Cobicistat (Tybost) was well-tolerated by HIV-positive patients with mild to moderate renal impairment who made the switch from ritonavir (Norvir) while continuing with the rest of their protease inhibitor (PI)-based regimen, according to 48-week safety and efficacy data from Study 118 led by C. McDonald and presented at ICAAC 2014.
Ritonavir is commonly used in combination with various PIs as a booster drug to increase patients' blood levels of the antiretrovirals. Cobicistat is used for the same purpose, but until recently only as one of the components in the single-tablet regimen Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir). On Sept. 24, 2014, the U.S. Food and Drug Administration approved cobicistat for use with either once-daily atazanavir (Reyataz) or once-daily darunavir (Prezista) in combination with other antiretroviral agents.
Because cobicistat may cause small increases in serum creatinine and decreases in estimated creatinine clearance (CrCl) without affecting actual renal glomerular function, estimated CrCl should be assessed in patients prior to starting them on cobicistat. It is also therefore currently only approved for patients with normal renal functioning, that is with a CrCl of 70 mL/min or more, when coadministered with tenofovir DF (Viread), which can itself cause renal problems.
Study 118 is a phase 3, open-label study that sought to evaluate the efficacy and renal safety profile of cobicistat-containing regimens in patients with mild to moderate renal impairment.
Study 118 initially enrolled 73 patients, most of whom were white men (77% white, 19% African American and 82% male), with a mean age of 54 years. Study participants started out on a regimen of atazanavir or darunavir plus ritonavir and two non-nucleoside reverse transcriptase inhibitors. All participants then switched from ritonavir to cobicistat, while the rest of their regimen remained the same. Median CrCl when switching to cobicistat was 71 mL/min (range: 42 mL/min to 98 mL/min). Since cobicistat is primarily eliminated through the liver, its dosing was not adjusted for patients with renal impairment.
Nineteen participants (26%) discontinued the study. Of these, seven patients (9.65% of the initial group) discontinued due to adverse events; two of them for renal problems, although no patient had laboratory evidence of proximal renal tubulopathy. Laboratory evidence in this case is defined as more than one concurrent tubular abnormality. Median CrCl dropped slightly during the early weeks of the study (median -3.8, interquartile range [IQR] -9 to 0.8), but stabilized after week 4. Median CrCl change at week 48 for those with a CrCl baseline of < 70 mL/min was -1.1 (IQR -6.5 to 6.3) and for those with a baseline CrCl of ≥ 70 mL/min it was -6.6 (IQR -12.4 to -0.7).
Treatment-emergent proteinuria (excessive serum proteins in the urine) rates were similar between study participants whose baseline CrCl was below 70 and those with a baseline CrCl above 70. At the start of the study, 43% of patients with a baseline CrCl < 70 mL/min had proteinuria, while 21% of those with a CrCl of 70 mL/min or more had such excessive protein levels. At week 48, the figures were 14% and 11%, respectively. No clinically relevant changes in cystatin C-based estimated glomerular filtration rate -- a marker of kidney function -- were observed.
All study participants had been virally suppressed (HIV RNA < 50 copies/mL) when they switched to cobicistat, and 82% had maintained that suppression at week 48. The cobicistat safety profile in study participants with a CrCl < 70 mL/min was consistent with that of previous phase 3 studies in patients without renal impairment and no patient developed resistance to any of the medications in their PI plus cobicistat regimen. As a result, the study authors concluded that "COBI [cobicistat] may be an option for patients with CrCl 50 to ≤ 70 mL/min."