Clinical trials of HIV antiretroviral therapy: Integrase inhibitors
- Paul E Sax, MD
Paul E Sax, MD
- Clinical Director, Division of Infectious Diseases
- Brigham and Women's Hospital
- Professor of Medicine
- Harvard Medical School
HIV-1 integrase is essential for viral replication; integrase inserts viral DNA into the cellular genome through two catalytic reactions. Loss of integrase activity disrupts the viral life cycle. Inhibitors of the integrase function have potent in vitro and in vivo antiviral activity.
This topic will discuss clinical trials data on the three integrase inhibitors available for clinical use: raltegravir, the first agent available in this class, elvitegravir, which is available in a co-formulated tablet in combination with cobicistat, tenofovir, and emtricitabine, and dolutegravir, which is approved for use in combination with abacavir/lamivudine and tenofovir/emtricitabine for individuals who are antiretroviral naïve, and is active in patients with multidrug HIV resistance.
The pharmacology of integrase inhibitors, as well as the indications for initiating antiretroviral therapy (ART) and the selection and monitoring of these regimens, is discussed elsewhere. (See "Patient monitoring during HIV antiretroviral therapy" and "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient" and "When to initiate antiretroviral therapy in HIV-infected patients" and "Selecting an antiretroviral regimen for treatment-experienced HIV-infected patients who are failing therapy".)
Raltegravir (MK-0518) is an integrase inhibitor with potent in vitro activity against both wild-type and multidrug-resistant HIV . It is metabolized by hepatic glucuronidation and has no effect on cytochrome 3A4 . Raltegravir is used for the treatment of antiretroviral naïve and experienced individuals. The risk of resistance is lower when coadministered with other active agents; when resistance occurs, it is associated with the emergence of mutations at several potential sites, most commonly Q148R or N155H. The clinical trials that support these recommendations are described below.
Treatment-naive patients — Raltegravir has demonstrated significant efficacy in treatment-naive patients. Studies show that raltegravir has rapid, potent, and durable efficacy with a lower rate of adverse events than efavirenz [3-5]. In treatment-naïve patients, raltegravir should be given twice daily.
- Murray JM, Emery S, Kelleher AD, et al. Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS 2007; 21:2315.
- Wong JK, Lampiris H. Covering all the bases: targeting HIV-1 integrase. J Acquir Immune Defic Syndr 2006; 43:507.
- Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006; 43:509.
- Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46:125.
- Lennox JL, DeJesus E, Lazzarin A, et al. 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; 374:796.
- Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63:77.
- Lennox JL, Dejesus E, Berger DS, et al. Raltegravir versus Efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr 2010; 55:39.
- Eron JJ Jr, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis 2011; 11:907.
- Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 2007; 369:1261.
- Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008; 359:339.
- Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008; 359:355.
- Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis 2010; 50:605.
- Eron JJ, Cooper DA, Steigbigel RT, et al. Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. Lancet Infect Dis 2013; 13:587.
- De Castro N, Braun J, Charreau I, et al. Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial. Clin Infect Dis 2009; 49:1259.
- Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet 2010; 375:396.
- Kilby JM. Switching HIV therapies: competing host and viral factors. Lancet 2010; 375:352.
- Vispo E, Barreiro P, Maida I, et al. Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial. HIV Clin Trials 2010; 11:197.
- Martínez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS 2010; 24:1697.
- Buzón MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 2010; 16:460.
- McMahon D, Jones J, Wiegand A, et al. Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis 2010; 50:912.
- Hatano H, Hayes TL, Dahl V, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis 2011; 203:960.
- Hatano H, et al. Raltegravir intensification in antiretroviral-treated patients exhibiting a suboptimal CD4+ T cell response. Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco, CA, Abst# 101LB.
- DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012; 379:2429.
- Rockstroh JK, DeJesus E, Henry K, et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013; 62:483.
- Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379:2439.
- Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013; 63:96.
- Molina JM, Lamarca A, Andrade-Villanueva J, et al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2012; 12:27.
- van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012; 12:111.
- Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382:700.
- Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369:1807.
- Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381:735.
- Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2013; 75:990.
- Song I, Borland J, Chen S, et al. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother 2012; 56:1627.
- Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS 2013; 27:1771.
- Feinberg et al. Once-daily dolutegravir is superior to darunavir/ritonavir in antiretroviral naive adults:48 week results from FLAMINGO. ICAAC 2013; Denver, CO. Abstract H-1464a
- Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis 2013; 207:740.
- Nichols G, et al. Phase 3 assessment of dolutegravir (DTG) 50mg twice daily in HIV-1-infected subjects with raltegravir (RAL) and/or elvitegravir (EVG) resistance in VIKING-3: week 24 results of all 183 patients enrolled. 7th IAS, Kuala Lumpur, 2013, Abstract TULBPE19
- Underwood MR, Johns BA, Sato A, et al. The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr 2012; 61:297.
- Treatment-naive patients
- - STARTMRK
- - QDMRK
- Treatment-experienced patients
- - BENCHMRK trials
- Switch studies
- - Switch from enfuvirtide to raltegravir
- - Switch from a protease inhibitor to raltegravir
- SWITCHMRK trials
- ODIS trial
- Spiral study
- Intensification strategies
- Treatment-naive patients
- Treatment-experienced patients
- Treatment naïve patients
- - Spring 1 trial
- - Single trial
- - Spring 2 trial
- - Flamingo trial
- Treatment-experienced patients
- - Viking
- - Sailing
- SUMMARY AND RECOMMENDATIONS