Persistent Inflammation and Endothelial Activation in HIV-1 Infected Patients after 12 Years of Antiretroviral Therapy

The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART).Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, β2-microglobulin, interleukin (IL) 8, tumor necrosis factor α (TNFα), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE-Selectin, and sP-Selectin.HIV infected patients had higher levels of β2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls.Discrete signs of systemic and vascular inflammation persist even after very long term cART

T Cell Subsets in HIV Infected Patients after Successful Combination Antiretroviral Therapy:Impact on Survival after 12 Years

OBJECTIVES: Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up. METHODS: A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997–1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression. RESULTS: Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91–0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death. CONCLUSIONS: Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment

Thromboelastography on plasma reveals delayed clot formation and accelerated clot lyses in HIV-1 infected persons compared with healthy controls

BACKGROUND: Thromboembolic events among HIV infected persons are a recognized clinical problem but the underlying mechanisms are poorly understood. To assess whether coagulation and fibrinolysis differ between long-term treated HIV infected individuals (HIV+) and healthy controls (CON), we investigated functional plasma coagulation by thrombelastography (TEG) and plasma markers of endothelial and platelet activation. METHODS: In 67 successfully long-term treated HIV+ and 15 CON we analyzed stored plasma samples by TEG, with or without addition of tissue-type plasminogen activator (tPA), and measured levels of C-reactive protein, thrombomodulin, syndecan-1, sVE-cadherin, soluble CD40 ligand (sCD40L), adrenaline and noradrenaline. RESULTS: Compared to CON, HIV+ had delayed clot formation (reaction (R)-time 14.2 min. vs. 11.2 min., p = 0.0004) and reduced clot formation rapidity (angle 22.6° vs. 48.6 °, p = <0.0001). Clot lyses induced by tPA was accelerated in HIV+ displaying enhanced clot degradation after 30 and 60 min (53.9 % vs. 24.2 %, p < 0.0001 and 77.4 % vs. 59.9 %, p < 0.0001, respectively). sCD40L and TEG R-time correlated negatively in both HIV+ and CON (Rho =−0.502, p < 0.001 and rho =−0.651, p = 0.012). DISCUSSION: No previous studies have examined plasma coagulation by TEG in HIV, however, we have previously demonstrated that HIV+ display hypocoagulability in whole blood by TEG in accordance with the results of this study. Others have reported of HIV associated changes in the hemostatic system in a pro-coagulant direction based on measurements of isolated components of the coagulation pahways. In disease conditions, the flowing blood may change from “normal” to hyper- or hypocoagulant or to hyper- or hypofibrinolytic. A balance may exist in the flowing blood, i.e. between blood cells and the plasma phase, so that pro-coagulant blood cells are balanced by a hypocoagulable plasma phase; thus alterations that may promote thromboembolic events in the patient may at the same time appear as a hypocoagulable profile when evaluated in vitro. CONCLUSION: Plasma from long-term treated HIV infected persons displays a hypocoagulable profile with reduced fibrinolytic resistance as compared to healthy controls

Kaplan-Meier plots.

<p>The observation period (days) is from 18 months (+/−6 months) after initiation of cART till death or 01/01/2010. The dotted line depicts the highest 50^th percentile and the full line depicts the lowest 50^th percentile. Analysis of survival linked to T cell subset are made with proportions of CD4+ and CD8+ cells respectively. Analysis using concentrations instead of proportions yielded similar results. Subsets were defined as naïve CD4/8(CD45RA+, CD62+), memory CD4/8 (CD45RA-, CD45R0+) and activated CD4 (HLA-DR+), and activated CD8 (HLA-DR+, CD38+).</p

Levels of β2-microglobulin, IL-8, TNFα, sICAM-1, sVCAM-1 and sE-Selectin in HIV infected patients (HIV+) after 12 years of successful cART compared to HIV negative controls.

<p>Please note that β2-microglobulin is shown on a logarithmic Y-axis. Means were compared using Mann-Whitney test and depicted as boxplots with Tukey whiskers (1.5 times the interquartile distance or to the highest or lowest point, whichever is shorter). * = p<0.05, ** = p<0.001.</p

Uni-and multivariate cox regression.

<p>The analysis only included subjects with complete data (N = 90).</p><p>HR: hazard ratio, CI: confidence interval, %: proportion of total CD4 or CD8 cells respectively.</p><p>Subsets were defined as naïve CD4/8(CD45RA+, CD62+), memory CD4/8 (CD45RA-, CD45R0+), activated CD4 (HLA-DR+), and activated CD8 (HLA-DR+, CD38+).</p