{"id":21346,"date":"2013-05-29T14:51:05","date_gmt":"2013-05-29T14:51:05","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=21346"},"modified":"2013-05-29T14:51:05","modified_gmt":"2013-05-29T14:51:05","slug":"cobicistat-compared-to-ritonavir-to-boost-atazanavir-in-treatment-naive-patients","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/21346","title":{"rendered":"Cobicistat compared to ritonavir to boost atazanavir in treatment naive patients"},"content":{"rendered":"

Simon Collins, HIV i-Base<\/strong><\/p>\n

Results from a recent randomised, 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.<\/strong> [1]<\/p>\n

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.<\/p>\n

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).<\/p>\n

The study included 692 treatment-naive patients, and reported that cobicistat was non-inferior to ritonavir as a booster for atazanavir based on viral efficacy <50 copies\/mL at 48 weeks.<\/p>\n

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.<\/p>\n

Mean (+\/\u2013SD) 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.<\/p>\n

Tenofovir DF\/FTC was used as a background NRTIs for all patients. Response rates were 85% vs 87% (difference \u20132.2%; 95% CI \u20137.4% 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).<\/p>\n

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%), diarrhoea (15% vs 20%), headache (11% vs 15%) and hyperbilirubinaemia (11% vs 100%); all cobicistat vs ritonavir respectively, no significant differences.<\/p>\n

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 (\u201312.9 vs \u20139.1 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.<\/p>\n

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.<\/p>\n

Cobicistat inhibits tubular secretion of creatine which reduces estimated but not actual GFR and has been reported in earlier studies. [2]<\/p>\n

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]<\/p>\n

Other ongoing formulations with cobicistat include:<\/p>\n