Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286

Immune activation plays a central role in human immunodeficiency virus (HIV) pathogenesis. The frequency of activated CD8+ T cells, as defined by the up-regulation of HLA-DR and CD38 on the cell surface, predicts disease progression in untreated HIV-positive persons [1] and a CD4+ T-cell increase with antiretroviral treatment (ART) [2, 3]. ART leads to a decline in immune activation in most HIV-infected patients, yet levels of activation do not normalize in most individuals [4, 5]. Moreover, up to 25% of individuals starting ART fail to achieve CD4+ T-cell counts >350 cells/mm3 even after 2 years of virally suppressive treatment, and these patients have higher levels (percentages) of activated (HLA-DR+CD38+) CD8+ T cells than patients with better immune restoration [6]. A 5% increase in activated CD8+ T cells is associated with 35 fewer CD4+ T cells gained during ART [2]. Incomplete immune recovery with ART is also associated with increased mortality, opportunistic infections, and cardiovascular disease and malignancies [7, 8]. Many mechanisms have been proposed to account for the elevated levels of immune activation, including the direct effects of HIV, the effects of coinfections such as cytomegalovirus, loss of normal immunoregulatory responses, and HIV-mediated destruction of mucosal barriers with chronic systemic exposure to gut microbial elements. HIV-infected individuals sustain a rapid and profound depletion of gut mucosal CD4+ T cells as early as a few days after infection [9]. These changes lead to defects in mucosal immune and epithelial barrier function that allows the translocation of gut microbial products, such as lipopolysaccharide (LPS) [10]; LPS levels are elevated in the plasma of HIV-infected individuals and associated with increased levels of immune activation [10]. ART does not fully reverse the deficits in gut mucosal CD4+ T cells [11, 12], and both the levels of gut microbial translocation and immune activation predict the extent of immune reconstitution with ART [6, 13]. Taken together, these data support a model that attributes CD4+ T-cell loss to activation driven partly by translocated gut microbial products. In addition, LPS levels are associated with risk of myocardial infarction [14], whereas levels of soluble CD14 (sCD14), another marker for microbial translocation, are associated with mortality in treated HIV-positive persons [15]. Antibiotics have been used in simian immunodeficiency virus-infected macaques to decrease plasma LPS levels, albeit transiently [10]. Rifaximin, a nonabsorbed oral antibiotic used to improve symptoms of hepatic encephalopathy in patients with cirrhosis, has also been shown to reduce plasma LPS levels. The administration of 28 days of 1200 mg/d of rifaximin led to a 50% decline in plasma LPS levels in alcoholic cirrhotics [16]. In addition, the use of rifaximin has been shown to be safe in alcoholic cirrhotics. We conducted AIDS Clinical Trials Group (ACTG) protocol A5286, a multicenter randomized, open-label pilot study of 4 weeks of treatment with rifaximin versus no study treatment in ART-treated HIV-infected subjects with incomplete immune recovery. We hypothesized that rifaximin use would be safe and would reduce gut microbial translocation and, consequently, would lower immune activation levels in HIV-infected subjects with incomplete CD4+ T-cell recovery during ART.