Lovastatin: Immunomodulatory Value Evaluation

Summary

The purpose of this study is to determine whether the long-term administration of statins may benefit the clinical and immunological evolution in HIV-1-infected individuals before the use of antiretroviral therapy is required.

Timeline

Start

2008-08

Primary completion

2011-07

Completion

2011-07

Publications

• Background UNAIDS and WHO. AIDS epidemic update 2004. Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO); 2004 December 2004
• Background Instituto Nacional de Salud. Programa Nacional de Prevención y control ITS/SIDA. Colombia 1983-2002. Bogotá: Instituto Nacional de Salud, Ministerio de Salud de la República de Colombia; 2003
• Background Cohen DE, Walker BD. Human immunodeficiency virus pathogenesis and prospects for immune control in patients with established infection. Clin Infect Dis. 2001 Jun 15;32(12):1756-68. doi: 10.1086/320759. Epub 2001 May 16.
• Background Giorgi JV, Liu Z, Hultin LE, Cumberland WG, Hennessey K, Detels R. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr (1988). 1993 Aug;6(8):904-12.
• Background Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, Hamann D, Prins M, Miedema F. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003 Sep 5;17(13):1881-8. doi: 10.1097/00002030-200309050-00006.
• Background Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26;338(13):853-60. doi: 10.1056/NEJM199803263381301.
• Background Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997 Nov 14;278(5341):1295-300. doi: 10.1126/science.278.5341.1295.
• Background Aberg JA, Zackin RA, Brobst SW, Evans SR, Alston BL, Henry WK, Glesby MJ, Torriani FJ, Yang Y, Owens SI, Fichtenbaum CJ; ACTG 5087 Study Team. A randomized trial of the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities: AIDS Clinical Trials Group Study 5087. AIDS Res Hum Retroviruses. 2005 Sep;21(9):757-67. doi: 10.1089/aid.2005.21.757.
• Background Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS. 2003 Apr 11;17(6):851-9. doi: 10.1097/00002030-200304110-00010.
• Background Fehr T, Kahlert C, Fierz W, Joller-Jemelka HI, Riesen WF, Rickli H, Wuthrich RP, Ammann P. Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis. 2004 Jul;175(1):83-90. doi: 10.1016/j.atherosclerosis.2004.02.016.
• Background Yilmaz A, Reiss C, Tantawi O, Weng A, Stumpf C, Raaz D, Ludwig J, Berger T, Steinkasserer A, Daniel WG, Garlichs CD. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis. 2004 Jan;172(1):85-93. doi: 10.1016/j.atherosclerosis.2003.10.002.
• Background Kwak B, Mulhaupt F, Veillard N, Pelli G, Mach F. The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells. Swiss Med Wkly. 2001 Jan 27;131(3-4):41-6. doi: 10.4414/smw.2001.06144.
• Background Liao Z, Cimakasky LM, Hampton R, Nguyen DH, Hildreth JE. Lipid rafts and HIV pathogenesis: host membrane cholesterol is required for infection by HIV type 1. AIDS Res Hum Retroviruses. 2001 Jul 20;17(11):1009-19. doi: 10.1089/088922201300343690.
• Background Del Real G, Jimenez-Baranda S, Lacalle RA, Mira E, Lucas P, Gomez-Mouton C, Carrera AC, Martinez-A C, Manes S. Blocking of HIV-1 infection by targeting CD4 to nonraft membrane domains. J Exp Med. 2002 Aug 5;196(3):293-301. doi: 10.1084/jem.20020308.
• Background del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, Gomez-Mouton C, Alegret M, Pena JM, Rodriguez-Zapata M, Alvarez-Mon M, Martinez-A C, Manes S. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med. 2004 Aug 16;200(4):541-7. doi: 10.1084/jem.20040061.
