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ARTEMIS: Phase III study design

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.

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ARTEMIS: Phase III study design

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  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 (N=343) 689 ARV-naïve patients – VL>5,000 – no CD4 entry restrictions 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

  3. 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

  4. ARTEMIS: baseline characteristics DRV/r QD (N=343) LPV/r overall* (N=346) Baseline demographics Male, n (%) Mean age, years (SD) Caucasian, n (%) 239 (70) 36 (9) 137 (40) 241 (70) 35 (9) 153 (44) Baseline disease characteristics Median HIV-1 RNA, copies/mL (range) Median CD4, cells/mm3 (range) HBV/HCV co-infected, n (%) CDC class C, n (%) 70,800 (835–5,580,000) 228 (4–750) 43 (13) 26 (8) 62,100(667–4,580,000) 218 (2–714) 48 (14) 34 (10) Stratification factors at screening CD4 count <200 cells/mm3 Plasma HIV-1 RNA ≥100,000 copies/mL 40% 36% 41% 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 <50 copies/mL at Week 48 (ITT-TLOVR) 100 DRV/r QD (N=343) LPV/r overall*(N=346) 90 84% 80 78% 70 60 Patients with viral load <50 copies/mL (% ± SE) 50 40 Estimated difference in response vs LPV/r for non-inferiority: Per-protocol = 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 Estimated difference in response vs LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) p<0.001 30 20 10 0 2 4 8 12 16 24 36 48 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

  6. 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

  7. 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

  8. Use of QD and BID dosing in ARTEMIS DRV/r (N=343) LPV/r (N=346) Dosing QD 343 (100%) 52 (15%) BID 0 267 (77%) BID/QD* 0 27 (8%) * Excluded from the analysis

  9. HBV/HCV co-infected, n (%) 43 (13) 39 (15) 5 (10) CDC class C, n (%) 26 (8) 24 (9) 8 (15) ARTEMIS: baseline characteristics DRV/r QD (N=343) LPV/r BID* (N=267) LPV/r QD* (N=52) Baseline demographics Male, n (%) 239 (70) 171 (64) 46 (88) Mean age, y (range) 36 (18–70) 34 (19–63) 40 (20–68) Caucasian, n (%) 137 (40) 118 (45) 24 (46) Baseline disease characteristics Median HIV-1 RNA, copies/mL (range) 70,800 (835–5,580,000) 61,800 (667–4,580,000) 58,850 (6,400–888,000) Median CD4, cells/mm3 (range) 228 (4–750) 218 (2–714) 228 (16–659) Stratification factors at screening CD4 <200 cells/mm3 40% 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

  10. 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) 100 Difference 9%* (95% CI -3; 21) 84 81 78 80 71 60 Patients with VL <50 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

  11. Baseline viral load ≥100,000 copies/mL 100 79* 80 71 67* 60 56* Patients with VL <50 copies/mL (%) 40 20 0 DRV/r QD LPV/r overall LPV/rQD† LPV/rBID† N = 226 175 34 226 120 92 18 117 *p<0.05 for DRV/r QD vs LPV/r overall and vs LPV/r QD Week 48 response by baseline viral load Baseline viral load <100,000 copies/mL 100 86 86 85 79 80 60 Patients with VL <50 copies/mL (%) 40 20 0 DRV/r QD LPV/r overall LPV/rQD† LPV/rBID† N = 226 175 34 226 †27 patients receiving LPV/r BID and QD during the study were excluded from this analysis

  12. ARTEMIS: virological failure (VF) and emergence of mutations DRV/r QD (N=343) LPV/r overall (N=346) LPV/r BID* (N=267) LPV/r QD* (N=52) VF (>50 copies/mL) 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 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

  13. 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 (N=343) LPV/r overall (N=346) LPV/r BID* (N=267) LPV/r QD* (N=52) Diarrhoea 14 (4)† 34 (10)† 22 (8)† 9 (17)† Nausea 6 (2) 10 (3) 8 (3) 0 (0) Rash (all types) 9 (3) 4 (1) 3 (1) 1 (2) • 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

  14. 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)† 69 (26)† 8 (15) 78 (23)† Low-density lipoprotein 44 (13) 31 (12) 4 (8) 36 (11) Triglycerides 10 (3)‡ 27 (10)‡ 9 (17)‡ 38 (11)‡ †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

  15. 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

  16. 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: • 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 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 Supported by Tibotec

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