|July 22, 2008
|September 30, 2011
|July 2011 (final data collection date for primary outcome measure)
|1. HIV-1 viral load measured as RNA copies per ml of peripheral blood 2. CD4 T-cell count measured as cells per ul of peripheral blood [ Time Frame: Before, 6 and twelve months after the intervention ] [ Designated as safety issue: No ]
|Same as current
|Complete list of historical versions of study NCT00721305 on ClinicalTrials.gov Archive Site
|CD8+ T cell count, CD4/CD8 ratio, Expression of CD38 and HLA-DR, Total serum cholesterol, Cellular cholesterol, Activity of LFA-1 and ICAM-1, Activity of Rho GTPases, Monthly frequency of AIDS defining diseases, hospitalization and mortality [ Time Frame: Before, 6 and twelve months after the intervention ] [ Designated as safety issue: No ]
|Same as current
|Lovastatin: Immunomodulatory Value Evaluation
|Antiretroviral Effect of Lovastatin on HIV-1-infected Individuals Without Highly Active Antiretroviral Therapy (HAART): A Phase-II Randomized Clinical Trial (RCT)
|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.
|Despite the fact that HAART produces a decrease in HIV-1 replication and plasma HIV-1 RNA levels, and allows an increase in the CD4 T-cell count that leads to a diminution in the incidence of opportunistic infections and mortality, the cost and complexity of HAART regimens, the growing list of long-term side effects, and the eventual development of resistance have underscored the immediate need for additional therapeutic approaches. Statins exert pleiotropic effects through a variety of mechanisms, among which there are several immunological effects that are related and unrelated to their cholesterol-lowering activity. HIV-1 requires cholesterol and lipid rafts for several key stages of its replication cycle; statins-mediated depletion of cholesterol alters the capacity of a cell to form lipid rafts and decreases the HIV-1 infectivity. On the other hand, statins may exert significant modulator effects in the balance of the cytokine network, and alter the activity of Rho GTPases and LFA-1 and ICAM-1 adhesion molecules. Preliminary studies showed that statins (Lovastatin) had anti HIV-1 activity, and that its administration was safe and efficient to control HIV-1 infection in chronically infected individuals who did not receive HAART (in terms of decreasing viral load and increasing CD4 T-cell count). Because very limited clinical data are available on this topic, this study will be conducted.
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
- Drug: Lovastatin
Lovastatin 40 mg daily (2 tablets of 20 mg each, p.o.), during twelve months until the end of the study, or before the end of the study if any AIDS defining disease or toxicity appear
Other Name: statin
- Other: placebo
Placebo will be administered daily (2 tablets which will look externally identical to intervention: wrapped in the same way, with the same size, shape and color), during twelve months until the end of the study, or before the end of the study if any AIDS defining disease or toxicity appear
- Experimental: 1
In this arm, subjects will receive 40 mg of Lovastatin (2 tablets of 20 mg each, p.o.), in a daily doses, during twelve months
Intervention: Drug: Lovastatin
- Placebo Comparator: 2
In this arm, subjects will receive placebo (2 tablets which will look externally identical to lovastatin: wrapped in the same way, with the same size, shape and color)
Intervention: Other: placebo
- United Nations Programme on HIV/AIDS (UNAIDS).; United Nations Development Programme (UNDP).. International consultation on the criminalization of HIV transmission: 31 October-2 November 2007, Geneva, Switzerland. Joint United Nations Programme on HIV/AIDS (UNAIDS) Geneva, United Nations Development Programme (UNDP), New York, 2007. Reprod Health Matters. 2009 Nov;17(34):180-6. doi: 10.1016/S0968-8080(09)34466-3.
- 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
- 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. Review.
- 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. 1993 Aug;6(8):904-12.
- 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.
- 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.
- 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.
- 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.
- 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.
- Fehr T, Kahlert C, Fierz W, Joller-Jemelka HI, Riesen WF, Rickli H, Wüthrich RP, Ammann P. Statin-induced immunomodulatory effects on human T cells in vivo. Atherosclerosis. 2004 Jul;175(1):83-90.
- 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.
- 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.
- 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.
- Del Real G, Jiménez-Baranda S, Lacalle RA, Mira E, Lucas P, Gómez-Moutón C, Carrera AC, Martínez-A C, Mañes S. Blocking of HIV-1 infection by targeting CD4 to nonraft membrane domains. J Exp Med. 2002 Aug 5;196(3):293-301.
- del Real G, Jiménez-Baranda S, Mira E, Lacalle RA, Lucas P, Gómez-Moutón C, Alegret M, Peña JM, Rodríguez-Zapata M, Alvarez-Mon M, Martínez-A C, Mañes S. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med. 2004 Aug 16;200(4):541-7.
- Giguère 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.
- 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.
- 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.
- Youssef S, Stüve 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.
- Illingworth DR, Tobert JA. HMG-CoA reductase inhibitors. Adv Protein Chem. 2001;56:77-114. Review.
