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Raltegravir, a New HIV Integrase Inhibitor

Because raltegravir inhibits a novel viral target, even HIV that is resistant to other antiretroviral-medication classes is sensitive to this drug.

Background: Raltegravir (Isentress) is the first in a new class of anti-HIV drugs that act by inhibiting the HIV integrase enzyme.

Spectrum of Action: HIV replication involves the conversion of viral RNA into DNA, which is then incorporated into the host cell genome through a process catalyzed by the HIV integrase enzyme. By blocking integrase, raltegravir inhibits HIV replication.

Clinical Trials: Raltegravir demonstrated potent antiretroviral activity in two multinational, randomized, double-blind, phase III clinical trials (BENCHMRK-1 and -2) involving a total of 699 treatment-experienced HIV-infected adults (ACC Apr 2 2007). In these industry-sponsored trials, raltegravir was compared with placebo (each together with optimized background therapy) in patients with triple-class–resistant HIV. In a pooled analysis, a significantly greater proportion of raltegravir recipients than placebo recipients had HIV RNA levels <50 copies/mL at week 24 (62.6% vs. 33.3%). The virologic response rate was higher for patients whose regimens contained at least one other active agent in addition to raltegravir. Raltegravir recipients had significantly greater CD4-count increases at week 24 than did placebo recipients (mean change, 89 vs. 35 cells/mm³).

Raltegravir has also been studied in a phase II trial involving 198 treatment-naive patients (ACC Sep 17 2007). Participants were randomized to receive tenofovir and lamivudine with either efavirenz or one of four doses of raltegravir. At week 48, 83% to 88% of participants in all raltegravir dose groups achieved HIV RNA levels <50 copies/mL. HIV RNA levels declined more rapidly in raltegravir recipients than in efavirenz recipients. A large phase III trial of raltegravir in treatment-naive patients is underway.

Pharmacology and Dosing: Raltegravir is administered orally, 400 mg twice daily, with or without food. The drug is metabolized primarily by glucuronidation and is not a known CYP450 inducer, inhibitor, or substrate. Raltegravir is 83% protein-bound. No data are available yet on the drug’s ability to penetrate the human central nervous system. No dose adjustment is recommended for patients with mild or moderate hepatic impairment or renal insufficiency.

Drug Resistance: Raltegravir resistance is associated with mutations at positions 148 (Q148H/K/R) or 155 (N155H) of HIV integrase occurring together with one or more additional substitutions. A third pathway to raltegravir resistance involves a mutation at position 143 (Y143C/H/R). There seems to be cross-resistance between raltegravir and elvitegravir, an integrase inhibitor being developed by Gilead (ACC Jul 9 2007).

Drug Interactions: The dose of raltegravir does not need to be adjusted when this medication is given with other antiretroviral agents. Although atazanavir increases raltegravir levels, no dose adjustment of either drug is recommended. Phenytoin, phenobarbital, and rifampin all reduce raltegravir levels; Merck’s recommendation that the raltegravir dose be increased to 800 mg twice daily when the drug is coadministered with any of these agents is under review by the FDA. At present, we do not have enough information to know whether raltegravir can be safely coadministered with these medications.

Side Effects: The rates of adverse events, such as nausea, headache, and diarrhea, were similar between raltegravir recipients and placebo recipients in clinical trials. Although elevated serum creatine kinase levels occurred slightly more often with raltegravir than with placebo, these increases did not typically lead to treatment discontinuation. Raltegravir should be used with caution in patients at increased risk for myopathy (e.g., those receiving concomitant medications that can cause rhabdomyolysis).

Cost and Availability: As of October 12, 2007, the wholesale acquisition cost of raltegravir is US$27 per day; a 1-month supply will therefore cost $810. Raltegravir is expected to be in pharmacies by the end of the month.

Comment: Raltegravir is an exciting new agent for treating HIV infection in patients whose virus is resistant to older medications. Because raltegravir inhibits a novel viral target, HIV that is resistant to other antiretroviral-medication classes is still sensitive to this drug. However, like all HIV medications, raltegravir must be given as part of a combination regimen. Fortunately, several other new drugs — maraviroc (for R5-tropic HIV), darunavir, tipranavir, and enfuvirtide — are now available for treatment of drug-resistant HIV. We are likely to use raltegravir in combination with these new agents in patients who have virologic failure because of multidrug resistance, with the expectation that most people treated with these novel cocktails will achieve virologic suppression. As a well-tolerated and potent medication with few drug interactions, raltegravir is an important addition to our expanding armamentarium of agents to treat HIV infection.

— Rajesh T. Gandhi, MD

Published in AIDS Clinical Care October 22, 2007

Citation(s):

Isentress (raltegravir) tablets [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2007. (http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf)

Raltegravir Review Team. Memorandum to the [Antiviral Drugs] Advisory Committee: Background package for NDA 22-145; raltegravir. August 8 , 2007. (http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4314b1-02-fda.pdf)