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SPIRAL Study: Switch PI/r to RAL

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

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SPIRAL Study: Switch PI/r to RAL

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  1. Switch to RAL-containingregimen- Canadian Study- CHEER- MontrealStudy- EASIER- SWITCHMRK- SPIRAL

  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(intention-to-treat) • Progression to AIDS • Death • Virologic failure • Discontinuation of study medication • Consent withdrawn, lost to follow-up • Virologic failure (on-treatment) • Progression to AIDS • Death • Virologic failure during treatment • Patients who withdrew consent, were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 • 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

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