Transcript Efficacy and Safety of Darunavir/ritonavir versus Lopinavir/ritonavir in ARV Treatment-Naïve HIV-1-Infected Patients at Week 48: ARTEMIS (TMC114-C211) DeJesus E, Ortiz R, Khanlou H, Voronin.

Efficacy and Safety of Darunavir/ritonavir versus
Lopinavir/ritonavir in ARV Treatment-Naïve
HIV-1-Infected Patients at Week 48:
ARTEMIS (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
ARTEMIS: Phase III study design
689 ARV-naïve
patients
VL>5,000;
no CD4 entry
DRV/r 800/100mg qd
+ TDF 300 mg and FTC 200 mg (N=343)
LPV/r 400/100mg bid or 800/200mg qd
+ TDF 300 mg and FTC 200 mg (N=346)
LPV dosing
LPV formulation
qd =
15%
Capsule only =
bid =
77%
Tablet only =
bid/qd =
7%
15%
2%
Capsule/tablet switch = 83%
Dosing was based on regulatory approval; switch was made
according to local regulatory approval and drug availability
ARTEMIS: Study objectives
• Primary end point
– Proportion of patients with an HIV RNA <50 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
ARTEMIS: Baseline characteristics
DRV/r qd
(N=343)
LPV/r qd or bid
(N=346)
104 (30)
105 (30)
36 (9)
35 (9)
40/23/23
44/21/22
70,800
(835–5,580,000)
62,100
(667–4,580,000)
228 (4–750)
218 (2–714)
43 (13)
48 (14)
Baseline demographics
Female, N (%)
Mean (±SD) age (yrs)
Caucasian/Black/Hispanic, %
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 <200 cells/mm3
40%
41%
Plasma HIV-1 RNA ≥100,000 cpm
36%
36%
ARTEMIS: Patient disposition
Incidence (%)
Discontinuation
DRV/r qd
(N=343)
LPV/r qd or bid
(N=346)
41 (12%)
56 (16%)
AE*
12 (3%)
24 (7%)
Lost to follow-up
14 (4%)
10 (3%)
Withdrawal of consent
4 (1%)
5 (1%)
Virologic failure
2 (<1%)
6 (2%)
Pregnancy
5 (1%)
3 (<1%)
Non-compliance
2 (<1%)
5 (1%)
Other
2 (<1%)
3 (<1%)
*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 0–83 weeks)
Patients with VL <50 copies/mL (% [±SE])
ARTEMIS: Viral load <50 copies/mL
to Week 48 (ITT-TLOVR)
100
DRV/r qd (N=343)
LPV/r qd or bid (N=346)
90
84%
78%
80
70
60
50
40
Estimated difference in response vs LPV/r for non-inferiority:
PP = 5.6% (95% CI –0.1;11.3) 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
ARTEMIS: Confirmed response by baseline
VL or CD4 at Week 48 (ITT-TLOVR)
DRV/r qd
100
†p<0.05
86
80
vs LPV/r
85
n=194 n=191
n=28
79†
67
60
40
20
Patients with VL <50 copies/mL (%)
Patients with VL <50 copies/mL (%)
100
LPV/r qd or bid
87
80
84
80
77
71
67
60
40
20
0
0
<100,000
≥100,000
0
226
226
†Chi
117
square analysis
120
50–200
>200
Baseline CD4 cell count (cells/mm3)
Baseline viral load (copies/mL)
N=
<50
N=
30
30
111
118
202 198
ARTEMIS: Responses by
LPV/r dosing schedule
Patients with VL <50 copies/mL (%)
100
78
80
84
81
71
60
40
20
0
N=
LPV/r
LPV/r* bid
346
267
LPV/r* qd
52
DRV/r qd
343
*27 patients receiving LPV/r bid and qd during the study were excluded from this analysis
ARTEMIS: Median change in absolute
CD4 cell count to Week 48 (ITT-NC=F)
Median change in CD4 cell count
from baseline (cells/mm3)
150
141 cells/mm3
137 cells/mm3
120
DRV/r qd (N=343)
LPV/r qd or bid (N=346)
90
60
30
0
2 4
8
12 16
24
Time (weeks)
36
48
ARTEMIS: Virologic failure (VF) and
emergence of mutations
DRV/r qd
LPV/r qd or bid
(N=343)
(N=346)
VF (> 50 cpm)
34 (10%)
49 (14%)
VF (> 400 cpm)
11 (3%)
18 (5%)
Paired baseline and VF
genotype available
10
18
0
1*
1†
2†
IAS-USA PI RAMS
IAS-USA NRTI mutations
VF by TLOVR
†
184V
*A71T, V77I
*IAS-USA mutations, Fall 2006; Johnson et al. Topics in HIV Medicine. 2006; 14:125-130
ARTEMIS: Grade 2–4 adverse events
DRV/r qd
LPV/r qd or bid
(N=343)
(N=346)
GI (all AEs)
23 (7)
47 (14)
p<0.01
Diarrhea
14 (4)
34 (10)
p<0.05
Nausea
6 (2)
10 (3)
9 (3)
4 (1)
Gr 2–4 AEs† ≥2%
incidence, n (%)
Rash (all types)
†At
least possibly related to study drug, excluding laboratory-related events
• No renal SAEs and no treatment discontinuations due to renal AEs
ARTEMIS: Grade 2–4 laboratory
abnormalities
Grade 2–4 laboratory abnormalities
≥2% incidence, n (%)
DRV/r qd
(N=343)
LPV/r qd or bid
(N=346)
Alanine aminotransferase
29 (8)
35 (10)
Aspartate aminotransferase
32 (9)
31 (9)
Hyperglycemia
22 (6)
23 (7)
Pancreatic amylase
23 (7)
17 (5)
Pancreatic lipase
6 (2)
6 (2)
Total cholesterol
44 (13)
78 (23)
Low-density lipoprotein
44 (13)
36 (11)
Triglycerides
10 (3)
38 (11)
No significant changes in calculated creatinine clearance between baseline and Week 48 visits
ARTEMIS: Mean fasting lipid levels over time
mM
ng/mL
Mean triglycerides
DRV/r qd (n=343)
LPV/r qd or bid (n=346)
250
2.9
2.3
200
1.7
150
1.1
100
2 4 8 12 16
24
36
Time (weeks)
DRV/r n= 343
LPV/r n= 346
320
313
= NCEP cut-off
Total cholesterol/HDL ratio
3.5
Mean total cholesterol/HDL ratio (± SE)
Mean triglyceride concentration ( ± SE)
300
5.5
DRV/r qd (n=343)
LPV/r qd or bid (n=346)
5.0
4.5
4.0
3.5
3.0
2 4 8 12 16
48
306
301
343
346
24
320
313
36
48
305
301
ARTEMIS: DRV plasma concentrations
for DRV/r 800mg/100mg
DRV plasma conc (ng/mL)
10,000
1,000
100
EC50 = 55 ng/mL for wild-type virus
(adjusted for protein binding)
10
0
4
8
12
16
20
24
Ctrough
36
Time post-dose (hours)
PK substudy – week 4 data
(mean ± SD; N=9)
Population PK study
(median, IQR, range; N=335)
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
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, FrankDetlef 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 ZorrillaMaldonado
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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