Presentación del Estudio Gardel

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GARDEL es un estudio multicéntrico internacional, diseñado por la Fundación Huésped que demostró que usando dos drogas se pueden obtener resultados similares al tradicional "coctel" con tres drogas. Esto permite tener una alternativa más simple, más económica y con menos efectos colaterales para los pacientes.

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Presentación del Estudio Gardel

  1. 1. Dual therapy with Lopinavir/ Ritonavir (LPV/r) and Lamivudine (3TC) is non-inferior to standard triple drug therapy in Naïve HIV-1 infected subjects : 48-week results of the GARDEL Study. ClinicalTrials.gov : # NCT01237444 Pedro Cahn on behalf of the GARDEL study group
  2. 2. Disclosure Information In compliance with the Conflict of Interest Policies, the European AIDS Clinical Society (EACS) requires the following disclosure to the participants: Pedro Cahn Research Support: Abbvie, Merck,ViiV. Speaker’s Bureau: N/A Board Member/Advisory Panel: Abbvie, Gilead, Merck, J&J, ViiV Stock/Shareholder: N/A Consultant: N/A Employee: N/A DSMB: J&J
  3. 3. Background • In the current era, achieving plasma viral load suppression below the level of detection is no longer a difficult task. • Current challenges include: tolerability, toxicities, user friendliness, pill count, simplicity, applicability to different populations (pregnant women, children, drug-users, elderly, etc) and cost. • Different strategies tested in naïve patients, including PI/rmonotherapy, generally failed to show non-inferiority when compared to standard triple-drug combinations.
  4. 4. Objectives • To compare the efficacy and safety of a dual therapy (DT) combination of LPV/r 400/100 mg BID+3TC 150 mg BID to a triple therapy (TT) with LPV/r 400/100 mg BID+3TC or FTC and a third investigator-selected NRTI in fixed-dose combination in ARV-naïve patients. • Primary endpoint % of patients with HIV-1 RNA< 50 copies/mL in an ITT-exposed analysis at 48 weeks (FDA-snapshot algorithm).* • Secondary objectives – % of patients with HIV-1 RNA< 400 copies/mL (ITT-e at 24 weeks by FDA-snapshot algorithm). – Safety, tolerability and resistance – Immunologic responses * Alpha 0.05, power 80%, 2-sided 95% CI, 12% margin
  5. 5. Study design Phase III, randomized, international , controlled, open-label study • Study included adult patients from Argentina, Chile, Mexico, Peru, Spain, US. Stratified by screening HIV-1 RNA (≤ or > 100,000 copies/mL) ARV- naive patients, 18 years HIV-1 RNA >1000 copies/ml No IAS-USA defined NRTI or PI resistance at screening* HB(s)Ag negative (N = 426) Wk 24 interim analysis Wk 48 primary endpoint DT: LPV/r 400/100mg BID + 3TC 150 mg BID (n=217) TT: LPV/r 400/100mg BID + 3TC or FTC and a third investigator-selected NRTI in fixed-dose combination (n=209) *Defined as > 1 major or > 2 minor LPV/r mutations) LPV major mutations include the following mutations: V32I; I47V/A; L76V; V82A/F/T/S
