HIV, ART & Endothelial Dysfunction
Reported by Jules Levin
9th Intl Workshop on Adverse Drug Reactions and Lipodystrophy
Sydney, Ausralia, July 19-21, 2007
This afternoon at the meeting were three interesting presentations on endeothelial function.
"Control of HIV viral replication is associated with rapid improvement in endothelial function sustained over 24 weeks: A5152s, a substudy of A5142"
Judith Currier UCLA, et al.
--major endothelial dysfunction was identified in subjects with untreated HIV-infection.
--all three class-sparing ART regimens rapidly improved endothelial function in the face of major increases in artherogenic lipids.
--increase in FMD was of similar magnitude, appeared after 4 weeks, and persisted at 24 weeks.
--There were no strong associations between changes in FMD and metabolic or inflammatory markers, despite major lipid differences between arms.
--Improvement in FMD was significantly associated with decrease in HIV RNA at week 24, regardless of baseline HIV RNA and CD4 count.
In this first prospective randomized evaluation of the effects of ART on endothelial function in ART na´ve infected patients:
--effective control of HIV replication improved endothelial function during the first 24 weeks of ART regardless of initial ART regimen and in the face of major increases in artherogenic lipid profiles.
--Improved vascular reactivity may signify decreased short-term CV risk.
Use of PIs has been associated with endothelial dysfunction and increased subclinical artherosclerosis. Other components of ART such as NRTIs and NNRTIs may also affect CV risk factors. The cardiovascular effects of treating viremia have not been investigated.
The objective of the study was to evaluate the effect of potent ART on endothelial function in treatment-na´ve HIV+ individuals.
--This is a substudy of 5142
--patients randomly assigned to one of 3 ART regimens:
PI sparing: efavirenz + NRTIs
NNRTI sparing: lopinavir/r and NRTIsd
NRTI sparing: lopinavir/r and efavirenz
--NRTIs: 3TC + d4T or AZT or tenofovir (not randomized.
--24 weeks study duration
performed at 5 sites in the USA
--25 patients per arm
--80% power to detect a 4% increase in FMD (alpha=0.05)
--4% improvement in FMD considered a clinically significant change
HIV RNA >2000 c/ml
Known CAD, PAD or CVD
Use of lipid lowering medications
Use of antioxidant vitamin supplements
Use of steroids or hormones > replacement doses
-high resolution B-mode ultrasonography
--bracial artery flow-mediated dilation (FMD), a marker of endothelial function (normal >8%)
--nitroglycerin-mediated vasodilation, a marker of endothelium independent vasodilation
--time-points: before starting on ART; after 4 weeks; after 24 weeks
--FMD readers were blinded to treatment arms and ART
Age: 35 across 3 arms
Race: about 55% white/32% Black/14% Latino
Current Smoker: about 44% across 3 arms
CD4 count: about 240 across all arms
HIV RNA: about 4.80 log c/ml.
(This data taken from abstract book, missed FMD data slide). Pre-ART FMD was impaired (4.0% [3.1] versus normal >7%). After 4 and 24 weeks of ART, FMD increased by 1.1% [2.8] (p=0.003) and 1.9% [3.0] (p>0.50). FMD improvement was similar in each arm (p>0.50). Of all metabolic and inflammatory markers analyzed, only variable associated with improvement in FMD was reduction in HIV RNA week 24.
No significant change in weight, BMI, insulin, QUICKI, CRP, adiponectin, SICAM, SVCAM, ADMA.
Significant increase in glucose in EFV arm at weeks 4 and 24 (p=0.02 and p=0.04).
Significant increase in lipoprotein (a) at weeks 4 and 24 in all arms (p=0.01).
No consistent correlations between changes in FMD and these variables.
Total and HDL chol increased significantly in each arm. (p<0.01); triglycerides in the LPV-containing arms only (p<0.01).
Change in HIV RNA and CD4 Over Time
Log HIV RNA decreased by about 2 and 3 logs at week 4 and week 24 (p<0.01).