Switch studies - SPIRAL study

Switch studies in virologically suppressed patients

Table of contents

Switch to RAL-containing regimen
SPIRAL Study: Switch PI/r to RAL
Original article : AIDS. 2010 Jul 17;24(11):1697-707 – E Martinez ; AIDS. 2012 Nov 28;26(18):2315-26 – E Martinez ; AIDS. 2012 Feb 20;26(4):475-81 – A Curran ; AIDS Res Hum Retroviruses. 2013 Feb;29(2):235-41 – E Martinez ; Atherosclerosis. 2012 Nov;225(1):200-7 – M Saumoy ; J Antimicrob Chemother. 2013 Feb;68(2):409-13 – M Masiá
Last update : 02/06/2015

Dr Anton Pozniak
Chelsea and Westminster Hospital
London, UK

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

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Consent withdrawn, lost to follow-up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

Back to Table of Contents