Effects of HIV integrase inhibitors on cardiovascular components
File(s)
Author(s)
Keniyopoullos, Renos
Type
Thesis
Abstract
Approximately 39 million people live with HIV (PLWH) today. With combination antiretroviral therapy
(cART), PLWH can no longer develop AIDS and maintain an undetectable viral load, but they have been
shown to acquire double the risk in developing a cardiovascular disease (CVD) compared to the general
population. Several antiretrovirals have been associated with off target effects on the endothelium and
platelets. In particular, integrase strand inhibitors (INSTIs), including bictegravir (BIC) and dolutegravir
(DTG), are largely used in clinics today, and recent studies associated DTG with an enhanced platelet
activity, highlighting the need to explore any possible impact DTG, or similar INSTIs may have on CVD
risk. Here, I hypothesize that DTG affects endothelial and platelet activation more than BIC and I aimed
to explore and compare the effects of the two, post in vitro treatment with clinically relevant
concentrations of the drugs, alone or in therapeutical combinations and conduct some ex vivo platelet
assays from PLWH to create a pilot study. Adhesion and permeability markers of Human Umbilical Vein
Endothelial Cells (HUVEC) and Human Coronary Endothelial Cells (HCAEC) were measured post
stimulation in flow cytometry or confocal microscopy. Platelet aggregation and surface activation
markers were measured in light transmission aggregometry and flow cytometry, respectively.
Additionally, platelet adhesion to collagen was measured under physiological conditions upon in vitro
treatment with INSTIs. Major findings show no effects of DTG or BIC on HUVEC or HCAEC. A higher
platelet aggregation profile is displayed in samples treated with INSTIs (especially DTG) versus vehicle
control, however this was not extended in ex vivo assays from patients. A neutral effect of INSTIs on the
endothelium was demonstrated, though clinical relevance of this yet to be determined. This pilot study
offers a template for future patient and pathophysiological studies to allow personalized treatments
with lower CVD risk.
(cART), PLWH can no longer develop AIDS and maintain an undetectable viral load, but they have been
shown to acquire double the risk in developing a cardiovascular disease (CVD) compared to the general
population. Several antiretrovirals have been associated with off target effects on the endothelium and
platelets. In particular, integrase strand inhibitors (INSTIs), including bictegravir (BIC) and dolutegravir
(DTG), are largely used in clinics today, and recent studies associated DTG with an enhanced platelet
activity, highlighting the need to explore any possible impact DTG, or similar INSTIs may have on CVD
risk. Here, I hypothesize that DTG affects endothelial and platelet activation more than BIC and I aimed
to explore and compare the effects of the two, post in vitro treatment with clinically relevant
concentrations of the drugs, alone or in therapeutical combinations and conduct some ex vivo platelet
assays from PLWH to create a pilot study. Adhesion and permeability markers of Human Umbilical Vein
Endothelial Cells (HUVEC) and Human Coronary Endothelial Cells (HCAEC) were measured post
stimulation in flow cytometry or confocal microscopy. Platelet aggregation and surface activation
markers were measured in light transmission aggregometry and flow cytometry, respectively.
Additionally, platelet adhesion to collagen was measured under physiological conditions upon in vitro
treatment with INSTIs. Major findings show no effects of DTG or BIC on HUVEC or HCAEC. A higher
platelet aggregation profile is displayed in samples treated with INSTIs (especially DTG) versus vehicle
control, however this was not extended in ex vivo assays from patients. A neutral effect of INSTIs on the
endothelium was demonstrated, though clinical relevance of this yet to be determined. This pilot study
offers a template for future patient and pathophysiological studies to allow personalized treatments
with lower CVD risk.
Version
Open Access
Date Issued
2024-08-15
Date Awarded
01/12/2024
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Emerson, Michael
Sponsor
NHLI Foundation
Grant Number
N/A
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)