The hepatitis B virus seroconversion to anti-HBe is frequently associated with HBV genotype changes and selection of preS2-defective particles in chronically infected children

Abstract

In order to investigate the generation and selection of hepatitis B virus mutants and the influence of interferon on their evolution, a longitudinal study including 22 patients was performed. The complete preS1/S2 open reading frame was analyzed by direct sequencing from serum samples obtained before and after seroconversion to anti-HBe in 11 children without alpha-interferon treatment. Furthermore, in 11 cases with therapy additional samples obtained during interferon therapy were investigated. The comparison of each patient's preS sequences analyzed before and during therapy did not show any nucleotide change, while in both groups numerous silent and missense mutations were found immediately after seroconversion. Surprisingly, in 7 cases the hepatitis B virus changed genotype from A to D (subtype adw to ayw) after seroconversion. Additional rearrangements were observed in 4 patients. In 3 cases the selection of preS2 start codon mutants was detected after seroconversion and in 1 individual a 183-nucleotide deletion was found during and after HBeAg positivity. In conclusion, the emergence of preS rearrangements and numerous base exchanges provide evidence for a strong selection process focused against the preS region. Moreover, the appearance of genotype changes after anti-HBe seroconversion reveales a thus far unrecognized event during the natural course of HBV infection in childhood.