Synergistic Interactions between Hepatitis B Virus Ribonuclease H Antagonists and Other Inhibitors [PublishAheadOfPrint]

Combination therapies are standard for management of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, however no such therapies are established for human hepatitis B virus (HBV). Recently we identified several promising inhibitors of HBV ribonuclease H (RNaseH) activity that have significant activity against viral replication in vitro. Here, we investigated in vitro antiviral efficacy of combinations of two RNaseH inhibitors with the current anti-HBV drug nucleoside analog lamivudine, with HAP12, an experimental core protein allosteric modulator, and with each other. Anti-HBV activities of the compounds were tested in a HepG2-derived cell line by monitoring intracellular core particle DNA levels, and cytotoxicity was assessed by MTS assay. The antiviral efficiencies of the drug combinations were evaluated using the median-effect equation derived from the mass-action law principle and combination index theorem of Chou and Talalay. We found that combinations of two RNaseH inhibitors from different chemical classes were synergistic with lamivudine against HBV DNA synthesis. Significant synergism was also observed for combination of the two RNaseH inhibitors. Combinations of RNaseH inhibitors with HAP12 had additive antiviral effects. Enhanced cytotoxicity was not observed in the combination experiments. Because of these synergistic and additive effects, the antiviral activity of combination of RNaseH inhibitors with drugs that act by two different mechanisms and with each other can be achieved by administering the compounds in combination at doses below the respective single drug doses.

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