Current management of HBV antiviral drug resistance

Long-term administration of oral anti-hepatitis B virus (HBV) nucleoside or nucleotide analogues therapy (NUC) is the first-line treatment option for most patients with chronic hepatitis B infection. Although NUC rapidly inhibits HBV replication in most patients, in the long term, this therapeutic regimen is challenged by the emergence of drug-resistant mutant virions, ultimately leading to treatment failure and liver disease progression. Indeed, viral resistance occurs most frequently in patients exposed to first-generation NUC (e.g., lamivudine), whereas second-generation regimens (e.g., adefovir and telbivudine) are definitively safer but still at risk of developing resistance. Third-generation NUCs (e.g., entecavir and tenofovir) are considered safe and unlikely to cause genetic resistance. Drug-resistant strains can be identified by close monitoring of serum levels of HBV DNA before they can attenuate the antiviral response, and can be rescued by a specific "add-on" strategy with a non-cross-resistant drug, to ensure complete long-lasting suppression of HBV. Entecavir and tenofovir are the recommended first-line options in naïve patients to minimize the risk of drug resistance. Tenofovir is the recommended rescue therapy in most patients who fail to respond to nucleoside analogues.