Background: Tenofovir alafenamide (TAF) is a novel tenofovir (TFV) prodrug that, when administered in the single tablet regimen elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), has >4-fold increase in intracellular TFV diphosphate and >90% lower plasma TFV levels compared to tenofovir disoproxil fumarate (TDF). Two Phase 3 studies of identical design were conducted in distinct geographic areas comparing 2 single tablet regimens, E/C/F/TAF and E/C/F/TDF, in treatment-naïve HIV-1+ adults.
Methods: Patients were randomized 1:1 to receive a single tablet regimen of E/C/F/TAF or E/C/F/TDF once daily in two Phase 3 double blind studies. Primary endpoint was Week 48 virologic response by FDA Snapshot algorithm in a pre-specified analysis of the combined studies.
Results: 1,733 subjects were randomized and treated: 15% women, 43% non-White, 23% viral load ≥100,000 copies/mL. Median baseline characteristics were: age 34 yrs, VL 4.58 log10c/mL, and CD4 count 427 cells/µL. The primary objective was met, as E/C/F/TAF was non-inferior to E/C/F/TDF with 92% and 90%, respectively, having HIV RNA <50 copies/mL at week 48 (difference +2%, 95% CI -0.7% to +4.7%, p=0.13). The rates of virologic success between E/C/F/TAF and E/C/F/TDF were similar across subgroups according to age, sex, race, baseline HIV”‘1 RNA level, baseline CD4 cell count, region (US versus ex”‘US), and study drug adherence. Mean change in CD4 count at Week 48 was 230 cells/µL in the E/C/F/TAF arm vs. 211 cells/µL for E/C/F/TDF (p=0.02). Virologic failure with resistance occurred in 0.8% in the E/C/F/TAF arm and 0.6% on E/C/F/TDF. Treatment related SAEs were rare: E/C/F/TAF 0.3% (n=3), E/C/F/TDF 0.2% (n=2). There were no reports of proximal renal tubulopathy (including Fanconi Syndrome) in either arm. No single AE led to discontinuation of more than 1 subject on E/C/F/TAF. Grade 2, 3, or 4 AEs occurring in ≥ 2% were: diarrhea (3.3% vs. 2.5%), nausea (2.2% vs. 2.0%), headache (2.9% vs. 2.1%), and URI (3.6% vs. 3.1%) in the E/C/F/TAF and E/C/F/TDF arms, respectively.
Conclusions: Through 48 weeks of treatment, high virologic response rates were seen in patients receiving E/C/F/TAF or E/C/F/TDF, and similar responses were seen across subgroups evaluated. Drug resistance was <1%. Both regimens were well tolerated, and no unique AEs associated with TAF occurred. These data support the use of E/C/F/TAF, the first TAF-based single tablet regimen, as a potential new regimen for initial treatment of patients with HIV-1 infection.