The introduction of antiretroviral therapy (ART) has resulted in dramatic reductions in acquired immune deficiency syndrome (AIDS) related morbidity and mortality. Therapy is not curative, however, and the nature of human immunodeficiency virus (HIV) replication during therapy remains unclear. Understanding mechanisms involved in HIV persistence will be useful in identifying effective strategies for HIV eradication. Immune activation (IA) plays a central role in the pathogenesis of HIV-infection, and may play a critical role in HIV persistence during therapy. In comparison with the levels detected in HIV uninfected subjects, both cellular markers of activation and biomarkers of inflammation are elevated in HIV-infected individuals. Levels of inflammatory cytokines and cellular markers of activation independently correlate with disease progression in HIV-infected subjects. Chronic, persistent IA is associated with the observed cluster of differentiation (CD4) depletion in untreated subjects and among ART- treated and virologically suppressed subjects and may contribute to the failure to reconstitute CD4 counts. IA also plays a role in the pathogenesis of non-AIDS related complications such as chronic kidney and coronary artery disease (CAD).
Although chronic persistent IA may play a role in HIV persistence, the source of immune activation itself is unknown. Low level viremia may represent a virologic stimulus for IA. Viremia persists at low levels during therapy, but it is not known whether HIV infection is maintained by ongoing cycles of replication in sanctuary sites, production from long-lived cells with integrated proviruses, or both. Using sensitive assays for HIV-1 viremia, we and others have detected the presence of persistent HIV viremia in the majority of subjects throughout prolonged antiretroviral therapy. Drug intensification studies suggest little contribution of active replication to levels of persistent viremia, suggesting that factors other than complete cycles of HIV replication may contribute to HIV-1 persistence. Activation of HIV-1 from long-lived cells in reservoir sites is another potential source of viremia, but the nature of such reservoirs is not yet well understood.
The mechanism of immune activation in HIV infection remains to be clarified and is likely multifactorial. Additional potential mechanisms of persistence include a central role for the gastrointestinal tract. The gastrointestinal epithelium and gut-associated lymphoid tissue (GALT) are thought to represent important barriers to microbial translocation, but HIV infection results in substantial destruction of both barriers. The reservoir of bacteria in the gastrointestinal tract is substantial, and small amounts of bacterial products are reported to translocate across the gastrointestinal tract into the bloodstream; microbial translocation across this defective GALT is an important driver of the observed immune activation in HIV infection. The precise effects of ART on gut microbial translocation remain uncertain; some studies suggest that ART incompletely reverses the effects of microbial translocation, others have failed to demonstrate any effect, yet other studies have demonstrated complete reversal with ART.
In this study, we will examine the potential role of bacterial translocation on IA by studying the effects of the antibiotic rifaximin on markers of microbial translocation, immune activation, and HIV viremia in the gut reservoir in ART treated aviremic subjects. Rifaximin is an orally administered antibiotic with potent qualitative and quantitative effects on gut bacterial flora. Rifaximin is not systemically absorbed, and drug effects appear to be confined to the gastrointestinal tract. Rifaximin has been studied as maintenance therapy in both inflammatory bowel disease (IBD) and hepatic encephalopathy (HE), disease states in which endogenous gut flora play an important role in the pathogenesis. It is anticipated that the use of rifaximin will result in an alteration and reduction in gut bacterial flora. We hypothesize that the reductions in gut bacterial flora will result in a corresponding reduction in bacterial translocation and reductions in biologically active lipopolysaccharides (LPS) levels leading to reductions in immune aced persons receiving Activation, and HIV.
In this protocol, the role of gut microbial translocation in the pathogenesis of HIV infection will be examined by performing a randomized, double-blind, placebo-controlled study of rifaximin with a case cross-over design in virologically-suppressed HIV-infected persons receiving ART.
