Isentress (raltegravir)

Isentress is an orally available human immunodeficiency virus integrase strand transfer inhibitor. Once a cell is infected with HIV, its RNA must be converted (reverse transcribed) into DNA. Integrase, a viral enzyme, helps to hide HIV's DNA inside the cell's DNA. Integrase inhibitors work by blocking this process, known as integration. Thus, Isentress prevents HIV DNA from entering healthy cell DNA.

Isentress, in combination with other antiretroviral agents, is specifically indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

Isentress is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 400 mg administered orally, twice daily with or without food.

FDA Approval
The FDA approval of Isentress is based on the results of two clinical trials. These randomized, double-blind, placebo-controlled trials were dubbed BENCHMARK-1 and BENCHMARK-2. The trials enrolled treatment-experienced HIV-infected subjects who had failed antiretroviral therapies (ARTs), and who had HIV virus resistant to at least one drug in each of the three available classes of oral ARTs. In both studies, subjects received 400mg or placebo, each dosed orally twice daily in combination with OBT. The trials were designed to compare Isentress plus optimized background therapy (OBT) to placebo plus OBT in terms of reduction in HIV viral load, change from baseline in CD4 cell counts and evaluation of safety and tolerability.

BENCHMARK-1
This trial enrolled subjects in Europe, Asia and Peru. The mean baseline viral load was 4.6 log10 copies/mL and the mean CD4 cell counts 156 cells/mm3 for the Isentress group and 4.5 log10 copies/mL and 153 cells/mm3, respectively, for the placebo group. In BENCHMARK-1, 77% of subjects receiving Isentress in combination with OBT achieved HIV RNA viral load reduction below 400 copies/mL compared to 41% of subjects receiving placebo plus OBT (p<0.001). In addition, 61% of subjects receiving Isentress plus OBT achieved viral load reduction to below 50 copies/mL compared to 33% of those receiving placebo plus OBT (p<0.001). Increases in CD4 cell counts from baseline were 83 and 31 cells/mm³ for subjects receiving Isentress and placebo, respectively (p<0.001).

BENCHMARK-2
This trial enrolled subjects in North, Central and South America. The mean baseline viral load was 4.7 log10 copies/mL for both the Isentress and placebo groups. The mean CD4 cell counts were 146 cells/mm3 for the Isentress group and 163 cells/mm3 for the placebo group. In BENCHMARK-2, 77% of subjects receiving Isentress in combination with OBT achieved HIV RNA viral load reduction to below 400 copies/mL compared to 43% of subjects receiving placebo plus OBT (p<0.001). In addition, 62% of subjects receiving Isentress plus OBT achieved RNA viral load reduction to below 50 copies/mL compared to 36% of those receiving placebo plus OBT (p<0.001). Increases in CD4 cell counts from baseline were 86 and 40 cells/mm³ for the subjects receiving Isentress and placebo, respectively (p<0.001). Treatment was generally well tolerated in both trials.

Adverse events associated with the use of Isentress may include, but are not limited to, the following:

• Diarrhea
• Nausea
• Headache
• Pyrexia
• Asthenia
• Fatigue
• Dizziness
• Acquired Lipodystrophy

Isentress is an orally available human immunodeficiency virus integrase strand transfer inhibitor. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection.

Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; the Protocol 004 Part II Study Team Rapid and Durable Antiretroviral Effect of the HIV-1 Integrase Inhibitor Raltegravir as Part of Combination Therapy in Treatment-Naive Patients With HIV-1 Infection: Results of a 48-Week Controlled Study. Journal of acquired immune deficiency syndromes 2007 Oct 1;46(2):125-133

Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA, Gottesdiener KM, Wagner JA Safety, Tolerability, and Pharmacokinetics of Raltegravir After Single and Multiple Doses in Healthy Subjects. Clinical pharmacology and therapeutics 2007 Aug 22

Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team Safety 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. Lancet 2007 Apr 14;369(9569):1261-9

Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. Journal of acquired immune deficiency syndromes 2006 Dec 15;43(5):509-15

For additional information regarding Isentress or HIV, please visit the Isentress web page.