Dataset Information

Pharmacological impact of antiretroviral therapy on platelet function to investigate human immunodeficiency virus-associated cardiovascular risk.

ABSTRACT:

Background and purpose

Some clinical studies have reported increased myocardial infarction in people living with human immunodeficiency virus (HIV) taking the antiretroviral abacavir sulphate (ABC). Given that clinical studies contain confounding variables (e.g., HIV-associated factors), we investigated the pharmacological effects of antiretrovirals on platelet function in HIV-negative volunteers in order to identify mechanisms of increased cardiovascular risk.

Experimental approach

Platelets were isolated from healthy volunteers and HIV-negative subjects enrolled on a Phase I clinical trial and platelet function evaluated using aggregometry and flow cytometry. In vivo platelet thromboembolism was monitored in anaesthetized mice.

Key results

Human platelet aggregation was unaffected by all antiretrovirals tested, but ABC treatment led uniquely to increased platelet granule release. ABC also interrupted NO-mediated inhibition of platelet aggregation and increased in vivo aggregation in mice. Another antiretroviral, tenofovir, did not affect platelet function. Furthermore, aggregation and activation of platelets isolated from 20 subjects taking clinically relevant doses of tenofovir were comparable to baseline samples.

Conclusions and implications

ABC can enhance platelet activation, independently of variables that confound clinical studies, suggesting a potential pharmacological effect that is absent with tenofovir. Mechanistically, we propose that ABC enhances platelet degranulation and interrupts NO-mediated platelet inhibition. The interaction of ABC with NO signalling is demonstrated by ABC-mediated enhancement of aggregation in vivo and in vitro that persisted in the presence of NO. Although an association between ABC and platelet activation has not been confirmed in patients, these findings provide evidence of a mechanistic link between platelet activation and antiretroviral therapy.

SUBMITTER: Taylor KA

PROVIDER: S-EPMC6433647 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Pharmacological impact of antiretroviral therapy on platelet function to investigate human immunodeficiency virus-associated cardiovascular risk.

Taylor Kirk A KA Smyth Erica E Rauzi Francesca F Cerrone Maddalena M Khawaja Akif A AA Gazzard Brian B Nelson Mark M Boffito Marta M Emerson Michael M

British journal of pharmacology 20190314 7

<h4>Background and purpose</h4>Some clinical studies have reported increased myocardial infarction in people living with human immunodeficiency virus (HIV) taking the antiretroviral abacavir sulphate (ABC). Given that clinical studies contain confounding variables (e.g., HIV-associated factors), we investigated the pharmacological effects of antiretrovirals on platelet function in HIV-negative volunteers in order to identify mechanisms of increased cardiovascular risk.<h4>Experimental approach</ ...[more]

PMID: 30681136

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Project description:IMPORTANCE:Individuals with human immunodeficiency virus (HIV) infection receiving combined antiretroviral therapy (ART) have an increased risk of myocardial infarction. Effects of ART on arterial inflammation among treatment-naive individuals with HIV are unknown. OBJECTIVE:To determine the effects of newly initiated ART on arterial inflammation and other immune/inflammatory indices in ART-naive patients with HIV infection. DESIGN, SETTING, PARTICIPANTS:Twelve treatment-naive HIV-infected individuals underwent fludeoxyglucose F 18 ([18F]-FDG) positron emission tomographic scanning for assessment of arterial inflammation, coronary computed tomographic angiography for assessment of subclinical atherosclerosis, and systemic immune and metabolic phenotyping before and 6 months after the initiation of therapy with elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (combined ART). Systemic immune and metabolic factors were also assessed in 12 prospectively recruited individuals without HIV serving as controls. The study began July 24, 2012, and was completed May 7, 2015. INTERVENTIONS:Combined ART in the HIV-infected cohort. MAIN OUTCOMES AND MEASURES:The primary outcome was change in aortic target-background ratio (TBR) on [18F]-FDG-PET with combined ART in the HIV-infected group. RESULTS:For the 12 participants with HIV infection (mean (SD) age, 35 [11] years), combined ART suppressed viral load (mean [SD] log viral load, from 4.3 [0.6] to 1.3 [0] copies/mL; P?<?.001), increased the CD4+ T-cell count (median [IQR], from 461 [332-663] to 687 [533-882] cells/mm3; P?<?.001), and markedly reduced percentages of circulating activated CD4+ T cells (human leukocyte antigen-D related [HLA-DR]+CD38+CD4+) (from 3.7 [1.8-5.0] to 1.3 [0.3-2.0]; P?=?.008) and CD8+ T cells (HLA-DR+CD38+CD8+) (from 18.3 [8.1-27.0] to 4.0 [1.5-7.8]; P?=?.008), increased the percentage of circulating classical CD14+CD16- monocytes (from 85.8 [83.7-90.8] to 91.8 [87.5-93.2]; P?=?.04), and reduced levels of CXCL10 (mean [SD] log CXCL10, from 2.4 [0.4] to 2.2 [0.4] pg/mL; P?=?.03). With combined ART, uptake of [18F]-FDG in the axillary lymph nodes, as measured by TBR, decreased from a median (IQR) of 3.7 (1.3-7.0) at baseline to 1.4 (0.9-1.9; P?=?.01) at study end. In contrast, no significant decrease was seen in aortic TBR in response to combined ART (mean [SD], 1.9 [0.2]; median [IQR], 2.0 [1.8-2.1] at baseline to 2.2?[0.4]; 2.1 [1.9-2.6], respectively, at study end; P?=?.04 by 2-way test, P?=?.98 for test of decrease by 1-way test). Changes in aortic TBR during combined ART were significantly associated with changes in lipoprotein-associated phospholipase A2 (n?=?10; r?=?0.67; P?=?.03). Coronary plaque increased among 3 participants with HIV infection with baseline plaque and developed de novo in 1 participant during combined ART. CONCLUSIONS AND RELEVANCE:Newly initiated combined ART in treatment-naive individuals with HIV infection had discordant effects to restore immune function without reducing arterial inflammation. Complementary strategies to reduce arterial inflammation among ART-treated HIV-infected individuals may be needed.

Dataset Information

Pharmacological impact of antiretroviral therapy on platelet function to investigate human immunodeficiency virus-associated cardiovascular risk.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Pharmacological impact of antiretroviral therapy on platelet function to investigate human immunodeficiency virus-associated cardiovascular risk.

Similar Datasets

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