Cobicistat compared to ritonavir to boost atazanavir in treatment naive patients

Simon Collins, HIV i-Base

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. [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).

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.

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%), diarrhoea (15% vs 20%), headache (11% vs 15%) and hyperbilirubinaemia (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:

  • elvitegravir/cobicistat/FTC/tenofavir alafenamide fumerate (TAF)
  • darunavir/cobicistat/FTC/TAF
  • atazanavir/cobicistat

Cobisistat was submitted to the FDA as a separate compound in June 2012 but has yet to receive FDA approval as a separate drug.


  1. Gallant JE et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1–infected patients: week 48 results. J Infect Dis. (2013) doi: 10.1093/infdis/jit122. First published online: 26 March 2013.
  2. German P et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. JAIDS, Volume 60 – Issue 3 – p 219–220 (1 July 2012).
  3. Food and Drug Administration Center for Drug Evaluation and Research. Summary minutes of the Antiviral Drugs Advisory Committee Meeting, May 11, 2012.

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