Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults

Pablo Tebas, Sergei Spitsin, Jeffrey S Barrett, Florin Tuluc, Okan Elci, James J Korelitz, Wayne Wagner, Angela Winters, Deborah Kim, Renae Catalano, Dwight L Evans, Steven D Douglas, Pablo Tebas, Sergei Spitsin, Jeffrey S Barrett, Florin Tuluc, Okan Elci, James J Korelitz, Wayne Wagner, Angela Winters, Deborah Kim, Renae Catalano, Dwight L Evans, Steven D Douglas

Abstract

Objective: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant - a neurokinin 1 receptor antagonist.

Design: Phase IB randomized, placebo-controlled, double-blinded study.

Methods: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks.

Results: There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (-4.8%; P = 0.04), plasma substance P (-34.0 pg/ml; P = 0.05) and soluble CD163 (-563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively).

Conclusion: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit.

Figures

Fig. 1
Fig. 1
Plasma levels of aprepitant in patients receiving 375 mg dose per day (dose–exposure relationship).
Fig. 2
Fig. 2
Viral load and CD4+ T-cell count by treatment arm.
Fig. 3
Fig. 3
Changes in cholesterol levels associated with aprepitant treatment.
Fig. 4
Fig. 4
Changes in pro-inflammatory markers associated with aprepitant treatment.

