Mesalamine to Reduce T cell Activation in HIV Infection
Peter Hunt, University of California San Francisco
Targeted Theme: Therapeutic Strategies for HIV
Innovative, Developmental, Exploratory Award (IDEA)
The vast majority of HIV-infected individuals can now achieve and maintain undetectable viremia on antiretroviral therapy. However, HIV-infected individuals continue to be at higher risk for non-AIDS-associated complications (i.e., cancer, cardiovascular disease, etc.), and have at least a 10-year shorter life expectancy than HIV-uninfected individuals. Persistent inflammation strongly predicts these complications and has been proposed as important mediator of this increased risk. The causes of persistent immune activation and inflammation during suppressive antiretroviral therapy are unclear, but likely include ongoing HIV RNA replication and/or release in lymphoid tissues and persistent microbial translocation. The causes of persistent microbial translocation also remain unknown, but may include local release of HIV RNA in GALT (which may cause epithelial cell apoptosis), and failure to reconstitute Th17 cells in the gut-associated lymphoid tissue (GALT), cells which are thought to be responsible both for maintaining the integrity of the mucosal barrier, and in clearing translocated microbial products. An inflammatory microenvironment in the GALT may also trigger a vicious cycle of microbial translocation via two distinct mechanisms. First, activation of latently infected CD4+ T cells in GALT may cause more local HIV RNA release. Second, since Th17 and regulatory T cells share a common progenitor, an inflammatory microenvironment may result in shunting of progenitors to a Treg pathway, impairing the restoration of Th17 cells, and propagating microbial translocation.
Mesalamine (5-aminosalicylic acid) is now available in a single pill once daily dosing regimen, is commonly used for the treatment of mild to moderate ulcerative colitis, has minimal toxicity, and has been shown to decrease GALT inflammation in HIV-uninfected individuals over an 8-week treatment period. It is only ~25% systemically bioavailable, acting primarily locally in the GALT. We hypothesize that mesalamine will also decrease GALT inflammation in HIV-infected individuals, blocking the vicious cycle of HIV RNA replication, Th17 depletion, and microbial translocation, and resulting in decreased systemic T cell activation levels.
To address this hypothesis, we will perform a randomized controlled trial of mesalamine vs. placebo in 30 HIV-infected patients maintaining treatment-mediated viral suppression for >1 year (<75 copies/ml), but persistently low CD4+ T cell counts (<350 cells/mm3). Oral mesalamine dosed at 2.4 grams/day vs. matching placebo will be administered for 12 weeks. Subjects will then crossed over into the other treatment arm for another 12 weeks. The primary outcome will be the reduction in activated CD8+ T cells at week 12 compared between treatment arms. Secondary outcomes will include changes in microbial translocation, soluble inflammatory biomarkers, GALT HIV RNA levels, and the % Th17, Treg, and HIV-specific T cells in both peripheral blood and GALT.
We expect that mesalamine will lead to greater decreases in week 12 T cell activation levels than placebo and that this effect will likely be mediated by reductions in GALT HIV RNA levels, increases in the % of GALT Th17 cells, and decreases in microbial translocation. We also expect that partial reductions in T cell activation will be sustained after a 12-week washout period as a consequence of interrupting the vicious cycle of inflammation and microbial translocation in GALT.