Clinical course of virologic breakthrough after emergence of YMDD mutations in HBeAg-positive chronic hepatitis B

Objective: High rate of resistance to lamivudine is a major problem in treating chronic hepatitis B (CHB) patients. We investigated the course of virologic breakthrough (VB) after emergence of YMDD mutants in CHB patients receiving lamivudine. Methods: Ninety-three consecutive HBeAg-positive CHB patients treated with lamivudine (100 mg/day) who developed YMDD mutants and VB were enrolled. The clinical breakthrough (CB) was defined by elevation of alanine aminotransferase (ALT) >2 times the upper limit of normal. Results: The median age was 47 years, and genotype of hepatitis B virus (HBV) was all C. The median duration of lamivudine administration was 39 months, and median pre-lamivudine ALT and HBV DNA were 165 IU/l and 1.2 × 10⁸ copies/ml. In all patients, CB concurred with VB or appeared some months following VB. When patients were divided into two groups according to time sequence of two breakthroughs - group 1 (VB followed by CB, n = 68) and group 2 (concurrent VB and CB, n = 25) - there was no difference in patient and virologic characteristics between the two groups. The median time from VB to CB was 8 months in group 1. Conclusion: VB might eventually progress to CB in HBeAg-positive patients harboring YMDD mutants with high pretreatment ALT and HBV DNA.