As with HIV, the distribution of variants of Hepatitis B virus (HBV) can shift in response to drug therapy. Although Hepatitis B virus replication is often controllable using nucleotide analogues that inhibit the viral DNA polymerase, drug-resistant variants often emerge following chronic treatment, as a result of mutations in the nucleotide binding site of this enzyme. Here, Ono and colleagues show that known HBV polymerase point mutants blunt the effect of these drugs but that they do so at the cost of reducing the baseline replication rate of the virus. However, second-site mutations occurring at one specific residue in the polymerase can restore the catalytic efficiency of the enzyme, generating a virus that is both drug-resistant and quick to replicate. Ono and coworkers also describe the effects of a battery of newly developed antiviral agents on this process, comparing wild-type HBV with several known polymerase point mutants. They confirm that the efficacy of lamivudine, now the standard drug used for controlling HBV, is greatly diminished in all of the drug-resistant viruses studied, but they show that some of the other agents retain significant activity against these variants. One drug, the purine analogue entecavir, stands out because of its thousand-fold greater potency than lamivudine and its ability to suppress replication of even the most vigorous drug-resistant mutants.
Journal of Clinical Investigation