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Similar 144-Week Results With Cobicistat or Ritonavir as Atazanavir Booster
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ICAAC 2014. September 5-9, 2014. Washington, DC
ICAAC: Cobicistat versus Ritonavir as Pharmacoenhancers of Atazanavir in Combination with Emtricitabine/Tenofovir DF - Phase 3 Randomized, Blinded, Active-Controlled Trial, Week 144 Results - (09/08/14)
Mark Mascolini
Virologic suppression and adverse event rates proved similar through 144 weeks in a randomized trial comparing atazanavir/cobicistat with atazanavir/ritonavir, both with tenofovir/emtricitabine [1]. Modest creatinine elevations with each regimen remained unchanged after week 48.
Cobicistat is a booster with no antiviral activity and no metabolizing enzyme or transporter induction activity. It is used to boost the integrase inhibitor elvitegravir in Stribild and is licensed in Europe (and under review in the US) as a stand-alone agent. Study 114 compared atazanavir/cobicistat with atazanavir/ritonavir in antiretroviral-naive people with a pretreatment viral load at or above 5000 copies, an estimated glomerular filtration rate (eGFR) at or above 70 mL/min, and any CD4 count.
This international, double-blind, active-controlled trial began with 344 naive people randomized to cobicistat and 348 randomized to ritonavir. Age averaged 37 in the cobicistat arm and 38 in the ritonavir arm, 83% and 82% were men, and 42% and 38% were nonwhite. Pretreatment CD4 counts averaged about 350 in both groups, and pretreatment viral loads were 4.78 log with cobicistat and 4.84 log with ritonavir (about 60,000 and 69,000 copies).
After 48 weeks sub-50-copy response rates in an FDA snapshot analysis were 85% in the cobicistat arm and 87% in the ritonavir arm (difference -2.2, 95% confidence interval [CI] -7.4% to 3.0%), a result establishing the noninferiority of the cobicistat regimen [2].
The new analysis extended findings to 144 weeks. After 144 weeks 50-copy response rates remained similar in the two treatment arms with the FDA snapshot analysis--72% with cobicistat and 74% with ritonavir (difference -2.1%, 95% CI -8.7% to 4.5%). Among people genotyped after virologic failure, neither protease inhibitor mutations now the K65R tenofovir mutation emerged in either arm.
Almost everyone in both study arms had at least one adverse event, and 11% in each group stopped treatment because of adverse events by week 144. Between study week 96 and week 144, 3 additional people stopped treatment because of adverse events in the cobicistat arm, as did 4 in the ritonavir arm.
Kidney-related discontinuation rates were 2.9% with cobicistat and 3.2% with ritonavir. Six people taking cobicistat (1.7%) and 7 taking ritonavir (2.0%) stopped treatment because of proximal renal tubulopathy. At 144 weeks median change in serum creatinine measured +0.13 mg/dL with cobicistat and +0.07 mg/dL with ritonavir, and those increases had not changed since week 48. Median change in eGFR through 144 weeks was -15.1 mL/min with cobicistat and -7.5 mL/min with ritonavir.
Through week 96 of the trial, 5.2% in the cobicistat arm and 3.2% in the ritonavir arm quit treatment because of hepatobiliary events (mostly high bilirubin). From week 96 to week 144, no one in the cobicistat arm and 1 more person the ritonavir arm quit because of hepatobiliary trouble.
Average fasting total cholesterol, low- or high-density lipoprotein (HDL) cholesterol, triglycerides, and glucose did not change significantly through 144 weeks in either group; nor did total-to-HDL cholesterol ratio.
Fixed-dose combinations of atazanavir/cobicistat and darunavir/cobicistat are in development.
References
1. Gallant JE, Koenig E, Andrade J, et al. Efficacy and safety of cobicistat compared to ritonavir as pharmacoenhancer for atazanavir plus emtricitabine tenofovir DF: week 144 results. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-647.
2. Gallant JE, Koenig E, Andrade-Villanueva J, 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;208:32-39.
http://www.ncbi.nlm.nih.gov/pubmed/23532097 and
http://www.natap.org/2012/IAS/IAS_02.htm
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