Despite virologic suppression, antiretroviral therapy is not sufficient to fully turn off immune activation in people living with HIV. This heightened immune activation and inflammation has been associated with increased mortality and several comorbidities, including metabolic and cardiovascular disease. The mechanisms causing HIV-associated immune activation however, remain incompletely understood, but alteration of intestinal integrity (or ?leaky gut?) and the resultant translocation of microbial products from the intestinal lumen to the systemic circulation appear to play a central factor. In obesity and diabetes, translocation of bacterial products has been shown to promote systemic and adipose tissue inflammation and lead to expansion of visceral adipose tissue and insulin resistance. The relationship between the ?leaky gut? and metabolic complications in HIV is unknown. In addition, no large randomized study has yet compared the effect on gut integrity markers of newer antiretroviral classes, namely Integrase Strand Transfer Inhibitors, to that of older classes such as protease inhibitors. In this application, we propose to leverage the highly established research infrastructure within the AIDS Clinical Trials Group and utilize repository specimens from a large completed clinical trial to study for the first time in the setting of well phenotyped HIV-infected individuals initiating first line ART the interplay between gut integrity markers/microbial translocation, immune activation and metabolic complications. ACTG A5257 is a randomized clinical trial comparing three arms of therapy: atazanavir (ATV)/ritonavir (r), darunavir (DRV)/r and raltegravir (RAL)-based ART, each administered with tenofovir/emtricitabine (TDF/FTC) backbone. A5260s is the metabolic sub-study of A5257 whose secondary aims were to evaluate longitudinal metabolic and cardiovascular outcomes at 0, 4, 24, 48 and 96 weeks post initiation of ART. Well-characterized data on the outcomes for this proposal have already been obtained and include soluble and cellular markers of immune activation, insulin resistance, and objective body composition measures. To better understand our findings and their specificity to HIV, we will also assess gut alterations in a group of HIV uninfected healthy controls, matched by demographics and BMI to the A5260s population. This proposal should provide novel significant observations relating to the effect of gut integrity on metabolic comorbidities in HIV, and the effect of different classes of antiretroviral therapies on markers of gut integrity.
Despite the advent of safer HIV therapies, high levels of systemic inflammation markers, accumulation of central fat and insulin resistance remain common and significant challenges facing HIV providers and threatening the well-being of individuals living with HIV. The mechanisms causing heightened inflammation and metabolic comorbidities remain incompletely understood, but alteration of intestinal integrity (or ?leaky gut?) and the resultant translocation of microbial (bacterial and fungal) products from the intestinal lumen to the systemic circulation appear to play a central factor. In this study, we will comprehensively study the effect of different type of HIV therapies on gut integrity markers, and the relationship between gut integrity markers, heightened inflammation, and metabolic abnormalities in HIV, specifically alterations in visceral fat and glucose metabolism. The results of this study should inform public health efforts to prevent or ameliorate the risk of metabolic abnormalities and other complications linked to heightened inflammation in HIV-infected subjects.