• Background Giguere JF, Tremblay MJ. Statin compounds reduce human immunodeficiency virus type 1 replication by preventing the interaction between virion-associated host intercellular adhesion molecule 1 and its natural cell surface ligand LFA-1. J Virol. 2004 Nov;78(21):12062-5. doi: 10.1128/JVI.78.21.12062-12065.2004.
• Background Hakamada-Taguchi R, Uehara Y, Kuribayashi K, Numabe A, Saito K, Negoro H, Fujita T, Toyo-oka T, Kato T. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development. Circ Res. 2003 Nov 14;93(10):948-56. doi: 10.1161/01.RES.0000101298.76864.14. Epub 2003 Oct 16.
• Background Shimada K, Miyauchi K, Daida H. Early intervention with atorvastatin modulates TH1/TH2 imbalance in patients with acute coronary syndrome: from bedside to bench. Circulation. 2004 May 11;109(18):e213-4; author reply e213-4. doi: 10.1161/01.CIR.0000127616.70152.5D. No abstract available.
• Background Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002 Nov 7;420(6911):78-84. doi: 10.1038/nature01158.
• Background Illingworth DR, Tobert JA. HMG-CoA reductase inhibitors. Adv Protein Chem. 2001;56:77-114. doi: 10.1016/s0065-3233(01)56003-9. No abstract available.
• Background Garcia PJ. Pleiotropic effects of statins: moving beyond cholesterol control. Curr Atheroscler Rep. 2005 Feb;7(1):34-9. doi: 10.1007/s11883-005-0073-6.
• Background Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int. 2003 Jan;63(1):12-23. doi: 10.1046/j.1523-1755.2003.00744.x.
• Background Vanhaecke J, Van Cleemput J, Van Lierde J, Daenen W, De Geest H. Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine. Transplantation. 1994 Jul 15;58(1):42-5.
• Background Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999 Sep;30(9):1969-73. doi: 10.1161/01.str.30.9.1969.
• Background Kallen J, Welzenbach K, Ramage P, Geyl D, Kriwacki R, Legge G, Cottens S, Weitz-Schmidt G, Hommel U. Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol. 1999 Sep 10;292(1):1-9. doi: 10.1006/jmbi.1999.3047.
• Background Issekutz TB. Inhibition of lymphocyte endothelial adhesion and in vivo lymphocyte migration to cutaneous inflammation by TA-3, a new monoclonal antibody to rat LFA-1. J Immunol. 1992 Nov 15;149(10):3394-402.
• Background Wallays G, Ceuppens JL. Ligation of leukocyte function-associated (LFA) molecule-1 provides an accessory signal for T-cell activation with pokeweed mitogen. Scand J Immunol. 1994 Feb;39(2):137-43. doi: 10.1111/j.1365-3083.1994.tb03352.x.
• Background Moncunill G, Negredo E, Bosch L, Vilarrasa J, Witvrouw M, Llano A, Clotet B, Este JA. Evaluation of the anti-HIV activity of statins. AIDS. 2005 Oct 14;19(15):1697-700. doi: 10.1097/01.aids.0000183517.60384.db.
• Background Sklar PA, Masur H, Grubb JR, Voell J, Witek J, Ono A, Freed EO, Maldarelli F. Pravastatin does not have a consistent antiviral effect in chronically HIV-infected individuals on antiretroviral therapy. AIDS. 2005 Jul 1;19(10):1109-11. doi: 10.1097/01.aids.0000174461.31794.50. No abstract available.
• Background Manfredi R, Calza L, Chiodo F. Long-term statin use does not act on the temporal trend of CD4 cell count in patients on virologically effective HAART. AIDS. 2006 Feb 14;20(3):455-7. doi: 10.1097/01.aids.0000199822.49488.50.
• Background Waters L, Stebbing J, Jones R, Mandalia S, Bower M, Stefanovic M, Nelson M, Gazzard B. The effect of statins on HIV rebound and blips. J Acquir Immune Defic Syndr. 2005 Aug 15;39(5):637-8. No abstract available.
