Once-daily raltegravir fails to demonstrate non-inferiority compared to twice-dailydosing in phase 3 treatment naive study

Merck (known as MSD in the UK) has reported initial results from the Phase III study investigating the safety and efficacy of an investigational 800 mg once daily dose of raltegravir (Isentress) tablets compared to the currently approved 400 mg twice-daily dose, each given in combination with a once-daily fixed-dose combination of emtricitabine and tenofovir (Truvada), in adult treatment-naive HIV-1-infected patients. Raltegravir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naive and treatment-experienced adults.

In the study, although the treatment regimen that included raltegravir once daily enabled more than 80 percent of patients to achieve viral suppression, raltegravir 800 mg once daily did not demonstrate non-inferiority to the treatment regimen that included raltegravir 400 mg twice daily.

Within this study, 775 patients were randomised, of which 770 patients received the study drug and are included in the current analyses. After 48 weeks in the study, 83.2% (n=318/382) of patients receiving the regimen including raltegravir 800 mg once-daily achieved undetectable viral levels (HIV-1 RNA <50 copies/mL), compared to 88.9% (n=343/386) of patients receiving the twice-daily regimen. The treatment difference between the 800 mg once daily group and 400 mg twice-daily group was -5.7%, with an associated 95% confidence interval (CI) of (-10.7%, -0.83%). The difference did not meet the pre-defined statistical criteria for non-inferiority.

The overall treatment difference observed between the once-daily and twice-daily groups was primarily due to results in patients with high viral load. Among patients with more than 100,000 copies/mL of HIV-RNA, 74.3 percent (n=113/152) of those in the once-daily group achieved viral suppression compared to 84.2 percent (n=128/152) of those in the twice-daily group. The safety and tolerability profiles of the two regimens were similar in the study, and were consistent with current prescribing information for raltegravir.

Based on these initial results, and following the recommendation of an independent Data Monitoring Committee, MSD will end the study. MSD is notifying clinical investigators of this decision this week and is recommending that patients should be transitioned to approved, marketed antiretroviral therapy (ART) as per local HIV-1 treatment guidelines. If raltegravir treatment is to be continued, the approved dose of 400 mg twice daily should be prescribed.

Results from this study will be submitted for presentation at an appropriate scientific meeting in 2011.

comment

There are insufficient data included in this press release to be able to comment much on these results, which are likely to be presented at CROI in two months.

While the results are disappointing, they may not rule out a role for once-daily dosing as a switch option (perhaps supported by drug level monitoring) in adherent patients who started treatment with a low baseline viral load and who are already suppressed on twice-daily raltegravir-based or other HAART combinations.

Although the pre-defined lower limit of the 95%CI (likely to be -10%) was lower than some similar studies (-12% is often used) these top-line results clearly do not support once-daily raltegravir as an option for treatment-naive patients with baseline viral load >100,000 copies/mL.

The development of integrase resistance is a significant loss to future treatment options, so that when a once-daily regimen is important, using drugs with a proven once-daily efficacy should be preferred.