- Garcia PJ. Pleiotropic effects of statins: moving beyond cholesterol control. Curr Atheroscler Rep. 2005 Feb;7(1):34-9. Review.
- Blanco-Colio LM, Tuñón J, Martín-Ventura JL, Egido J. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int. 2003 Jan;63(1):12-23. Review.
- 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.
- Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999 Sep;30(9):1969-73. Review.
- 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.
- 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.
- 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.
- Moncunill G, Negredo E, Bosch L, Vilarrasa J, Witvrouw M, Llano A, Clotet B, Esté JA. Evaluation of the anti-HIV activity of statins. AIDS. 2005 Oct 14;19(15):1697-700.
- 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.
- 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.
- 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.
- Bonnet F, Balestre E, Thiébaut R, Mercié P, Dupon M, Morlat P, Dabis F; Groupe d'Epidémiologie 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.
- 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.
- 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.
- 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.
- 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. Review.
- Mañes S, del Real G, Lacalle RA, Lucas P, Gómez-Moutón C, Sánchez-Palomino S, Delgado R, Alcamí J, Mira E, Martínez-A C. Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection. EMBO Rep. 2000 Aug;1(2):190-6.
- Moore JP, Trkola A, Dragic T. Co-receptors for HIV-1 entry. Curr Opin Immunol. 1997 Aug;9(4):551-62. Review.
- Nguyen DH, Taub DD. Inhibition of chemokine receptor function by membrane cholesterol oxidation. Exp Cell Res. 2003 Nov 15;291(1):36-45.
- 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.
- 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.
- Mazière 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.
- 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.
- 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.
- 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.
- Sáez-Cirión A, Nir S, Lorizate M, Agirre A, Cruz A, Pérez-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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Albi E, Viola Magni MP. The role of intranuclear lipids. Biol Cell. 2004 Oct;96(8):657-67. Review.
- Fernández C, Lobo Md Mdel V, Gómez-Coronado D, Lasunción MA. Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation. Exp Cell Res. 2004 Oct 15;300(1):109-20.
- 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.
- Tremblay MJ, Fortin JF, Cantin R. The acquisition of host-encoded proteins by nascent HIV-1. Immunol Today. 1998 Aug;19(8):346-51. Review.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. Review.
- Raggatt LJ, Partridge NC. HMG-CoA reductase inhibitors as immunomodulators: potential use in transplant rejection. Drugs. 2002;62(15):2185-91. Review.
- 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.
- 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.
- 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.
- 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.
- Liang KY, Zeger SL. Regression analysis for correlated data. Annu Rev Public Health. 1993;14:43-68. Review.
- 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 naïve patients (NCT00721305). J Infect. 2012 Dec;65(6):549-58. doi: 10.1016/j.jinf.2012.10.016.
- Montoya CJ, Jaimes F, Higuita EA, Convers-Páez S, Estrada S, Gutierrez F, Amariles P, Giraldo N, Peñaloza 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.
|July 2011 (final data collection date for primary outcome measure)
- Inability or unwillingness of patients to give written informed consent.
- Main residence outside Medellin and its metropolitan area, or any indication of difficulties in the follow-up period
- Participation in other clinical trials
- Evidence that the patient will exhibit low adherence to intervention and follow-up (Morisky-Green test)
- Pregnancy or breastfeeding
- Any type of antiretroviral treatment before admission to the study, and therapy with lipid-lowering drugs during the last six months
- Antecedents of allergy, contraindications or intolerance to statins
- Patients receiving medications which can generate relevant interactions with lovastatin: clarithromycin, erythromycin, azithromycin, itraconazole, ketoconazole, nefodozone, cimetidine, rifampin, phenobarbital, carbamazepine, phenytoin.
- Unwillingness to avoid the consumption of Citrus paradise (grapefruit juice) or Saint John's Wort (Hypericum)
- Opportunistic infections or any type of AIDS-defining disease
- Chronic active hepatitis (B or C)
- Any hepatocellular disease, indicated by elevation of liver enzymes (AST or ALT) more than twice the reference value
- Renal failure, indicated by serum creatinine ≥ 2 mg/dl
- Myopathy, indicated by an elevation of creatine phosphokinase (CPK) more than five times the reference values
- Infection or acute disease that requires in-patient treatment
- Active substance-related disorders
|18 Years and older (Adult, Senior)
|Contact information is only displayed when the study is recruiting subjects
|Carlos Julio Montoya Guarin, Universidad de Antioquia
|Universidad de Antioquia
- Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS)
- Laboratorio Clínico Congregación Mariana
- Laboratorios Laproff S.A.
- Humax Pharmaceutical
||Carlos J Montoya, MD, PhD
||Universidad de Antioquia
||Maria T Rugeles, PhD
||Universidad de Antioquia
||Fabian A Jaimes, MD, PhD
||Universidad de Antioquia
|Universidad de Antioquia