PMO-156 Plasma HBsAG levels correlate with liver cccDNA in tolerant children with infancy acquired chronic hepatitis B infection

Abstract

Plasma HBsAg reflects the transcriptional activity of covalently closed circular (ccc) DNA within the liver rather than the absolute amount of cccDNA copies. Only limited information is available on the interaction of plasma HBsAg, expression of HBsAg and HBcAg within the liver and liver relaxed circular (RC) HBV DNA and cccDNA in patients with infancy-acquired chronic hepatitis B (CHB) and its relationship to therapy response. Aims: To evaluate whether: 1) there is a relationship between plasma HBsAg and HBV DNA levels and liver HBsAg/HBcAg expression and liver RC HBV DNA and cccDNA and 2) baseline plasma HBsAg and HBV DNA levels and liver HBsAg/HBcAg expression and liver RC HBV DNA and cccDNA quantity can predict response to combination therapy with lamivudine (LAM) and interferon-$α$ (IFN) in tolerant children with infancy-acquired CHB. Patients: 23 children (8 males, median age 10.2 yrs) with infancy-acquired CHB (all HBeAg+) in tolerant stage underwent liver biopsy prior to antiviral therapy and were treated for 52 weeks [lead-in LAM (3mg/kg/d) for 9 weeks; LAM+IFN-$α$ (5MU/m2 TIW) from week 9 for 44 weeks], were divided according to treatment response: 5 responders (R=anti-HBs seroconversion) and 18 non-responders (NR). Methods: Plasma HBsAg and HBV DNA levels were measured at therapy baseline by Abbott ARCHITECT {®} assay and real-time TaqMan PCR [both log10 IU/ml]. Baseline liver RC HBV DNA and cccDNA was quantified by real-time TaqMan PCR [log10 copies/ng genomic DNA]. Immunostaining of formalin-fixed, paraffin-embedded liver specimens assessed HBsAg and HBcAg expression [{#} of positive cells per 1000 hepatocytes]. Results are presented as median. Results: At baseline plasma HBsAg levels were lower in R then NR (4.36 vs. 4.75, p=0.02), but HBV DNA viral load was similar (8.94 vs. 8.98). Baseline liver HBV DNA (3.82 vs. 4.71, p=0.16) and cccDNA (1.98 vs. 2.26, p=0.18) tended to be lower in R than NR, while liver HBsAg expression was lower in R than NR (0.5 vs. 4.7, p=0.03) and HBcAg expression was similar between R and NR. There were positive bivariate correlations between plasma HBsAg levels and liver cccDNA (r=0.41, p=0.05), HBcAg liver expression and cccDNA (r=0.44, p=0.05), liver RC HBV DNA and cccDNA (r=0.67, p=0.04) and a trend towards correlation between plasma HBsAg and HBsAg liver expression (r=0.38, p=0.07). Conclusions: Plasma HBsAg levels correlate with liver cccDNA in tolerant children with infancy-acquired CHB infection suggesting that plasma HBsAg levels act as a surrogate marker of liver cccDNA in tolerant patients. Lower baseline HBsAg plasma levels and lower HBsAg liver expression was associated with therapy response.