Safety and Efficacy Study Comparing Raltegravir to a Protease Inhibitor in Treatment-naïve, HIV/Hepatitis C Drug Users

Summary

The purpose of this study is to compare how safe, tolerable, and effective a novel drug, raltegravir, is to a commonly used combination, atazanavir/ritonavir, as initial treatment in HIV/Hepatitis C co-infected injecting drug users on a methadone program.

Timeline

Start

2010-08

Primary completion

2012-12

Completion

2012-12

Publications

• Background Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Campbell H, Strohmaier KM, Wan H, Danovich RM, Teppler H; Protocol 004 Part II Study Team. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr. 2009 Nov 1;52(3):350-6. doi: 10.1097/QAI.0b013e3181b064b0.
• Background Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ, Barnard RJ, Miller MD, DiNubile MJ, Nguyen BY, Leavitt R, Sklar P; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806. doi: 10.1016/S0140-6736(09)60918-1. Epub 2009 Aug 3.
• Background O'Connor PG, Selwyn PA, Schottenfeld RS. Medical care for injection-drug users with human immunodeficiency virus infection. N Engl J Med. 1994 Aug 18;331(7):450-9. doi: 10.1056/NEJM199408183310707. No abstract available.
• Background Waldrop-Valverde D, Valverde E. Homelessness and psychological distress as contributors to antiretroviral nonadherence in HIV-positive injecting drug users. AIDS Patient Care STDS. 2005 May;19(5):326-34. doi: 10.1089/apc.2005.19.326.
• Background Lucas GM, Cheever LW, Chaisson RE, Moore RD. Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection. J Acquir Immune Defic Syndr. 2001 Jul 1;27(3):251-9. doi: 10.1097/00126334-200107010-00006.
• Background Lucas GM, Griswold M, Gebo KA, Keruly J, Chaisson RE, Moore RD. Illicit drug use and HIV-1 disease progression: a longitudinal study in the era of highly active antiretroviral therapy. Am J Epidemiol. 2006 Mar 1;163(5):412-20. doi: 10.1093/aje/kwj059. Epub 2006 Jan 4.
• Background Lucas GM, Mullen BA, Weidle PJ, Hader S, McCaul ME, Moore RD. Directly administered antiretroviral therapy in methadone clinics is associated with improved HIV treatment outcomes, compared with outcomes among concurrent comparison groups. Clin Infect Dis. 2006 Jun 1;42(11):1628-35. doi: 10.1086/503905. Epub 2006 Apr 28.
• Background Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001 Aug 15;33(4):562-9. doi: 10.1086/321909. Epub 2001 Jul 6.
• Background Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.
• Background Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA, Gottesdiener KM, Wagner JA. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther. 2008 Feb;83(2):293-9. doi: 10.1038/sj.clpt.6100281. Epub 2007 Aug 22.
• Background Furlan V, Demirdjian S, Bourdon O, Magdalou J, Taburet AM. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther. 1999 May;289(2):1169-75.
• Background Iwamoto M, Hanley WD, Petry AS, Friedman EJ, Kost JT, Breidinger SA, Lasseter KC, Robson R, Lunde NM, Wenning LA, Stone JA, Wagner JA. Lack of a clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother. 2009 May;53(5):1747-52. doi: 10.1128/AAC.01194-08. Epub 2009 Feb 17.
• Background Le Tiec C, Barrail A, Goujard C, Taburet AM. Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet. 2005;44(10):1035-50. doi: 10.2165/00003088-200544100-00003.
• Background Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ, von Moltke LL. Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005 Jun;33(6):764-70. doi: 10.1124/dmd.104.002931. Epub 2005 Mar 11.
• 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 Ehret GB, Voide C, Gex-Fabry M, Chabert J, Shah D, Broers B, Piguet V, Musset T, Gaspoz JM, Perrier A, Dayer P, Desmeules JA. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med. 2006 Jun 26;166(12):1280-7. doi: 10.1001/archinte.166.12.1280.
• Background Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med. 2002 Sep 17;137(6):501-4. doi: 10.7326/0003-4819-137-6-200209170-00010.
• Background Katchman AN, McGroary KA, Kilborn MJ, Kornick CA, Manfredi PL, Woosley RL, Ebert SN. Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther. 2002 Nov;303(2):688-94. doi: 10.1124/jpet.102.038240.
• Background Anson BD, Ackerman MJ, Tester DJ, Will ML, Delisle BP, Anderson CL, January CT. Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2434-41. doi: 10.1152/ajpheart.00891.2003. Epub 2004 Feb 19.
• Background Anson BD, Weaver JG, Ackerman MJ, Akinsete O, Henry K, January CT, Badley AD. Blockade of HERG channels by HIV protease inhibitors. Lancet. 2005 Feb 19-25;365(9460):682-6. doi: 10.1016/S0140-6736(05)17950-1.
• Background Ly T, Ruiz ME. Prolonged QT interval and torsades de pointes associated with atazanavir therapy. Clin Infect Dis. 2007 Mar 15;44(6):e67-8. doi: 10.1086/511875. Epub 2007 Feb 1.
• Background Josephson F, Bertilsson L, Bottiger Y, Flamholc L, Gisslen M, Ormaasen V, Sonnerborg A, Diczfalusy U. CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4beta-hydroxycholesterol levels. Eur J Clin Pharmacol. 2008 Aug;64(8):775-81. doi: 10.1007/s00228-008-0492-8. Epub 2008 May 6.
• Background Gallagher DP, Kieran J, Sheehan G, Lambert J, Mahon N, Mallon PW. Ritonavir-boosted atazanavir, methadone, and ventricular tachycardia: 2 case reports. Clin Infect Dis. 2008 Aug 1;47(3):e36-8. doi: 10.1086/589869.
• Background Nordin C, Kohli A, Beca S, Zaharia V, Grant T, Leider J, Marantz P. Importance of hepatitis C coinfection in the development of QT prolongation in HIV-infected patients. J Electrocardiol. 2006 Apr;39(2):199-205. doi: 10.1016/j.jelectrocard.2005.09.001. Epub 2005 Nov 28.
• Background Iwamoto M, Kost JT, Mistry GC, Wenning LA, Breidinger SA, Marbury TC, Stone JA, Gottesdiener KM, Bloomfield DM, Wagner JA. Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. J Clin Pharmacol. 2008 Jun;48(6):726-33. doi: 10.1177/0091270008318007. Epub 2008 Apr 25.

Drugs

Indications