Switch to RAL-containing regimen - PowerPoint Presentation

1. Switch to RAL-containing regimenCanadian StudyCHEERMontreal StudyEASIERSWITCHMRKSPIRALSwitch ER

2. DesignEndpointsPrimary: 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 analysisSecondary: virologic failure (confirmed HIV-1 RNA > 50 c/mL), CD4, fasting lipids, adverse eventsSwitch to RAL 400 mg bid + continue other ARVsContinue PI/r + other ARVs* Randomisation was stratified by current use of lipid-lowering therapy** Median time with virologic suppression was > 6 yearsMartinez E, AIDS 2010;24:1697-1707SPIRALSPIRAL Study: Switch PI/r to RALRandomisation*1 : 1Open-labelHIV+ ≥ 18 yearsOn 2 ARV + PI/r HIV RNA < 50 c/mL > 6 months**Raltegravir-naïveN = 140N = 142W48

3. Treatment failure (intention-to-treat)Progression to AIDSDeathVirologic failureDiscontinuation of study medicationConsent withdrawn, lost to follow-upVirologic failure (on-treatment)Progression to AIDSDeathVirologic failure during treatmentPatients who withdrew consent, were lost to follow-up, switched or stopped study medication were censoredChanges in plasma lipidsAnalysis by intention-to-treatMartinez E, AIDS 2010;24:1697-1707SPIRALSPIRAL Study: Switch PI/r to RAL

4. RALPI/rPatients included in the efficacy analysis139134Female19%28%ARV backbone: TDF + FTC/3TC ; ABC + 3TC/FTC58% ; 19%55% ; 20%PI/r at entry: LPV/r ; ATV/r ; FPV/r43% ; 37% ; 11%45% ; 33% ; 13%Patients on their first ARV regimen12%10%Patients with previous suboptimal ARV therapy*41%35%Patients with previous virologic failure40%36%Patients with previous suboptimal ARV therapy or virologic failure57%49%CD4 cell count (/mm3), median (IQR)529 (377-780)509 (369-726)Lipid-lowering therapy at entry19%21%Discontinuation before W48, n (%)13 (9%)14 (10%)For adverse event33For virologic failure22Baseline characteristics and patient disposition* 1 or 2 NRTI exclusivelySPIRAL Study: Switch PI/r to RALMartinez E, AIDS 2010;24:1697-1707SPIRAL

5. Results: efficacy analysesMartinez E, AIDS 2010;24:1697-1707SPIRAL Study: Switch PI/r to RALSPIRALAbsence of treatment failure95% CI for the ≠= -5.2 ; 10.6Primary efficacyendpointAbsence of virologic failure- 5.9 ; 17.6- 11.2 ; 10.9- 3.5 ; 7.5- 3.9 ; 13.9- 9.3 ; 7.6Prior virologic failure orsuboptimal therapy%89.288.69096.997.296.486.683.189.995.193.196.9020406080100139N=1347965606972585664All patientsYesNoPrior virologic failure orsuboptimal therapyAll patientsYesNo128122RALPI/r

6. SPIRAL Study: Switch PI/r to RAL134131124121116139138132130124Log rank p = 0.4775Weeks0.648121620242832364044480.70.80.910134122119119116139128126125124Log rank p = 0.46020.648121620242832364044480.70.80.910WeeksMartinez E, AIDS 2010;24:1697-1707SPIRALTime to treatment failureby treatment groupTime to virologic failureby treatment groupRALPI/r

7. Virologic failureFirst of 2 consecutive measurements of HIV RNA ≥ 50 c/mL separated by a minimum of 2 weeksVF at W48 : 4 (2.9%) in the RAL arm vs 6 (4.4%) in the PI/r armNo difference in patients with and without VF regardingDemographics, HIV parameters, N(t)RTI backbone, PI, duration of viral suppression at entryMedian time with virologic suppression prior to inclusion : 62.85 months in patients without previous VF vs 65 months in patients with previous VF74/250 patients (50%) had previous VF with prior genotypic resistance testsGSS 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 armSPIRAL Study: Switch PI/r to RALBlanco JL. Antiviral Therapy 2015, epub ahead of printSPIRAL

8. Percentage changes in fasting lipid concentrations from baseline to W48 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/dLSPIRAL Study: Switch PI/r to RALMartinez E, AIDS 2010;24:1697-1707SPIRALp < 0.0001p < 0.0001p < 0.001p < 0.0001p < 0.05-22.09-11.18-6.49-3.17-4.854.721.822.965.84-1.28-20-15-10-50510TriglyceridesTotalcholesterolLDLcholesterolHDLcholesterolTotal to HDLcholesterol ratio%-25RALPI/r

9. Martinez E, AIDS 2010;24:1697-1707SPIRAL Study: Switch PI/r to RALAt 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%, respectivelyDifferences in total cholesterol and triglycerides changes in patients assigned to RAL were significant when switching from LPV/r but not from ATV/rThere were no difference in the overall incidence of adverse events in the 2 groupsThe incidences of serious adverse events and events leading to drug discontinuation were similarly low in both groupsSPIRAL

