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Raltegravir

A Review of its Use in the Management of HIV Infection in Treatment-Experienced Patients

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Summary

Abstract

Raltegravir (Isentress®), an integrase inhibitor, inhibits the insertion of HIV-1 complementary DNA into the host genome. It is indicated in combination with other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple ART agents. It is the first of a new class of ART agents to be approved that, as a result of a different mechanism of action to other ART agents, has good activity against multidrug-resistant HIV-1 strains.

In clinical trials in treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of oral raltegravir to an optimized background therapy (OBT) regimen improved virological and immunological responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Raltegravir therapy was generally well tolerated, with a similar incidence of mild to moderate adverse events in the treatment and placebo arms. The introduction of integrase inhibitors extends the options available for managing treatment-experienced patients with multiple-drug-resistant HIV-1 infection. Results to date suggest that the combination of raltegravir and OBT will be a valuable treatment option for this difficult-to-treat patient group.

Pharmacological Properties

Raltegravir is a selective inhibitor of integrase, an HIV-1-specific enzyme that is responsible for the insertion of viral complimentary DNA into the host genome. In in vitro studies, the 95% inhibitory concentration (IC95) of raltegravir in human T-lymphoid cells infected with a laboratory strain of HIV-1 was 31 nmol/L and ranged from 6 to 50 nmol/L in human peripheral blood mono-nuclear cells, infected with clinical isolates of HIV-1, including strains resistant to other classes of ART. Specific mutations within the HIV-1 integrase gene (predominantly at Q148, N155 or Y143) are correlated with virological resistance to raltegravir. Patients with higher baseline levels of HIV-1 RNA and less active OBT regimens are at the highest risk of integrase mutations arising during treatment.

Oral raltegravir is rapidly absorbed, with a mean maximum plasma concentration reached at a median time of ≈1 hour. The mean plasma concentration of raltegravir at the end of a 12-hour dose administration interval after a 400 mg dose exceeded the IC95 against HIV-1 in vitro. Raltegravir is metabolized in humans through uridine diphosphate-glucuronosyltransferase-mediated glucuronidation in the liver, and is eliminated in faeces and urine. The mean elimination half-life of raltegravir is 7–12 hours. Raltegravir does not significantly affect the activity of the cytochrome P450 system and therefore is not expected to interact with other ART agents that are substrates for these enzymes.

Therapeutic Efficacy

In the two phase III BENCHMRK trials (n = 699), orally administered raltegravir 400 mg twice daily plus OBT improved both virological and immunological outcomes in treatment-experienced patients with HIV-1 infection, evidence of viral replication and HIV-1 strains resistant to multiple ART agents. At 16 weeks in the individual trials and at 48 weeks in the combined analysis, raltegravir plus OBT reduced HIV-1 RNA levels to <400 copies/mL (primary endpoint) and <50 copies/mL in a significantly greater number of patients and significantly increased CD4+ cell counts from baseline when compared with placebo plus OBT. Moreover, prespecified subgroup analyses indicated that in the BENCHMRK trials, the greater efficacy of raltegravir plus OBT compared with placebo plus OBT was maintained in patients with baseline characteristics that typically predict a poor response to ART therapy, for example, higher HIV-1 RNA levels, lower CD4+ cell counts and less active OBT regimens.

Tolerability

Raltegravir was generally well tolerated when used in combination with OBT regimens in treatment-experienced patients with HIV-1 infection in trials of up to 48 weeks’ duration. The majority of adverse events were mild to moderate in severity, and of similar incidence in the raltegravir plus OBT and placebo plus OBT treatment arms; treatment-related discontinuations were uncommon. The most common drug-related adverse events reported were diarrhoea, headache, nausea and fatigue.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Jamie D. Croxtall & Susan J. Keam

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Jamie D. Croxtall & Susan J. Keam

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  1. Jamie D. Croxtall
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  2. Susan J. Keam
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Corresponding author

Correspondence to Jamie D. Croxtall.

Additional information

Various sections of the manuscript reviewed by: F. Cainelli, School of Medicine, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana; B. Gazzard, St Stephen’s Centre, Chelsea and Westminster Hospital, London, UK; D.T. Jayaweera, Division of Infectious Diseases, University of Miami School of Medicine, Miami, Florida, USA; M. Nelson, HIV Medicine, Chelsea and Westminster Hospital, London, UK; R. Wood, Institute of Infectious Disease and Molecular Medicine, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘raltegravir’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘raltegravir’. Searches were last updated 20 May 2009.

Selection: Studies in patients with HIV infection who received raltegravir. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Raltegravir, HIV infection, antiretroviral therapy, integrase inhibitor, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Croxtall, J.D., Keam, S.J. Raltegravir. Drugs 69, 1059–1075 (2009). https://doi.org/10.2165/00003495-200969080-00007

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