Raltegravir (Isentress) is an HIV-1 integrase strand-transfer inhibitor with potent antiretroviral activity. It belongs to a new class of antiretrovirals called integrase inhibitors. The drug works against HIV's integrase protein, blocking its ability to integrate its genetic code into human cells.
Raltegravir (Isentress), formerly known as MK-0518, is the first licensed integrase inhibitor. It was given marketing approval in the US in 2007 and in Europe in early 2008 for use by treatment-experienced people. Raltegravir’s approval was based upon the results from the BENCHMRK I and II studies that showed it had a durable anti-HIV effect in people with limited treatment options.
The drug was approved for use in initial antiretroviral regimens by both the UK and US in 2009, based on 48-week data from the STARTMRK clinical trial. As an initial regimen, raltegravir (given in combination with tenofovir and emtricitabine) sustained viral suppression at rates equivalent to an efavirenz-based regimen. (Mena)
Raltegravir was approved for once-daily dosing in the European Union and United States in 2017.
Raltegravir’s approval for use in antiretroviral-experienced people was based upon the results from the BENCHMRK 1 and 2 studies that demonstrated a durable anti-HIV effect in people with limited treatment options. The STARTMRK clinical studies demonstrated the drug's safety and efficacy in treatment-naive individuals and in 2009, raltegravir was approved for use as a first-line regimen.
In an early phase II dose-ranging study (Protocol 005) of raltegravir, treatment-experienced people with documented multiple antiretroviral class resistance and viral load above 5000 copies/ml were randomised to one of three raltegravir doses or placebo added to an optimised background regimen. At 24 weeks, raltegravir at any of the three doses (200mg, 400mg, or 600mg) provided better viral suppression than placebo (over 70% with viral load < 400 copies/ml vs 17% in placebo arm) with no dose-related toxicities. (Grinsztejn)
BENCHMRK 1 and 2 studies are identical, international phase III studies that examined the efficacy of raltegravir in people with triple-class resistant HIV. Nearly 700 people with a median viral load over 50,000 copies/ml were randomised on a 2:1 basis to raltegravir 400mg twice daily or placebo, with a physician-selected optimised treatment background (OTB).
At week 16, using intent-to-treat analysis, the raltegravir arm was found to be superior; 76% of people had viral load levels below 400 copies/ml vs 42% of those on placebo with OTB. Viral load less than 50 copies/ml was reached by 62% on the raltegravir arm vs 35% of those on placebo. By week 48, those levels were basically unchanged (62% vs 32% respectively). On the basis of these results, raltegravir gained marketing approval in the EU and US. (Cooper) (Steigbigel)
In treatment-naive patients, the second part of Protocol 004, a dose-ranging phase II study exploring raltegravir’s safety and efficacy, reported durable and potent antiretroviral activity at weeks 24 and 48. The study arms looked at raltegravir vs efavirenz, both against a treatment background of tenofovir and lamivudine. (Markowitz, 2007)
At week 96, raltegravir had a sustained antiretroviral effect, similar in effect to the efavirenz treatment arm. Viral load was suppressed to less than 400 copies/ml in 84% of the participants in each group and less than 50 copies/ml in 83% of those on raltegravir vs 84% on the efavirenz arm. CD4 cell count increases were similar: 221 cells vs 232 cells/mm3 for the raltegravir and efavirenz arms respectively. Raltegravir had a faster initial viral load decline; whether this is of consequence long-term is not known. (Markowitz, 2009)
The STARTMRK study is a large phase III study with a similar design to Protocol 004. Week 48 results demonstrated the non-inferiority of raltegravir to efavirenz. Viral load below 50 copies/ml in the raltegravir and efavirenz arms respectively were 86% vs 82%, a non-significant difference. In the raltegravir arm, the mean CD4 cell increase was 189 cells/mm3 vs 163 cells/mm3 in the efavirenz arm.
Raltegravir (Isentress) is available in 400mg or 600mg tablets and standard dosing is one 400mg tablet taken twice a day or two 600mg tablets taken once a day.
Raltegravir can be taken with or without food. As with all anti-HIV drugs, it is important to take the drug as prescribed in order to maintain the right level of the drug in the blood. If blood levels of the drug fall too low, resistance to raltegravir can develop and this may affect future treatment options.
The most commonly reported side-effects of raltegravir are headache and insomnia. Severe rash and hypersensitivity reaction are rare side-effects.
Resistance to raltegravir has been observed more frequently after viral rebound in treatment-experienced people than in those experiencing failure of their first antiretroviral regimen. (Hazuda) (Cooper)
A study of US patients with resistance to either raltegravir or elvitegravir predicted that based on the observed mutation patterns, approximately 12% would have high-level resistance to dolutegravir. (Hurt)
Raltegravir is not metabolised through the CYP3A enzyme, so is unlikely to have important interactions with other anti-HIV drugs. Caution should be used when co-administering raltegravir with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g. rifampicin) due to reduced plasma concentrations of raltegravir.
Raltegravir is approved for use in children and adolescents aged 2 to 16 years.
A small study in pregnant women has shown that raltegravir is safe and effective during pregnancy, while a second study reported no adverse birth outcomes in infants exposed to raltegravir during gestation. (Blonk)(Trahan)
Mena A et al. A pilot study assessing Raltegravir (Isentress) QD versus BID in HIV patients inclluded in a simplification trial. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Franciso, abstract H-920, 2009.
Grinsztejn B 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 randomized controlled trial. The Lancet, 369: 1261-1269, 2007.
Cooper DA et al. Subgroup and resistance analysis of raltegravir for resistant HIV-1 infection. New England Journal of Medicine, 359: 355-365, 2008.
Steigbigel RT et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. New England Journal of Medicine, 359: 339-54, 2008.
Markowitz M 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. Journal of Acquired Immune Deficiency Syndromes, 46:125-33, 2007.
Markowitz M et al. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. Journal of Acquired Immune Deficiency Syndromes, 52: 350-356, 2009.
Hazuda DJ et al. Analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from the Benchmrk 1 and 2. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-898, 2008.
Hurt CB et al. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012. Clinical Infectious Diseases, 58: 423-31, 2014.
Blonk MI et al. Raltegravir in HIV-1-infected pregnant women: pharmacokinetics, safety, and efficacy. Clinical Infectious Diseases, 61: 809-16, 2015.
Trahan MJ (Kakkar F presenting) Raltegravir for prevention of mother-to-child transmission of HIV. Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract TUAB0105, 2015.