Results from a recent randomized, double-blind, double placebo, phase III study comparing cobicistat to ritonavir to boost atazanavir were published in the 26 March edition of the Journal of Infectious Diseases.1
Cobicistat is an inhibitor of cytochrome P450 3A4 is currently approved as one component of the four-in-one fixed dose combination Stribild, where it boosts the integrase inhibitor elvitegravir.
It is a weak inhibitor of CYP2D6 but not other CYP or UGT pathways and has a similar effect to ritonavir on other drug transporters including P-gp, BCRP, and OATP1B1/3. Unlike ritonavir, cobicistat has no activity against HIV, but it is not always interchangeable with ritonavir (for example, it can't be used to boost tipranavir).
Although the side effect profile appears to offer few advantages compared to ritonavir, cobicistat is being coformulated with both atazanavir and darunavir to simplify dosing. These studies provide a clearer data set for the efficacy and safety of cobicistat compared to ritonavir, as use in Stribild is complicated by the impact of elvitegravir.
Mean (+/-SD) baseline characteristics included: age 37 years (+/-9.8), CD4 350 (+/- 170) cells/mm3 (17% <200 and 14% >500) with median viral load 4.8 log copies/mL. Approximately 17% were women with 60% white, 18% black and 28% Hispanic. As with studies as part of Stribild, baseline entry criteria included no prior renal disease, defined as eGFR levels >70 mL/min.
Tenofovir DF/FTC was used as a background NRTIs for all patients. Response rates were 85% vs 87% (difference -2.2%; 95% CI -7.4% to +3.0%, p=0.40) in the cobicistat vs ritonavir groups respectively, using FDA ITT snapshot analysis, with no difference for the approximately 40% of patients with viral load >100,000 copies/mL at baseline (86% suppressed in each arm).
Side effects were generally mild and broadly comparable, accounting for 7% of patients discontinuing in each arm. The most commonly reported side effects (in >10% patients) included jaundice (21% vs 16%), scleral icterus (yellow eyes, 18% each arm), nausea (~17%), diarrhea (15% vs 20%), headache (11% vs 15%) and hyperbilirubinemia (11% vs 100%); all cobicistat vs ritonavir respectively, no significant differences.
Median increases in serum creatinine were 0.13 vs 0.09 mg/dL were greater in the cobicistat group (p< 0.001) most occurring by week 8 and stable thereafter, with 6 compared to 5 patients discontinuing for renal events. This was associated with a corresponding decrease in eGFR (-12.9 vs -9.1 mL/min respectively, p<0.001. In the cobicistat group, 1/6 was due to reduced eGFR, and 5/6 with laboratory markers associated with proximal tubopathy compared to 2/5 in the ritonavir group. These resolved on discontinuation.
Increases in total cholesterol (+5 vs +9 mg/dL, + = 0.081) and triglycerides (+19 vs +32 mg/dL, p=0.063) were numerically higher with ritonavir but not statistically different.
Cobicistat inhibits tubular secretion of creatine which reduces estimated but not actual GFR and has been reported in earlier studies.2
For clinical management, an increase of 0.4 mg/dL or greater may be able to be used as a conservative cut-off to address concerns about potential tenofovir renal tubular toxicity.3
Other ongoing formulations with cobicistat include:
Cobicistat was submitted to the FDA as a separate compound in June 2012 but has yet to receive FDA approval as a separate drug.
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