  6. 6. Patient Disposition at Week 48 543 SCREEENED 426 RANDOMIZED (10 not exposed) Dual therapy (DT) 214 Triple therapy (TT) 202 Discontinued Discontinued 16 (7.5%) 27 (14.3%) Completed W 48 Completed W 48 198 (92.5%) 175 (85.7%)
  7. 7. Baseline Characteristics DT n=214 TT n=202 Gender, male: n (%) 179 (83.6) 168 (83.1) Age, years: median (range) 34 (19–67) 35 (18–68) Mode of transmission n (%) MSM Heterosexual Other 132 (61.6) 74 (34.5) 8 (3.7) 119 (58.9) 75 (37.1) 8 (3.7) 4.87 (4.30-5.35) 4.87 (4.34-5.33) HIV RNA > 100,000 copies/mL: n (%) 94 (43.9) 86 (42.6) CD4 count, cells/mm3:(median-IQR) 319 (215-422) 329 (226-414) 45 (21.1) 38 (18.8) CDC stage 3 n (%) 6 (2.8) 6 (2.9) Background NRTIs N/A ABC/3TC:19 TDF/FTC: 74 ZDV/3TC: 109 Baseline Characteristics HIV RNA, log 10 : (median-IQR) CD4 count ≤ 200 cells/mm3: n (%)
  8. 8. Viral load <400 copies/mL at week 24 and 48 (ITTe) 100% DT TT 93.5% 90% 91,6% 85,6% 90.6% 80% (p= 0.078, difference +5,9% [CI95%:-0,6% to +12,5%]) 70% 60% 50% 40% 30% 20% 10% 0% BSL W4 W8 W12 W24 W36 W48
  9. 9. Viral load <50 copies/mL at week 48 (ITTe) 100% 90% DT 80% 88.3% TT (p= 0.171, difference +4.6% [CI95%:-2.2% to +11.8%]) 70% 83.7% 60% 50% 40% 30% 20% 10% 0% BSL W4 W8 W12 W24 W36 W48
  10. 10. Viral load <50 copies/mL at week 48 (ITTe), baseline VL > 100.000 copies/mL 100% TT 87.2% (p= 0.145, difference +9.3% [CI95%:-2.8% to +21.5%]) 77.9% 90% DT 80% 70% 60% 50% 40% 30% 20% 10% 0% BSL W4 W8 W12 W24 W36 W48
  11. 11. Viral load <50 copies/mL at week 48 W48 (VL=< 50 copies) VL Week 48 50c ITT exposed -Snapshot (n=416) VL Week 48 50c ITT exposed -Snapshot , Baseline VL> 100 k (n=180) VL Week 48 50c LOCF Exposed (n=416) VL Week 48 50c Observed (n=373) DT (N=214) TT (N=202) DIFFERENCE [CI 95%] p 88.3% 83.7% 4.6%; [-2.2% to 11.8%] 0.171 87.2% 77.9% 9.3% [-2.8 to 21.5] 0.145 91.1% 87.1% 4.0%; [-2.5% to 10.5%] 0.245 96.6% -1.1%; [-5.6% to 3.4%] 95.5% 0.777
  12. 12. CD4 increase from BL to W48 570 550 530 510 490 470 450 430 410 390 370 350 330 310 + 227 cells/mm3 + 217 cells/mm3 DT BSL W4 W12 W24 TT p=0.625 W36 W48
  13. 13. Virologic Outcome at W48 DT (n=214) TT (n=202) P [IC95%] 189 (88.3%) 169 (83.7%) 0.171 [-2.2% ; +11.8%] HIV – RNA >50 copies/mL (n; %) 10 (4.7%) 12 (5.9%) 0.720 [-6.1%; +3.5%] No Virologic data at week 48 window Reasons: Discontinued study due to adverse event or death 2 (0.9 %)* 10 (4.9 %)** 0.03 [-7.8%; -3.0%] Discontinued study for other reasons*** 13 (6.1%) 11 (5.4%) 0.948 [-4.3; +5.6] HIV – RNA < 50 copies/mL (n; %) * 1 death: Sepsis, 1 nephrotic syndrome ** 2 Rash, 3 anemia, 5 GI intolerance *** (Non compliance with study procedures, consent withdrawal, adherence, opportunistic infection, lost to follow-up, pregnancy)
  14. 14. Grade 2-3 Adverse Events DT (N=214) Total # AEs grade 2-3 AEs (possible– probably drug-related )*/ # pts TT (N=202) 65/43 88 /48 Drug-related (≥2% pts in either arm);# pts (%) ** Hyperlipidemia 23 (10.7) Diarrhea 14 (6.5) Nausea 2 (0.9) Dyspepsia 2(0.9) SAEs Possible –probably Drug1 (0.46) related*** 16 (7.9) 14 (6.9) 9(4.4) 6(2.9) * Investigator defined ** Multiple occurrences of the same adverse event in one individual counted only once *** Gastritis 0
