The Molecular Epidemiology of Hepatitis B Virus and Its Resistance-Associated Mutations in the Polymerase Gene in the Americas

The hepatitis B virus (HBV) is a DNA virus of major public health concern whose error-prone polymerase has driven the emergence of ten distinct genotypes and a multitude of resistance-associated mutations (RAMs). Herein, we conducted a retrospective observational study analyzing 8152 hepatitis B virus (HBV) sequences from 27 regions across the Americas, retrieved from GenBank, to construct a database and examine associations among HBV genotypes/subtypes, geographic distribution, resistance-associated mutations (RAMs), and resistance to nucleos(t)ide analogs (NAs) used in the treatment of chronic infection. Following phylogenetic analysis, mutations at clinically relevant sites in the reverse transcriptase domain were identified and classified by resistance to NAs. Genotypes A (21.1% A2 and 14.7% A1) and D predominated across the retrieved database, whereas genotypes E, G, H, and I each accounted for fewer than 3% of the sequences. Among the sequences in the database, 10.6% harbored RAMs, with genotypes G, A, and H predominating in this category. The most frequently observed RAM was L180M + M204V/I, which is associated with resistance to LMV, ETV, and TBV, whereas resistance to ADV and TDF remained rare. Genotypes G and A2 were significantly associated with a higher likelihood of harboring multiple RAMs (as evaluated by logistic regression), along with an increased risk of resistance to LMV, ETV, and TBV; the opposite was true for subtype A1. Notably, genotypes H and B5 were associated with an elevated risk of TDF resistance. A comprehensive understanding of RAMs and circulating genotypes in the Americas is essential for identifying high-risk populations and establishing geographically targeted therapeutic strategies.