• Background Bonnet F, Balestre E, Thiebaut R, Mercie P, Dupon M, Morlat P, Dabis F; Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA). Fibrates or statins and lipid plasma levels in 245 patients treated with highly active antiretroviral therapy. Aquitaine Cohort, France, 1999-2001. HIV Med. 2004 May;5(3):133-9. doi: 10.1111/j.1468-1293.2004.00200.x.
• Background Benesic A, Zilly M, Kluge F, Weissbrich B, Winzer R, Klinker H, Langmann P. Lipid lowering therapy with fluvastatin and pravastatin in patients with HIV infection and antiretroviral therapy: comparison of efficacy and interaction with indinavir. Infection. 2004 Aug;32(4):229-33. doi: 10.1007/s15010-004-3136-7.
• Background Hulgan T, Sterling TR, Daugherty J, Arbogast PG, Raffanti S, Ray W. Prescribing of contraindicated protease inhibitor and statin combinations among HIV-infected persons. J Acquir Immune Defic Syndr. 2005 Mar 1;38(3):277-82.
• Background Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacotherapy. 2000 Sep;20(9):1066-71. doi: 10.1592/phco.20.13.1066.35033.
• Background van der Goot FG, Harder T. Raft membrane domains: from a liquid-ordered membrane phase to a site of pathogen attack. Semin Immunol. 2001 Apr;13(2):89-97. doi: 10.1006/smim.2000.0300.
• Background Manes S, del Real G, Lacalle RA, Lucas P, Gomez-Mouton C, Sanchez-Palomino S, Delgado R, Alcami J, Mira E, Martinez-A C. Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection. EMBO Rep. 2000 Aug;1(2):190-6. doi: 10.1093/embo-reports/kvd025.
• Background Moore JP, Trkola A, Dragic T. Co-receptors for HIV-1 entry. Curr Opin Immunol. 1997 Aug;9(4):551-62. doi: 10.1016/s0952-7915(97)80110-0.
• Background Nguyen DH, Taub DD. Inhibition of chemokine receptor function by membrane cholesterol oxidation. Exp Cell Res. 2003 Nov 15;291(1):36-45. doi: 10.1016/s0014-4827(03)00345-8.
• Background Alfsen A, Iniguez P, Bouguyon E, Bomsel M. Secretory IgA specific for a conserved epitope on gp41 envelope glycoprotein inhibits epithelial transcytosis of HIV-1. J Immunol. 2001 May 15;166(10):6257-65. doi: 10.4049/jimmunol.166.10.6257.
• Background Gummuluru S, Rogel M, Stamatatos L, Emerman M. Binding of human immunodeficiency virus type 1 to immature dendritic cells can occur independently of DC-SIGN and mannose binding C-type lectin receptors via a cholesterol-dependent pathway. J Virol. 2003 Dec;77(23):12865-74. doi: 10.1128/jvi.77.23.12865-12874.2003.
• Background Maziere JC, Landureau JC, Giral P, Auclair M, Fall L, Lachgar A, Achour A, Zagury D. Lovastatin inhibits HIV-1 expression in H9 human T lymphocytes cultured in cholesterol-poor medium. Biomed Pharmacother. 1994;48(2):63-7. doi: 10.1016/0753-3322(94)90077-9.
• Background Guyader M, Kiyokawa E, Abrami L, Turelli P, Trono D. Role for human immunodeficiency virus type 1 membrane cholesterol in viral internalization. J Virol. 2002 Oct;76(20):10356-64. doi: 10.1128/jvi.76.20.10356-10364.2002.
• Background Viard M, Parolini I, Sargiacomo M, Fecchi K, Ramoni C, Ablan S, Ruscetti FW, Wang JM, Blumenthal R. Role of cholesterol in human immunodeficiency virus type 1 envelope protein-mediated fusion with host cells. J Virol. 2002 Nov;76(22):11584-95. doi: 10.1128/jvi.76.22.11584-11595.2002.
