Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection

AIDS-related complications and mortality have decreased dramatically in the combination antiretroviral therapy (cART) era, but the risk of cardiovascular disease and other morbidities linked to chronic immune dysfunction and inflammation remains high [1]. Increased CD8 T-cell activation and inflammatory markers are associated with impaired CD4 T-cell recovery and excess mortality in ART recipients [1, 2]. Systemic translocation of microbial products such as lipopolysaccharide (LPS) across a permeable gut mucosa may contribute to persistent inflammation [2]. Individuals with chronic human immunodeficiency virus (HIV) infection have increased circulating levels of LPS, LPS-binding protein (LBP), and soluble CD14 (sCD14), an LPS coreceptor [2]. ART decreases but does not normalize these levels [2]. Thus, an agent that decreases levels of LPS and its inflammatory consequences may improve clinical outcomes in HIV infection. Sevelamer carbonate, a phosphate-lowering drug, decreases circulating LPS levels in patients with renal insufficiency, possibly by binding chylomicron-LPS complexes and preventing their reabsorption; in this population, sevelamer also reduces levels of sCD14, interleukin 6 (IL-6), C-reactive protein (CRP), and total and low-density lipoprotein (LDL) cholesterol [3–6]. These effects may contribute to the decreased mortality risk observed in sevelamer-treated patients undergoing dialysis [7]. Given the possible role of microbial translocation in HIV-associated inflammation and the potential for its reversal by sevelamer, we performed a single-arm, open-label clinical trial (AIDS Clinical Trials Group [ACTG] A5296), to test the hypothesis that 8 weeks of sevelamer treatment would decrease plasma LPS and sCD14 levels. We studied its effects in subjects who were not receiving cART because (1) sevelamer-cART interactions are unknown, (2) sevelamer might exacerbate tenofovir's phosphate-lowering effect, and (3) microbial translocation is more consistently elevated in untreated disease, increasing the likelihood of seeing an effect.