Comparative Study of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate, Each with Elvitegravir, Cobicistat, and Emtricitabine, for HIV Treatment
Andrew Zolopa*1, R Ortiz2, P Sax3, I Brar4, R Elion5, H Wang6, C Callebaut6, S Ramanathan6, M Fordyce6, and S McCallister6
1Stanford Univ, Palo Alto, CA, US; 2Orlando Imm Ctr, FL, US; 3Brigham and Women’s Hosp, Harvard Med Sch, Boston MA, US; 4Henry Ford Hosp, Detroit, MI, US; 5George Washington Univ Hosp, Washington, DC, US; and 6Gilead Sci, Foster City, CA, US
Background: Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), has ~ 90% lower plasma TFV levels and a 5-fold increase in intracellular TFV diphosphate (DP), compared to TDF, at a dose substantially lower than TDF. We report week-24 results from an ongoing randomized, double-blind, active-controlled, phase 2 trial comparing a single tablet regimen (STR) of elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and TAF (E/C/F/TAF) with an STR of EVG/COBI/FTC/TDF (E/C/F/TDF) as initial HIV therapy.
Methods: HIV+ treatment-naive adults were randomized 2:1 to blinded E/C/F/TAF or E/C/F/TDF once daily. All subjects had HIV-1 RNA >5000 copies/mL, eGFR ≥70 mL/min, and sensitivity to FTC and TFV. The primary endpoint was % of subjects with HIV-1 RNA <50 copies/mL at week 24 per FDA snapshot. Bone mineral density (BMD) was assessed by DEXA at baseline and week 24.
Results: A total of 170 subjects (97% male, 32% non-white, 21% HIV-1 RNA >100,000 copies/mL) were treated. At week 24, 87% of subjects on E/C/F/TAF and 90% on E/C/F/TDF had HIV-1 RNA <50 copies/mL (Snapshot, ITT). Mean CD4 cell count increase was 163 for E/C/F/TAF and 177 for E/C/F/TDF. Safety profile was similar in both arms, with 5 adverse events (any grade) occurring in ≥10% of subjects: nausea (18% E/C/F/TAF, 12% E/C/F/TDF), diarrhea (12%, 12%), fatigue (12%, 9%), headache (10%, 10%), and upper respiratory tract infection (7%, 12%). In the E/C/F/TAF arm, TFV-DP in PBMCs was ~5-fold higher (AUCtau 11.5 vs 2.2 μM*h) and plasma TFV exposures were 91% lower (AUCtau 326 vs 3,800 ng·hr/mL), compared to E/C/F/TDF arm. Consistent with COBI use, both arms had an increase in serum creatinine and reduction in eGFR by week 2, that appeared stable to week 24, but the magnitude was significantly less for E/C/F/TAF than for E/C/F/TDF (–4.9 mL/min vs –11.8 mL/min, p = 0.032). No proximal renal tubulopathy cases and no discontinuations for renal events occurred. The mean % decrease in BMD was significantly less in the E/C/F/TAF arm for both spine (mean [SD] –0.8 (3.4) vs –2.5 (2.5), p = 0.002) and hip (mean [SD] –0.3 [1.8] vs –2.0 [2.7], p <0.001).
Conclusions: In this first phase 2 study comparing 2 tenofovir prodrugs, E/C/F/TAF demonstrated comparable efficacy and a statistically significant improvement in the renal and bone safety profile at 24 weeks as compared to E/C/F/TDF. These results support further investigation of the E/C/F/TAF STR in phase 3 trials.