• Background Vincent N, Genin C, Malvoisin E. Identification of a conserved domain of the HIV-1 transmembrane protein gp41 which interacts with cholesteryl groups. Biochim Biophys Acta. 2002 Dec 23;1567(1-2):157-64. doi: 10.1016/s0005-2736(02)00611-9.
• Background Saez-Cirion A, Nir S, Lorizate M, Agirre A, Cruz A, Perez-Gil J, Nieva JL. Sphingomyelin and cholesterol promote HIV-1 gp41 pretransmembrane sequence surface aggregation and membrane restructuring. J Biol Chem. 2002 Jun 14;277(24):21776-85. doi: 10.1074/jbc.M202255200. Epub 2002 Apr 2.
• Background Campbell SM, Crowe SM, Mak J. Virion-associated cholesterol is critical for the maintenance of HIV-1 structure and infectivity. AIDS. 2002 Nov 22;16(17):2253-61. doi: 10.1097/00002030-200211220-00004.
• Background Liao Z, Graham DR, Hildreth JE. Lipid rafts and HIV pathogenesis: virion-associated cholesterol is required for fusion and infection of susceptible cells. AIDS Res Hum Retroviruses. 2003 Aug;19(8):675-87. doi: 10.1089/088922203322280900.
• Background Lee YM, Liu B, Yu XF. Formation of virus assembly intermediate complexes in the cytoplasm by wild-type and assembly-defective mutant human immunodeficiency virus type 1 and their association with membranes. J Virol. 1999 Jul;73(7):5654-62. doi: 10.1128/JVI.73.7.5654-5662.1999.
• Background Lindwasser OW, Resh MD. Human immunodeficiency virus type 1 Gag contains a dileucine-like motif that regulates association with multivesicular bodies. J Virol. 2004 Jun;78(11):6013-23. doi: 10.1128/JVI.78.11.6013-6023.2004.
• Background Fortin JF, Cantin R, Lamontagne G, Tremblay M. Host-derived ICAM-1 glycoproteins incorporated on human immunodeficiency virus type 1 are biologically active and enhance viral infectivity. J Virol. 1997 May;71(5):3588-96. doi: 10.1128/JVI.71.5.3588-3596.1997.
• Background Nguyen DH, Hildreth JE. Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts. J Virol. 2000 Apr;74(7):3264-72. doi: 10.1128/jvi.74.7.3264-3272.2000.
• Background Zheng YH, Plemenitas A, Fielding CJ, Peterlin BM. Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8460-5. doi: 10.1073/pnas.1437453100. Epub 2003 Jun 24.
• Background Wang JK, Kiyokawa E, Verdin E, Trono D. The Nef protein of HIV-1 associates with rafts and primes T cells for activation. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):394-9. doi: 10.1073/pnas.97.1.394.
• Background Albi E, Viola Magni MP. The role of intranuclear lipids. Biol Cell. 2004 Oct;96(8):657-67. doi: 10.1016/j.biolcel.2004.05.004.
• Background Fernandez C, Lobo Md Mdel V, Gomez-Coronado D, Lasuncion MA. Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation. Exp Cell Res. 2004 Oct 15;300(1):109-20. doi: 10.1016/j.yexcr.2004.06.029.
• Background Butini L, De Fougerolles AR, Vaccarezza M, Graziosi C, Cohen DI, Montroni M, Springer TA, Pantaleo G, Fauci AS. Intercellular adhesion molecules (ICAM)-1 ICAM-2 and ICAM-3 function as counter-receptors for lymphocyte function-associated molecule 1 in human immunodeficiency virus-mediated syncytia formation. Eur J Immunol. 1994 Sep;24(9):2191-5. doi: 10.1002/eji.1830240939.
• Background Tremblay MJ, Fortin JF, Cantin R. The acquisition of host-encoded proteins by nascent HIV-1. Immunol Today. 1998 Aug;19(8):346-51. doi: 10.1016/s0167-5699(98)01286-9. No abstract available.
• Background Park SW, Royal W 3rd, Semba RD, Wiegand GW, Griffin DE. Expression of adhesion molecules and CD28 on T lymphocytes during human immunodeficiency virus infection. Clin Diagn Lab Immunol. 1998 Jul;5(4):583-7. doi: 10.1128/CDLI.5.4.583-587.1998.
