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Cobicistat Noninferior to Ritonavir as Atazanavir Booster at 48 Weeks
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
As a booster of atazanavir in antiretroviral-naive adults, cobicistat proved noninferior to ritonavir through 48 weeks when given with tenofovir/emtricitabine (TDF/FTC) [1]. Side effect rates were similar in the two arms of this double-blind, double-dummy trial, although cholesterol and triglyceride gains were slightly greater with ritonavir.
Cobicistat, a pharmacoenhancer with no antiviral activity, is being studied as part of a 4-in-1 coformulation with elvitegravir and TDF/FTC as well as a booster of atazanavir and other agents. This international trial enrolled antiretroviral-naive adults with a viral load at or above 5000 copies, any CD4 count, and an estimated glomerular filtration rate at or above 70 mL/min. The primary endpoint was the percentage of people with a viral load below 50 copies at week 48 by the snapshot method (which figures the percentage of responders at a single point).
The analysis involved 692 people randomized and receiving at least one dose of study drugs. Median age was 37 in the cobicistat group and 38 in the ritonavir group, and about 60% of study participants were white. Men made up about 83% of each treatment arm. Median pretreatment viral load stood at 4.78 log10 copies/mL in the cobicistat group and 4.84 log10 copies/mL in the ritonavir group. Respective pretreatment median CD4 counts were 353 and 351, and fewer than 20% in each arm had a starting CD4 count under 200.
At 48 weeks, 85% in the cobicistat arm and 87% in the ritonavir arm had a viral load under 50 copies by the snapshot analysis. The between-group difference (-2.2%, 95% confidence interval -7.4 to 3.0) indicated that cobicistat is noninferior to ritonavir as an atazanavir booster in previously untreated people. Additional analyses showed no virologic response difference between cobicistat and ritonavir, including time to loss of virologic response (83% and 85%), missing data equal failure (89% and 90%), and missing data excluded (97% and 96%). Rates of virologic nonsuppression were 6% in the cobicistat group and 4% in the ritonavir group.
Among participants with a pretreatment viral load above 100,000 copies, 86% in each arm had a sub-50 load at week 48. Resistance mutations emerged in 2 people taking cobicistat (both M184V/I) and in none taking ritonavir. No protease inhibitor mutations emerged in the 12 people analyzed in each arm.
Adverse events rates were similar with cobicistat and ritonavir, including serious adverse events (11% and 7%), discontinuation for any adverse event (7% and 7%), and discontinuation for bilirubin-related adverse events (3.5% and 3.2%) or renal adverse events (1.7% and 1.4%). Median bilirubin gains through 48 weeks were 1.9 mg/dL with cobicistat and 1.7 mg/dL with ritonavir. Respective increases in serum creatinine were 0.13 and 0.09 mg/dL.
People randomized to cobicistat had lower week-48 cholesterol increases than did those randomized to ritonavir (4 versus 10 mg/dL) and lower triglyceride gains (16 versus 24 mg/dL).
Average steady-state atazanavir trough concentrations were comparable with cobicistat (796.1 ng/mL) and ritonavir (853.4 ng/mL).
Regulatory agencies in Europe and the United States are considering cobicistat as a stand-alone agent.
Reference
1. Gallant J, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results. XIX International AIDS Conference. July 22-27, 2012. Abstract TUAB0103.
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