Pharmacology Update

Raltegravir Tablets (Isentress™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved the second of two new antiretroviral agents from new drug classes. Raltegravir is the first integrase strand transfer inhibitor and follows closely on the approval of maraviroc, a CCR5 co-receptor antagonist. Integrase is an enzyme that is essential for HIV-1 replication by catalyzing the insertion of HIV DNA into the genome of the host cell. Raltegravir is marketed by Merck & Company as Isentress.


Raltegravir is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infections in treatment-experienced adults who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.1


The recommended dose is 400 mg taken orally twice daily. It may be taken without regard to meals. Dosage adjustment is not needed for patients with renal impairment or mild to moderate hepatic impairment.1

Raltegravir is available as 400 mg tablets.

Potential Advantages

Raltegravir has a different target of antiretroviral action than existing drugs. It does not interact with substrates, inhibitors, or inducers of CYP 450 isoenyzmes and does not inhibit UDP-glucuronosyltransferases or P-glycoprotein-mediated transport.1

Potential Disadvantages

The most common adverse events are diarrhea (17%), headache (10%), nausea (10%), and pyrexia (5%). Elevation of creatine kinase has been reported with frequencies of grade 2 to 4 elevations of about 2%. Myopathy and rhabdomyolysis have been reported.1 Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT1A1) and should not be used with strong inducers of this enzyme (eg, rifampin). It can be used with atazanavir, a strong inhibitor of UGT1A1.1


Raltegravir is the first integrase strand transfer inhibitor to be approved. Integrase is one of the three enzymes essential for viral replication. Raltegravir has shown in vitro activity against multidrug resistant and both CCR5 and CXCR4 tropic virus.2 FDA approval was based on two ongoing, 24-week, randomized, phase III, double-blind, placebo-controlled studies (BENCHMRK 1 and BENCHMRK 2) in treatment-experienced adult subjects with documented resistance to at least one drug in each of the 3 classes (NRTI, NNRTI, PI) (n = 699).1 Subjects were randomized to raltegravir (400 mg twice daily) and optimized background therapy (OBT) or placebo plus OBT stratified by degree of resistance and enfuvirtide use. Selection of OBT was by the investigator with consideration of genotypic/phenotypic results and prior antiretroviral therapy. The median baseline plasma HIV-1 RNA values were 4.8 log10 copies/ml and 4.7 log10 copies/ml for raltegravir and placebo. Median baseline CD4+ values were 119 cells/mm3 and 123 cells/mm3 respectively. At 24-weeks, mean changes in viral loads were -1.85 log10 copies/ml for raltegravir and -0.84 for placebo. Mean increases in CD4+ were 89 cells/mm3 and 35 cells/mm3 respectively. Approximately 2/3rd of subjects with data at 24-weeks (62%) achieved viral load < 50 copies/ml with raltegravir compared to 1/3rd for placebo. Thirteen percent of subjects showed a rebound in viral RNA (>400 copies/ml or > 1 log10 increase above nadir) after achieving a 1 log10 decline or <400 copies/ml. Raltegravir appears to be well tolerated.1,3 In a small study involving treatment naïve subjects (n = 198), raltegravir was found to be as effective as efavirenz when combined with tenofovir and lamivudine.4 It is currently not FDA approved for this use. Raltegravir is expected to cost about $9850 per year.

Clinical Implications

Raltegravir offers a drug that targets a different aspect of HIV-1 replication. The long-term safety and effectiveness is not known as approval was based on improvement in surrogate endpoints.


1. Isentress Product Information. Merck & Co. October 2007.

2. Miller M, et al. 16th International AIDS Conference; Toronto, Canada, Aug 13-18, 2006. Abstract THAA0302.

3. Grinsztejn B, et al. Lancet. 2007;369(9569)1261-1269.

4. Markowitz M, et al. J Acquir Immune Defic Syndr. 2007;46:125-133.