HBV drug resistance : Its relevance in clinical practice

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Drug resistance can be considered as a natural response to the selective pressure of the drug. An increase in HBV DNA can be a good indicator of the presence of a resistant HBV mutant population. The nucleoside analogues Lamivudine, Adefovir, Entecavir etc. are oral drugs used for Hepatitis B viral infection. Resistance to HBV drugs arises due to mutations in the polymerase gene. The HBV polymerase can be divided into 4 domains: 1) the terminal protein, 2) the variable spacer domain, 3) the polymerase/reverse transcriptase and 4) the RNase. Drug resistance to Lamivudine is associated with mutations in the very conserved catalytic polymerase /reverse transcriptase domain, located specifically at a locus of four amino acids consisting of tyrosine-methionine-aspartate-aspartate, termed the YMDD motif at position 204:M204V/I. Adefovir resistance mutations are at amino acid residues 181,236/238:A181T/V and N236T/N238D. The Entecavir resistance mutations are at amino acid residues 184, 202 and 250 of the polymerase: T184X, S202I/G/L and M250L/V. There are several assays available that identify resistance mutation like polymerase chain reaction, real time PCR with specific probes, hybridization methods (line probe assay) and restriction fragment length polymorphism (RFLP).The best approach for patients with Lamivudine resistance is to continue Lamivudine and add Adefovir. Lamivudine is effective in suppressing serum HBV DNA levels in patients with Adefovir resistance. Entecavir resistance mutations are sensitive to Adefovir and Tenofovir. The careful selection of a first-line agent is essential to avoid the occurrence of resistance and the development of cross resistance to other agents. The most effective therapy of antiviral-resistant HBV is prevention through judicious use of nucleos(t)ide analogue therapy.