Background and Aims: Hepatitis B virus (HBV) precore (PC) and dual basal core promoter (BCP) mutations halt and down-regulate hepatitis B e antigen (HBeAg) production respectively. PC mutation is rarely associated with HBV genotype A. We sought to examine the association of these variants with HBV genotypes, age, and HBeAg status in a racially diverse population in North America. Prospective study included 1,036 (808 adults, 228 children) participants in the Hepatitis B Research Network. PC and BCP variants were determined by Sanger sequencing, and dominant HBV species (>50%) were reported. Approach and Results: Median age was 36.3 years (range, 2-80), 44.6% HBeAg(+), 74.2% Asians, 13.3% black, and 9.7% white. The dominant PC variant was present in 29.4% participants, including 20 with subgenotype A1 or A2. Seventeen of 20 participants with genotype A and PC had a compensatory C1858T mutation. In the HBeAg(+) cohort, the prevalence of PC and/or BCP variants increased from 14.4% in the first two decades to 51% after 40 years of age. Among those aged 2-18, 52% and 83% with dominant PC and BCP variants were HBeAg(+) compared to 3.8% and 29% in the >40 years age group. HBeAg clearance rates were significantly higher for those with dominant PC or BCP variants: 24.4 and 15.0 per 100 person-years compared to 6.0 in wild-type HBV (P < 0.0001). Conclusions: PC variants can be present in HBV genotype A and are usually associated with C1858T, which preserves the pregenome encapsidation sequence. Selection of PC and BCP variants occurred at a young age, with increasing prevalence across age groups. HBeAg(+) participants with dominant PC and BCP variants progressed to the HBeAg(−) phase of chronic HBV infection significantly faster. This finding has potential clinical and therapeutic implications.
Bibliographical noteFunding Information:
In addition to the authors, the HBRN would like to acknowledge the contributions of the following: Jay Hoofnagle, M.D., for critical review and data interpretation of the manuscript.Harvard Consortium: Jianghe Niu, Ph.D., Karen Joanie Camoverde Reyes, M.D., Saad Choudhry, M.B.B.S., Pir Ahmad Shah, M.B.B.S., Imad Nasser, M.D. (Beth Israel Deaconess Medical Center, Boston, MA), Arley Donovan, Nifasha Rusibamayila, Cara Foley (Massachusetts General Hospital, Boston, MA).
© 2020 by the American Association for the Study of Liver Diseases.