Darunavir Non-inferior to Lopinavir in HIV

SAO PAULO, Brazil, July 6 -- The novel protease inhibitor darunavir (Prezista) is non-inferior to the top-line protease inhibitor in patients with moderate experience with anti-HIV drugs, researchers found.
In the randomized, controlled, phase III TITAN trial, darunavir was non-inferior to lopinavir (Kaletra) when both drugs were given with ritonavir, according to José Valdez Madruga, M.D., of Centro de Referência e Treinamento DST/AIDS, here.
Indeed, at week 48 of the trial, significantly more patients (at P<0.001) taking darunavir had achieved a viral load of less than 400 copies of HIV RNA per mL of blood, Dr. Madruga and colleagues reported in the July 6 issue of The Lancet.
The estimated least square mean treatment difference was 9% -- 77% for darunavir-ritonavir and 68% for lopinavir-ritonavir -- with a 95% confidence interval from 2% to 16%. The study design stipulated that darunavir would be considered non-inferior if the lower limit of the 95% confidence interval did not exceed minus12%.
In the analysis of an intent-to-treat population, the figures were 77% for darunavir and 67% for lopinavir, significant at P=0.008, Dr. Madruga and colleagues reported.
Also, 71% of darunavir patients were below 50 copies of viral HIV RNA per mL of plasma, compared with 60% of lopinavir patients, a difference that was significant at P=0.005.
The combination of lopinavir and ritonavir is the preferred protease inhibitor for initial combination therapy, under the Department of Health and Human services HIV treatment guidelines.
Darunavir has already been shown to be effective in people with highly resistant HIV and is approved for that indication. (See Darunavir Effective in Resistant HIV and FDA Approves Prezista for HIV Salvage Therapy.)
But the TITAN trial enrolled 595 patients in several countries who had a broader experience of HIV drugs -- intended to be similar to the range of patients seen in clinical practice.
They had been on highly active anti-retroviral therapy (HAART) for at least 12 weeks. About two-thirds had previously received protease inhibitors, but none had not been treated with lopinavir.
They were randomized to get either 600 milligrams of darunavir or 400 milligrams of lopinavir twice daily (along with 100 milligrams of ritonavir). The protease inhibitors were combined in an optimized background regimen of other HIV drugs.
Adverse events were similar between the groups and grade 3 or 4 events occurred in 27% of darunavir-ritonavir patients and 30% of lopinavir-ritonavir patients.
The study shows, the researchers concluded, that the drug is "highly effective therapy across the range of treatment-experienced patients."
But it's unlikely that the results will prompt a large-scale switch from lopinavir to darunavir, according to Bernard Hirschel, M.D., and Thomas Perneger, M.D., Ph.D., both of Geneva University Hospital in Switzerland.
For one thing, they said in an accompanying comment, darunavir is specifically designed to be "resistant to resistance" and to be a replacement for other protease inhibitors once resistance develops.
But the main use of lopinavir is for initial highly active anti-retroviral therapy, where resistance is not an issue.
And the other reason, they said, is that darunavir is more expensive than lopinavir.
They did acknowledge, however, that, in the TITAN trial, darunavir "performed impressively."
The study was sponsored by Tibotec Pharmaceuticals, which is developing darunavir. Dr. Madruga has had financial links with Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Merck Sharp and Dohme, Pfizer, Schering-Plough, and Tibotec. Other authors also reported links to Tibotec, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Boehringer Ingelheim, Gilead Sciences, Janssen-Cilag, Hoffmann-LaRoche, Merck Sharp and Dohme, and Abbott. Eric Lefebvre, M.D., is a full-time employee of Janssen-Cilag. Marie-Pierre de Béthune, Ph.D., Frank Tomaka, M.D., Martine De Pauw, PharmD, Tony Vangeneugden, and Sabrina Spinosa-Guzman, M.D., are full-time employees of Tibotec.Primary source: The LancetSource reference: Madruga JV et al. "Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial." Lancet 2007; 370: 49-58. Additional source: The LancetSource reference: Hirschel B and Perneger T. "No patient left behind -- better treatments for resistant HIV infection." Lancet 2007; 370:3-5.