Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B

Lamivudine is a nucleoside analogue with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase conferring resistance to lamivudine may emerge after 9-10 months therapy with an incidence of 38 and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occur as the result of CLT-mediated hepatocytolysis directed against YMDD mutants. Although viral clearance with or without emergence of distinct lamivudine-resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those that occur during the natural course of wild-type HBV chronic infection. In addition, some mutations may generate S gene truncation near 'transactivity-on-region'. Thus, the benefit of prolonged lamivudine therapy must be balanced against concern about YMDD mutants. Currently, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity, thereby increasing efficacy and shortening the duration of lamivudine therapy. New drugs and new strategies are needed to better achieve the goals of therapy and minimize the problem of YMDD mutants.