Predictive value of HBV DNA levels at frequent time points during early and maintenance phase of 5-year laminudine and mutational profiles of reverse transcriptase (RT) and surface (S) genes

Abstract

BACKGROUND: The optimal time points and levels of HBV DNA during initial therapy with lamivudine (LAM) to predict the 5-year outcome are unknown. AIMS: To identify 1) the optimal time and HBV DNA levels during early treatment phase associated with good response (GR) (HBV DNA level 2000 copies/mL); 2) the mutational profiles after 5-year LAM treatment. PATIENTS AND METHODS: HBV DNA levels at baseline, week (wk) 0,2,4,8,16,24,32 and yearly till 5 years were measured by VERSANT® HBV DNA 3.0 assay (Bayer HealthCare LLC, NY) in 74 Chinese chronic hepatitis B patients on continuous LAM treatment. Determination of parts of the nucleotide sequence of RT and S genes by TRUGENE® HBV Genotyping Kit (Bayer HealthCare LLC) were completed in 50 patients. RESULTS: 20 (27%) patients had GR at year 5. Table shows the percentages of patients achieving GR at 5 years according to the cut-off HBV DNA levels of 4 logs at different early time points. Compared to patients with HBV DNA levels still 4 logs at wk 12, patients with HBV DNA level 4 logs had significantly higher rate of HBeAg seroconversion (20.3 vs. 90%, p0.001), ALT normalization (51.5% vs. 100%, p 0.008) and lower chance of YMDD mutations (62.8% vs. 0%, p 0.002) at year 5. The corresponding figures as assessed at wk 24 are 18.6% vs. 73.3%, p 0.001; 48.3% vs. 92.3%, p 0.007; 62.5% vs. 20%, p 0.03 respectively. The sensitivity and specificity of using this cut-off level for determination of GR at 5 years are 50% and 100% for wk 12, and 60% and 96.2% for wk 24. Mutations of YMDD motif with M204I/V were associated with L180M and V173L (both p0.05). Because of the overlapping of RT and S genes, corresponding S mutations with E164D (with V173L), I195M (with M204I), W196L/M/S/V/X (with M204V)(all p0.05) were observed. These S mutants decrease the anti-HBs binding affinity (Torresi et al., 2002). 2 patients had the vaccine escape S mutation G145R/A at baseline, while 6 developed this mutation during LAM treatment. CONCLUSIONS: HBV DNA level 4 logs copies/mL at wk 12 during LAM treatment had excellent predictive value for long-term outcome. GR only occurred in 15.6% of patients who failed to achieve this target. Only 4.5% of patients with HBV DNA levels 4 logs at wk 48 achieved GR at year 5. Potential impact of RT mutations associated with S mutations affecting anti-HBs binding affinity should be addressed. Week