Mena, Álvaro MD*; Meijide, Héctor MD*; Vázquez, Pilar MD*; Castro, Ángeles MD, PhD*†; López, Soledad MD, PhD*; Bello, Laura MD*; Serrano, Joaquín MD*; Baliñas, Josefa*; Pedreira, José D MD, PhD*†
To the Editors:
HIV infection carries an increased risk of cardiovascular disease (CVD). In the Strategies for Management of Anti-Retroviral Study, episodic use of antiretroviral treatment (ART) guided by CD4 count was associated with 84% higher risk of death compared with the continuous ART strategy1; most of deaths were attributed to serious non-AIDS diseases; subsequently increased levels of high-sensitivity C-reactive protein, interleukin-6, and D-dimer associated with mortality had been reported.2
Studies using stored plasma of Swiss-Thai-Australia Treatment Interruption Trial3 and Strategies for Management of Anti-Retroviral Study found elevated levels of some cardiovascular markers in ART-naive patients, with a significant change in some of them after starting ART,4,5 improving the CVD profile. Also a correlation between HIV RNA replication and levels of biomarkers involved in endothelial activation, systemic inflammation, and coagulation cascade was reported.
Platelet activation and aggregation are central processes in the pathophysiology of atherosclerosis. Mean platelet volume (MPV) is a simple and accurate way to estimate platelet activity. Larger platelets are more active, contain more prothrombotic agents, and are more likely to aggregate.6 Recently, in general population, MPV has been shown as an independent risk factor for myocardial infarction7 and peripheral artery disease8; also is associated with a worse prognosis in stroke or acute coronary syndrome.
Scores applied to calculate the risk of CVD in general population underestimate the presence of subclinical atherosclerosis in HIV-infected patients, and biomarkers measured in trials to evaluate platelet activity are expensive and are not available in daily clinical practice. It is necessary to find new strategies to estimate the cardiovascular risk in this population.
We investigated whether HIV replication modified the MPV during the asymptomatic HIV infection and the influence of other cardiovascular risk factors.
PATIENTS AND METHODS
This retrospective study included patients followed at a reference hospital of Spain, in whom the HIV infection was diagnosed between January 2006 and December 2008. Follow-up of each patient was finished when the ART was started, if necessary, or in December 2010.
A detailed clinical history, physical examination, and laboratory parameters were recorded at baseline (the first consultation after HIV infection diagnosis) and each 4 months. It included smoking status, AIDS-related diseases, CVD, lipid profile, glucose, hemogram (collected in EDTA) including platelet count and MPV, plasma HIV-RNA level, and CD4 cell count.
Patients were excluded if they were <18 years and if they had previously or during the follow-up any of these: AIDS-related disease, clinical CVD, use of antiplatelet, antihypertensive, hypolipidemic, or antidiabetic drugs.
Categorical variables were summarized with percentages and continuous with median (interquartile range). Changes in variables were analyzed from baseline to the last control with paired Student t test or the Wilcoxon signed-rank test.
Pearson correlation coefficient was used to assess correlations between basal, final determination, and changes in all variables each others. The estimation of factors associated with changes in MPV was calculated using a multiple linear regression model.
All analyses were done with SPSS version 16.0. Statistical significance was defined as a 2-sided, P < 0.05.
A total of 183 ART-naive HIV-infected patients were included as follows: 81% men, median age 35 years (IQR = 30-42) and were followed a median of 22 months (IQR = 12-38). Smokers were 75 patients (41%) at baseline, and none stopped smoking during the follow-up. The route of infection was as follows: 42 (23%) intravenous drug use, 79 (43%) men who have sex with men, and 62 (34%) heterosexual. All were necessarily Centers for Disease Control and Prevention stage A. Coinfected with hepatitis C virus were 37 patients (20%) and 6 (3%) with hepatitis B virus.
Table 1 summarizes baseline, last determination, and changes in lipid profile, glucose, HIV-RNA, CD4 count, platelet count, and MPV. Platelets and CD4 counts decreased significantly, whereas MPV and HIV RNA had a significant increase. Little changes in lipids and fasting glucose were shown, achieving statistical significance only in decreasing of LDL cholesterol (P = 0.009).
