Effect of lamivudine therapy on the serum covalently closed circular DNA of chronic hepatitis B infection

Abstract

BACKGROUND: In a recent study we demonstrated that serum covalently closed circular (ccc) hepatitis B virus (HBV) DNA is present in 93% of HBeAg-positive patients and that it correlates well with intrahepatic cccDNA (r=0.52, p=O.O04)(Wong DKH et al Hepatology 2004 in press). Serum cccDNA is good marker for intrahepatic cccDNA and has the advantage of easy monitoring. The effect of lamivudine on ccc DNA in HBV infection is unknown. AIM: To determine the effect of one-year lamivudine treatment on serum cccDNA level. PATIENTS AND METHODS: Total HBV DNA and cccDNA levels at baseline, week 24 and 52 were measured in 82 lamindine-treated patients, 17 of whom acted as controls when they received placebo in the first year. RESULTS: There was a significant reduction in the cccDNA levels from baseline (median 3.0 X lo6 copieslml) to week 24 (33,476 copies/ml) and week 52 (48,694 copieslml) (p < 0.001 for both) in lamivudine-treated patients. The median reduction in serum cccDNA level at week 24 and 52 were 2.21 and 2.12 logs respectively, which were significantly greater than those of patients taking placebo (0.31 log, p < 0.001; 0.2 log, p < 0.001 respectively). Fifteen patients (18.3%) developed YMDD mutations by week 52. The median logarithmic reduction of cccDNA at week 52 was significantly less in patients with YMDD mutations compared to patients without YMDD mutations (0.8 vs. 2.35 logs respectively, p < 0.001). Compared to patients without YMDD mutations at week 52, patients with YMDD mutations had a significantly lesser median logarithmic reduction of total HBV DNA and cccDNA levels at week 24 [total HBV DNA 4.44 vs. 3.65 respectively, p=0.02; cccDNA: 2.27 vs. 1.65 respectively, p=O.O16)]. CONCLUSIONS: One-year lamivudine treatment decreased the serum cccDNA level by 2 logs. The chance of emergence of YMDD mutations at week 52 was related to the magnitude of viral suppression at week 24.