Nucleoside analogues for chronic hepatitis B.

Hepatitis B virus replicates inside the hepatocyte through an intermediate step of reverse transcription mediated by the viral polymerase. We describe five nucleoside/nucleotide analogues that interfere with the replication mechanisms of the hepatitis B virus. The resemblance of nucleoside analogues to natural nucleosides may lead to direct cytotoxicity. Therefore, antiviral activity should always be interpreted in the light of cellular toxicity. In addition, prolonged therapy with a nucleoside analogue may induce mutations in the viral polymerase, causing structural and configurational changes of the polymerase resulting in a decreased affinity for the nucleoside analogue. Subsequently, the mutated virus is capable of renewed replication during continued antiviral pressure of the nucleoside analogue. The best antiviral strategy in the future is probably combination therapy, either with several nucleoside analogues or with a nucleoside analogue and interferon.