HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk
CIRCULATION RESEARCH
Authors: Khawaja, Akif A.; Taylor, Kirk A.; Lovell, Andrew O.; Nelson, Mark; Gazzard, Brian; Boffito, Marta; Emerson, Michael
Abstract
Rationale: People living with HIV on effective antiretroviral therapy are at increased risk of cardiovascular complications, possibly due to off-target drug effects. Some studies have associated antiretroviral therapy with increased risk of myocardial infarction and endothelial dysfunction, but a link between endothelial function and antiretrovirals has not been established. Objective: To determine the effects of antiretrovirals in common clinical use upon in vitro endothelial function to better understand cardiovascular risk in people living with HIV. Methods and Results: Human umbilical cord vein endothelial cells or human coronary artery endothelial cells were pretreated with the antiretrovirals abacavir sulphate (ABC), tenofovir disoproxil fumarate, or tenofovir alafenamide. Expression of adhesion molecules, ectonucleotidases (CD39 and CD73), tissue factor (TF), endothelial-derived microparticle (EMP) numbers and phenotype, and platelet activation were evaluated by flow cytometry. TF and ectonucleotidase activities were measured using colourimetric plate-based assays. ABC-treated endothelial cells had higher levels of ICAM (intercellular adhesion molecule)-1 and TF expression following TNF (tumor necrosis factor)-alpha stimulation. In contrast, tenofovir disoproxil fumarate and tenofovir alafenamide treatment gave rise to greater populations of CD39(+)CD73(+) cells. These cell surface differences were also observed within EMP repertoires. ABC-treated cells and EMP had greater TF activity, while tenofovir disoproxil fumarate- and tenofovir alafenamide-treated cells and EMP displayed higher ectonucleotidase activity. Finally, EMP isolated from ABC-treated cells enhanced collagen-evoked platelet integrin activation and alpha-granule release. Conclusions: We report differential effects of antiretrovirals used in the treatment of HIV upon endothelial function. ABC treatment led to an inflammatory, prothrombotic endothelial phenotype that promoted platelet activation. In contrast, tenofovir disoproxil fumarate and tenofovir alafenamide conferred potentially cardioprotective properties associated with ectonucleotidase activity. These observations establish a link between antiretrovirals and specific functional effects that provide insight into cardiovascular disease in people living with HIV.
How to manage IBD in the 'elderly'
FRONTLINE GASTROENTEROLOGY
Authors: Segal, Jonathan P.; Htet, Hein Myat Thu; Limdi, Jimmy; Hayee, Bu'Hussain
Abstract
As the incidence of inflammatory bowel disease (IBD) rises and the global population ages, the number of older people living with these conditions will inevitably increase. The challenges posed by comorbid conditions, polypharmacy, the unintended consequences of long-term treatment and the real but often underestimated mismatch between chronological and biological ages underpin management. Significantly, there may be differences in disease characteristics, presentation and management of an older patient with IBD, together with other unique challenges. Importantly, clinical trials often exclude older patients, so treatment decisions are frequently pragmatic, extrapolated from a number of sources of evidence and perhaps primarily dictated by concerns around adverse effects. This review aimed to discuss the epidemiology, clinical features and considerations with management in older patients with IBD.