  15. 15. Selected Laboratory Abnormalities A DT TT (N=214) (N=202) # pts with selected treatment-emergent Grade 3-4 laboratory abnormalities, n (%) Hemoglobin WBC Platelet count SGPT/ALT SGOT/AST Creatinine Glucose Total Cholesterol Triglycerides LDL-cholesterol p= NS in all laboratory abnormalities shown 2 (0.9%) 0 4 (1.9%) 0 1 (0.5%) 0 0 18 (8.4%) 8 (3.7%) 21 (9.8%) 2 (1.0%) 0 3 (1.5%) 0 0 0 3(1.5%) 14 (6.9%) 17 (8.4%) 13 (6.4%)
  16. 16. Protocol-Defined Virologic Failure and Emergent Resistance Mutations PDVF: 2 measurements of HIV-1 RNA at least 1 week apart >400 copies/mL at week 24 > 50 copies/mL at week 48 Emergent resistance mutations, in samples successfully amplified: DT: 2 out of 5 both M184V TT: 0 out of 8 DT Number of patients, n (%) (N=214) Confirmed virological failures TT (N=202) 10 (4.6 %) 12 (5.9 %)* 236 (183-17,687) 1027 (123-4,880) Never suppressed 2 8 Rebounders 8 4 Primary PI RAMs 0 0 NRTI RAMs (M184V) 2 0 HIV-1 RNA at failure (copies/ml) (median-IQR) *p=0.72
  17. 17. GARDEL: conclusions • Our results demonstrate that DT with LPV/r+3TC was noninferior to triple therapy after 48 weeks of treatment, regardless of baseline viral load. • The DT regimen showed fewer discontinuations due to safety and tolerability . • Virologic failure, occurring at similarly low levels in both treatment arms, did not result in PI resistance development, preserving a wide range of drugs for 2nd line ARV therapy. • These results suggest that a dual LPV/r+3TC regimen warrants further clinical research and consideration as a potential therapeutic option for ARV naïve subjects.
  18. 18. Acknowledgments We thank everyone who has contributed to the success of this study, including : •All study participants and their families •The GARDEL clinical investigators and their staff The GARDEL Study Team: Investigators: Argentina: Liliana Calanni, Arnaldo Casiro, Isabel Cassetti, Jorge Galíndez, Norma Luna , Sergio Lupo, Marcelo Martins, Ángel Mínguez, Patricia Patterson Chile: Juan Ballesteros Jaña, Carlos J. Beltrán Buendía Mexico: Jaime F. Andrade-Villanueva, Juan G Sierra Madero Peru: Javier R. Lama, Fernando Mendo Spain: Jose Ramon Arribas, José María Gatell United States: Roberto Andrade, Joseph C. Gathe, José Serpa Alvarez Steering Committee: José Arribas, Carlos Beltrán , Pedro Cahn , Ricardo Diaz , Joseph Gathe , Javier Lama , Juan Sierra Madero, Annette Meints , Michael Norton, Nav Thoofer, Mark Wainberg , Sharon Walmsley , Jean Van Wyk. DSMB: Roberto Arduino – Jean-Francois Delfrassy – Julio Montaner GARDEL Coordination Team: Valeria Álvarez, María Inés Figueroa , María José Rolón. With the support of Agustina Argüello, Leandro Cahn, Adriana Corera, Agustina Enz, Kurt Frieder, Joaquín Magneres, Mariano de Stefano, Omar Sued. And to Marisol Martinez and Roger Trinh This study was funded by AbbVie Lamivudine was provided by ViiV/GSK

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