HBV pre-core mutant in genotype-D infected children is selected during HBeAg/anti-HBe seroconversion and leads to HBeAg negative chronic hepatitis B in adulthood.

Selection of HBeAg defective HBV mutants (mt) during childhood might influence infection outcome in adults. Aim of this study was to correlate the dynamics of pre-core HBV mutant (pre-C mt) selection with virological/clinical outcomes in children followed-up until adulthood. Eighty subjects (50-M/30-F), 70 HBeAg-positive (87.5%), and 10 (12.5%) HBeAg-negative/anti-HBe-positive at the admission, mostly genotype D infected (91.2%), with median age of 6.5 (range: 0.2-17) years, were followed-up for 14.3 years (range: 1.1-24.5); 46 (57.5%) received IFN treatment. HBV-DNA and q-HBsAg were tested by commercial assays, Pre-Core 1896 mt by direct-sequence, oligo-hybridization-assay, and allele-specific-PCR (sensitivity: 30%, 10%, and 0.1% of total viremia). HBeAg/anti-HBe seroconversion (SC) occurred in 55/70 (78.6%) children. After SC, 8 (14.6%) developed HBeAg-negative chronic hepatitis (CHB), 41 (74.5%) remain with HBeAg-negative chronic infection, and 6 (10.9%) lost HBsAg. Baseline HBV-DNA and HBsAg were lower in SC than in no-SC children (median: 7.35 vs 8.95 Log IU/mL, P = 0.005, and 4.72 vs 5.04 Log IU/mL, P = 0.015). The prevalence of pre-C mt increased rapidly (10-40%) around SC. Eventually, pre-C mt was detected in 100% of CHB, in 33% of chronic infections without disease, and in 16% of subjects who cleared HBsAg (P < 0.001). HBV-DNA levels remained slightly higher in carriers of HBeAg negative infection with dominant/mixed pre-C mt populations, than in those with dominant pre-C wt (mean Log IU/mL: 3.83 and 3.42 vs 2.67, P = 0.007). In conclusion, pre-C-mt is selected during HBeAg/anti-HBe SC in children with poor control of HBV replication, leading to HBeAg-negative chronic-active-hepatitis during adulthood.