Elsevier

The Lancet

Volume 369, Issue 9569, 14–20 April 2007, Pages 1261-1269
The Lancet

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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

https://doi.org/10.1016/S0140-6736(07)60597-2Get rights and content

Summary

Background

Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients.

Methods

HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00105157.

Findings

179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9·9 years (range 0·4–17·3 years) and the mean baseline viral load was 4·7 (SD 0·5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was −1·80 (95% CI −2·10 to −1·50) log10 copies per mL in the 200 mg group, −1·87 (−2·16 to −1·58) log10 copies per mL in the 400 mg group, −1·84 (−2·10 to −1·58) log10 copies per mL in the 600 mg group, and −0·35 (−0·61 to −0·09) log10 copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities.

Interpretation

In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.

Introduction

Current HIV treatment models use combination therapy to achieve maximum and durable suppression of viral replication to reduce HIV-related morbidity and mortality.1, 2, 3 However, despite the success of highly active antiretroviral therapy, the long-term use of antiretroviral therapies is currently limited by the development of resistance and by toxicity associated with many of these treatments.4, 5, 6, 7, 8, 9 In HIV-infected patients with demonstrable plasma viraemia during treatment, between 76% and 91% had virus resistant to one or more antiretroviral drugs.7, 9, 10 Multidrug-resistant HIV infection and cross-resistance to agents within a class restrict effective treatment options1, 2, 3 and create an urgent need for new classes of antiretroviral drugs.

Integrase is one of three viral enzymes essential for HIV replication, catalysing the insertion of HIV DNA into the genome of the host cell.11, 12 Integration is required for stable maintenance of the viral genome as well as for efficient viral gene expression and replication. Because HIV-1 integrase represents a distinct therapeutic target, HIV-1 integrase inhibitors would be expected to maintain activity against HIV-1 resistant to the other classes of antiretroviral drugs.11 Raltegravir—also known as MK-0518—is an HIV-1 integrase strand transfer inhibitor that has been shown to be active against multidrug-resistant HIV-1 and both CCR5-trophic and CXCR4-trophic HIV-1 in vitro.11, 12 Raltegravir is additive or synergistic in vitro with currently available antiretroviral drugs. Strains of HIV resistant to raltegravir remain susceptible to other agents.12 The drug has been shown to have potent antiretroviral effects, with a mean decrease from baseline in HIV-1 RNA concentrations of about 2 log10 copies per mL after 10 days of monotherapy.13 In combination with tenofovir and lamivudine, raltegravir suppressed HIV-1 RNA concentrations to below 50 copies per mL in about 90% of patients infected with HIV-1 after 24 weeks.14

This report summarises the 24-week results of a phase II dose-ranging study that aimed to assess the safety and efficacy of raltegravir compared with that of placebo, all in combination with optimised background therapy, in treatment-experienced patients infected with multidrug-resistant HIV-1.

Section snippets

Patients

Non-pregnant HIV-1-seropositive patients aged over 18 years with plasma HIV-1 RNA viral load above 5000 copies per mL and CD4 cell counts above 50 cells per μL, on stable antiretroviral therapy for more than 3 months, and infected with HIV-1 with documented genotypic or phenotypic resistance to at least one non-nucleoside reverse transcriptase inhibitor (NNRTI), one nucleoside reverse transcriptase inhibitor (NRTI), and one protease inhibitor (PI) were eligible. Other eligibility criteria

Results

This preplanned analysis of the continuing study was based on 24-week study data extracted from a database frozen on Dec 1, 2006. At the time of this analysis, all patients had completed at least 24 weeks of double-blind therapy. 179 patients were randomly assigned to treatment groups between April 22, 2005, and Dec 7, 2005; 178 patients received at least one dose of study drug. Figure 1 shows the trial profile.

The demographic and other baseline characteristics of the patients were much the

Discussion

This study shows that raltegravir has a rapid, potent, and sustained antiretroviral effect in patients with advanced HIV-1 infection who had failed previous therapy, with triple-class resistant virus, and with a limited number of active antiretroviral drugs in their background regimen. The limited magnitude of the efficacy response in the placebo group was consistent with data reported in RESIST and TORO studies.16, 17, 18

In both substudies, the antiretroviral efficacy of raltegravir was much

References (22)

  • JC Couto-Fernandez et al.

    Human immunodeficiency virus type 1 (HIV-1) genotyping in Rio de Janeiro, Brazil: assessing subtype and drug-resistance associated mutations in HIV-1 infected individuals failing highly active antiretroviral therapy

    Mem Inst Oswaldo Cruz

    (2005)
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