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.
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
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.
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.
Labels: drugs in development, tenofovir