Transcript ARTEMIS: Efficacy and safety of lopinavir (BID vs QD) and

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
ARTEMIS: Phase III study design
• Multinational study, conducted across 26 countries
689 ARV-naïve
patients
– VL>5,000
– no CD4 entry
restrictions
DRV/r 800/100mg QD
+ TDF 300mg and FTC 200mg QD (N=343)
LPV/r 400/100mg BID or 800/200mg QD
+ TDF 300mg and FTC 200mg QD (N=346)
DRV/r = darunavir/ritonavir; TDF = tenofovir; FTC = emtricitabine; LPV/r = lopinavir/ritonavir
DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
ARTEMIS: study objectives
• Primary end point
– proportion of patients with an HIV RNA <50
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
ARTEMIS: baseline characteristics
DRV/r QD
(N=343)
LPV/r overall*
(N=346)
Baseline demographics
Male, n (%)
239 (70)
241 (70)
36 (9)
35 (9)
137 (40)
153 (44)
70,800
62,100
(835–5,580,000)
(667–4,580,000)
228 (4–750)
218 (2–714)
HBV/HCV co-infected, n (%)
43 (13)
48 (14)
CDC class C, n (%)
26 (8)
34 (10)
CD4 count <200 cells/mm3
40%
41%
Plasma HIV-1 RNA ≥100,000 copies/mL
36%
36%
Mean age, years (SD)
Caucasian, n (%)
Baseline disease characteristics
Median HIV-1 RNA, copies/mL
(range)
Median CD4, cells/mm3 (range)
Stratification factors at screening
*Includes all patients receiving LPV/r, regardless of BID or QD dosing schedule
DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
ARTEMIS primary endpoint: viral load
<50 copies/mL at Week 48 (ITT-TLOVR)
100
DRV/r QD (N=343)
LPV/r overall* (N=346)
Patients with viral load
<50 copies/mL (% ± SE)
90
84%
78%
80
70
60
50
40
Estimated difference in response vs LPV/r for non-inferiority:
PP = 5.6% (95%
Per-protocol
= 5.6%
CI –0.1;11.3)
(95% CI -0.1;11.3)
p<0.001 p<0.001
Estimated difference in response vs LPV/r for superiority:
ITT = 5.5% (95% CI -0.3;11.2) p=0.062
30
20
10
0
2 4
8
12
16
24
Time (weeks)
36
48
*Includes all patients receiving LPV/r, regardless of BID or QD dosing schedule
DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
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 570
2. Mildvan D, et al. 14th CROI 2007. Abstract 138
3. DeJesus E, et al. 47th ICAAC 2007. Abstract H-718b
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
Use of QD and BID dosing
in ARTEMIS
Dosing
QD
DRV/r
(N=343)
LPV/r
(N=346)
343 (100%)
52 (15%)
BID
0
267 (77%)
BID/QD*
0
27 (8%)
* Excluded
from the analysis
ARTEMIS: baseline characteristics
DRV/r QD
(N=343)
LPV/r BID*
(N=267)
LPV/r QD*
(N=52)
239 (70)
171 (64)
46 (88)
36 (18–70)
34 (19–63)
137 (40)
118 (45)
Baseline demographics
Male, n (%)
Mean age, y (range)
Caucasian, n (%)
Baseline disease characteristics
Median HIV-1 RNA,
copies/mL (range)
70,800
(835–5,580,000)
40 (20–68)
24 (46)
61,800
58,850
(667–4,580,000) (6,400–888,000)
Median CD4,
cells/mm3 (range)
228 (4–750)
218 (2–714)
228 (16–659)
CDC class C, n (%)
26 (8)
24 (9)
8 (15)
HBV/HCV co-infected, n (%)
43 (13)
39 (15)
5 (10)
CD4 <200 cells/mm3
40%
41%
37%
Plasma HIV-1 RNA
≥100,000 copies/mL
36%
35%
35%
Stratification factors at screening
*27 patients receiving LPV/r BID and QD during the study were excluded from this analysis
Week 48 response by QD and
BID dosing (ITT-TLOVR)
Difference 3% (95% CI -3; 9)
Difference 13% (95% CI 1; 24; p<0.05)
Patients with VL <50 copies/mL (%)
100
Difference 9%* (95% CI -3; 21)
78
80
84
81
71
60
40
20
0
LPV/r overall
LPV/r BID†
346
267
N=
†27
LPV/r QD†
52
DRV/r QD
343
*Difference rounded
patients receiving LPV/r BID and QD during the study were excluded from this analysis
Week 48 response by baseline viral load
Baseline viral load <100,000 copies/mL
85
86
86
79
80
60
40
20
Baseline viral load ≥100,000 copies/mL
79*
80
67*
71
60
56*
40
20
0
0
LPV/r
overall
N=
100
Patients with VL <50 copies/mL (%)
Patients with VL <50 copies/mL (%)
100
226
LPV/r
BID†
175
†27
LPV/r
QD†
DRV/r
QD
LPV/r
overall
LPV/r
BID†
LPV/r
QD†
DRV/r
QD
34
226
120
92
18
117
*p<0.05 for DRV/r QD vs LPV/r overall and vs LPV/r QD
patients receiving LPV/r BID and QD during the study were excluded from this analysis
ARTEMIS: virological failure (VF)
and emergence of mutations
DRV/r QD
(N=343)
LPV/r overall
(N=346)
34 (10%)
49 (14%)
31 (12%)
10 (19%)
Paired baseline and VF
genotype available (n)
10
18
11
4
IAS-USA1 PI RAMS
0
1†
1†
0
IAS-USA1 NRTI RAMS
1‡
2‡
1‡
1‡
VF (>50 copies/mL)
LPV/r BID* LPV/r QD*
(N=267)
(N=52)
VF by TLOVR non-VF censored (at any time, regardless of reason for discontinuation)
†A71T, V77I
‡M184V or M184I/V
1. Johnson VA, et al. Top HIV Med 2006;14:125–130
*27 patients receiving LPV/r BID and QD during the study were excluded from this analysis
ARTEMIS: grade 2–4 AEs in ≥2% of patients
(at least possibly related to study drug, excluding lab-related events)
Incidence, n (%)
DRV/r QD LPV/r overall LPV/r BID* LPV/r QD*
(N=343)
(N=346)
(N=267)
(N=52)
14 (4)†
34 (10)†
22 (8)†
Nausea
6 (2)
10 (3)
8 (3)
0 (0)
Rash (all types)
9 (3)
4 (1)
3 (1)
1 (2)
Diarrhoea
9 (17)†
• No renal SAEs and no treatment discontinuations due to renal AEs
†p<0.05
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
ARTEMIS: grade 2–4 lipid
abnormalities in ≥2% of patients
Incidence, n (%)
DRV/r QD
(N=343)
LPV/r overall
(N=346)
LPV/r BID*
(N=267)
LPV/r QD*
(N=52)
Total cholesterol
44 (13)†
78 (23)†
69 (26)†
8 (15)
Low-density lipoprotein
44 (13)
36 (11)
31 (12)
4 (8)
Triglycerides
10 (3)‡
38 (11)‡
27 (10)‡
9 (17)‡
†p<0.05
for DRV/r QD vs LPV/r overall and vs LPV/r BID
‡p<0.05 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
ARTEMIS: conclusions
• At Week 48, 84% of DRV/r patients versus 78% of LPV/r patients
achieved a viral load <50 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 (<50 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
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 ZorrillaMaldonado
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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