Correlation of YMDD mutation and breakthrough hepatitis with hepatitis B virus DNA and serum ALT during lamivudine treatment


  • Grant sponsor: Ministry of Health, Labour and Welfare of Japan.

Dr Mariko Kobayashi, B.S., Research Institute for Hepatology, Toranomon Hospital, 1-3-1, Kajigaya, Takatsu-ku, Kawasaki City 213-8587, Kanagawa, Japan. Email:


Aim:  Continuous lamivudine treatment is associated with high frequency of drug resistance. We analyzed the incidence of tyrosine-methionine-aspartate-aspartate (YMDD) motif mutant and breakthrough hepatitis (BTH) in hepatitis B virus (HBV) DNA positive patients receiving lamivudine for > 1 year and correlated it with HBV DNA and alanine aminotransferase (ALT) levels to evaluate if these measurements can provide a practical option for monitoring patients in clinical practice and define early switch from lamivudine therapy.

Methods:  Of the 929 patients receiving lamivudine for > 1 year, 359 patients who maintained an ALT level of ≤ 40 IU/L during the course of lamivudine treatment were stratified into two groups based on the duration of lamivudine treatment – one receiving lamivudine for < 3 years and the other for ≥ 3 years.

Results:  The incidence of YMDD motif in patients receiving lamivudine for < 3 years was 27% in patients with ALT ≤ 20 IU/L, 58% with ALT ≤ 30 IU/L, and 63% with ALT ≤ 40 IU/L, (P = 0.002). The corresponding incidence of BTH was 2%, 7%, and 48% (P < 0.001). The incidence of YMDD motif and BTH in these patients was 7% and 2% with HBV DNA < 2.6 (log copies/mL) and ALT ≤ 20 IU/L, while with ALT at 21–30, the YMDD motif mutant was 16% and BTH was 0%.

Conclusion:  Correlation of ALT and HBV DNA levels with YMDD motif mutant and BTH indicates that these measurements can be used in clinical practice for deciding early switch from lamivudine to other suitable antiviral therapies.