10. Martinez E, AIDS 2010;24:1697-1707SPIRAL Study: Switch PI/r to RAL vs continuation of PI/rConclusionsIn 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 resultsIn non inferior efficacyAnd a better lipid profileSPIRAL

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 RALSPIRALMartinez E, AIDS 2012;26:2315-26Markers of inflammationEndothelial dysfunctionInsulinresistanceHyper-coagulabilityMCP-1hsCRPOPGIL-6IL-10TNF-aICAM-1VCAM-1E-selectinP-selectinAdiponectinInsulinD-dimer-70-60-50-40-30-20-1001020%

12. Correlations between ∆ biomarkers and ∆ lipidsNo correlations between ∆ OPG, ∆ IL-6, ∆ IL-10, ∆ TNF-alpha, ∆ ICAM-1, ∆ VCAM-1, ∆ E-selectin, ∆ P-selectin, ∆ Adiponectin, ∆ D-dimer and any changes in lipidsConclusionSwitching 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 hypercoagulabilityThere were few and weak significant correlations between changes in lipids and changes in biomarkers suggesting that decreases in biomarkers were rather independent of lipid changesSPIRAL Study: Switch PI/r to RALSPIRAL∆ Triglycerides∆ Total cholesterol∆ LDL cholesterol∆ HDL cholesterol∆ hsCRP--0.2415 (p=0.0016)-∆ MCP-1-0.1608 (p=0.032)0.1608 (p=0.032)0.1807 (p=0.0202)∆ Insulin0.2842 (p=0.0001)- 0.2125 (p=0.004)--Martinez E, AIDS 2012;26:2315-26Data expressed Spearman’s rho (p)

13. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition)Proceduresat baseline and W48Whole body, lumbar and hip DEXA scansCT scan of abdomen (single cut 5 mm thick, at L4)Standardized protocol performed by a single radiologist unaware of patient’s treatmentEndpointsPrimary: 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;26:475-81SPIRAL

14. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition)RALPI/rPatients included in the SPIRAL-LIP substudy, n3935Female20%31%ARV backbone: TDF ; ABC ; ZDV62% ; 33% ; 3% 69% ; 23% ; 17%PI/r at entry: LPV/r ; ATV/r ; FPV/r43% ; 51% ; 3%46% ; 34% ; 0%Time on previous PI/r, months (median)35.730HCV co-infection28%17%Weight, kg (median)7068.5BMI, kg/m2 (median)23.423.6Baseline characteristics of the 74 participantsSPIRALCurran A, AIDS 2012;26:475-81

15. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition)RALPI/rDifference* (IQR) PI/r vs RALCT scanVAT (cm2)10.920,7 (p=0.002)11.4 (- 9.5 ; 38.2)VAT (%)12.811.91.6 (- 1.4 ; 1.9)TAT (cm2)3.721.4 (p=0.013)10.9 (- 22.8 ; 44.8)SAT (cm2)- 3.25.12.1 (-18.0 ; 18.5)SAT (%)- 1.93.6- 1.1 (- 4.1 ; 1.9)SAT/VAT- 0.25- 0.11- 0.15 (-0.66 ; 0.15)DEXA scanLimb fat (kg)3217185 (- 383 ; 795)Trunk fat (kg)- 28382323 (- 988 ; 1768)Total fat (kg)- 389307293 (- 1304 ; 2816)Limb/trunk ratio0- 0.02- 0.01 (- 0.05 ; 0.05)Body fat distribution (median change from baseline to week 48)* p not significant for all measuresSPIRALCurran A, AIDS 2012;26:475-81

16. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition)Curran A, AIDS 2012;64:475-81SPIRAL382RALPI/r21.423.73.611.912.810.920.75.1-3.2-1.9-0.11-0.2517132- 28307-359-0.020cm2%TATSATVATVATSATSAT/VAT%LimbfatTrunkfatTotalfatLimb/trunkratiogMedian valuesAll differences PI/r vs RAL not significant0+-0+-

17. RALPI/rDifference (IQR) PI/r vs RALpDEXA scanTotal BMD (g/cm2)0.01 (p=0.002)00.01 (- 0.01 ; 0.02)0.079Femoral neck BMD (g/cm2)0- 0.010.01 (- 0.02 ; 0.02)0.032Femoral neck T score0.04- 0.100.01 (- 0.18 ; 0.18)0.016Total hip BMD (g/cm2)0.01 (p=0.015)00.01 (- 0.01 ; 0.02)nsTotal hip T score0.12 (p=0.004)0.010.11 (- 0.05 ; 0.20)nsL1-L4 BMD (g/cm2)00.020 (- 0.02 ; 0.04)nsL1-L4 T score0.030.100.09 (- 0.11 ; 0.31)nsBone composition (median change from baseline to week 48)BMD: bone mineral densityNo significant differences in BMD or T scores in either group even when controlling for TDF useSPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition)SPIRALCurran A, AIDS 2012;26:475-81

