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Martinez E et al . AIDS 2010

Martinez E. 1 , Larrousse M. 1 , Llibre J.M. 2 , Gutierrez F. 3 , Saumoy M. 4 , Antela A. 5 , Knobel H. 6 , Pich J. 1 , Perez I. 1 , J. Murillas 7 , J. Portilla 8 , J. Berenguer 9 , E. Ribera 10 and Gatell J.M. 1 , for the SPIRAL study group.

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Martinez E et al . AIDS 2010

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  1. Martinez E.1, Larrousse M.1, Llibre J.M.2, Gutierrez F.3, Saumoy M.4, Antela A.5, Knobel H.6, Pich J.1, Perez I.1, J. Murillas7, J. Portilla8, J. Berenguer9, E. Ribera10 and Gatell J.M.1, for the SPIRAL study group 1Hospital Clínic, Barcelona, Spain; 2Hospital Germans Trias i Pujol, Badalona, Spain; 3Hospital General Universitario de Elche, Elche, Spain; 4Hospital de Bellvitge, Hospitalet de Llobregat, Spain; 5Hospital de Santiago, Santiago de Compostela, Spain; and 6Hospital del Mar, Barcelona, Spain;7Hospital Son Dureta, Palma de Mallorca, Spain; 8Hospital Univ. de Alicante, Alicante, Spain;9Hospital Gregorio Marañón, Madrid, Spain; 10Hospital Vall d’Hebrón, Barcelona, Spain . An Open-label, Randomized, 48-Week Study to Assess the Safety, Tolerability and Activity ofRaltegravir when Replacing the Ritonavir-boosted PI Component of HAART in HIV-InfectedIndividuals with Viral Load Suppression on a Ritonavir-Boosted PI Containing Regimen.The SPIRAL Study Martinez E et al . AIDS 2010

  2. SPIRAL study group HOSPITAL ELCHE ELCHE F. Gutiérrez M. Masiá S. Padilla V. Sánchez HOSPITAL BELLVITGE HOSPITALET M. Saumoy D. Podzamczer HOSPITAL CLINIC BARCELONA E. Martínez M. Larrousse J. Pich I. Pérez D. García N. Ramos H. Beleta A. Pejenaute J.A. Arnaiz J.M. Gatell HOSPITAL GERMANS TRIAS I PUJOL BADALONA J.M. Llibre B. Clotet R. Guerola HOSPITAL SANTIAGO SANTIAGO DE COMPOSTELA A. Antela A. Prieto E. Losada HOSPITAL SON DURETA PALMA MALLORCA J. Murillas HOSPITAL MAR BARCELONA H. Knobel A. González J. Mercadal HOSPITAL GREGORIO MARAÑÓN MADRID J. Berenguer P. Miralles M. Sánchez-Conde M. Ramírez I. Gutiérrez HOSPITAL VALL D’HEBRÓN BARCELONA E. Ribera A. Currán HOSPITAL MATARÓ MATARÓ Ll. Force P. Barrufet HOSPITAL UNIV. ALICANTE. ALICANTE J. Portilla L. Giner HOSPITAL LA PAZ MADRID J.R. Arribas M. Montes J.M. Castro HOSPITAL RAMÓN Y CAJAL. MADRID F. Dronda S. Moreno HOSPITAL CLÍNICO SAN CARLOS MADRID V. Estrada HOSPITAL PARC TAULÍ SABADELL F. Segura E. Penelo M.J. Amengual HOSPITAL JOAN XXIII TARRAGONA F. Vidal J. Peraire HOSPITAL GRANOLLERS GRANOLLERS E. Deig HOSPITAL SANT PAU BARCELONA P. Domingo

  3. Background » PI/r-based cART is an effective therapy for HIV-infected patients, but it has been associated with a higher risk of cardiovascular disease due at least in part to lipid effects. » Raltegravir-based cART may show a better lipid profile while being as effective as PI/r-based cART in selected patients.

  4. Higher risk of myocardial infarction with longer exposure to protease inhibitors D:A:D study Adjusted relative rate/year of PI: 1.15 (1.06, 1.25) Adjusted relative rate/year of NNRTI: 0.94 (0.74, 1.19) 10 8 6 Number of MIs per 1000 PYFU (IC 95%) 4 2 0 0 <1 1–2 2–3 3–4 4–5 5–6 >6 Years of exposure to PI or NNRTI Friis-Møller, et al. N Engl J Med. 2007;326:1723-1735

  5. Objective » To demonstrate the non-inferiority of raltegravir vs. PI/r-based cART when administered for 48 weeks to HIV-1 seropositive patients with virologic suppression.

  6. Study Design Study Population (N = 286) Patients on current PI/r + at least 2 ARV for > 6 months VL<50 cp/mL within 180 days 1:1 Randomization Stratified by presence or not of lipid lowering agents Switch to Raltegravir† (N = 143) Continue with boosted PI (N = 143) Baseline Analysis, Week 48 * Raltegravir 400mg BID (maintaining other antiretrovirals unchanged).

  7. Primary end-point »The proportion of patients free of treatment failure for any reason through Week 48 (ITT, S=F) • Includes virologic rebound (two consecutive > 50 cp/mL), discontinuation of study therapy or lost to follow-up, progression to a new CDC event or death. • Non-inferiority study of Raltegravir vs. boosted PI. Lower limit of 95% CI of estimated difference ≥ 12.5%.

  8. Secondary end-points » The proportion of patients with virologic failure at or prior to Week 48 (confirmed virological failure defined as the first of two consecutive HIV RNA ≥ 50 cp/mL at least 2 weeks apart) (OT). » Change in CD4+ cells. » Time to treatment and virologic failure. » Safety (adverse events leading to drug discontinuation and serious adverse events). » Evolution of fasting plasma lipids.

