Chronic hepatitis B carriers with acute on chronic liver failure show increased HBV surface gene mutations, including immune escape variants

Shan Gao, Shivali S. Joshi, Carla Osiowy, Y. Chen, Carla S. Coffin, Z-P. Duan

The pathogenesis of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) is not well understood. The aim of this study was to investigate whether there is an association between HBV polymerase (P)/overlapping surface (S) gene and basal core promoter (BCP)/precore (PC) variants and development of ACLF in CHB. Two CHB patient cohorts were compared: (i) ACLF (N = 12) (11/12 M, median age 52 yrs., 5/9 genotype C, 6/12 HBeAg+), (ii) 27 treatment native CHB carriers (15/27 M, median age 44 yrs., 9 genotype B, 10 genotype C, 1 genotype A, 5 genotype D, 2 genotype E). Clonal sequencing of PCR-amplified HBV P/S and BCP/PC gene fragments was done and HBV diversity, frequency of immune escape (IE) and drug resistance (DR) mutations and mutations in BCP/PC gene (G1896A and A1762T/G1764A), were compared between each group. Our data showed the incidence of IE and clusters of mutations in the HBV S region was significantly greater in ACLF patients vs. treatment naïve CHB patients (p < 0.05). Additionally, a significantly higher frequency of G1896A and A1762T/G1764A mutations were found in HBeAg negative than in ACLF patients (p < 0.0001). In our study, ACLF was not associated with a specific genomic mutation. However, higher frequency of IE mutations along with various mutations clustering in the HBV S region could contribute to or be an outcome of ACLF in CHB infection. (words 226).