References

    1. Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 2012; 37:377–388.
    1. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 2013; 119:51–83.
    1. Heaton RK, Clifford DB, Franklin DR, Jr, Woods SP, Ake C, Vaida F, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010; 75:2087–2096.
    1. McGuire JL, Barrett JS, Vezina HE, Spitsin S, Douglas SD. Adjuvant therapies for HIV-associated neurocognitive disorders. Ann Clin Transl Neurol 2014; 1:938–952.
    1. Douglas SD, Leeman SE. Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci 2011; 1217:83–95.
    1. Tuluc F, Lai JP, Kilpatrick LE, Evans DL, Douglas SD. Neurokinin 1 receptor isoforms and the control of innate immunity. Trends Immunol 2009; 30:271–276.
    1. Douglas SD, Lai JP, Tuluc F, Schwartz L, Kilpatrick LE. Neurokinin-1 receptor expression and function in human macrophages and brain: perspective on the role in HIV neuropathogenesis. Ann N Y Acad Sci 2008; 1144:90–96.
    1. Ho WZ, Douglas SD. Substance P and neurokinin-1 receptor modulation of HIV. J Neuroimmunol 2004; 157:48–55.
    1. Li Y, Douglas SD, Song L, Sun S, Ho WZ. Substance P enhances HIV-1 replication in latently infected human immune cells. J Neuroimmunol 2001; 121:67–75.
    1. Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, Leserman J, et al. Elevated substance P levels in HIV-infected men. AIDS 2001; 15:2043–2045.
    1. Douglas SD, Cnaan A, Lynch KG, Benton T, Zhao H, Gettes DR, et al. Elevated substance P levels in HIV-infected women in comparison to HIV-negative women. AIDS Res Hum Retroviruses 2008; 24:375–378.
    1. Bost KL. Tachykinin-modulated antiviral responses. Front Biosci 2004; 9:1994–1998.
    1. Ho WZ, Cnaan A, Li YH, Zhao H, Lee HR, Song L, et al. Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. AIDS Res Hum Retroviruses 1996; 12:195–198.
    1. Lai JP, Ho WZ, Zhan GX, Yi Y, Collman RG, Douglas SD. Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. Proc Natl Acad Sci U S A 2001; 98:3970–3975.
    1. Wang X, Douglas SD, Lai JP, Tuluc F, Tebas P, Ho WZ. Neurokinin-1 receptor antagonist (aprepitant) inhibits drug-resistant HIV-1 infection of macrophages in vitro. J Neuroimmune Pharmacol 2007; 2:42–48.
    1. Manak MM, Moshkoff DA, Nguyen LT, Meshki J, Tebas P, Tuluc F, et al. Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. AIDS 2010; 24:2789–2796.
    1. Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002; 63 Suppl 11:18–24.
    1. Monaco-Shawver L, Schwartz L, Tuluc F, Guo CJ, Lai JP, Gunnam SM, et al. Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor. J Leukoc Biol 2011; 89:113–125.
    1. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281:1640–1645.
    1. Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, et al. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol 2013; 27:424–434.
    1. Ratti E, Carpenter DJ, Zamuner S, Fernandes S, Squassante L, Danker-Hopfe H, et al. Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia. Sleep 2013; 36:1823–1830.
    1. Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev 2014; 94:265–301.
    1. Tuluc F, Meshki J, Spitsin S, Douglas SD. HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J Leukoc Biol 2014; 96:143–150.
    1. Graversen JH, Madsen M, Moestrup SK. CD163: a signal receptor scavenging haptoglobin-hemoglobin complexes from plasma. Int J Biochem Cell Biol 2002; 34:309–314.
    1. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, et al. Identification of the haemoglobin scavenger receptor. Nature 2001; 409:198–201.
    1. Moller HJ, Peterslund NA, Graversen JH, Moestrup SK. Identification of the hemoglobin scavenger receptor/CD163 as a natural soluble protein in plasma. Blood 2002; 99:378–380.
    1. Fischer-Smith T, Tedaldi EM, Rappaport J. CD163/CD16 coexpression by circulating monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression. AIDS Res Hum Retroviruses 2008; 24:417–421.
    1. Kim WK, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J, et al. CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 2006; 168:822–834.
    1. Soulas C, Conerly C, Kim WK, Burdo TH, Alvarez X, Lackner AA, et al. Recently infiltrating MAC387(+) monocytes/macrophages a third macrophage population involved in SIV and HIV encephalitic lesion formation. Am J Pathol 2011; 178:2121–2135.
    1. Tippett E, Cheng WJ, Westhorpe C, Cameron PU, Brew BJ, Lewin SR, et al. Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals. PLoS One 2011; 6:e19968.
    1. Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, Letendre S, et al. Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after antiretroviral therapy. J Infect Dis 2011; 204:154–163.
    1. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis 2011; 204:1227–1236.
    1. Moller HJ. Soluble CD163. Scand J Clin Lab Invest 2012; 72:1–13.
    1. Burdo TH, Weiffenbach A, Woods SP, Letendre S, Ellis RJ, Williams KC. Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection. AIDS 2013; 27:1387–1395.
    1. Hunt PW. HIV and inflammation: mechanisms and consequences. Curr HIV/AIDS Rep 2012; 9:139–147.
    1. Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 2010; 16:452–459.
    1. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 2006; 27:195–201.
    1. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443:350–354.
    1. Holm M, Pettersen FO, Kvale D. PD-1 predicts CD4 loss rate in chronic HIV-1 infection better than HIV RNA and CD38 but not in cryopreserved samples. Curr HIV Res 2008; 6:49–58.
    1. Trabattoni D, Saresella M, Biasin M, Boasso A, Piacentini L, Ferrante P, et al. B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood 2003; 101:2514–2520.
    1. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 2006; 12:1198–1202.
    1. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439:682–687.
    1. Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 2006; 203:2223–2227.
    1. Tebas P, Tuluc F, Barrett JS, Wagner W, Kim D, Zhao H, et al. A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults. PLoS One 2011; 6:e24180.
    1. Wu D, Paul DJ, Zhao X, Douglas SD, Barrett JS. A sensitive and rapid liquid chromatography-tandem mass spectrometry method for the quantification of the novel neurokinin-1 receptor antagonist aprepitant in rhesus macaque plasma, and cerebral spinal fluid, and human plasma with application in translational NeuroAIDs research. J Pharm Biomed Anal 2009; 49:739–745.
    1. Campbell DE, Bruckner P, Tustin NB, Tustin R, 3rd, Douglas SD. Novel method for determination of substance P levels in unextracted human plasma by using acidification. Clin Vaccine Immunol 2009; 16:594–596.
    1. Barrett JS, Bajaj G, McGuire J, Wu D, Spitsin S, Moorthy G, et al. Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant. Curr HIV Res 2014; 12:121–131.
    1. EMA. EPAR scientific discussion. (2006).
    1. Barrett JS, Moorthy WD, Srivastata G, Barrett P, Spitsin KJ, Tuluc S, et al. Preclinical activity predicts higher dosing requirements for the NK-1r antagonist aprepitant in HIV-associated neurocognitive disorders (HAND): Dispositional and pharmacologic rationale for multimodal therapeutic window. Clin Pharmacol Therapeut 2013; 93 Suppl 1:S17.PI-9.
    1. Lai JP, Ho WZ, Yang JH, Wang X, Song L, Douglas SD. A nonpeptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes. J Neuroimmunol 2002; 128:101–108.
    1. Kepler CK, Markova DZ, Hilibrand AS, Vaccaro AR, Risbud MV, Albert TJ, et al. Substance P stimulates production of inflammatory cytokines in human disc cells. Spine (Phila Pa 1976) 2013; 38:E1291–E1299.
    1. Spitsin S, Tuluc F, Meshki J, Ping Lai J, Tustin Iii R, Douglas SD. Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. Neuroimmunomodulation 2013; 20:247–255.
    1. Giannarelli C, Klein RS, Badimon JJ. Cardiovascular implications of HIV-induced dyslipidemia. Atherosclerosis 2011; 219:384–389.
    1. Fu J, Liu B, Liu P, Liu L, Li G, Wu B, et al. Substance P is associated with the development of obesity, chronic inflammation and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2011; 119:177–181.
    1. Karagiannides I, Stavrakis D, Bakirtzi K, Kokkotou E, Pirtskhalava T, Nayeb-Hashemi H, et al. Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. Endocrinology 2011; 152:2197–2205.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe