Anti-HBV Activity of Combinations of Tenofovir and Nucleoside Analogs By
Liz Highleyman
Treatment for chronic hepatitis B is limited
by the emergence of resistant virus, and studies to date indicate that the best
results may be achieved using combinations of antiviral agents.
As presented
at the recent 57th Annual Meeting of the American Association for the Study of
Liver Diseases in Boston assessed the in vitro activity of the nucleotide
analog tenofovir DF (Viread) -- which is approved for the treatment of HIV but
not yet for hepatitis B -- against various nucleoside analog agents:
Tenofovir
is active against both wild-type HBV and variants carrying YMDD mutations, which
confer resistance to lamivudine, emtricitabine, and telbivudine, and are required
for entecavir resistance.
The researchers used 2 stably transfected cell
lines expressing wild-type HBV for the drug combination studies. Agents were administered
for 4 days with 1 drug media replacement. Intracellular HBV DNA was then extracted
and quantified using the TaqMan PCR assay. The combination of (emtricitabine +
emtricitabine) was tested as a control. Results
As expected, the emtricitabine + emtricitabine control combination demonstrated
additive antiviral effect by both MacSynergy and isobologram analyses.
The following drug combinations had additive antiviral effects as indicated by
synergy volumes when analyzed using MacSynergy (synergy values between -25 µM2%
and +25 µM2% at 95% confidence intervals are considered additive):
Isobologram analysis demonstrated slightly a synergistic effect for the emtricitabine
+ tenofovir combination, with "D" values ranging from -0.39 to -0.26
("D" values represent deviation from additivity; values between -0.5
to -0.1 indicate weak synergy, values between -0.1 to 0.1 indicative additivity).
"D"
values for the other combinations indicated additive to weakly synergistic activity:
-
lamivudine + tenofovir: 0.13 to -0.25; - telbivudine + tenofovir: -0.03 to
-0.14; - entecavir + tenofovir: 0.01 to -0.15.
The activity of the emtricitabine + tenofovir combination was also tested in a
different cell line with constitutive HBV expression, which indicated an additive
antiviral effect.
No cytotoxic effects were observed with any of the combinations tested.
Conclusion
In
conclusion, the researchers wrote, "Tenofovir demonstrated additive to slight
synergistic anti-HBV activity when tested in combination with [emtricitabine],
and additive activities with [lamivudine, entecavir, and telbivudine]. It therefore
could potentially form an important component in combination regimens with anti-HBV
nucleoside analogs in long term HBV treatment.
The tenofovir + emtricitabine
combination makes up the Truvada co-formulated pill marketed for HIV treatment;
the 2 drugs are also components of the recently approved one-pill, once-daily
Atripla co-formulation. Clinical Virology, Gilead Sciences, Inc, Durham,
NC, and Foster City, CA.
