Abstract
The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts <350 cells/mm3 and plasma HIV RNA levels <40 copies/ml on antiretroviral therapy (ART) to add mesalamine vs. placebo to their existing regimen for 12 weeks followed by a 12 week crossover to the other arm. Compared to placebo-treated subjects, mesalamine-treated subjects did not experience any significant change in the percent CD38+HLA-DR+ peripheral blood CD4+ and CD8+ T cells at week 12 (P = 0.38 and P = 0.63, respectively), or in the CD4+ T cell count at week 12 (P = 0.83). The percent CD38+HLA-DR+ CD4+ and CD8+ T cells also did not change significantly in rectal tissue (P = 0.86, P = 0.84, respectively). During the period of mesalamine administration, plasma sCD14, IL-6, D-dimer, and kynurenine to tryptophan ratio were not changed significantly at week 12 and were similarly unchanged at week 24. This study suggests that, at least under the conditions studied, the persistent immune activation associated with HIV infection is not impacted by the anti-inflammatory effects of mesalamine.Trial RegistrationClinicalTrials.gov NCT01090102
Highlights
In the analysis restricted to individuals who were not taking aspirin or nonsteroidal anti-inflammatory drugs (NSAID), we did not observe an effect of mesalamine on biomarkers of T cell activation or innate
Observational studies and theoretical considerations have suggested that targeting mucosal inflammation during chronic HIV infection might improve intestinal barrier function, reduce microbial translocation (MT), and thereby have beneficial immunologic effects
Given the absence of an observed effect of mesalamine, these pathways may not be critical to the immune activation and MT associated with HIV disease
Summary
Despite effective antiretroviral therapy (ART), HIV-infected individuals – those with incomplete CD4+ T cell recovery on ART - continue to have a shorter life expectancy than the general population and remain at higher risk for morbidities that are normally associated with aging. [1, 2, 3, 4] Increased immune activation has been linked to microbial translocation (MT) during both untreated and treated HIV infection. [5, 6, 7, 8] Observations in pathogenic simian immunodeficiency virus infection and HIV infection underscore the relationship of such MT with disruption of mucosal immune and intestinal epithelial homeostasis. [9, 10, 11] Since persistent inflammation appears to be a major mediator of this increased risk of morbidity and mortality, and since epithelial barrier dysfunction persists during treated HIV infection, interventions targeting the mucosal lining and serving to decrease immune activation warrant investigation. [12, 13, 14, 15, 16, 17].In the setting of inflammatory bowel disease, several lines of evidence suggest that anti-inflammatory agents that improve gut mucosal integrity can reduce mucosal and systemic inflammation. [18, 19, 20, 21, 22] systemic nonsteroidal anti-inflammatory drugs (NSAID) have been shown to decrease inflammation during HIV infection, [23, 24, 25] the toxicities associated with chronic systemic NSAIDs (i.e., renal toxicity, liver toxicity, gastrointestinal bleeding, and cardiovascular events) limit their widespread use in HIV-infected individuals. [9, 10, 11] Since persistent inflammation appears to be a major mediator of this increased risk of morbidity and mortality, and since epithelial barrier dysfunction persists during treated HIV infection, interventions targeting the mucosal lining and serving to decrease immune activation warrant investigation. We hypothesized that mesalamine would decrease GALT inflammation in HIVinfected individuals, blocking the vicious cycle of local HIV replication, Th17 depletion, epithelial damage and MT, thereby resulting in a decreased level of systemic T cell activation. To test this possibility, we performed a randomized placebo-controlled trial of mesalamine among HIV-infected subjects maintaining ART-mediated viral suppression. We performed serial rectal biopsies on a subset of participants to determine the effects of mesalamine on gut-associated lymphoid tissue (GALT). [26]
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