Prospective Evaluation of Etravirine for HIV-infected Patients in Need of Lipid-lowering Drugs

Summary

Dyslipidaemia, characterized by raised triglyceride and low-density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol levels, is common in HIV-infected individuals, and has been associated with HIV infection itself and antiretroviral therapy (ART). These abnormalities are well-established markers of cardiovascular (CVD) risk in the general population. Studies have suggested an increased risk of CVD associated with ART exposure over and above that conveyed by traditional cardiovascular risk factors. In HIV population to reduce lipid parameters, the most usual clinical strategy remains to add a statin treatment. Recent studies suggested ART switch can represent an interesting alternative to statins to reduce lipid plasma levels. The purpose of this study is to evaluate the frequency with which the replacement of LPV/r (lopinavir/ritonavir), ATZ/r (atazanavir/ritonavir), DRV/r (darunavir/ritonavir) or EFV (efavirenz) by ETR (Etravirin) in dyslipidemic patients with suppressed viremia would obviate the necessity to administer statins. A prospective, phase III study in which the statin treatment of dyslipidemic HIV patients on antiretroviral drugs (ARVs) will be interrupted during 4 weeks is proposed. At week 4, patients qualifying for a lipid lowering drug (calculated LDL-C≥ 3mmol/L) will replace EFV, LPV/r, DRV/r or ATZ/r by ETR. The proportion of patients not qualifying anymore for a statin treatment at 12 weeks (i.e. after 8 weeks of ETR treatment) will be determined. Additionally, the lipid level changes will be assessed at 12 weeks. Inflammatory markers will be measured at baseline, at drug switch and at the end of the study Study drug will be provided by the drug manufacturer (Janssen-Cilag, AG). Compliance for study drug will be done at week-4 and week-12, Returned study medication will be counted and the amount notified on the Case Report Form (CRF).

Timeline

Start

2011-12

Primary completion

2013-07

Completion

2013-08

Publications

• Background Riddler SA, Li X, Chu H, Kingsley LA, Dobs A, Evans R, Palella F, Visscher B, Chmiel JS, Sharrett A. Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy. HIV Med. 2007 Jul;8(5):280-7. doi: 10.1111/j.1468-1293.2007.00470.x.
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• Background Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella F, Visscher B, Evans R, Kingsley LA. Impact of HIV infection and HAART on serum lipids in men. JAMA. 2003 Jun 11;289(22):2978-82. doi: 10.1001/jama.289.22.2978.
• Background Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998 May 7;12(7):F51-8. doi: 10.1097/00002030-199807000-00003.
• Background Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN, Lo JC, Schambelan M. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr. 2000 Jan 1;23(1):35-43. doi: 10.1097/00126334-200001010-00005.
• Background Thiebaut R, Daucourt V, Mercie P, Ekouevi DK, Malvy D, Morlat P, Dupon M, Neau D, Farbos S, Marimoutou C, Dabis F. Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Groupe d'Epidemiologie Clinique du Syndrome d'Immunodeficience Acquise en Aquitaine. Clin Infect Dis. 2000 Dec;31(6):1482-7. doi: 10.1086/317477. Epub 2000 Nov 29.
• Background Wand H, Calmy A, Carey DL, Samaras K, Carr A, Law MG, Cooper DA, Emery S; INITIO Trial International Coordinating Committee. Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS. 2007 Nov 30;21(18):2445-53. doi: 10.1097/QAD.0b013e3282efad32.
• Background Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD; Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003 Nov 20;349(21):1993-2003. doi: 10.1056/NEJMoa030218.
• Background DAD Study Group; Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte Ad, El-Sadr W, Thiebaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007 Apr 26;356(17):1723-35. doi: 10.1056/NEJMoa062744.
• Background Carey D, Amin J, Boyd M, Petoumenos K, Emery S. Lipid profiles in HIV-infected adults receiving atazanavir and atazanavir/ritonavir: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2010 Sep;65(9):1878-88. doi: 10.1093/jac/dkq231. Epub 2010 Jun 16.
• Background Sension M, Andrade Neto JL, Grinsztejn B, Molina JM, Zavala I, Gonzalez-Garcia J, Donnelly A, Phiri P, Ledesma E, McGrath D; 067 Study Group. Improvement in lipid profiles in antiretroviral-experienced HIV-positive patients with hyperlipidemia after a switch to unboosted atazanavir. J Acquir Immune Defic Syndr. 2009 Jun 1;51(2):153-62. doi: 10.1097/QAI.0b013e3181a5701c.
• Background Nguyen A, Calmy A, Delhumeau C, Mercier IK, Cavassini M, Fayet-Mello A, Elzi L, Genne D, Rauch A, Bernasconi E, Hirschel B; Swiss HIV Cohort Study. A randomized crossover study to compare efavirenz and etravirine treatment. AIDS. 2011 Jan 2;25(1):57-63. doi: 10.1097/QAD.0b013e32833f9f63.
• Background Ruxrungtham K, Pedro RJ, Latiff GH, Conradie F, Domingo P, Lupo S, Pumpradit W, Vingerhoets JH, Peeters M, Peeters I, Kakuda TN, De Smedt G, Woodfall B; TMC125-C227 study group. Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naive, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227. HIV Med. 2008 Nov;9(10):883-96. doi: 10.1111/j.1468-1293.2008.00644.x. Epub 2008 Sep 14.
• Background Spencer FA, Allegrone J, Goldberg RJ, Gore JM, Fox KA, Granger CB, Mehta RH, Brieger D; GRACE Investigators. Association of statin therapy with outcomes of acute coronary syndromes: the GRACE study. Ann Intern Med. 2004 Jun 1;140(11):857-66. doi: 10.7326/0003-4819-140-11-200406010-00006.
• Background McGowan MP; Treating to New Target (TNT) Study Group. There is no evidence for an increase in acute coronary syndromes after short-term abrupt discontinuation of statins in stable cardiac patients. Circulation. 2004 Oct 19;110(16):2333-5. doi: 10.1161/01.CIR.0000145118.55201.15. Epub 2004 Oct 11.
• Ciaffi L, Cavassini M, Genne D, Delhumeau C, Spycher Elbes R, Hill A, Wandeler G, Fehr J, Stoeckle M, Schmid P, Hirschel B, Montecucco F, Calmy A; Swiss HIV Cohort Study. Switch to etravirine for HIV-positive patients receiving statin treatment: a prospective study. Eur J Clin Invest. 2015 Jul;45(7):720-30. doi: 10.1111/eci.12464.

Drugs

Indications