Proteinuria, albuminuria and bone mineral density (BMD) improved significantly in HIV-positive people with mild or moderate renal impairment who switched to once-daily coformulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (E/C/F/TAF, Genvoya) for 48 weeks. Creatinine clearance did not change significantly after the switch in this single-arm open-label study.
TAF is licensed as part of three fixed-dose coformulations: E/C/F/TAF (Genvoya), rilpivirine/F/TAF (Odefsey) and F/TAF (Descovy). Compared with tenofovir disoproxil fumarate (TDF, Viread), TAF delivers less tenofovir to plasma and more to target cells and so should have a better toxicity profile. TDF is well known for its impact on kidney function and BMD. E/C/F/TAF proved virologically noninferior to E/C/F/TDF in two randomized phase 3 trials and had less renal and bone toxicity indicated by standard markers.
In the new study, an international team recruited adults with a viral load below 50 copies/mL for at least six months, a CD4 count at or above 50 cells/mm3 and mild to moderately impaired renal function, defined as an estimated glomerular filtration rate (eGFR) between 30 and 69 mL/min. The study excluded patients with a new AIDS illness within 30 days of screening and patients positive for hepatitis B surface antigen or hepatitis C antibody. All participants switched from their ongoing antiretroviral regimen to once-daily coformulated E/C/F/TAF.
The 242 study participants had a median age of 58 years (range 24 to 82) and a median CD4 count of 632 cells/mm3; 21% were women; and 18% were black. Median eGFR by the Cockroft-Gault formula stood at 56 mL/min; 42% of participants had significant proteinuria (urine protein to creatinine ratio >200 mg/g); and 49% had significant albuminuria (urine albumin to creatinine ratio ≥30 mg/g). Two-thirds of study participants (65%) switched from a TDF-containing combination.
Through 48 weeks, creatinine clearance did not change significantly regardless of whether baseline eGFR lay above or below 50 mL/min or whether the previous regimen included TDF. In a 32-patient substudy, iohexol-determined actual GFR did not change through 24 weeks of E/C/F/TAF therapy. Albuminuria, total proteinuria and tubular proteinuria all improved significantly through 48 weeks in patients switching from a TDF regimen; these measures of renal function did not change significantly in patients switching from a non-TDF regimen. Overall prevalence of significant proteinuria decreased from 42% to 11%, while prevalence of significant albuminuria fell from 49% to 21%.
Hip and spine BMD increased by an average 1.47% and 2.29%, respectively, through 48 weeks after the switch to E/C/F/TAF. BMD improved significantly only in patients switching from a TDF regimen while remaining stable in those switching from non-TDF regimens. Total to high-density lipoprotein cholesterol ratio did not change significantly with E/C/F/TAF in patients initially taking a TDF regimen or a non-TDF regimen.
Eight patients (3%) discontinued the study drug because of adverse events, including two because of a decreased glomerular filtration rate determined by the Cockroft-Gault formula. No study participants had laboratory evidence of proximal renal tubulopathy or Fanconi syndrome.
Through 48 weeks, 222 study participants (92%) maintained a viral load below 50 copies/mL, and three patients had virologic failure. Pharmacokinetic analysis in 30 patients determined that elvitegravir and cobicistat concentrations were equivalent to those in HIV-positive people taking E/C/F/TAF without renal impairment, regardless of whether eGFR lay above or below 50 mL/min. Emtricitabine concentrations were higher in study participants than in HIV-positive patients taking E/C/F/TAF without renal impairment because emtricitabine is primarily cleared by the kidneys.
The researchers propose that the renal and bone improvements seen in patients who switched from a TDF regimen "likely represent a reduction in the off-target renal and bone effects of plasma [tenofovir] concentrations, which are 90% lower with TAF." They stress that participants with eGFR below 50 mL/min, who currently need TDF and FTC dose adjustments, had stable eGFR and significantly improved tubular function through 48 weeks taking E/C/F/TAF without dose adjustment.