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

HIV Infection Clinical Trial

— ETRALL  

Official title:

Phase III Prospective Multicentric Trial Evaluating Etravirine for HIV Infected Patients in Need of Lipid Lowering Drugs: the ETRALL Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01543035
• Other study ID #: ETRALL DR3215
• Status: Completed
• Phase: Phase 3
• First received: February 27, 2012
• Last updated: December 11, 2013
• Start date: December 2011
• Est. completion date: August 2013

Study information

• Verified date: December 2013
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: Swissmedic
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: August 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• On statin treatment for at least 3 months (fluvastatin, simvastatin, pravastatin, rosuvastatin, or atorvastatin) for primary prevention of cardiovascular disease

• HIV Ribonucleic Acid (RNA) below 50 copies/mL, minimum duration 3 months

• On a stable (> 3 months) ARV treatment including at least one of the following drugs:

LPV/r, ATZ/r, DRV/r, or EFV

• No previous virological escape or virological escape documented with a genotype at the time of failure only showing a K103M mutation.

Exclusion Criteria:

• Probability of cardiovascular complications of > 20% according to the Swiss GSLA ("Groupe de travail Lipide et Athérosclérose"/Swiss Atherosclerosis Association) guidelines

• Previous cardiovascular disease (including stroke)

• Known diabetes

• Known intolerance of ETR

• Presence of a documented drug mutation (excluding the K103M)

• Regimen including non-boosted ATZ

• Known hyperlipidemia before ARV initiation

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV Infection
• HIV Infections

Intervention

Drug:
• stop statin and switch to an antiretroviral drug with less impact on lipid metabolism
Switch from a boosted PI or efavirenz based ART regimen to etravirine 400 mg/day once daily for patients in need of lipid lowering drugs (statin) after one month wash out of statin

Locations

Country	Name	City	State
Switzerland	Universitätsspital Basel Klinik für Infektiologie & Spitalhygiene	Bale
Switzerland	Inselspital PKT2B / Poliklinik für Infektiologie	Berne
Switzerland	HUG /Division des Maladies infectieuses Unité VIH/SIDA	Geneva
Switzerland	Hôpital Neuchâtelois - La Chaux-de-Fonds Service des Maladies infectieuses	La Chaux-de-Fonds
Switzerland	CHUV / Service des maladies infectieuses Médecine 2	Lausanne
Switzerland	Kantonsspital / Infektiologie und Spitalhygiene Departement Innere Medizin	St Gallen
Switzerland	Universitätsspital Zürich Division of Infectious Diseases and Hospital Epidemiology Department of Internal Medicine	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
Calmy Alexandra	Janssen-Cilag A.G., Switzerland

Country where clinical trial is conducted

Switzerland, 

References & Publications (15)

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. Review. — View Citation

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. — View Citation

DAD Study Group, Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte Ad, El-Sadr W, Thiébaut 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. — View Citation

Friis-Møller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, Thiébaut 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. Erratum in: N Engl J Med. 2004 Feb 26;350(9):955. — View Citation

Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992 May;74(5):1045-52. — View Citation

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. Epub 2004 Oct 11. — View Citation

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. — View Citation

Nguyen A, Calmy A, Delhumeau C, Mercier IK, Cavassini M, Fayet-Mello A, Elzi L, Genné 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. Erratum in: AIDS. 2011 Mar 13;25(5):729. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. — View Citation

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. — View Citation

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. — View Citation

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-naïve, 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. — View Citation

Sension M, Andrade Neto JL, Grinsztejn B, Molina JM, Zavala I, González-García 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. — View Citation

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. — View Citation

Thiébaut R, Daucourt V, Mercié P, Ekouévi 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'Epidémiologie Clinique du Syndrome d'Immunodéficience Acquise en Aquitaine. Clin Infect Dis. 2000 Dec;31(6):1482-7. Epub 2000 Nov 29. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients not qualifying anymore for statin treatment		12 weeks	No
Secondary	fasting lipids changes		12 weeks	No