People living with HIV infection have increased risk of cardiovascular disease (CVD), despite effective antiretroviral therapy. Emerging evidence show that residual persistent immune dysregulation contributes to CVD risk in the HIV population. In addition, metabolic disorders including insulin resistance, dyslipidemia and increased visceral adiposity are common in people with HIV and also contribute significantly to excess CVD risk. The key hypothesis of this grant application is that CCR2 and CCR5 drive inflammatory macrophages and T- cells into tissues including arterial intima causing atherosclerosis, and into adipose tissue causing insulin resistance. We expect that dual antagonism of CCR2 and CCR5 chemokine receptors will reduce immune activation, reduce inflammation in the vasculature, reduce adipose tissue inflammation and reduce insulin resistance. To test our hypotheses, we propose a multicenter placebo-controlled, double-blind, 24-week long, randomized trial of cenicriviroc vs. placebo (in 2:1 ratio) in 93 adult men and women living with HIV with suppressed HIV-1 RNA on stable ART who have increased CVD risk to 1) determine the impact of dual CCR2/CCR5 antagonism with cenicriviroc on arterial inflammation and circulating soluble and cellular markers of inflammation and immune activation and 2) To determine the impact of dual CCR2/CCR5 antagonism with CVC on insulin resistance and adipose tissue inflammation, gene expression, and immune cells. This proposal will leverage the clinical trial infrastructure of the ACTG and the extensive scientific expertise of collaborating investigators and laboratories within the ACTG.
This study will assess whether a novel class of drugs (dual CCR2/CCR5 antagonists), can be used to improve vascular and metabolic health in people living with HIV. The study will determine if the intervention reduces arterial inflammation, (a primary disease-causing feature of plaque in the arteries), reduces adipose tissue inflammation, and improves insulin resistance (the driver of diabetes). The study will be performed across multiple sites in the United States, in collaboration with an established AIDS research network.
