPV/r QD demonstrated significant
  differences in
• virological response (lt50 copies/mL) in patients
  with high viral load
• incidence of treatment-related, moderate to
  severe diarrhoea
• incidence of treatment-emergent, moderate to
  severe triglyceride elevations
• Once-daily DRV/r is safe and effective in
  treatment-naïve patients

Studies evaluating once-daily DRV/r 800/100mg in
treatment-experienced patients are ongoing
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ARTEMIS acknowledgements

• The patients and their families for their
  participation and support during the study
• Gilead Sciences for their collaboration
• The ARTEMIS (TMC114-C211) study team,
  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, Norbert Vetter
• Belgium Nathan Clumeck, Jean-Christophe Goffard,
  Beatrijs Van der Gucht, Eric Van Wijngaerden
• Canada Joss Dewet, Donald 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 Michelle Bentata, Laurent Cotte, Pierre
  Dellamonica, Jacques Durant, Pierre-Marie Girard,
  Christine Katlama, Thierry Prazuck, Dominique
  Salmon, Patrick Yeni
• Germany Keikawus Arasteh, Johannes Bogner, 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 Amalia Rodriguez, Nestor Sosa Puerto
Rico Javier Morales Ramirez, Carmen
Zorrilla-Maldonado Russia Natalia Dushkina, Oleg
Kozyrev, Valery Kulagin, Alexander Pronin,
Vladimir Rafalsky, Oleg Romanenko, Elena
Vinogradova, Evgeniy Voronin, Alexey
Yakovlev Singapore Poh Lian Lim South Africa
Ezio Baraldi, Francesca Conradie, 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, 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, Mahmoud
Mustafa, Robert Myers, Jeffrey Nadler, Brian
Onbirbak, Roberto Ortiz, Daniel Pearce, Gerald
Pierone, Jayashree Ravishankar, Afsoon Roberts,
Barry Rodwick, Kunthavi Sathasivam, Stefan
Schneider, Michael Sension, Paul Skolnik,
Charurut Somboonwit, Aimee Wilkin, Michael
Wohlfeiler, Bienvenido Yangco
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