1. 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

2. ARTEMIS: Phase III study design
DRV/r 800/100mg qd
+ TDF 300 mg and FTC 200 mg (N=343)
689 ARV-naïve patients
VL>5,000; no CD4 entry
LPV/r 400/100mg bid or 800/200mg qd
+ TDF 300 mg and FTC 200 mg (N=346)
LPV dosing
LPV formulation
qd = %
Capsule only = %
bid = %
Tablet only = %
bid/qd = 7%
Capsule/tablet switch = 83%
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 <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

4. ARTEMIS: Baseline characteristics
DRV/r qd
(N=343)
LPV/r qd or bid
(N=346)
Baseline demographics
Female, N (%)
Mean (±SD) age (yrs)
Caucasian/Black/Hispanic, %
104 (30)
36 (9)
40/23/23
105 (30)
35 (9)
44/21/22
Baseline disease characteristics
Median HIV-1 RNA (cpm)
(range)
Median CD4 (cells/mm3 [range])
HBV/HCV co-infected, n (%)
70,800
(835–5,580,000)
228 (4–750)
43 (13)
62,100 (667–4,580,000)
218 (2–714)
48 (14)
Stratification factors at screening
CD4 count <200 cells/mm3
Plasma HIV-1 RNA ≥100,000 cpm
40%
36%
41%
36%

5. ARTEMIS: Patient disposition
Incidence (%)
DRV/r qd
(N=343)
LPV/r qd or bid
(N=346)
Discontinuation
41 (12%)
56 (16%)
AE*
12 (3%)
24 (7%)
3 (<1%)
5 (1%)
Pregnancy
2 (<1%)
Non-compliance
Other
4 (1%)
Withdrawal of consent
6 (2%)
Virologic failure
10 (3%)
14 (4%)
Lost to follow-up
*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)

6. 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% 80
78% 70 60
Patients with VL <50 copies/mL (% [±SE]) 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 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 2 4 8 12 16 24 36 48
Time (weeks)

7. ARTEMIS: Confirmed response by baseline VL or CD4 at Week 48 (ITT-TLOVR)
LPV/r qd or bid
DRV/r qd
100 87 67 71 77
<50
>200 20 40 60 80
100 84
50–200
Baseline CD4 cell count (cells/mm3)
Patients with VL <50 copies/mL (%)
N =
†p<0.05 vs LPV/r 86 85
n=194
n=191
n=28
79† 80 67 60
Patients with VL <50 copies/mL (%) 40 20
<100,000
≥100,000
Baseline viral load (copies/mL)
N =
†Chi square analysis

8. ARTEMIS: Responses by LPV/r dosing schedule
100
343
DRV/r qd 84
*27 patients receiving LPV/r bid and qd during the study were excluded from this analysis
267
LPV/r* bid 81 52
LPV/r* qd 71 78 80 60
Patients with VL <50 copies/mL (%) 40 20
LPV/r
N =
346

9. Median change in CD4 cell count from baseline (cells/mm3)
ARTEMIS: Median change in absolute CD4 cell count to Week 48 (ITT-NC=F)
150
141 cells/mm3
137 cells/mm3
120
LPV/r qd or bid (N=346)
DRV/r qd (N=343) 90
Median change in CD4 cell count
from baseline (cells/mm3) 60 30 2 4 8 12 16 24 36 48
Time (weeks)

10. 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%) 10 18
Paired baseline and VF genotype available
IAS-USA PI RAMS 1*
IAS-USA NRTI mutations 1† 2†
†184V
*A71T, V77I
VF by TLOVR
*IAS-USA mutations, Fall 2006; Johnson et al. Topics in HIV Medicine. 2006; 14:

11. ARTEMIS: Grade 2–4 adverse events
Gr 2–4 AEs† ≥2% incidence, n (%)
DRV/r qd
LPV/r qd or bid
(N=343)
(N=346)
GI (all AEs)
23 (7)
47 (14)
Diarrhea
14 (4)
34 (10)
Nausea
6 (2)
10 (3)
Rash (all types)
9 (3)
4 (1)
p<0.01
p<0.05
†At least possibly related to study drug, excluding laboratory-related events
No renal SAEs and no treatment discontinuations due to renal AEs

12. ARTEMIS: Grade 2–4 laboratory abnormalities
≥2% incidence, n (%)
DRV/r qd
(N=343)
LPV/r qd or bid
(N=346)
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)
10 (3)
35 (10)
31 (9)
23 (7)
17 (5)
6 (2)
78 (23)
36 (11)
38 (11)
Worst
Grade
DRV/rtv
N = 343
LPV/rtv
N = 346
Creatinine
Grade 1 12 (3.5) 9 (2.6)
Grade (0.3)
Grade 3 1 (0.3) 1 (0.3)
Grade 4 0
No significant changes in calculated creatinine clearance between baseline and Week 48 visits

13. ARTEMIS: Mean fasting lipid levels over time
ng/mL mM
Mean triglycerides
Total cholesterol/HDL ratio
300
250
200
150
100
3.5
5.5
DRV/r qd (n=343) LPV/r qd or bid (n=346)
DRV/r qd (n=343) LPV/r qd or bid (n=346)
2.9
5.0
4.5
Mean total cholesterol/HDL ratio (± SE)
2.3
Mean triglyceride concentration ( ± SE)
4.0
1.7
3.5
1.1
3.0
Time (weeks)
DRV/r n= LPV/r n=
= NCEP cut-off

14. ARTEMIS: DRV plasma concentrations for DRV/r 800mg/100mg
10,000 36
Population PK study (median, IQR, range; N=335)
Ctrough
1,000
DRV plasma conc (ng/mL)
100
EC50 = 55 ng/mL for wild-type virus (adjusted for protein binding) 10
Time post-dose (hours)
PK substudy – week 4 data (mean ± SD; N=9)

15. 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

16. 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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