18. SPIRAL Study: Switch PI/r to RALSPIRAL-LIP substudy (body composition)ConclusionAlthough 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 TATSwitching to RAL led to a significant increase in femoral neck BMD when comparing between groupsSPIRALCurran A, AIDS 2012;26:475-81

19. SPIRAL Study: Comparison of ABC/3TC vs TDF/FTC Martinez E, AIDS Res Hum Retroviruses. 2013 Feb;29(2):235-41In the RAL group, decrease in triglycerides and increase in HDL cholesterol at W48 tended to be more pronounced with ABC/3TC than with TDF/FTCDifferences 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 significantSwitch to RALContinuation of PI/rNRTI ABC/3TC(N = 27)TDF/FTC(N = 73)ABC/3TC(N = 27)TDF/FTC(N = 70)Treatment failure* 3 (11.1%)8 (11%) 4 (14.8%) 12 (17.1%)Virologic failure (confirmed HIV-1 RNA > 50 c/mL) 1 (3.7%) 3 (4.1%) 2 (7.4%) 4 (5.7%)Discontinuation due to AE 0004 (GFR decrease, N = 3), BMD decrease, N = 1)* Treatment failure: virologic failure, discontinuation of NRTI due to adverse event, consent withdrawal, loss to follow-upSPIRAL

20. SPIRAL-MET substudy: LDL subclasses and lipoprotein-phospholipase A2 activity81 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 subfractionsPhenotype intermediate : LDL size 26.0-26.8 nmPhenotype B : LDL size < 26.0 nm with a predominance of small, dense LDL subfractionsTotal lipoprotein-associated phosholipase A2 (Lp-PLA2)Proproteinconvertasesubtilisin/kexin type 9 (PCSK9)Standard lipid parametersInsulin, C-peptide, HOMA indexCardiovascular risk assessment (Framingham equation)Saumoy M, Atherosclerosis 2012;225:200-7SPIRAL

21. RAL (n = 40)PI/r (n = 41)Age, years (median)4443Female15%27%ARV backbone: TDF/FTC ; ABC/3TC43% ; 35%74%PI/r at entry: LPV/r ; ATV/r ; FPV/r43% ; 38% ; 10%37% ; 39% ; 12%Time on previous PI/r, months (median)35.730Weight, kg (median)7371BMI, kg/m2 (median)24.524.4Cardiovascular risk estimation (Framingham)7.428.27Lipid lowering therapy17.5%22.8%Baseline characteristicsLipid parameters were not significantly different between groups, except Apo B, which was lower in the RAL arm (p = 0.035)Saumoy M, Atherosclerosis 2012;225:200-7SPIRAL-MET substudySPIRAL

22. Results Insulin, waistSignificant 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 armAt 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 groupNo change in number of patients on lipid-lowering therapyCardiovascular risk assessment at W48Increase in the PI/r arm (0.8% ; p = 0.032)No change in the RAL armNo change between arms at W48Significant 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 groupSaumoy M, Atherosclerosis 2012;225:200-7SPIRAL-MET substudySPIRAL

23. Saumoy M, Atherosclerosis 2012;225:200-7SPIRAL-MET: median changes in lipid parameters between baseline and W48 according to therapy0.60.06-0,810.07-0.36-0.04-0.110.10-0.710.05-0.490.29-0.32-0.01-0.12-0.04-0.110.030,.110.40.20.0-0.2-0,4-0.6-0.8-1.00.150.100.050.00-0.05-0.10-0.15-0.20-0.25< 0.0010.0230.108< 0.001< 0.0010.0260.004< 0.0010.073PI/r (N = 41)RAL (N = 40)Median change mmol/l (W48 – baseline)Median change g/l (W48 – baseline)TCLDL-cHDL-cNon-HDL-cTGTC/HDL-cApo A1Apo BApo A1/Apo BpSPIRAL

24. LDLc phenotype A: large & low density of cholesterol esters (non-atherogenic) LDLc phenotype B: small & high density of cholesterol esters (atherogenic) Saumoy M, Atherosclerosis 2012;225:200-7100806040200AIntermediateBBaselineW48BaselineW48BaselineW48Group 1 (n = 21)**Group 2 (n = 19)RAL (n = 40)Group 1: LPV/r, FPV/rGroup 2: ATV/r, SQV/r0.439*0.088*< 0.001*% LDL-c particles phenotype* 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)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 W48SPIRALLDLc phenotype

25. SPIRAL substudy: endothelial function35 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 W48Total cholesterol, LDL cholesterol and triglycerides decreased at W16 and W32 in the RAL arm, while no changes were observed in the PI/r armTriglyceride levels were significantly lower in the RAL arm than in the PI/r arm at W16, 32 and 48No 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 differencesMedian baseline FMD values within normal range ( > 5%) + limited sample size might have precluded detection of any RAL effect or clinically relevant differencesSPIRALMasia M, JAC 2013;68:409-413