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E/C/F/TAF Kind to Kidneys of People With Stable Renal Impairment
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ICAAC 2015, September 17-21, 2015, San Diego
Mark Mascolini
Trial participants with an estimated glomerular filtration rate (eGFR) below 50 mL/min maintained or improved kidney function after switching from a suppressive regimen to elvitegravir/cobicistat plus emtricitabine/tenofovir alafenamide (E/C/F/TAF), according to results of a 48-week analysis [1]. Actual GFR measured by iohexol clearance did not change through 24 weeks in a substudy.
TAF is an investigational tenofovir prodrug that proved virologically noninferior to tenofovir disoproxil fumarate (TDF) when each was combined with E/C/F in two double-blind trials that enrolled antiretroviral-naive adults [2]. Those trials also confirmed better bone and kidney safety signals with E/C/F/TAF than with E/C/F/TDF. In a trial of patients with viral control while taking a TDF regimen for at least 96 weeks, switching to E/C/F/TAF improved HIV control as well as bone and kidney markers [3].
The TDF dosing interval must be lengthened for people with GFR below 50 mL/min. But TAF is not cleared by kidneys and yields tenofovir levels in plasma 91% lower than those measured with TDF.
The post hoc analysis presented at ICAAC 2015 involved people taking a suppressive TDF or non-TDF regimen with a stable eGFR between 30 and 69 mL/min [1]. Everyone switched from their suppressive regimen to once-daily coformulated E/C/F/TAF. The 80 study participants with baseline eGFR below 50 mL/min averaged 59 years in age, compared with 58 years in 162 people with baseline eGFR between 50 and 69 mL/min. Respective proportions of women were 26% and 18% and of blacks 18% and 19%. Median CD4 counts lay above 600 in both groups. Half in the sub-50-mL/min group had hypertension, compared with one third in the 50-to-69 group. Median eGFR measured 43 mL/min in the sub-50 group and 60 mL/min in the 50-to-69 group. Respective proportions switching from TDF were 58% and 69%.
Forty-eight weeks after the switch in people starting at an eGFR below 50 mL/min, eGFR rose nonsignificantly from the baseline value when calculated by the Cockroft-Gault method (+0.6 mL/min), the CKD-EPI method (+1.4 mL/min), of the cystatin C method (+1.1 mL/min). eGFR changes in the group with baseline eGFR of 50 to 69 mL/min were also minimal through 48 weeks. Study participants with the lowest 5% of baseline eGFRs had significant increases through 48 weeks (median +6.4 mL/min, P = 0.03).
Measuring actual GFR by iohexol clearance in 10 people in the sub-50-mL/min group and 21 in the 50-to-69 group, the researchers recorded a nonsignificant gain of about 2 mL/min in both groups 24 weeks after the switch to E/C/F/TAF.
After 48 weeks of E/C/F/TAF in the baseline sub-50-mL/min group, the investigators measured significant improvement in proteinuria (median UPCR 270 to 139 mg/g), beta-2 microglobulin (median B-2 Mg:Cr 3871 to 1071 ug/g), albuminuria (median UACR 53 to 25 mg/g), and retinol binding protein (median RBP:Cr 1360 to 424 ug/g). Markers of proteinuria also consistently dropped in people with a baseline eGFR of 50 to 69 mL/min. Proportions of people with clinically relevant proteinuria (UPCR > 200 mg/g) through 48 weeks fell from 56% to 25% in the sub-50-mL/min group and from 35% to 9% in the 50-to-69 group. Proportions of participants with clinically relevant albuminuria (>30 mg/g) also declined in both groups.
When the researchers compared trial participants with a baseline eGFR below versus above 50 mL/min, they found little difference in rates of serious adverse events (11% versus 11%), grade 2 to 4 adverse events (9% versus 8%), and potential emtricitabine adverse reactions (46% versus 52%).
Only two people stopped study drug because of decreased GFR, and neither had evidence of renal tubulopathy. No cases of proximal renal tubulopathy or Fanconi syndrome developed during the study.
The researchers suggested their findings support switching to single-tablet E/C/F/TAF in adults with virologic control an eGFR of 30 to 50 mL/min.
References
1. Gupta S, Post F, Pozniak A, et al. Safety of once daily elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in patients with GFT less than 50 ml/min: 48 week results. ICAAC 2015, September 17-21, 2015, San Diego. Abstract 2199.
2. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385:2606-2615.
3. Mills T, Andrade J, DiPerri G, et al. Switching from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen: data in virologically suppressed adults through 48 weeks of treatment. IAS 2015. 8th Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2015. Vancouver. Abstract TUAB0102. http://www.natap.org/2015/IAS/IAS_24.htm
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