Current or recent, but not cumulative, exposure to abacavir has been associated with some cohorts and randomized trials, with an approximate two-fold increased risk of cardiovascular disease (CVD) [1–6]. Even though abacavir increases cholesterol levels, the above ‘on-off’ association has lead to the hypothesis that abacavir induces vascular disease through an acute proinflammatory or prothrombotic effect rather than any change in plasma lipid levels.
Abacavir has been associated in vitro or cross-sectionally in vivo with increased platelet aggregation, increased neutrophil endothelial aggregation, and reduced endothelial function [7–9]. There are no prospective data, however, linking abacavir therapy with abnormal vascular function.
Increased arterial stiffness is associated with CVD in the general population. Applanation tonometry can measure aortic stiffness by determining the augmentation index (AIx) from a radial artery waveform . In HIV+ adults, AIx is increased in those receiving antiretroviral therapy (ART) and correlates with higher Framingham risk score (FRS) [11–15].
The two-fold relative risk (RR) associated with abacavir is fairly constant regardless of underlying cardiovascular risk and so the greatest absolute increase in risk was found in those with higher underlying FRS. Therefore, it seems possible that greater absolute changes in vascular function might be observed in those with higher underlying CVD risk, a group that has not been specifically studied.
We hypothesized that switching from abacavir to tenofovir in adults with high cardiovascular risk would result in improved arterial function (arterial stiffness). We evaluated changes in arterial stiffness and changes in FRS, traditional cardiovascular risk factors, and cardiovascular biomarkers associated with cardiovascular disease [16–23].
We recruited 20 men with 10-year risk of a fatal or nonfatal myocardial infarction (FRS) above 10% (http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof), normal renal function, and undetectable plasma HIV viral load for at least the preceding 6 months to switch from abacavir to tenofovir. We excluded patients with an active, intercurrent illness (such as a bacterial infection) in the preceding 30 days, whose ART had been modified in the previous 3 months or in whom arterial tonometry would be impossible (e.g. atrial fibrillation). The study was approved by the St Vincent's Hospital Human Research Ethics Committee and registered at the Australian New Zealand Clinical Trial Registry (ACTRN12609000014257). All patients provided their written, informed consent.
All assessments were performed after a minimum 10-h overnight fast. C-reactive protein was measured using the Olympus high-sensitivity immunoturbidimetric assay [Integrated Sciences, Sydney, Australia; lower limit of detection (LLD) 0.2 mg/l, coefficient of variation 5.5%]. D-dimer was measured using the VIDAS D-dimer exclusion assay (BioMerieux South Africa, Marcy-L'Etoile, France; LLD 0.045 mg/l fibrinogen equivalent units, coefficient of variation 4%). Interleukin (IL)-6 was measured using cytometric bead array (CBA) human IL-6 flex set with the CBA human soluble protein master buffer kit (BD Bioscience, San Jose, USA; LLD 0.2 pg/ml, coefficient of variation 6.7%).
The AIx is augmentation divided by pulse pressure multiplied by 100, where augmentation equals the first aortic SBP peak minus the second aortic SBP peak, and pulse pressure is aortic SBP minus aortic DBP. Patients were assessed before venesection and were advised not to exercise vigorously or to drink alcohol for the preceding 12 h. Heart rate-adjusted AIx was derived using applanation tonometry (SphygmoCor SCOR-PVx tonometer, AtCor Medical, Sydney, Australia), which was performed in duplicate at the left radial artery (wrist) after at least 15 min rest. A validated transfer function was then used to derive the central (aortic) AIx.
Comparisons between time points were by repeated measures. Cardiac biomarker values were not normally distributed and so log-transformed values were used for all analyses. Statistical analysis was performed using PASW Statistics, version 17.0 (Chicago, Illinois, USA).
Abacavir was switched to tenofovir in 20 men [median 56 years, eight (40%) receiving a ritonavir-boosted protease inhibitor, 12 (60%) receiving efavirenz or nevirapine, mean 10-year FRS 15% (SD 4%), five (25%) with prior cardiovascular disease); all but one switched from abacavir–lamivudine to tenofovir–emtricitabine. No patient altered their other antiretroviral, antihypertensive (n = 9), antiplatelet (n = 5), lipid-lowering (n = 11), or diabetic therapy (n = 2) on study; only one of eight smokers stopped smoking (at week 12).
Mean baseline AIx was elevated at 22% (SD six) [24,25]. After switching, AIx declined acutely by an absolute 4.0% at week 4 (P = 0.03) and remained 2.7% lower at week 24 (P = 0.067), at which point all patients remained on tenofovir and had undetectable viral loads (Table 1).
FRS also declined at week 4 (mean 2.3% decline; P = 0.01), with no significant change in any FRS component except for a significant decrease in fasting total cholesterol (0.8 mmol/l; P = 0.002). After adjustment for change in FRS, the changes in AIx at weeks 4 and 24 were nonsignificant (P = 0.50 and 0.72, respectively).
No cardiovascular biomarker changed significantly at week 4; plasma levels had all declined significantly at week 12, but only IL-6 remained significantly below baseline at week 24.
These nonrandomized, pilot data suggest that switching from abacavir to tenofovir in patients with elevated FRS reduces arterial stiffness, a change that may be contributed to by reduction in total cholesterol rather than by an inflammatory or thrombotic mechanism.
The rapid decline in AIx and FRS, we observed, is in keeping with the association of abacavir with current but not cumulative use of abacavir . It is noteworthy that there was an absolute 3% decline in FRS from a baseline 15%, which is less than the two-fold RR found in the largest study.
Our study has obvious limitations: it was relatively small and only recruited men at moderate or higher CVD risk. The lack of randomization cannot exclude the possibility that the observed results were owing to regression to the mean, although FRS has far lower variability in patients with stable risk factors, or owing to patients being more adherent to their lipid-lowering or antihypertensive therapy after switching. The duration of abacavir has not been associated with CVD risk, but rather its current or recent use . Therefore, we did not record abacavir duration and so could not determine whether change in AIx correlated with abacavir duration. These findings should be evaluated in a randomized trial.
We thank the patients for their time and commitment, and Leo McHugh for assistance with statistical analyses.
A.C. is a recipient of a Practitioner Fellowship from the Australian National Health and Medical Research Council. The study was partially funded by unrestricted educational grants from the Balnaves Foundation and Bristol-Myers Squibb. A.C. has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences and Merck; consultancy fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Merck; lecture sponsorships from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Merck; and has served on advisory boards for Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Roche.
A.C. designed the study, recruited patients, and drafted the manuscript. R.R. and K. S. implemented the study. All authors reviewed all data and analyses, and wrote the manuscript.
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