Idenix Pharmaceuticals (IDIX)

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In vitro anti-HBV activity of telbivudine/tenofovir and telbivudine/entecavir combinations
A. Patty1; B. Li1; I. Serra1; D. N. Standring1; M. Seifer1
1. Idenix Pharmaceuticals, Cambridge, MA, USA.


Background: Several nucleoside (entecavir, lamivudine and telbivudine) and nucleotide (adefovir) analogs are approved for the treatment of hepatitis B virus (HBV) infection and several others, including tenofovir, are in clinical development. These drugs are effective against HBV but all have been associated with the emergence of drug-resistant mutants. Combinations of antiviral agents with complementary resistance profiles may offer the potential for enhanced suppression of HBV replication and reduced drug resistance. In this study, the L-nucleoside telbivudine was combined with either tenofovir, a nucleotide analog, or entecavir, a nucleoside analog.

Methods: Drug combinations were evaluated in stably transfected human liver cells expressing replication-competent HBV nucleocapsids and virions. The anti-HBV efficacy of each drug alone and in combination was determined using in vitro endogenous HBV polymerase assays after 10 days of drug treatment. In vitro cytotoxicity was determined by standard cell viability staining. MacSynergy II, CombiTool, and isobologram plots were used to analyze the data.

Results: Telbivudine/tenofovir and telbivudine/entecavir combinations exerted greater anti-HBV in vitro activity than telbivudine, tenofovir or entecavir alone. Bliss independence analysis (MacSynergy) revealed that the interaction volumes of all 2-drug combinations were <25 μM2 suggesting that the antiviral in vitro interactions between the 2 drugs in each combination are additive. Similar results were obtained with CombiTool (Loewe additivity model); two-drug combination points were clustered around the zero-interaction plane consistent with an interpretation of additivity. Telbivudine/tenofovir exhibited an additive interaction in isobolograms, as implied by D values fluctuating around 0, however an average D value of -0.16 was calculated for telbivudine/entecavir suggesting weak but statistically significant synergy (P = 0.0012). There was no evidence of in vitro cytotoxicity with either of these combinations.

Conclusions: Telbivudine demonstrated additive to weakly synergistic anti-HBV activity in vitro when combined with tenofovir or entecavir. These data support the investigation of telbivudine as a component in multi-drug therapy of chronic HBV infection, particularly combinations with drugs exhibiting different resistance patterns such as nucleotide analogs.