Fast track — ArticlesSafety 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
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)
New antiretroviral drugs
Clin Microbiol Infect
(2003)- et al.
Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug resistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials
Lancet
(2006) - et al.
PA update: DHHS guidelines for the treatment of HIV infection
JAAPA
(2006) - et al.
Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA Panel
JAMA
(2006) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents
(2006)Emerging anti-HIV drugs
Expert Opin Emerg Drugs
(2005)- et al.
Screening and selecting for optimized antiretroviral drugs: rising to the challenge of drug resistance
Curr Med Res Opin
(2006) - et al.
Effects of drug resistance on viral load in patients failing antiretroviral therapy
J Med Virol
(2006) - et al.
Drug-class-wide resistance to antiretrovirals in HIV-infected patients therapy: prevalence, risk factors and virological outcome
Antivir Ther
(2006) - et al.
The prevalence of antiretroviral drug resistance in the United States
AIDS
(2004)