The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial

Ma Somsouk, Richard M Dunham, Michelle Cohen, Rebecca Albright, Mohamed Abdel-Mohsen, Teri Liegler, Jeffrey Lifson, Michael Piatak, Robert Gorelick, Yong Huang, Yuaner Wu, Priscilla Y Hsue, Jeffrey N Martin, Steven G Deeks, Joseph M McCune, Peter W Hunt, Ma Somsouk, Richard M Dunham, Michelle Cohen, Rebecca Albright, Mohamed Abdel-Mohsen, Teri Liegler, Jeffrey Lifson, Michael Piatak, Robert Gorelick, Yong Huang, Yuaner Wu, Priscilla Y Hsue, Jeffrey N Martin, Steven G Deeks, Joseph M McCune, Peter W Hunt

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 registration: ClinicalTrials.gov NCT01090102.

Conflict of interest statement

Competing Interests: This study was funded in part by an investigator-initiated research grant from Salix Pharmaceuticals, Inc. Co-authors JL, MP, and RG are employed by Leidos Biomedical Research Inc. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Enrollment, allocation, and follow-up for…
Figure 1. Enrollment, allocation, and follow-up for trial subjects.
The outcomes of the 41 screened subjects are described in the flow diagram.
Figure 2. Changes in peripheral blood T…
Figure 2. Changes in peripheral blood T cell activation and soluble markers of inflammation during mesalamine.
Estimated mean changes (with 95% CI) in the frequency of activated (CD38+ HLA-DR+) CD8+ (A) and CD4+ (B) T cells, sCD14 (C), IL-6 (D), D-dimer (E), and kynurenine to tryptophan (K:T) ratio (F) in peripheral blood are plotted for placebo-treated (blue) and mesalamine-treated (red) subjects. P values are provided for the changes within each indicated interval both within arms and between arms.

