The new boosting agent cobicistat works as well as ritonavir (Norvir) as a pharmaco-enhancer or booster for the first-line protease inhibitor atazanavir (Reyataz) at 48 weeks, according to a report presented last week at the 19th International AIDS Conference in Washington, DC.
Some antiretroviral drugs, including most protease inhibitors and the experimental integrase inhibitor elvitegravir, have trouble reaching effective levels in the body. Boosters like ritonavir and cobicistat inhibit the activity of the CYP3A enzyme in the liver, which slows processing and raises blood levels of other drugs metabolised by the same pathway. Unlike ritonavir, however, cobicistat is not itself active against HIV.
Joel Gallant from Johns Hopkins School of Medicine presented findings from a phase III randomised controlled trial comparing the safety and efficacy of cobicistat against ritonavir when used as part of a first-line regimen with atazanavir and the nucleoside reverse transcriptase inhibitor duo tenofovir/emtricitabine (the drugs in Truvada).
Study 114 included 692 treatment-naive participants. About 80% were men, about 60% were white and the average age was about 38 years. The mean CD4 T-cell count was about 350 cells/mm3, with 17% having less than 200 cells/mm3.
People with poor kidney function were not included in this trial, as earlier studies suggested cobicistat might cause kidney toxicity. Further research indicated that the observed increase in serum creatinine was likely to have been due to the drug's effect on tubular secretion, not impaired filtration, meaning it altered estimated but not actual glomerular filtration rate (GFR). In Study 114, the median estimated GFR at baseline was about 114 mL/min (using the Cockcroft-Gault method) and people with estimated GFR below 70 mL/min were excluded.
By 48 weeks 15% of cobicistat recipients and 11% of ritonavir recipients had stopped the study. Half of all discontinuations in the cobicistat arm and two-thirds in the ritonavir arm were due to adverse events, with small numbers stopping for various other reasons including loss to follow-up, protocol violations or pregnancy.
The primary analysis at 48 weeks showed that 85% of people taking cobicistat and 87% taking ritonavir suppressed HIV viral load below 50 copies/mL in an intent-to-treat 'snapshot' analysis, showing that cobicistat is non-inferior to ritonavir. Virological non-suppression was seen in 6% of cobicistat recipients and 4% of ritonavir recipients.
In a more traditional intent-to-treat missing equals failure analysis, response rates were 89% for cobicistat and 90% for ritonavir. When people with missing data were excluded, the as-treated response rates were 97% and 96%, respectively.
Response rates withcobicistat and ritonavir were similar when comparing people with high (>100,000 copies/mL) or low viral load, as well as those with CD4 counts above or below 350 cells/mm3.
CD4 cell gains at 48 were similar, at 213 and 219 cells/mm3, respectively. Gallant noted that CD4 counts had not yet plateaued and were still rising at the time of this analysis.
Serious adverse event rates were statistically similar in both arms, 11% with cobicistat vs 7% with ritonavir. In both arms, 7% stopped treatment due to adverse events, including similar numbers due to bilirubin-related events and kidney problems. Elevated bilirubin (hyperbilirubinemia)¾a known side-effect of atazanavir¾was more common among cobicistat recipients (65% vs 57%, respectively).
Serum creatinine rose a bit more (0.13 vs 0.09 mg/min) and estimated GFR fell more (-13 vs -9 mL/min) in the cobicistat arm. Five of six people who stopped taking cobicistat and two of five who stopped ritonavir due to kidney problems experienced proximal tubule dysfunction.
Turning to blood lipid elevations - a side-effect of ritonavir - levels of total cholesterol, LDL "bad" cholesterol and triglycerides rose more the in ritonavir arm, while HDL "good" cholesterol rose more in the cobicistat arm, but these differences did not reach statistical significance.
The researchers concluded that cobicistat plus atazanavir and tenofovir/emtricitabine "demonstrated non-inferior efficacy" to a corresponding regimen with ritonavir, and that cobicistat was well-tolerated. Rates of discontinuation due to kidney side-effects were "low and comparable", they added, and rates of bilirubin-related discontinuation were similar.
Cobicistat as a single agent has been submitted for regulatory approval in Europe and the US. Cobicistat is part of the single-tablet regimen known as the Quad (with elvitegravir, tenofovir and emtricitabine), which is under review for treatment-naive people. Gilead is also looking at other cobicistat coformulations that include atazanavir, darunavir and the tenofovir pro-drug GS-7340.
Gallant 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. 19th International AIDS Conference, Washington, DC, abstract TUAB0103, 2012. [http://pag.aids2012.org/Abstracts.aspx?SID=202&AID=13085]