HEPATITIS-B VIRUS-STRAINS WITH MUTATIONS IN THE CORE PROMOTER IN PATIENTS WITH FULMINANT-HEPATITIS

Objective: Fulminant hepatitis B can be induced by hepatitis B virus ( HBV) strains with mutations in the precore region that cannot encode h epatitis B e antigen (HBeAg). Such mutations are rarely seen in HBV DN A clones from patients with fulminant hepatitis B in the United States and France. Thus, the other mutations in HBV strains causing fulminan t hepatitis B need to be identified. Design: Retrospective clinical, s erologic, and molecular biological studies of patients with fulminant hepatitis B. Setting: University and city hospitals in Japan. Patients : 43 patients with fulminant hepatitis B. Measurements: The precore re gion coding fora part of the HBeAg precursor and the core promoter reg ulating the transcription of precore messenger RNA were sequenced in H BV DNA clones. Results: A point mutation from G to A at nucleotide 189 6 in the precore region was detected in 519 (98%) of 529 HBV DNA clone s from 38 patients. Two point mutations in the core promoter, from A t o T at nucleotide 1762 and from G to A at nucleotide 1764, were detect ed in all 130 clones from the remaining 5 patients, who did not have m utations in the precore region, and in 20 (63%) of 32 clones from a pa tient with chronic hepatitis B who had transmitted HBV to 1 of these o ther 5 patients. Mutations in the core promoter were also detected in clones from 26 (68%) of the 38 patients with the precore mutation at n ucleotide 1896. Neither HBeAg nor antibody to HBeAg was detected in 37 (90%) of the 41 patients tested. Conclusions: In Japan, fulminant hep atitis B is closely associated with HBV strains that do not produce HB eAg because of mutations in the precore region, which affect translati on of HBeAg, or because of mutations in the core promoter, which affec t transcription of the HBeAg coding region.