December 2007

New HIV Medication Approval: Raltegravir (Isentress®)

Crystal Irwin, PharmD

Raltegravir is the newest FDA approved medication for the treatment of HIV/AIDS. The medication received accelerated approval on October 12, 2007 and is the first medication in a new class of agents called integrase inhibitors. It is indicated for the treatment of HIV-1 infection in combination with other agents for treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple antiretroviral agents. The recommended dose of raltegravir is one 400-mg tablet twice daily. No dosage adjustment is necessary in patients with mild to moderate hepatic or severe renal impairment.

Raltegravir inhibits the HIV-1 encoded enzyme integrase. Integrase is required for viral replication and is necessary for the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome. More specifically, integrase, aided by viral and cellular proteins, transports the viral double-stranded DNA into the host cell nucleus and provides the permanent insertion, of the viral double-stranded DNA to the host cell genome, which, in turn, provides viral access to the host cellular machinery for gene expression. Following integration, transcription and translation produce viral precursor proteins. This key step in HIV replication, insertion of the viral double-stranded DNA into the host cell genome, is believed to be mediated by integrase in at least three, and possibly, four, steps: (1 ) assembly of proviral DNA; (2) 3'-end processing causing assembly of the pre-integration complex; (3) 3'-end joining or DNA strand transfer, i.e., integration; and (4) gap filling, a repair function. Blocking integrase prevents the formation of the HIV-1 provirus and thus prevents propagation of the viral infection.

Raltegravir was approved after data from two ongoing Phase III multi-center, double-blind, randomized, placebo-controlled studies (BENCHMRK-1 and BENCHMRK-2) in 699 treatment-experienced adult patients with documented resistance to at least one drug in each of three classes (NRTIs, NNRTIs and PIs) of antiretroviral therapies showed that Raltegravir 400 mg dosed twice daily in combination with optimized background therapy (OBT) was significantly more effective at both reducing levels of HIV viral RNA and increasing CD4 cell counts in these patients living with HIV, when compared to a regimen of placebo plus OBT.

Results from these studies were positive, showing that after 24 weeks of therapy, 75.5% of patients (216 out of 286) receiving the combination of raltegravir with OBT achieved HIV viral RNA load reduction to below 400 copies/mL compared to 39.3% of patients (59 out of 150) receiving placebo plus OBT.  In addition, after 24 weeks of therapy, 62.6%of patients (179 out of 286) receiving the combination achieved viral load reduction to below 50 copies/mL compared to 33.3% of patients (50 out of 150) in the placebo group. 

The most commonly reported adverse events in patients taking raltegravir were mild and included diarrhea, headache, nausea and fever. Elevations in creatinine kinase were observed in subjects who received raltegravir and there have been reports of myopathy and rhabdomyolysis. However, at this point, the relationship of raltegravir to these events is not known.  Thus, raltegravir should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

Raltegravir is not metabolized by cytochrome P450 enzymes and has not been shown to inhibit or induce these enzymes. Based on the results of drug interaction studies and the clinical trials data, there is no reason to adjustment the dose of raltegravir when coadministering with other antiretroviral agents.

Raltegravir is an excellent new treatment option for patients with known resistance to other HIV agents. There are no significant drug interactions, the pill burden is low and thus far there are no reports of serious adverse reactions. It should be noted, however, that raltegravir is not approved for use in pregnant, pediatric, and/or treatment-naïve patients.

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