Clinical Trials Review Articles Adverse Effects FDA Information
Raltegravir is the first approved HIV integrase inhibitor, and is indicated in the treatment of HIV infection in combination with other antiretroviral agents in treatment-naive patients and treatment-experienced patients with evidence of HIV replication despite ongoing antiretroviral therapy. Raltegravir is active against HIV-2 and a wide range of wild-type and drug-resistant HIV-1isolates, including both CCR5 coreceptor–using strains and CXCR4 coreceptor–using strains. Additive to synergistic activity against HIV-1 was observed when raltegravir was combined with other antiretroviral agents.
Raltegravir is metabolized through glucuronidation, and drugs inducing glucuronidation enzyme, UGT1A1, such as rifampin, significantly reduce raltegravir concentration and should not be used. Phenytoin and Phenobarbital also have similar effects, but this has not been well investigated. Despite interactions between raltegravir and selected antiretroviral drugs, such as tenoovir, efaviranz, etravirine, atazanavir, ritonavir, tipranavir, none of these interactions are thought be clinical significant.
It has been confirmed that significant resistance to raltegravir is the consequence of multiple integrase gene substitutions. Three main drug-resistance pathways associated with treatment failure has been demonstrated. Although clinical data on cross-resistance to other integrase inhibitor, such as elvitegravir, are lacking, certain resistance pathways produce high-level phenotypic resistance to both drugs.
The most common adverse events were transient mild-to-moderate headache and fatigue. A higher percentage of grade 3 and 4 creatine phosphokinase elevations while less significant changes in lipid levels has been reported in the raltegravir arm than in the efavirenz arm over 96 weeks. To date, no strong evidence supports raltegravir is associated with the development of malignancies despite mildly higher incidence of cancer in the early report.
Compared with placebo plus optimized background regimen, raltegravir plus optimized background regimen demonstrated significantly better efficacy on sustained virologic suppression and comparable incidence of serious drug-related adverse events, death, and cancer through week 96 in triple class–resistant HIV-infected patients.
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. Lennox JL, Dejesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ, Barnard RJ, Miller MD, Dinubile MJ, Nguyen BY, Leavitt R, Sklar P; for the STARTMRK investigators. Lancet. 2009 Jul 31. [Epub ahead of print]
This study concluded the efficacy of initial raltegravir-based and efavirenz-based combination therapy was comparable in treatment-naïve subgroups based on HIV RAN level, CD4 cell counts, viral subtypes, and demographics (race, region, sex, and age).
Substituting raltegravir for enfuvirtide demonstrated noninferiority in maintenance of virologic suppression and lower incidence of great III/IV laboratory abnormalities and adverse events through week 24 following switch.
Switching from stable lopinavir/ritonavir-based to raltegravir-based combination antiretroviral therapy improved lipid profiles but did not show non-inferior virologic efficacy.
Compared with placebo plus optimized background regimen, raltegravir plus optimized background regimen demonstrated significantly greater efficacy on sustained virologic suppression and similar incidence of serious drug-related adverse events through week 48 in triple class–resistant HIV-infected patients.
This article concisely summarized current publications of raltegravir regarding its clinical pharmacology, drug interactions, clinical trials, safety, toxicities, drug resistances, and clinical uses.
Development of malignancies has been a concern of raltegravir use, and this extensive review demonstrated no difference in risk for cancer in HIV-positive patients treated with raltetravir or other antiretroviral therapy by summarizing the cancer rates from available data of multiple clinical studies.
Adverse Drug Reactions and Warnings
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