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Design :

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

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• Consent withdrawn, lost to follow-up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

Baseline characteristics and patient disposition :

Results: Efficacy analyses :

• 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

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

Percentage changes in fasting lipid concentrations from baseline to W48 :

• 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

Cardiovascular biomarkers: median (95% CI) difference of percent change from baseline to W48, RAL (N = 119) minus PI/r (N = 114) :

Correlations between ∆ biomarkers and ∆ 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

SPIRAL Study: Switch PI/r to RAL
SPIRAL-LIP substudy (body composition)

Procedures at 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)

Baseline characteristics of the 74 participants :

Body fat distribution (median change from baseline to week 48) :

Bone composition (median change from baseline to week 48) :

• No significant differences in BMD or T scores in either group even when controlling for TDF use

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

SPIRAL Study: Comparison of ABC/3TC vs TDF/FTC

• 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-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)
• Proprotein convertase subtilisin/kexin type 9 (PCSK9)
• Standard lipid parameters
• Insulin, C-peptide, HOMA index
• Cardiovascular risk assessment (Framingham equation)

SPIRAL-MET substudy

Baseline characteristics :

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

Median changes in lipid parameters between baseline and W48 according to therapy

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 :

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