What is the Impact of Current HIV Medication Regimens on Endothelial Dysfunction?

Metabolic and endocrine perturbations including insulin resistance, diabetes, and dyslipidemia have been of significant concern in human immunodeficiency virus (HIV)-infected individuals. HIV-infected individuals may be at risk of accelerated atherosclerotic cardiovascular disease (CVD) and metabolic syndrome. HIV infection itself and first-generation antiretroviral (ART) therapies, have been associated with adipose tissue/ lipodystrophic changes and disorders of glucose and lipid metabolism. More recent data suggest that immune activation and inflammation from chronic HIV infection may play an important role in HIV-associated metabolic dysfunction. Given the recent advances in ART, an increasing number of HIV-infected individuals are virologically controlled and living longer; as such, the trajectory of HIV-associated morbidity has shifted from one of primarily acute opportunistic infections and immune deficiency/dysfunction to one that includes chronic metabolic complications such as CVD. It is therefore important to discern the effect of current HIV medications on endothelial dysfunction and cardio-metabolic health.

Endothelial progenitor cells (EPCs), are an established biomarker for cardiovascular risk outcome measures. EPCs have been defined as CD34+ cells thereby identifying a defined homogenous population from heterogeneous peripheral blood derived mononuclear cells. We and others have previously shown that EPCs can act as a cellular biomarker that is more reliable than plasma-based markers for CVD risk estimation. Though these studies were not specifically directed towards HIV positive population one can postulate that CD34+ cells will act as an efficient biomarker for endothelial function in this population of interest.

Regarding treatment regimens for HIV, in general, the initial regimen for HIV-infected individuals usually includes two NRTIs plus an INSTI, an NNRTI, or a PI boosted with either cobicistat or ritonavir. Previously, protease inhibitors such as indinavir, and reverse transcriptase inhibitors such as AZT or d4t, have been implicated in mitochondrial dysfunction and oxidative stress, altered adipogenesis and differentiation, and impaired glucose and lipid homeostasis. Newer ART agents have been suggested to have lesser impact on metabolic parameters. However, these newer agents may trigger poorly understood processes that may have a negative impact on endothelium and numerous metabolic pathways.

Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will include NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) plus one of the following:

1: an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine (Group A) 2. a boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination] (Group B), and 3: an Integrase inhibitor (dolutegravir) (Group C) We are including an integrase inhibitor because these agents have become the most popular initial regimen for newly infected HIV individuals. To avoid effect of medication within the three groups we have identified specific drugs within each class.