New Tenofovir Formulation Requires Lower Doses, Reducing Side Effects
—Christine. M. Kukka, Project Manager, HBV Advocate
A new formulation of the antiviral tenofovir, which has proven highly effective against hepatitis B, appears to be very effective at lower doses in a recent clinical trial. The lower dose means a reduced risk of side effects such as kidney problems or bone loss when used over long periods of time.
The new formulation, called tenofovir alafenamide, is absorbed more effectively by cells so it requires lower dosing, according to a report presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy. The drug was tested in HIV-infected individuals and was found to produce five-fold higher concentrations of tenofovir in cells infected with HIV.
Phase III trials in HIV patients are currently underway. Clinical trails of the new tenofovir formulation in people infected with hepatitis B are eagerly awaited.
Background: TAF is a novel tenofovir (TFV) prodrug that has 5-fold higher intracellular TFV diphosphate and 91% lower plasma TFV levels. Week 24 data from a double-blind study comparing the E/C/F/TAF single tablet regimen to E/C/F/TDF (Stribild) showed a high proportion of patients in both arms with undetectable HIV-1 viral load.
Methods: Treatment-naïve adults were randomized 2:1 to once daily treatment with E/C/F/TAF or E/C/F/TDF. Week 48 efficacy and safety data are described, including tests of renal function and bone mineral density (BMD).
Results: Of 170 patients treated, 88.4% on E/C/F/TAF and 87.9% on E/C/F/TDF had HIV-1 RNA <50 copies/mL (FDA Snapshot, ITT) at Week 48. No virologic failure or resistance occurred in patients on E/C/F/TAF. Nearly all adverse events were of mild to moderate severity and there were no treatment-related SAEs or renal discontinuations in either arm. The median creatinine increase (mg/dL) and eGFR reduction (mL/min) was +0.07 and -5.5 for E/C/F/TAF and +0.10 and -10.1 for E/C/F/TDF (p=0.077, p=0.041). Exploratory markers of proximal renal tubulopathy were different between the arms: urine retinol binding protein/creatinine ratio (µg/g) and urine β-2 microglobulin/creatinine ratio (µg/g) was -0.1 and -33.6 for E/C/F/TAF and +20.7 and +0.4 for E/C/F/TDF (p=0.001, p=0.008). Patients on E/C/F/TAF had less change in BMD at spine (median % change -1.0 vs. -3.37, p<.001) and hip (median % change -0.62 vs. -2.39, p<0.001); there were no pathologic fractures in either arm.
Conclusions: These Week 48 data show comparably high efficacy rates for two E/C/F-based STRs containing either TAF or TDF. Patients on E/C/F/TAF had less change in eGFR, in exploratory markers of renal tubulopathy, and in spine and hip BMD. These data are currently being evaluated in Phase 3 clinical trials.