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.
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
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.
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.
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
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.
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.
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
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.