Impact of Tenofovir Versus Abacavir on HIV-Related Endothelial Dysfunction

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Ischemic cardiovascular events are a frequent complication of long-lasting HIV infection and have been attributed either to the infection itself or to antiretroviral therapy (ART). ^{1 –3} Some cohort studies suggested that in particular abacavir may be associated with an increased cardiovascular risk, but the pathogenic mechanisms remain unknown. ⁴ Recently, abacavir use was significantly associated with incident cardiovascular disease in HIV-infected veterans ¹ and it was related to higher risk of acute myocardial infarction (AMI). ⁵ Endothelial dysfunction is a central mechanism in atherosclerosis and a marker of cardiovascular risk. ^6,7 We have previously shown that HIV-infected patients present an endothelial dysfunction that tends to improve upon ART, suggesting that the infection itself rather than therapy is responsible for endothelial damage. ⁸

In the present study we compared treatment with abacavir (ABC) and tenofovir (TDF) for their impact on endothelial dysfunction.

In a retrospective, case-control study, plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and monocyte chemoattractant protein-1 (MCP-1), two markers of endothelial dysfunction, ^6,8 were measured by flow cytometry using a bead-based assay (FlowCytomix, Bender MedSystems, Vienna, Austria) ⁸ in 69 HIV-infected patients, before starting therapy and after 6–12 months of either ABC (n=35, 18 females, age 44±12 years) or TDF (n=34, 17 females, age 43±11 years). The two groups were similar for baseline immune-virologic status and all patients showed an increase of CD4⁺ count and a lowering of viral load after therapy, without differences between ABC and TDF. Twenty-one patients were recalled 28–34 months after the beginning of therapy (11 ABC and 10 TDF) for the measurement of peripheral vascular endothelial function by finger arterial pulse wave amplitude with the Endo-PAT2000 system, and of circulating endothelial cells (CECs) by flow cytometry. ^{9 –11}

Two control groups were included: 20 HIV-infected patients (6 females, age 42±9 years), from whom blood samples were collected at diagnosis and after 6–12 months without therapy, and 10 healthy age- and gender-matched controls. All results are expressed as means±standard error of the mean (SEM). Differences between groups were assessed by using one-way analysis of variance (ANOVA) with the Kruskal-Wallis post hoc test, using the GraphPad Prism version 4.00 for Windows software (GraphPad, San Diego, CA).

At diagnosis endothelial activation markers were significantly higher in HIV-infected patients than in healthy controls (sVCAM-1: 783±157 versus 518±53 ng/mL, p<0.05; MCP-1: 293±22 versus 228±20 pg/mL, p<0.05). After 6–12 months of treatment, sVCAM-1 and MCP-1 decreased significantly in the TDF group, although not to normal levels, but not in the ABC group, while in untreated patients endothelial dysfunction did not change, or even slightly worsened, at follow-up (Fig. 1A and B). Upon reevaluation after 28–34 months of treatment endothelial function, as assessed by peripheral arterial tonometry and CECs, was still significantly altered in HIV-infected patients as compared with healthy controls (Fig. 1C), with ABC-treated patients showing significantly higher CECs than controls and tendentially higher than TDF-treated patients (Fig. 1D); moreover, in ABC-treated but not in TDF-treated patients, CECs inversely correlated with endothelial function (Fig. 1E and F).

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FIG. 1.

Effect of abacavir (ABC) or tenofovir (TDF) treatment on various parameters of endothelial function. Mean change in plasma biomarkers, soluble vascular cell adhesion molecule-1 (sVCAM-1) (A) and monocyte chemoattractant protein-1 (MCP-1) (B), from baseline to 6–12 months, in HIV-infected patients stratified by treatment (*p<0.05 versus untreated). (C) Endothelial function, as assessed by peripheral arterial tonometry and expressed as reactive hyperemia index (RHI), in ABC- or TDF-treated HIV-infected patients as compared with healthy controls (*p=0.0037). (D) Circulating endothelial cells (CECs) in ABC- or TDF-treated HIV-infected patients and healthy controls (*p<0.05 versus controls). In the ABC group (r ²=0.81, p=0.0001) (E), but not in the TDF group (r ²: 0.2496, p=ns) (F), a significant inverse correlation was evident between endothelial dysfunction (RHI) and CECs.

Endothelial dysfunction detected by impaired peripheral arterial tonometry and increased CECs, two parameters not previously measured in HIV-infected patients, is a reliable marker of vascular damage and predicts late cardiovascular ischemic events. ^9,12 Therefore, our data confirm that chronic HIV-infection impairs endothelial function and show that antiretroviral treatment with TDF, but less with ABC, improves it. Very recent data showing that TDF selectively decreases the production of cardiovascular disease-related inflammatory cytokines are supportive of our conclusions. ¹³ Whether persistent endothelial dysfunction in ABC-treated patients contributes to the suggested increased cardiovascular risk associated with ABC use needs to be assessed in prospective studies.