Merck’s Integrase Inhibitor Raltegravir Demonstrates High Potency in Patients with Drug-resistant HIV

The experimental HIV integrase inhibitor raltegravir (Isentress; formerly MK-0518) rapidly and effectively decreases HIV RNA levels to below 50 copies/mL in treatment-experienced patients unresponsive to other antiretrovirals, according to results of a Phase IIb study published in the April 14, 2007 issue of The Lancet.

Integrase inhibitors are a new class of anti-HIV drugs that target the integrase enzyme of HIV and prevent the virus from inserting its genes into the DNA of uninfected host cells; in this class, raltegravir is the agent furthest along in the development process.

With the development of integrase inhibitors, scientists have accomplished the important goal of successfully targeting all 3 enzymes required for HIV replication: reverse transcriptase, protease, and integrase.

• raltegravir 200 mg: 45 patients;
  
  
• 1 patient in this group never started treatment and was excluded from analysis;
  
  
• raltegravir 400 mg: 45 patients;
  
  
• raltegravir 600 mg: 45 patients;
  
  
• placebo: 45 patients.

Raltegravir or placebo were used in conjunction with an optimized background antiretroviral regimen.

Study participants had HIV RNA viral loads greater than 5000 copies/mL, CD4 cell counts above 50 cells/mm³, and documented genotypic and phenotypic resistance to at least 1 nucleoside reverse transcriptase inhibitor (NRTI), 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), and 1 protease inhibitor (PI). At baseline, the median duration of prior antiretroviral therapy was 9.9 years and the mean baseline viral load was 4.7 log₁₀ copies/mL.

The primary endpoints of the study were safety and change in viral load from baseline at week 24.

Results

• At week 24, the mean changes in viral load from baseline were as follows:
  
  
• −1.80 log₁₀ copies/mL in the raltegravir 200 mg group;
• −1.87 log₁₀ copies/mL in the raltegravir 400 mg group;
• −1.84 log₁₀ copies/mL in the raltegravir 600 mg group;
• −0.35 log₁₀ copies/mL in the placebo group.
  
  
• After 24 weeks, 65% of patients taking raltegravir achieved undetectable HIV viral loads (< 50 copies/mL).
  
  
• The safety profile of raltegravir at all doses was similar to that of placebo.
  
  
• No dose-related toxicities were reported.
  
  
• 4 patients discontinued therapy due to adverse events:
  
  
• 3 (2%) of the 133 patients in all raltegravir groups combined;
• 1 (2%) of the 45 patients in the placebo group.
  
  
• 41 patients discontinued due to lack of efficacy:
  
  
• 14 (11%) of the 133 patients in all raltegravir groups combined;
• 27 (60%) of the 45 patients in the placebo group.

Conclusion

The study authors concluded that for patients who have few remaining treatment options, raltegravir at all doses studied was safe and provided potent viral suppression. They added that raltegravir is a "clinically relevant" HIV-1 integrase inhibitor that represents "a major advance in basic and clinical science."

In an editorial that accompanied the report in The Lancet, Pedro Cahn, MD, and Omar Sued, MD, of the Department of Clinical Research at the Fundacion Huesped in Buenos Aires, Argentina, wrote that in this study, “raltegravir showed unprecedented levels of virological efficacy.” Further, they added, “If no long-term, unexpected side effects or resistance issues emerge, raltegravir will have a major role in salvage therapy, particularly in combination with another new drug.”

Merck is expected to apply for FDA approval of raltegravir by the summer of 2007.

See also on HIV and Hepatitis.com:

Integrase Inhibitor Raltegravir Demonstrates Potent Activity against HIV at 16-24 Weeks

HIV Integrase Inhibitor MK-0518 Monotherapy Demonstrates Potent Anti-HIV Activity in 10-day Study

04/20/07

References

B Grinsztejn, N Bach-Yen, C Katlama, and others. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomized controlled trial. The Lancet 369(9569): 1261-1269. April 14, 2007.

P Cahn and O Sued. Raltegravir: a new antiretroviral class for salvage therapy. The Lancet 369(9569): 1235-1236. April 14, 2007.