  9. Baseline Characteristics (I)

  10. Baseline Characteristics (III)

  11. In December 2008 when Switchmrk studies were interrupted the DSMB examined the Spiral study and recommended to continue the Spiral study

  12. Patients assessed for eligibility (n=339) Patients enrolled (n=282) Assigned to Raltegravir (n=142) Excluded: 3 Valid cases: 139 Assigned to PI/r (n=140) Excluded: 6 Valid cases: 134 • Continuing assigned therapy 126† (91%) • Discontinued 13 (9%) • Adverse events 3 • Virological failure 2 • Lost to follow-up 1 • Patient decission 5 • Other 2 • Continuing assigned therapy 120* (90%) • Discontinued 14 (10%) • Adverse events 3 • Virological failure 2 • Lost to follow-up 4 • Patient decission 4 • Other 1 † 2 subjects with virological failure * 4 subjects with virological failure Patient Disposition at week 48

  13. RALTEGRAVIR PI/r 97% 95% 116/122 124/128 Difference Estimate (95% CI) 1.8% (–3.5%, 7.5%) Patients free of Treatment Failure and Virologic Failure (≥ 50 cp/mL) through Week 48 Free of Virologic Failure (≥ 50 cp/mL) (OT) Free of Treatment Failure (ITT, S=F) 97% 96% 89% 87% 124/139 116/134 Difference Estimate (95% CI) 2.6% (–5.2%, 10.6%)

  14. Time to virological failure

  15. RAL PI/r

  16. Patients with Virological Failure

  17. CD4 Changes » Median changes in CD4 cell count were: +46 cells/mm3 (Raltegracir arm) and +44 cells/mm3 (PI/r arm) through Week 48 (p=0.33)

  18. Adverse Events (II)

  19. LIPIDS. Change in mean Fasting Lipid Parametersthrough Week 48

  20. LIPIDS. Percentage above NCEP treatment recommendations at baseline and through 48

  21. Substudies » Metabolic substudy (n=40+41) » Body fat composition (n=39+34) » Adipose tissue biopsies (n=3+3) » Relation between prior resistance and virologic failure substudy (n= 113) » Inflamatory markers substudy (n= 80+80)

  22. Comparison between pooled analysis of SWITCHMRK studies at 24 weeks and SPIRAL study at 48 weeks RAL PI/r SM SPIRAL

  23. Protocol 032 (SWITCHMRK-1) and Protocol 033 (SWITCHMRK-2) Efficacy at 24 Weeks: Subgroup Analysis – SWITCHMRK-1 and -2 Combined Data1,a LPV/r as First Regimen History of Virologic Failure Difference (95% CI)b −2.5 (−10.6, 5.4) −8.3 (−14.8, −2.1) −15.3 (−24.9, −6.2) −1.0 (−6.9, 4.9) c c 128 130 219 222 111 123 228 221 LPV/r First Regimen LPV/R Not First Regimen Prior Virologic Failure No Prior Virologic Failure CI = confidence interval; LPV/r = lopinavir/ritonavir; RAL = raltegravir. aAll patients who did not complete the study were regarded as failures. bCalculated by the method of Miettinen and Nurminen. cPlus existing baseline regimen. 1. Eron JJ et al. Lancet.2010 Jan 13; [Epub ahead of print].

  24. Compared with SPIRAL, Switchmrk studies 1 & 2: • Double blinded & Double dummy • 24 weeks • No need to confirm VL>50 for the main end point • Different backbone of NRTI´s • Substantially shorter median duration of virological suppression before entry • Shorter minimum duration of virological suppression before entry • All Lopinavir/r Yet, response rate was very haig in both arms in both studies. Probably among the highest ever seen in switching studies

  25. AIDS, 2007

  26. Conclusions of SPIRAL study: » In patients with sustained virological suppression on PI/r-based cART, switching from PI/r to raltegravir demonstrated non-inferior efficacy and resulted in a better lipid profile at 48 weeks than continuing PI/r.

  27. Back up slides

  28. D:A:D: Cumulative Antiretroviral Exposure and Risk of MI RR of Cumulative Exposure/Yr*(95% CI) NNRTI PI 1.20 1.13 1.10 1.00 0.90 IDV NFV LPV/RTV SQV NVP EFV # PYFU: 68,469 56,529 37,136 44,657 61,855 58,946# MI: 298 197 150 221 228 221 *Expressed as risk/yr. Expected to have more impact the longer the pt is on the drug. Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.

  29. Baseline Characteristics ‡1 PT in the RAL Gp and 3 PTs in the LPVr Gp did not report any concurrent ART *All patients in SWITCHMRK were on LPV/r†In SWITCHMRK, NRTI could be FTC or 3TC

  30. Baseline Characteristics (II)

  31. RALTEGRAVIR PI/r 89% 89% 87% 87% 124/139 127/142 116/134 122/140 Difference Estimate (95% CI) 2.6% (–5.2%, 10.6%) Difference Estimate (95% CI) 2.3% (–5.4%, 10.0%) Patients free of Treatment Failure through Week 48:sensitivity analysis Free of Treatment Failure by sensitivity analysis Free of Treatment Failure

  32. Comparison between pooled analysis of SWITCHMRK studies at 24 weeks and SPIRAL study at 48 weeks RAL PI/r SM SPIRAL

  33. Comparison between pooled analysis of SWITCHMRK studies at 24 weeks and SPIRAL study at 48 weeks RAL PI/r SM SPIRAL

  34. Adverse Events (I)

  35. Lipid lowering agents

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