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Pharmacological impact of antiretroviral therapy on platelet function to investigate HIV-associated cardiovascular risk

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Title: Pharmacological impact of antiretroviral therapy on platelet function to investigate HIV-associated cardiovascular risk
Authors: Taylor, KA
Smyth, E
Rauzi, F
Cerrone, M
Khawaja, AA
Gazzard, B
Nelson, M
Boffito, M
Emerson, M
Item Type: Journal Article
Abstract: Background and purpose Some clinical studies have reported increased myocardial infarction in people living with HIV taking the antiretroviral abacavir sulphate (ABC). Given that clinical studies contain confounding variables (e.g. HIV status), we investigated the pharmacological impact 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 anaesthetised 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 nitric oxide (NO)‐mediated inhibition of platelet aggregation and increased in vivo aggregation in mice. An alternative antiretroviral, tenofovir, did not affect platelet function. Furthermore, aggregation and activation of platelets isolated from twenty subjects taking clinically‐relevant doses of tenofovir were comparable to baseline samples. Conclusions and implications ABC can enhance platelet activation, independently of HIV status 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 supported by data demonstrating ABC‐mediated enhancement of aggregation in vivo and in vitro responses that persist 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.
Issue Date: Apr-2019
Date of Acceptance: 14-Dec-2018
URI: http://hdl.handle.net/10044/1/66716
DOI: https://doi.org/10.1111/bph.14589
ISSN: 0007-1188
Publisher: Wiley
Start Page: 879
End Page: 889
Journal / Book Title: British Journal of Pharmacology
Volume: 176
Issue: 7
Copyright Statement: © 2019 Wiley. This is the accepted version of the following article: Taylor KA, Smyth E, Rauzi F, et al. Pharmacological impact of antiretroviral therapy on platelet function to investigate HIV‐associated cardiovascular risk. Br J Pharmacol. 2019, which has been published in final form at https://dx.doi.org/10.1111/bph.14589
Sponsor/Funder: St Stephen's Aids Trust
NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research)
Gilead Sciences Inc
Gilead Sciences Inc
Funder's Grant Number: N/A
NC/M000079/1
PO 801315445
CO-UK-311-4087
Keywords: Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
TENOFOVIR DISOPROXIL FUMARATE
MYOCARDIAL-INFARCTION
NITRIC-OXIDE
HIV-1 INFECTION
CONCISE GUIDE
DOUBLE-BLIND
ABACAVIR
ALAFENAMIDE
EMTRICITABINE
INFLAMMATION
1115 Pharmacology and Pharmaceutical Sciences
Pharmacology & Pharmacy
Publication Status: Published
Online Publication Date: 2019-01-25
Appears in Collections:National Heart and Lung Institute