References

    1. Deeks SG, Phillips AN (2009) HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. Bmj 338:a3172.
    1. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, et al. (2007) Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 146:87–95.
    1. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, et al. (2007) HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 46:72–77.
    1. Antiretroviral Therapy Cohort Collaboration (2008) Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 372:293–299.
    1. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371.
    1. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, et al. (2009) Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199:1177–1185.
    1. Marchetti G, Bellistri GM, Borghi E, Tincati C, Ferramosca S, et al. (2008) Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. Aids 22:2035–2038.
    1. Cassol E, Malfeld S, Mahasha P, van der Merwe S, Cassol S, et al. (2010) Persistent Microbial Translocation and Immune Activation in HIV-1-Infected South Africans Receiving Combination Antiretroviral Therapy. J Infect Dis 202:723–733.
    1. Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, et al. (2010) Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog 6:e1001052.
    1. Li Q, Estes JD, Duan L, Jessurun J, Pambuccian S, et al. (2008) Simian immunodeficiency virus-induced intestinal cell apoptosis is the underlying mechanism of the regenerative enteropathy of early infection. J Infect Dis 197:420–429.
    1. Kristoff J, Haret-Richter G, Ma D, Ribeiro RM, Xu C, et al. (2014) Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication. J Clin Invest 124:2802–2806.
    1. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, et al. (2003) T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 187:1534–1543.
    1. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, et al. (2008) Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 5:e203.
    1. Brown TT, Tassiopoulos K, Bosch RJ, Shikuma C, McComsey GA (2010) Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy. Diabetes Care 33:2244–2249.
    1. Ford ES, Greenwald JH, Richterman AG, Rupert A, Dutcher L, et al. (2010) Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS 24:1509–1517.
    1. Tien PC, Choi AI, Zolopa AR, Benson C, Tracy R, et al. (2010) Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. JAIDS Journal of Acquired Immune Deficiency Syndromes 55:316.
    1. Justice AC, Freiberg MS, Tracy R, Kuller L, Tate JP, et al. (2012) Does an Index Composed of Clinical Data Reflect Effects of Inflammation, Coagulation, and Monocyte Activation on Mortality Among Those Aging With HIV? Clin Infect Dis 54:984–994.
    1. Kamm MA, Sandborn WJ, Gassull M, Schreiber S, Jackowski L, et al. (2007) Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 132: 66–75; quiz 432–433.
    1. Sutherland L, Macdonald JK (2006) Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev: CD000543.
    1. Anton P, Elliot J, Quigley MF, Olsson J, Tiang P, et al. (2001) Use of Asacol, a mucosal anti-inflammatory medication, is safe as adjunctive HIV therapy and is associated with mild decreases in mucosal RANTES. 1st IAS Conference on HIV Pathogenesis and Treatment, July, Buenos Aires A663.
    1. Kamat A, Ancuta P, Blumberg RS, Gabuzda D (2010) Serological markers for inflammatory bowel disease in AIDS patients with evidence of microbial translocation. PLoS One 5:e15533.
    1. Rodriguez-Torres M, Rodriguez-Orengo JF, Rios-Bedoya CF, Fernandez-Carbia A, Salgado-Mercado R, et al. (2006) Double-blind pilot study of mesalamine vs. placebo for treatment of chronic diarrhea and nonspecific colitis in immunocompetent HIV patients. Dig Dis Sci 51:161–167.
    1. Pettersen FO, Torheim EA, Dahm AE, Aaberge IS, Lind A, et al. (2011) An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J Virol 85:6557–6566.
    1. Kvale D, Ormaasen V, Kran AM, Johansson CC, Aukrust P, et al. (2006) Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment. AIDS 20:813–820.
    1. Johansson CC, Bryn T, Aandahl EM, Areklett MA, Aukrust P, et al. (2004) Treatment with type-2 selective and non-selective cyclooxygenase inhibitors improves T-cell proliferation in HIV-infected patients on highly active antiretroviral therapy. AIDS 18:951–952.
    1. Frieri G, Giacomelli R, Pimpo M, Palumbo G, Passacantando A, et al. (2000) Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis. Gut 47:410–414.
    1. Salix (2009) Encapsulated mesalamine granules (Apriso) for ulcerative colitis. Med Lett Drugs Ther 51:38–39.
    1. Lichtenstein GR, Gordon GL, Zakko S, Murthy U, Sedghi S, et al. (2010) Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial. Aliment Pharmacol Ther 32:990–999.
    1. Love BL, Miller AD (2012) Extended-release mesalamine granules for ulcerative colitis. Ann Pharmacother 46:1529–1536.
    1. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, et al. (2003) New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 41:4531–4536.
    1. Lin PK, Brown DM (1992) Synthesis of oligodeoxyribonucleotides containing degenerate bases and their use as primers in the polymerase chain reaction. Nucleic Acids Res 20:5149–5152.
    1. Byakwaga H, Boum Y 2nd, Huang Y, Muzoora C, Kembabazi A, et al. (2014) The Kynurenine Pathway of Tryptophan Catabolism, CD4+ T-Cell Recovery, and Mortality Among HIV-Infected Ugandans Initiating Antiretroviral Therapy. J Infect Dis 210:383–391.
    1. Hsue PY, Hunt PW, Wu Y, Schnell A, Ho JE, et al. (2009) Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. Aids 23:2021–2027.
