[Show abstract][Hide abstract] ABSTRACT: Controversial data were recently published concerning the association of hepatitis B virus (HBV) variants with fulminant hepatitis (FH). In this study, we first analyzed the complete nucleotide sequences of HBV genomes isolated from serum samples from a surgeon and his mother, who was accidentally infected by the son; both died of FH. The infecting viruses were genetically almost identical in both patients; all the clones examined carried a double nucleotide mutation in the start codon of the pre-S2 region that prevented the synthesis of the corresponding protein. Analyses of different serum samples from the son revealed only wild-type precore sequences in a high viremic serum, whereas hepatitis B e antigen (HBeAg)-defective strains were prevalent when the viremia had decreased. Subsequently, we extended the analysis to the viral genomes isolated from 18 additional patients with acute HBV infection and different clinical behaviors: 3 of 5 patients with FH and without previous liver disease had pre-S2 start codon mutations preventing pre-S2 protein synthesis, whereas none of the 13 control cases had similar genomic rearrangements. Analysis of the precore region showed that viral populations normally producing HBeAg were the only or the prevalent viral strains in all of these cases. In summary, our results support the hypothesis that the pre-S2 protein is not essential for HBV infectivity. They also show that infection by pre-S2-defective virus is frequently associated with FH, indicating that this variant might play a pathogenetic role in cases of acute liver failure. Finally, they suggest that the emergence of HBeAg-defective viruses might be a late event in the course of FH, occurring when HBeAg-producing viruses have been mostly cleared.