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Arch Hellen Med, 26(3), May-June 2009, 295-306


The problem of viral resistance in chronic hepatitis B therapy

2nd Department of Medicine, Medical School, University of Athens, "Hippokration" General Hospital of Athens, Athens, Greece

Available agents for the treatment of chronic HBV infection include interferon-alpha, the nucleoside analogues lamivudine, telbivudine, entecavir and the noucleotide analogue adefovir and tenofovir. When nucleoside-nucleotide analogues are used, patients require a long duration of treatment, especially in HBeAg negative disease, with the potential for developing antiviral resistance, which limits their long-term effectiveness. Interferon-alpha lacks viral resistance selection. Resistance rates vary by compound. Lamivudine is associated with the development of viral resistance in up to 70% within 5 years, adefovir dipivoxil in 29% after 5 years, entecavir in <1% in naive patients for up to 4 years (39% in 4 years in lamivudine-resistant patients) and telbivudine in 22% after 2 years of therapy. Clinical consequences of nucleoside-noucleotide resistance include loss of viral response (i.e., a rise in serum HBV DNA), biochemical dysfunction with an increase in aminotransferases, and overt hepatic failure (in patients with more advanced underlying liver disease). The initial choice of antiviral agent should take into consideration both the potency and the incidence of resistance, with serial HBV DNA determination to confirm adequate viral suppression. A suboptimal response to therapy with continued high-level replication identifies a patient at high risk for viral resistance, and is an indication for a change in antiviral strategy. Routine on-treatment monitoring of HBV DNA levels is imperative for detecting virologic breakthrough as early as possible, and for transitioning patients to rescue therapy before biochemical failure and loss of response occurs. For lamivudine resistant HBV infection, adefovir or tenofovir, and for adefovir resistance lamivudine should be added. In conclusion, monitoring for drug resistance during therapy and its prompt management are crucial in managing the antiviral treatment of HBV patients.

Key words: Adefovir, Entecavir, Hepatitis B, Hepatitis B virus, Lamivudine, Noucleoside analogues, Noucleotide analogues, Telbivudine, Viral mutans, Viral mutations, Viral resistance.

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