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Switch to RAL-containing regimen

Canadian Study evaluating the switch from PI/r to RAL in HIV-infected adults, demonstrating non-inferior efficacy and improved lipid profile.

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Switch to RAL-containing regimen

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  1. Switch to RAL-containing regimen • Canadian Study • CHEER • Montreal Study • EASIER • SWITCHMRK • SPIRAL • Switch ER

  2. SPIRAL Study: Switch PI/r to RAL • Design Randomisation* 1 : 1 Open-label W48 N = 142 HIV+ ≥ 18 years On 2 ARV + PI/r HIV RNA < 50 c/mL > 6 months** Raltegravir-naïve N = 140 * Randomisation was stratified by current use of lipid-lowering therapy ** Median time with virologic suppression was > 6 years • Endpoints • Primary: non inferiority in the proportion of patients with treatment failure at W48* (non completer = failure, intent-to-treat analysis), lower limit of the 95% CI for the difference = - 12.5%, 80% power ; • * events occurring in the 2 weeks after W48 were included in the analysis • Secondary: virologic failure (confirmed HIV-1 RNA > 50 c/mL), CD4, fasting lipids, adverse events Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  3. SPIRAL Study: Switch PI/r to RAL • Treatment failure (intention-to-treat) • Progression to AIDS • Death • Virologic failure • Discontinuation of study medication • Consent withdrawn, lost to follow-up • Virologic failure (on-treatment) • Progression to AIDS • Death • Virologic failure during treatment • Patients who withdrew consent, were lost to follow-up, switched or stopped study medication were censored • Changes in plasma lipids • Analysis by intention-to-treat Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  4. SPIRAL Study: Switch PI/r to RAL Baseline characteristics and patient disposition * 1 or 2 NRTI exclusively Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  5. % 96.9 96.9 97.2 100 96.4 95.1 93.1 90 89.2 89.9 88.6 86.6 83.1 80 60 40 20 N= 139 134 79 65 60 69 128 122 72 58 56 64 0 All patients Prior virologic failure or suboptimal therapy All patients Prior virologic failure or suboptimal therapy Yes No Yes No SPIRAL Study: Switch PI/r to RAL Results: efficacy analyses Primary efficacy endpoint RAL PI/r Absence of treatment failure Absence of virologic failure 95% CI for the ≠= -5.2 ; 10.6 - 5.9 ; 17.6 - 11.2 ; 10.9 - 3.5 ; 7.5 - 3.9 ; 13.9 - 9.3 ; 7.6 Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  6. 1 1 0.9 0.9 0.8 0.8 0.7 0.7 Log rank p = 0.4775 Log rank p = 0.4602 0.6 0.6 0 4 8 12 16 20 24 28 32 36 40 44 48 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Weeks SPIRAL Study: Switch PI/r to RAL Time to treatment failureby treatment group Time to virologic failureby treatment group RAL PI/r 134 131 124 121 116 134 122 119 119 116 139 138 132 130 124 139 128 126 125 124 Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  7. SPIRAL Study: Switch PI/r to RAL • Virologic failure • First of 2 consecutive measurements of HIV RNA ≥ 50 c/mL separated by a minimum of 2 weeks • VF at W48 : 4 (2.9%) in the RAL arm vs 6 (4.4%) in the PI/r arm • No difference in patients with and without VF regarding • Demographics, HIV parameters, N(t)RTI backbone, PI, duration of viral suppression at entry • Median time with virologic suppression prior to inclusion : 62.85 months in patients without previous VF vs 65 months in patients with previous VF • 74/250 patients (50%) had previous VF with prior genotypic resistance tests • GSS for backbone N(t)RTI was < 1 in 15/38 (39%) in the RAL group and in 9/36 (25%) in the PI/r group : VF developed in 0/15 vs 2/9 (22%), respectively (p=0.13) • Moreover 0/11 subjects with GSS ≤ 0.5 backbone activity developed VF in the RAL arm Blanco JL. Antiviral Therapy 2015, epub ahead of print SPIRAL