• Background Pearce-Pratt R, Phillips DM. Studies of adhesion of lymphocytic cells: implications for sexual transmission of human immunodeficiency virus. Biol Reprod. 1993 Mar;48(3):431-45. doi: 10.1095/biolreprod48.3.431.
• Background Schrier RD, McCutchan JA, Wiley CA. Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages. J Virol. 1993 Oct;67(10):5713-20. doi: 10.1128/JVI.67.10.5713-5720.1993.
• Background Fujiwara M, Tsunoda R, Shigeta S, Yokota T, Baba M. Human follicular dendritic cells remain uninfected and capture human immunodeficiency virus type 1 through CD54-CD11a interaction. J Virol. 1999 May;73(5):3603-7. doi: 10.1128/JVI.73.5.3603-3607.1999.
• Background Tsunetsugu-Yokota Y, Yasuda S, Sugimoto A, Yagi T, Azuma M, Yagita H, Akagawa K, Takemori T. Efficient virus transmission from dendritic cells to CD4+ T cells in response to antigen depends on close contact through adhesion molecules. Virology. 1997 Dec 22;239(2):259-68. doi: 10.1006/viro.1997.8895.
• Background Hioe CE, Chien PC Jr, Lu C, Springer TA, Wang XH, Bandres J, Tuen M. LFA-1 expression on target cells promotes human immunodeficiency virus type 1 infection and transmission. J Virol. 2001 Jan;75(2):1077-82. doi: 10.1128/JVI.75.2.1077-1082.2001.
• Background Hildreth JE, Orentas RJ. Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation. Science. 1989 Jun 2;244(4908):1075-8. doi: 10.1126/science.2543075.
• Background Graaf MR, Richel DJ, van Noorden CJ, Guchelaar HJ. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat Rev. 2004 Nov;30(7):609-41. doi: 10.1016/j.ctrv.2004.06.010.
• Background Raggatt LJ, Partridge NC. HMG-CoA reductase inhibitors as immunomodulators: potential use in transplant rejection. Drugs. 2002;62(15):2185-91. doi: 10.2165/00003495-200262150-00002.
• Background Leung BP, Sattar N, Crilly A, Prach M, McCarey DW, Payne H, Madhok R, Campbell C, Gracie JA, Liew FY, McInnes IB. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003 Feb 1;170(3):1524-30. doi: 10.4049/jimmunol.170.3.1524.
• Background McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol. 2004 Mar 1;172(5):2903-8. doi: 10.4049/jimmunol.172.5.2903.
• Background Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002 Aug 7;40(3):567-72. doi: 10.1016/s0735-1097(02)02030-2. No abstract available.
• Background Liao Z, Roos JW, Hildreth JE. Increased infectivity of HIV type 1 particles bound to cell surface and solid-phase ICAM-1 and VCAM-1 through acquired adhesion molecules LFA-1 and VLA-4. AIDS Res Hum Retroviruses. 2000 Mar 1;16(4):355-66. doi: 10.1089/088922200309232.
• Background Liang KY, Zeger SL. Regression analysis for correlated data. Annu Rev Public Health. 1993;14:43-68. doi: 10.1146/annurev.pu.14.050193.000355. No abstract available.
• Montoya CJ, Higuita EA, Estrada S, Gutierrez FJ, Amariles P, Giraldo NA, Jimenez MM, Velasquez CP, Leon AL, Rugeles MT, Jaimes FA. Randomized clinical trial of lovastatin in HIV-infected, HAART naive patients (NCT00721305). J Infect. 2012 Dec;65(6):549-58. doi: 10.1016/j.jinf.2012.10.016. Epub 2012 Oct 17.
• Montoya CJ, Jaimes F, Higuita EA, Convers-Paez S, Estrada S, Gutierrez F, Amariles P, Giraldo N, Penaloza C, Rugeles MT. Antiretroviral effect of lovastatin on HIV-1-infected individuals without highly active antiretroviral therapy (The LIVE study): a phase-II randomized clinical trial. Trials. 2009 Jun 18;10:41. doi: 10.1186/1745-6215-10-41.

Drugs

Indications