Advances in HBV DNA assays are key to determine best long-term treatment strategies for Hepatitis B

For the 350 million people chronically infected with HBV, the two therapeutic approaches currently available are immunomodulatory agents and antiviral chemotherapy. The first therapeutic agent was interferon-alpha (IFN-alpha), whose dual mode of action includes both antiviral and immunomodulatory effects. Unfortunately, extended IFN-alpha treatment is effective in no more than 15-25% of patients, and is associated with a wide spectrum of adverse reactions, although these limitations will be partially obviated by the likely approval of peginterferon-alpha for use in chronic HBV in the near future.

It is the nucleoside analogue named lamivudine that has become the gold standard worldwide for use in patients with chronic hepatitis B. Nevertheless, lamivudine-induced decreases in viral load are difficult to sustain over time due to occurrence of viral drug resistance. The drug resistance is associated with mutations in the very conserved catalytic polymerase /reverse transcriptase domain of the gene located at the YMDD motif.

The recent arrival of nucleotide analogue of HBV therapy is adefovir dipivoxil, whose antiviral efficacy was confirmed in large-scale clinical trials in both HBeAg-positive and HBeAg-negative chronic hepatitis B patients, achieving more than a 3-log decrease in viral load, drop in serum ALT levels, and improvement in liver histology after one to two years of treatment. Although virus resistant mutants did not seem to occur in adefovir-treated patients in 48 weeks and then up to 60 weeks of treatment, this did not turn out to be the case upon treatment after 96 weeks. The newly discovered mutant to adefovir (rtN236T) is located downstream from the YMDD motif in the D domain of the viral polymerase.

Clinically relevant prediction and monitoring of viral resistance require the use of existing tools such as drug resistance and viral load testing. It might also have to extend to include the detection of mutations in the precore and core promoter regions as well as HBV genotyping.

Advances in molecular diagnosis of drug resistance using highly sensitive methodologies such as DNA hybridization assays can pinpoint the type of mutation responsible and, more importantly, detect upcoming viral resistance at an early stage when the variant represents only a minor fraction of the total viral population. Such new tools are especially relevant for patients at high risk for disease progression or acute exacerbation.

The diagnostic developments play important roles in HBV patient management, and in determining the best long-term treatment strategies (sequential, combined, etc.) for the use of the new drugs. At the same time, it is desirable to integrate the HBV diagnostic testing with new therapeutic agents in order to ensure optimized, tailored patient treatment.

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