The HIV-1 integrase inhibitor raltegravir (MK-0518) is safe and effective in treatment-experienced patients with multidrug-resistant virus, according to the results of a phase 2, randomized controlled trial study reported in the April 14 issue of The Lancet.
"Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains, including those resistant to currently available antiretroviral drugs," write Beatriz Grinsztejn, from the Evandro Chagas Clinical Research Institute/Oswaldo Cruz Foundation in Rio de Janeiro, Brazil, and colleagues from the Protocol 005 Team. "The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients."
HIV-infected patients eligible for this multicenter, triple-blind, dose-ranging study had HIV-1 RNA viral load higher than 5000 copies/mL, CD4 cell counts greater than 50 cells/μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one nonnucleoside reverse transcriptase inhibitor, and one protease inhibitor. The main outcome measures were change in viral load from baseline at week 24 and safety; analysis was by modified intention-to-treat.
Of 179 patients eligible for randomization, 44 patients were randomized to oral treatment twice daily with raltegravir 200 mg, 45 to raltegravir 400 mg, 45 to raltegravir 600 mg, and 45 to placebo. One patient in the 200-mg group did not receive treatment and was therefore excluded from analysis.
Median duration of previous antiretroviral treatment was 9.9 years (range, 0.4 - 17.3 years), and mean baseline viral load was 4.7 ± 0.5) log10 copies per mL. Of 4 patients who discontinued because of adverse events, 3 (2%) were in the raltegravir groups and 1 patient (2%) was in the placebo group.
Of 41 patients who discontinued because of lack of efficacy, 14 (11%) were in the raltegravir groups and 27 (60%) were in the placebo group. Mean change in viral load from baseline at week 24 was –1.80 (95% confidence interval [CI], –2.10 to –1.50) log10 copies/mL in the 200-mg group, –1.87 (95% CI, –2.16 to –1.58) log10 copies/mL in the 400-mg group, –1.84 (95% CI, –2.10 to –1.58) log10 copies/mL in the 600-mg group, and –0.35 (95% CI, –0.61 to –0.09) log10 copies/mL in the placebo group. At all doses, raltegravir had a safety profile similar to that of placebo, with no dose-related toxicities.
"In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen," the authors write. "The safety profile of raltegravir is comparable with that of placebo at all doses studied."
Raltegravir is manufactured by Merck & Co, which employs 4 of the authors. Some of the other authors report various financial relationships with Merck & Co, Abbott, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Virgo, Boehringer Ingelheim, and/or Pfizer.
In an accompanying editorial, Pedro Cahn and Omar Sued, from the Fundación Huesped in Buenos Aires, Argentina, call these results "encouraging."
"Raltegravir showed a good safety profile and high potency in naive and experienced patients, achieving virological suppression even in patients with limited options," Drs. Cahn and Sued write. "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. 48-week data for naive patients are eagerly expected. Should these data show similar efficacy to efavirenz-based regimens, raltegravir could be considered as a new option to build into initial regimens for highly active antiretroviral therapy."
"Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains, including those resistant to currently available antiretroviral drugs," write Beatriz Grinsztejn, from the Evandro Chagas Clinical Research Institute/Oswaldo Cruz Foundation in Rio de Janeiro, Brazil, and colleagues from the Protocol 005 Team. "The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients."
HIV-infected patients eligible for this multicenter, triple-blind, dose-ranging study had HIV-1 RNA viral load higher than 5000 copies/mL, CD4 cell counts greater than 50 cells/μL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one nonnucleoside reverse transcriptase inhibitor, and one protease inhibitor. The main outcome measures were change in viral load from baseline at week 24 and safety; analysis was by modified intention-to-treat.
Of 179 patients eligible for randomization, 44 patients were randomized to oral treatment twice daily with raltegravir 200 mg, 45 to raltegravir 400 mg, 45 to raltegravir 600 mg, and 45 to placebo. One patient in the 200-mg group did not receive treatment and was therefore excluded from analysis.
Median duration of previous antiretroviral treatment was 9.9 years (range, 0.4 - 17.3 years), and mean baseline viral load was 4.7 ± 0.5) log10 copies per mL. Of 4 patients who discontinued because of adverse events, 3 (2%) were in the raltegravir groups and 1 patient (2%) was in the placebo group.
Of 41 patients who discontinued because of lack of efficacy, 14 (11%) were in the raltegravir groups and 27 (60%) were in the placebo group. Mean change in viral load from baseline at week 24 was –1.80 (95% confidence interval [CI], –2.10 to –1.50) log10 copies/mL in the 200-mg group, –1.87 (95% CI, –2.16 to –1.58) log10 copies/mL in the 400-mg group, –1.84 (95% CI, –2.10 to –1.58) log10 copies/mL in the 600-mg group, and –0.35 (95% CI, –0.61 to –0.09) log10 copies/mL in the placebo group. At all doses, raltegravir had a safety profile similar to that of placebo, with no dose-related toxicities.
"In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen," the authors write. "The safety profile of raltegravir is comparable with that of placebo at all doses studied."
Raltegravir is manufactured by Merck & Co, which employs 4 of the authors. Some of the other authors report various financial relationships with Merck & Co, Abbott, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Virgo, Boehringer Ingelheim, and/or Pfizer.
In an accompanying editorial, Pedro Cahn and Omar Sued, from the Fundación Huesped in Buenos Aires, Argentina, call these results "encouraging."
"Raltegravir showed a good safety profile and high potency in naive and experienced patients, achieving virological suppression even in patients with limited options," Drs. Cahn and Sued write. "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. 48-week data for naive patients are eagerly expected. Should these data show similar efficacy to efavirenz-based regimens, raltegravir could be considered as a new option to build into initial regimens for highly active antiretroviral therapy."
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