    1. Ho JE, Scherzer R, Hecht FM, Maka K, Selby V, et al. (2012) The association of CD4+ T-cell count on cardiovascular risk in treated HIV disease. Aids.
    1. Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, et al. (2011) Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation 123:163–169.
    1. Huang AL, Silver AE, Shvenke E, Schopfer DW, Jahangir E, et al. (2007) Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol 27:2113–2119.
    1. Donald AE, Halcox JP, Charakida M, Storry C, Wallace SM, et al. (2008) Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J Am Coll Cardiol 51:1959–1964.
    1. Ferre AL, Hunt PW, Critchfield JW, Young DH, Morris MM, et al. (2009) Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood 113:3978–3989.
    1. Shacklett BL, Yang O, Hausner MA, Elliott J, Hultin L, et al. (2003) Optimization of methods to assess human mucosal T-cell responses to HIV infection. J Immunol Methods 279:17–31.
    1. Kumar AM, Borodowsky I, Fernandez B, Gonzalez L, Kumar M (2007) Human immunodeficiency virus type 1 RNA Levels in different regions of human brain: quantification using real-time reverse transcriptase-polymerase chain reaction. J Neurovirol 13:210–224.
    1. Peskar BM, Dreyling KW, Peskar BA, May B, Goebell H (1986) Enhanced formation of sulfidopeptide-leukotrienes in ulcerative colitis and Crohn’s disease: inhibition by sulfasalazine and 5-aminosalicylic acid. Agents Actions 18:381–383.
    1. Nielsen OH, Bukhave K, Elmgreen J, Ahnfelt-Ronne I (1987) Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid. Dig Dis Sci 32:577–582.
    1. Weber CK, Liptay S, Wirth T, Adler G, Schmid RM (2000) Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 119:1209–1218.
    1. Managlia E, Katzman RB, Brown JB, Barrett TA (2013) Antioxidant properties of mesalamine in colitis inhibit phosphoinositide 3-kinase signaling in progenitor cells. Inflamm Bowel Dis 19:2051–2060.
    1. Baan B, Dihal AA, Hoff E, Bos CL, Voorneveld PW, et al. (2012) 5-Aminosalicylic acid inhibits cell cycle progression in a phospholipase D dependent manner in colorectal cancer. Gut 61:1708–1715.
    1. Joo K, Lee Y, Choi D, Han J, Hong S, et al. (2009) An anti-inflammatory mechanism of taurine conjugated 5-aminosalicylic acid against experimental colitis: taurine chloramine potentiates inhibitory effect of 5-aminosalicylic acid on IL-1beta-mediated NFkappaB activation. Eur J Pharmacol 618:91–97.
    1. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, et al. (2005) Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 201:1205–1215.
    1. Alvarez S, Serramia MJ, Fresno M, Munoz-Fernandez M (2005) Human immunodeficiency virus type 1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in neuroblastoma cells through a nuclear factor-kappaB and activating protein-1 mediated mechanism. J Neurochem 94:850–861.
    1. Pereira CF, Boven LA, Middel J, Verhoef J, Nottet HS (2000) Induction of cyclooxygenase-2 expression during HIV-1-infected monocyte-derived macrophage and human brain microvascular endothelial cell interactions. J Leukoc Biol 68:423–428.
    1. Corasaniti MT, Strongoli MC, Piccirilli S, Nistico R, Costa A, et al. (2000) Apoptosis induced by gp120 in the neocortex of rat involves enhanced expression of cyclooxygenase type 2 and is prevented by NMDA receptor antagonists and by the 21-aminosteroid U-74389G. Biochem Biophys Res Commun 274:664–669.
    1. Stolfi C, Fina D, Caruso R, Caprioli F, Sarra M, et al. (2008) Cyclooxygenase-2-dependent and -independent inhibition of proliferation of colon cancer cells by 5-aminosalicylic acid. Biochem Pharmacol 75:668–676.
    1. Munding J, Ziebarth W, Pox CP, Ladigan S, Reiser M, et al. (2012) The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the beta-catenin signaling pathway. Carcinogenesis 33:637–643.
    1. O’Brien M, Montenont E, Hu L, Nardi MA, Valdes V, et al. (2013) Aspirin attenuates platelet activation and immune activation in HIV-1-infected subjects on antiretroviral therapy: a pilot study. J Acquir Immune Defic Syndr 63:280–288.
    1. Sandler NG, Zhang X, Bosch RJ, Funderburg NT, Choi AI, et al. (2014) 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. J Infect Dis.
    1. Tenorio AR, Wilson CC, Chan ES, Bosch RJ, Macatangay BJ, et al. (2014) Rifaximin has marginal impact on immune activation in immune non-responders to ART- ACTG A5286. Conference on Retroviruses and Opportunistic Infection Oral Presentation: Abs. 339.
    1. Gori A, Rizzardini G, Van’t Land B, Amor KB, van Schaik J, et al. (2011) Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial. Mucosal Immunol 4:554–563.
    1. Stiksrud B, Nowak P, Kvale D, Thalme A, Birkeland S, et al. (2014) Reduced D-dimer levels and inflammation markers after probiotic supplement in HIV-infected on ART. Conference on Retroviruses and Opportunistic Infection: Abs. 342.
    1. Buzon MJ, Massanella M, Llibre JM, Esteve A, Dahl V, et al. (2010) HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 16:460–465.
    1. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, et al. (2011) Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis 203:1474–1483.
    1. Prideaux L, De Cruz P, Ng SC, Kamm MA (2012) Serological antibodies in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 18:1340–1355.
    1. Hunt PW (2010) Th17, gut, and HIV: therapeutic implications. Curr Opin HIV AIDS 5:189–193.
    1. Kim CJ, Nazli A, Rojas OL, Chege D, Alidina Z, et al. (2012) A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol 5:670–680.
    1. Abraham C, Cho JH (2009) Inflammatory bowel disease. N Engl J Med 361:2066–2078.

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