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. 2021 May;73(5):1637-1651.
doi: 10.1002/hep.31506.

Precore and Basal Core Promoter Hepatitis B Virus (HBV) Variants Are Present From a Young Age and Differ Across HBV Genotypes

Daryl T Y Lau  1 , Lilia Ganova-Raeva  2 , Junyao Wang  3 , Douglas Mogul  4 , Raymond T Chung  5 , Mauricio Lisker-Melman  6 , Kyong-Mi Chang  7 , Obaid S Shaikh  8 , Harry L A Janssen  9 , Abdus S Wahed  3 , Anna S Lok  10 ; Hepatitis B Research Network
Collaborators, Affiliations

Precore and Basal Core Promoter Hepatitis B Virus (HBV) Variants Are Present From a Young Age and Differ Across HBV Genotypes

Daryl T Y Lau et al. Hepatology. 2021 May.

Abstract

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.

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Figures

FIG. 1.
FIG. 1.
PC and BCP variants by HBeAg status.
FIG. 2.
FIG. 2.
Prevalence of PC and BCP variants across HBV genotypes and HBeAg status. (A) HBeAg(+) participants; (B) HBeAg(−) participants.
FIG. 3.
FIG. 3.
(A) Prevalence of PC G1896A variant in HBV genotype A. (Bi) HBV pregenome encapsidation sequence. (Bii) Stem-loop configurations of HBV genotype A with and without substitution at nt1986 (PC) and nt1858 positions. The stem-loop energy (kcal/mol) indicates the thermodynamic stability of the HBV pregenome encapsidation sequence. Lower energy numbers indicate stronger bonds between base pairs.
FIG. 4.
FIG. 4.
PC and BCP variants by age and HBeAg status. (A) HBeAg(+) participats; (B) HBeAg(−) participants.
FIG. 5.
FIG. 5.
Distribution of WT, BCP, PC, and combination of BCP and PC variants across age groups. (A) WT indicates dominant WT at both BCP and PC regions. Overall P value < 0.001 for the prevalence of BCP or PC variants across age groups. Distribution of qHBeAg by age among HBeAg(+) participants with WT, BCP, PC, and combination of BCP and PC variants. (B) Distribution of qHBeAg by age WT indicates dominant WT at both BCP and PC regions.
FIG. 6.
FIG. 6.
Distribution of HBV DNA by HBV variants, age, and HBeAg status. (A) HBeAg(+) participats; (B) HBeAg(−) participants.
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