  8. SPIRAL Study: Switch PI/r to RAL • At entry, median total cholesterol (TC) was 198 mg/dL, 15% of the patients had TC > 240 mg/dL, 12% LDL-cholesterol > 160 mg/dL, 40% triglycerides > 200 mg/dL Percentage changes in fasting lipid concentrations from baseline to W48 Triglycerides Total cholesterol LDLcholesterol HDLcholesterol Total to HDLcholesterol ratio 10 5.84 4.72 5 2.96 1.82 % 0 -1.28 -3.17 -5 -4.85 p < 0.0001 -6.49 p < 0.05 -10 p < 0.001 -11.18 -15 p < 0.0001 RAL PI/r -20 -22.09 -25 p < 0.0001 Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  9. SPIRAL Study: Switch PI/r to RAL • At W48, significantly less patients had triglycerides > 200 mg/dL or total cholesterol > 240 mg/dL in the RAL group compared to the PI/r group: 14.6% vs 28.9% and 3.7% vs 17.2%, respectively • Differences in total cholesterol and triglycerides changes in patients assigned to RAL were significant when switching from LPV/r but not from ATV/r • There were no difference in the overall incidence of adverse events in the 2 groups • The incidences of serious adverse events and events leading to drug discontinuation were similarly low in both groups Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  10. SPIRAL Study: Switch PI/r to RAL vs continuation of PI/r • Conclusions • In HIV-infected adults with sustained plasma HIV-1 RNA < 50 c/mL on PI/r-containing ARV therapy, switching from the PI/r component to raltegravir results • In non inferior efficacy • And a better lipid profile Martinez E, AIDS 2010;24:1697-1707 SPIRAL

  11. Cardiovascular biomarkers: median (95% CI) difference of percent change from baseline to W48, RAL (N = 119) minus PI/r (N = 114) SPIRAL Study: Switch PI/r to RAL % 20 10 0 - 10 - 20 - 30 - 40 - 50 - 60 OPG IL-10 TNF-a hsCRP MCP-1 Insulin IL-6 ICAM-1 D-dimer VCAM-1 - 70 E-selectin P-selectin Adiponectin Markers of inflammation Endothelial dysfunction Insulin resistance Hyper- coagulability Martinez E, AIDS 2012;26:2315-26 SPIRAL

  12. Correlations between ∆ biomarkers and ∆ lipids SPIRAL Study: Switch PI/r to RAL Data expressed Spearman’s rho (p) No correlations between ∆ OPG, ∆ IL-6, ∆ IL-10, ∆ TNF-alpha, ∆ ICAM-1, ∆ VCAM-1, ∆ E-selectin, ∆ P-selectin, ∆ Adiponectin, ∆ D-dimer and any changes in lipids • Conclusion • Switching from PI/r to RAL led not only to significant changes in plasma lipids but also to significant changes in several cardiovascular biomarkers associated with inflammation, insulin resistance and hypercoagulability • There were few and weak significant correlations between changes in lipids and changes in biomarkers suggesting that decreases in biomarkers were rather independent of lipid changes Martinez E, AIDS 2012;26:2315-26 SPIRAL

  13. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition) • Proceduresat baseline and W48 • Whole body, lumbar and hip DEXA scans • CT scan of abdomen (single cut 5 mm thick, at L4) • Standardized protocol performed by a single radiologist unaware of patient’s treatment • Endpoints • Primary: change in visceral adipose tissue (VAT) area (cm2) • Secondary: changes in limb fat, trunk fat, total fat, total adipose tissue area, subcutaneous adipose tissue (SAT) area, SAT/VAT ratios, changes in bone mineral density and T scores in total body, spine (L1-L4) and hip (femoral neck and total hip) Curran A, AIDS 2012;26:475-81 SPIRAL

  14. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition) Baseline characteristics of the 74 participants Curran A, AIDS 2012;26:475-81 SPIRAL

  15. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition) Body fat distribution (median change from baseline to week 48) * p not significant for all measures Curran A, AIDS 2012;26:475-81 SPIRAL

  16. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition) RAL PI/r g 382 cm2 + 307 21.4 20.7 + % 12.8 171 11.9 10.9 5.1 23.7 3.6 Total fat 32 0 0 0 % -0.02 -0.25 -0.11 -1.9 - 28 -3.2 - TAT SAT VAT SAT VAT SAT/VAT Limb fat Trunk fat Limb/trunk ratio - Median values All differences PI/r vs RAL not significant -359 Curran A, AIDS 2012;64:475-81 SPIRAL

  17. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition) Bone composition (median change from baseline to week 48) BMD: bone mineral density • No significant differences in BMD or T scores in either group even when controlling for TDF use Curran A, AIDS 2012;26:475-81 SPIRAL

  18. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition) • Conclusion • Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT • Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups Curran A, AIDS 2012;26:475-81 SPIRAL

  19. SPIRAL Study: Comparison of ABC/3TC vs TDF/FTC * Treatment failure: virologic failure, discontinuation of NRTI due to adverse event, consent withdrawal, loss to follow-up • In the RAL group, decrease in triglycerides and increase in HDL cholesterol at W48 tended to be more pronounced with ABC/3TC than with TDF/FTC • Differences in total-to-HDL cholesterol ratio between both combinations of NRTIs tended to be higher in the RAL group although differences at 48 weeks were not significant SPIRAL Martinez E, AIDS Res Hum Retroviruses. 2013 Feb;29(2):235-41

