The profile of mutational clusters associated with lamivudine resistance can be constrained by HBV genotypes

Background/Aims: To investigate the different clusters of mutations associated with lamivudine resistance in HBV genotypes D and A. Methods: HBV reverse transcriptase sequences of 89 HBV-infected patients failing lamivudine treatment were analyzed. The association of mutations with HBV genotypes was assessed by Chi-Squared test and multivariate logistic regression analysis. Covariate analysis was based on hierarchical clustering. Results: In genotype A, the rtM204V (prevalence: 68.2%) was the main sign of lamivudine failure. Multivariate analysis confirmed that genotype A is the only predictor for rtM204V emergence (OR: 14.5 [95% CI: 1.3-158], P = 0.02). Covariate analysis showed that rtM204V clusters with rtL180M, rtL229V (corresponding to sF220L in the HBsAg), and, interestingly, with HBsAg mutation sS207N (bootstrap = 0.95). Both sF220L and sS207N co-localized in the fourth transmembrane HBsAg domain. In contrast, in genotype D the primary mutations rtM204V and rtM204I occurred with similar prevalence (39.1% versus 45.3%, P = 0.47), and showed a distinct pattern of compensatory mutations. rtM204V clusters with mutations localized in the RT-B domain (rtV173L, rtL180M, and rtT184A/S) (bootstrap = 0.94), while rtM204I clusters with mutations localized in the RT-A domain (rtS53N, rtT54Y, and rtL80I/V) (bootstrap = 0.96) (without associations with HBsAg specific mutations). Conclusions: HBV genotype plays an important role in driving RT evolution under lamivudine treatment, and thus can be relevant for therapeutic sequencing, immunological response and disease progression.