Pearson correlation coefficients between all variables with the change in MPV are shown in Table 1. The change in MPV was significantly positively correlated with basal HIV RNA viral load and time of follow-up and negatively with basal MPV. After adjustment in linear regression model, these 3 variables were associated with the change in MPV.
Traditionally much of data with reference to CVD in HIV-infected patients have focused on the effect of ART therapy. However, data reported of treatment interruption trials1,3 and recent results analyzing biomarkers of CVD in samples of these trials have demonstrated that HIV infection without ART leads to a increase in CVD-associated morbimortality. All of this suggests that, in terms of CVD, the risk associated with adverse metabolic effects of ART may be outweighed by the benefits of suppressing viral load and improving immunological function. HIV replication has been shown as an important factor in the upregulation of inflammation, thrombotic activity, and coagulation.2,4,5
Platelet size may be determined by megakaryocyte ploidy, which is regulated by thrombopoietin and interleukin-6, that has been strongly related to mortality in general population and in HIV infected.2 Other studies had evaluated the association of HIV replication with mediators in the coagulation pathways and thrombotic activity4,5; in them, D-dimer levels were correlated with HIV RNA levels. Thus reducing inflammation and thrombotic activity is an additional objective in the management of HIV infection; it seems that patients on ART have levels of inflammatory and endothelial activations biomarkers similar to healthy controls.9 In our study, basal MPV is only inversely correlated with platelet count, as expected,7,8 but the increase in MPV, independently of other factors, is strongly associated with the HIV RNA level and the time that could translate an inflammatory and thrombotic effect of HIV infection. Smaller platelets have higher increases in MPV. We have not found association between the CD4 cells count and changes in MPV.
In 39,531 participants from the general population, the risk of myocardial infarction increased by 38% if MPV was ≥7.4 fL, independent of established cardiovascular risk factors7; 82% of our patients were over of this value at the HIV infection diagnosis and 100% after 22 months of follow-up. Another great cohort of general population found a 25% increased odds of peripheral artery disease for each fL increase in MPV, after adjustment for atherosclerotic risk factors8; in our study, 35% of HIV-infected untreated patients presented an increase of MPV ≥1 fL.
To our knowledge, these are the first data linking the MPV with HIV infection, a way to estimate platelet activity, available in daily clinical practice, and not like much of the marker studied that are research tools, yet to be included in routine clinical decision-making.
This study has limitations that may impact our findings. First, the retrospective design, with a relatively small population and without a comparative arm, each case was considered its own control. Second, it was focused on MPV and does not provide data on platelet function directly, but there is controversy over the optimal method of measuring platelet activity. Furthermore, we did not use an indirect method of measuring cardiovascular complications, as intimamedia thickness, and we did not incorporate other biomarkers. Current data are unable to quantify the clinical event risk associated with changes in MPV in HIV-infected persons.
In summary, we have found a larger MPV, a marker of atherothrombosis, in HIV-infected treatment-naive patients; and MPV increases significantly during the untreated asymptomatic HIV infection. Our study associates HIV RNA levels and changes in MPV, independent of others cardiovascular risk factors. Further studies are required to assess whether MPV provides added value in being able to identify HIV patients at increased CVD risk, population in whom traditional scores underestimate the risk, and whether therapeutic modification of this marker may lead to improved cardiovascular care.
Álvaro Mena, MD*
Héctor Meijide, MD*
Pilar Vázquez, MD*
Ángeles Castro, MD, PhD*†
Soledad Lòpez, MD, PhD*
Laura Bello, MD*
Joaquín Serrano, MD*
José D. Pedreira, MD, PhD*†
*HIV Unit, Internal Medicine Service, Universitary Hospital of A Coruña, A Coruña, Spain; †Department of Medicine. University of A Coruña, A Coruña, Spain.
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© 2011 Lippincott Williams & Wilkins, Inc.