Raltegravir (Isentress) is an HIV-1 integrase strand-transfer inhibitor with potent antiretroviral activity. It belongs to a 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 1 and 2 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 were 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. (Lennox)
Raltegravir has been tested in a two-drug regimen combined with darunavir boosted by ritonavir. The NEAT 001 / ANRS 143 study randomised 805 people to start treatment with either raltegravir and boosted darunavir or boosted darunavir combined with tenofovir disoproxil fuamarate and emtricitabine. After 96 weeks, levels of viral suppression were equivalent in the two study arms (89% vs 93%) but virologic failure occurred more frequently in the two-drug arm in people with baseline viral loads above 100,000 copies/ml. Two-drug treatment was inferior to three-drug treatment in people with pre-treatment CD4 counts below 200. (Raffi)
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 common side effects of raltegravir are headache and insomnia. Severe rash and hypersensitivity reaction are rare side effects.
An analysis of eight clinical trials of new drugs introduced after 2003 found that weight gain was significantly greater in people taking an integrase inhibitor. Raltegravir was less strongly associated with weight gain than newer integrase inhibitors (dolutegravir and bictegravir). (Sax) Another study, of people who started treatment in the United States between 2007 and 2016, found that weight gain was greater in people taking dolutegravir or raltegravir than in people taking elvitegravir or efavirenz. (Bourgi)
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. Chewable tablets or granules are available for children under 12.
A large randomised clinical trial has shown that raltegravir is superior to efavirenz in suppressing viral load in women who start treatment during pregnancy. (Joao) The British HIV Association recommends that raltegravir should be dosed twice daily (400mg) during pregnancy to maintain adequate blood levels.
Raltegravir has not been associated with adverse birth outcomes in infants exposed during gestation. (Trahan) (Shamsuddin)
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.
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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.
Lennox JL 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, 374: 796-806, 2009.
Raffi F et al. First-line raltegravir + darunavir-ritonavir is non-inferior to tenofovir-emtricitabine + darunavir-ritonavir: The NEAT 001/ANRS 143 randomized trial. 21st Conference on Retroviruses and Opportunistic Infections, abstract 84LB, 2014.
Sax P et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clinical Infectious Diseases, 71: 1379-89, 2019.
Bourgi K et al. Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada. Journal of the International AIDS Society, 23: e25484, 2020.
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.
Joao EC et al. Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial. Lancet HIV, 7: e322-e331, 2020.
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.
Shamsuddin H et al. Evaluation of neural tube defects (NTDs) after exposure to raltegravir during pregnancy. Journal of Acquired Immune Deficiency Syndromes, 81: 247-50, 2019.