  20. SPIRAL-MET substudy: LDL subclasses and lipoprotein-phospholipase A2 activity • 81 patients, PI/r group (N = 41), RAL group (N = 40) • Baseline and week 48 assessment : • LDL size and phenotype : • Phenotype A : LDL size > 26.8 nm with predominance of large buoyant LDL subfractions • Phenotype intermediate : LDL size 26.0-26.8 nm • Phenotype B : LDL size < 26.0 nm with a predominance of small, dense LDL subfractions • Total lipoprotein-associated phosholipase A2 (Lp-PLA2) • Proproteinconvertasesubtilisin/kexin type 9 (PCSK9) • Standard lipid parameters • Insulin, C-peptide, HOMA index • Cardiovascular risk assessment (Framingham equation) SPIRAL Saumoy M, Atherosclerosis 2012;225:200-7

  21. SPIRAL-MET substudy • Baseline characteristics Lipid parameters were not significantly different between groups, except Apo B, which was lower in the RAL arm (p = 0.035) SPIRAL Saumoy M, Atherosclerosis 2012;225:200-7

  22. SPIRAL-MET substudy • Results • Insulin, waist • Significant difference in insulin levels between arms favorable to RAL at W48 (p = 0.020) • HOMA index decreased in RAL group (p = 0.032) at W48, remaining unchanged in the PI/r arm • At W48, increase in waist circumference (3.95 cm ; p = 0.004) and waist-to-hip ratio (0.01 ; p = 0.022) in the PI/r arm, where as no change in RAL group • No change in number of patients on lipid-lowering therapy • Cardiovascular risk assessment at W48 • Increase in the PI/r arm (0.8% ; p = 0.032) • No change in the RAL arm • No change between arms at W48 • Significant increase of systolic (+ 5 mm Hg ; p = 0.016) and diastolic (+ 8,5 mm Hg ; p = 0.005) blood pressure in the RAL arm, no change in the PI/r group SPIRAL Saumoy M, Atherosclerosis 2012;225:200-7

  23. SPIRAL-MET: median changes in lipid parameters between baseline and W48 according to therapy PI/r (N = 41) RAL (N = 40) 0.6 0.15 0,.11 0.4 0.10 0.29 0.2 0.05 0.03 0.10 0.07 0.06 0.05 0.0 0.00 -0.04 -0.01 Median change g/l (W48 – baseline) Median change mmol/l (W48 – baseline) -0.11 -0.2 -0.05 -0.04 -0.32 -0,4 -0.10 -0.36 -0.11 -0.12 -0.49 -0.6 -0.15 -0.71 -0.8 -0.20 -0,81 -1.0 -0.25 p < 0.001 0.023 0.108 < 0.001 < 0.001 0.026 0.004 < 0.001 0.073 TC LDL-c HDL-c Non-HDL-c TG TC/HDL-c Apo A1 Apo B Apo A1/Apo B SPIRAL Saumoy M, Atherosclerosis 2012;225:200-7

  24. SPIRAL-MET: median changes in the percentage of LDL-c phenotype in RAL arm and PI arm stratified by PI/r used (group 1 vs group 2) at W48 LDLc phenotype 100 A Intermediate B 80 Group 1: LPV/r, FPV/r Group 2: ATV/r, SQV/r 60 0.088* % LDL-c particles phenotype < 0.001* 40 0.439* 20 0 Baseline W48 Baseline W48 Baseline W48 Group 1 (n = 21)** Group 2 (n = 19) RAL (n = 40) * Homogeneity marginal test to compare proportions at baseline and W48 in each arm** Statistically significant difference between LPV and RAL at W48 (Pearson Chi-square test) LDLc phenotype A: large & low density of cholesterol esters (non-atherogenic) LDLc phenotype B: small & high density of cholesterol esters (atherogenic) SPIRAL Saumoy M, Atherosclerosis 2012;225:200-7

  25. SPIRAL substudy: endothelial function • 35 patients, PI/r group (n = 16), RAL group (n = 19) • Endothelial function was evaluated through flow-mediated dilatation (FMD) of the brachial artery at baseline, W24 and W48 • Total cholesterol, LDL cholesterol and triglycerides decreased at W16 and W32 in the RAL arm, while no changes were observed in the PI/r arm • Triglyceride levels were significantly lower in the RAL arm than in the PI/r arm at W16, 32 and 48 • No significant changes from baseline occurred in FMD at W24 and W48 within or between the RAL and PI/r arms. Adjustment for baseline artery diameter did not have a significant effect on the FMD differences • Median baseline FMD values within normal range ( > 5%) + limited sample size might have precluded detection of any RAL effect or clinically relevant differences SPIRAL Masia M, JAC 2013;68:409-413

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