The first antiviral (lamivudine), a nucleoside analog (NA), was approved to treat chronic HBV infection. This first-generation antiviral exhibited drug resistance at ~6 months of treatment. Throughout the next ~20 years, various antivirals were approved that built on the initial success of lamivudine. However, it wasn’t until 2005 when entecavir was approved that NAs began to exhibit a high barrier of resistance.