Resistance of Hepatitis B Virus to Antiviral Drugs: Current Aspects and Directions for Future Investigation

Despite the existence of vaccines, chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Interferon therapy successfully controls infection in only a small percentage of chronically infected individuals. The recent approval of the nucleoside analogue lamivudine for the treatment of chronic HBV infection has ushered in a new era of antiviral therapy. While lamivudine is highly effective at controlling viral infection short-term, prolonged therapy has been associated with an increasing incidence of viral resistance. Thus, it appears that lamivudine alone will not be sufficient to control chronic viral infection in the majority of individuals. In addition to lamivudine, several new nucleoside and nucleotide analogues that show promising antihepadnaviral activity are in various stages of development. Lamivudine resistance has been found to confer cross-resistance to some of these compounds and it is likely that resistance to newer antivirals may also develop during prolonged use. Drug resistance therefore poses a major threat to nucleoside analogue-based therapies for chronic HBV infection. Fortunately, combination chemotherapy (antiviral therapy with two or more agents) can minimize the chance that resistance will develop and can be expected to achieve sustained reductions in viral load, provided that suitable combinations of agents are chosen. Here we review the basis of drug resistance in HBV, with emphasis on aspects that are likely to affect drug choice in future.