Detection of hepatitis B virus resistance to antivirals.
The development of new nucleoside analogs, that inhibit the HBV reverse transcriptase activity, such as lamivudine, famciclovir and others, has provided recently an alternative to interferon therapy for chronic hepatitis B. However, 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 transcriptase inhibitor is required to eradicate viral infection. Recently, it has been reported that lamivudine therapy for chronic hepatitis B in immune competent patients may be associated with the selection of resistant strains in aproximately 20% of the patients after 12 months of therapy. Sequence analysis 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 to valine (M552V) or to isoleucine (M5521) change. Recent reports on larger series of patients pointed that other mutations residing outside of the C domain but mainly in the B domain of the viral polymerase (L528M) could be associated 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 M5521. In vitro studies performed in cell culture showed that these mutants have a decreased replication capacity and are indeed resistant to lamivudine. With the development of new antiviral options, genotyping assays and quantitative determination of viremia with highly sensitive assay are clearly warranted for an optimal monitoring of antiviral therapy of chronic hepatitis B. In view of the experimental and clinical data, the capacity of new antiviral strategies based on combination of new inhibitors, including adefavir and entecavir, with immune modulators needs to be further evaluated in animal models and clinical trials to prevent the emergence of resistant viral strains.
Zoulim
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INSERM Unit 271, 151 Cours Albert Thomas, 69003, Lyon, France. zoulim@lyon151.inserm.fr
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D006515:Hepatitis B virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D012194:RNA-Directed DNA Polymerase / Q000235:genetics
D000998:Antiviral Agents; D012194:RNA-Directed DNA Polymerase