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DeJesus E, Ortiz R, Khanlou H, Voronin E, Van Lunzen J, Andrade-Villanueva J, Fourie J,

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,

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DeJesus E, Ortiz R, Khanlou H, Voronin E, Van Lunzen J, Andrade-Villanueva J, Fourie J,

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  1. Efficacy and Safety of Darunavir/ritonavir versus Lopinavir/ritonavir in ARV Treatment-NaïveHIV-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) 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. 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%) 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%) *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/mLto 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 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)

  7. DRV/r qd LPV/r qd or bid 100 87 84 80 80 77 71 67 60 Patients with VL <50 copies/mL (%) 40 20 0 0 <50 50–200 >200 Baseline CD4 cell count (cells/mm3) N = 30 30 111 118 202 198 ARTEMIS: Confirmed response by baseline VL or CD4 at Week 48 (ITT-TLOVR) 100 †p<0.05 vs LPV/r 86 85 n=194 79† n=191 n=28 80 67 60 Patients with VL <50 copies/mL (%) 40 20 0 <100,000 ≥100,000 Baseline viral load (copies/mL) N = 226 226 117 120 †Chi square analysis

  8. 84 81 71 DRV/r qd LPV/r* bid LPV/r* qd 343 267 52 *27 patients receiving LPV/r bid and qd during the study were excluded from this analysis ARTEMIS: Responses by LPV/r dosing schedule 100 78 80 60 Patients with VL <50 copies/mL (%) 40 20 0 LPV/r 346 N =

  9. DRV/r qd (N=343) LPV/r qd or bid(N=346) ARTEMIS:Median change in absoluteCD4 cell count to Week 48 (ITT-NC=F) 150 141 cells/mm3 137 cells/mm3 120 90 Median change in CD4 cell count from baseline (cells/mm3) 60 30 0 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 0 1* 1† IAS-USA NRTI mutations 2† †184V *A71T, V77I VF by TLOVR *IAS-USA mutations, Fall 2006; Johnson et al. Topics in HIV Medicine. 2006; 14:125-130

  11. ARTEMIS: Grade 2–4 adverse events 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 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) 44 (13) 10 (3) 35 (10) 31 (9) 23 (7) 17 (5) 6 (2) 78 (23) 36 (11) 38 (11) No significant changes in calculated creatinine clearance between baseline and Week 48 visits

  13. 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 4 8 12 16 24 36 48 ARTEMIS: Mean fasting lipid levels over time mM ng/mL Total cholesterol/HDL ratio Mean triglycerides 3.5 300 250 200 150 100 5.5 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 2 4 8 12 16 24 36 48 Time (weeks) DRV/r n=LPV/r n= 343 320 305 346 313 301 343 320 306 346 313 301 = NCEP cut-off

  14. Ctrough 36 Population PK study (median, IQR, range; N=335) ARTEMIS: DRV plasma concentrations for DRV/r 800mg/100mg 10,000 1,000 DRV plasma conc (ng/mL) 100 EC50 = 55 ng/mL for wild-type virus(adjusted for protein binding) 10 0 4 8 12 16 20 24 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: • 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 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 Supported by Tibotec

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