Detection of hepatitis B virus resistance to antivirals

The development of new nucleoside analogs, that inhibit the HBV reverse tra nscriptase activity, such as lamivudine, famciclovir and others, has provid ed recently an alternative to interferon therapy for chronic hepatitis B. H owever, due to the kinetics of viral replication with a high rate of virus production, a relatively long half-life of virus CCC DNA in the nucleus of infected hepatocytes, long-term antiviral therapy with a reverse transcript ase inhibitor is required to eradicate viral infection. Recently, it has be en reported that lamivudine therapy for chronic hepatitis B in immune compe tent patients may be associated with the selection of resistant strains in aproximately 20% of the patients after 12 months of therapy. Sequence analy sis of the reverse transcriptase domain of resistant viral strains, at the time of viral breakthrough, revealed the occurrence of mutations located in the YMDD motif within the C domain of the viral enzyme with a methionine t o valine (M552V) or to isoleucine (M5521) change. Recent reports on larger series of patients pointed that other mutations residing outside of the C d omain but mainly in the B domain of the viral polymerase (L528M) could be a ssociated with these mutations in the YMDD motif. The lamivudine resistant mutants, selected in vivo, can be classified in 2 main groups: group I with a double mutation L528M and M552V, and group II with a single mutation M55 21. In vitro studies performed in cell culture showed that these mutants ha ve a decreased replication capacity and are indeed resistant to lamivudine. With the development of new antiviral options, genotyping assays and quant itative determination of viremia with highly sensitive assay are clearly wa rranted for an optimal monitoring of antiviral therapy of chronic hepatitis B. In view of the experimental and clinical data, the capacity of new anti viral strategies based on combination of new inhibitors, including adefavir and entecavir, with immune modulators needs to be further evaluated in ani mal models and clinical trials to prevent the emergence of resistant viral strains. (C) 2001 Elsevier Science B.V. All rights reserved.