Background: Off-target renal and bone side effects may occur with tenofovir disoproxil fumarate (TDF) use. Compared with TDF, tenofovir alafenamide (TAF) results in significantly reduced plasma tenofovir (TFV) and may have less renal and bone toxicity.
Methods: Treatment naïve HIV-1+ adults were randomized 1:1 to a single tablet regimen of E/C/F/TAF or E/C/F/TDF once daily in two double blind studies. Assessments included measures of renal function and bone mineral density (BMD). Four pre-specified secondary safety endpoints were tested: serum creatinine, treatment-emergent proteinuria, spine and hip BMD. Week 48 off-target side effects data are described.
Results: Combined, the two studies randomized and treated 1,733 subjects. Plasma TFV was >90% lower (mean [%CV] AUCtau 297 (20) vs. 3,410 (25) nghr/mL) in the E/C/F/TAF arm, compared to the E/C/F/TDF arm. Serum creatinine (mean [SD] change: +0.08 [0.124] vs +0.11 [0.217] mg/dL, p<0.001), quantified proteinuria (UPCR, median [Q1, Q3] % change; -3 [-35, +43] vs +20 [-23, +76], p<0.001), albuminuria (UACR, median [Q1, Q3] % change; -5 [-33, +36] vs +7 [-27, +62], p=0.001), retinol binding protein (RBP:Cr, median [Q1, Q3] % change; +9 [-23, +49] vs +51 [+3, +133]), beta-2-microglobulin (β-2-Mg:Cr, median [Q1, Q3] % change; -32 [-57, +4] vs +24 [-34, +168]), and fractional excretion of phosphate (median [Q1, Q3] % change; +0.9 [-2.0, +4.5] vs +1.7 [-1.6, +5.3]), all favored E/C/F/TAF. There were no cases of proximal tubulopathy in either arm. Mean (SD) % decrease in BMD was significantly less in the E/C/F/TAF arm for both lumbar spine (-1.30 [3.08] vs -2.86 [3.25], p<0.001) and total hip (-0.66 [3.26] vs -2.95 [3.41], p<0.001). Increases from baseline in bone turnover biomarkers (C-telopeptide and P1NP) and parathyroid hormone were significantly smaller in the E/C/F/TAF group compared with the E/C/F/TDF arm (p < 0.001 for all). Increases in fasting lipid parameters (total cholesterol, HDL, direct LDL, and triglycerides) were greater in the E/C/F/TAF arm (p < 0.001 for all).
Conclusions: Through 48 weeks, subjects receiving E/C/F/TAF had significantly better outcomes related to renal and bone health than those treated with E/C/F/TDF; lipid outcomes favored E/C/F/TDF. Collectively these data demonstrate important safety benefits of TAF relative to TDF, especially given the aging of the HIV population and the need for long-term treatment.