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Influence of Mutations in the Hepatitis B Virus Genome on Virus Replication and Drug Resistance - Implications for Novel Antiviral Strategies

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Persistent infection with the hepatitis B virus (HBV) represents a major health problem worldwide with over 350 million patients at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double-stranded DNA virus with four overlapping genes and a unique life cycle, creating an intracellular pool of covalently closed circular DNA molecules for persistence and an RNA template for replication via reverse transcription. Mutations occur frequently, and particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select escape mutants. For example, HBeAg-negative chronic HBV infection with either basal core promoter or precore mutations is predominant in many parts of the world. Therapy of HBV infection with the nucleoside analogue lamivudine frequently leads to the selection of drug-resistant strains with polymerase mutations. Treatment options for chronic HBV infection include at present either interferon-alpha or the oral nucleos(t)ide analogues lamivudine or adefovir. However, these drugs have drawbacks, including possible serious side effects and low response rates in HBeAg-negative patients in the case of interferon or recurrence of viremia after cessation of therapy and development of escape mutants after a long period of treatment with nucleoside inhibitors. Recent advances of in vitro and in vivo models allow to study new antiviral strategies, including novel nucleoside analogues, nucleocapsid inhibitors or small interfering RNA. This review summarises the impact of clinically relevant mutations in the HBV genome on viral replication and drug sensitivity, the current status of therapy and promising future perspectives on novel drug regimens.
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Keywords: adefovir; cccdna; hepatitis b virus; interferon-alpha; lamivudine; rna interference; sirna; ymdd

Document Type: Review Article

Affiliations: Hannover Medical School, Dept. of Gastroenterology, Hepatology and Endocrinology, Carl-Neuberg- Strasse 1, D-30625 Hannover, Germany.

Publication date: 2004-10-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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