Pathogenesis of chronic liver disease in patients with chronic hepatitis B virus infection without serum HBeAg

Chronic hepatitis B in patients lacking hepatitis B e antigen has been attributed to a hepatitis B virus variant (G-to-A mutation at nucleotide 1896 in the precore region of the genome). We therefore assessed the frequency and significance of this variant among 43 United States patients (10 with chronic hepatitis B seropositive for e antigen, 19 seronegative for e antigen, and 14 healthy carriers). Sera were tested for HBV DNA by polymerase chain reaction and branched DNA assay. The A₁₈₉₆ variant was detected by direct sequencing and ligase chain reaction. Serum HBV DNA was more frequently found among patients with e antigen-positive than e antigen-negative chronic hepatitis B. Viral titers were generally higher in those with e antigen. None of the e antigen-positive and only 24% of e antigen-negative patients harbored the A₁₈₉₆ variant. Patients infected with the variant were more often Asian, had had hepatitis B for longer and had higher levels of viral DNA than HBeAg-negative patients with the wild-type virus. The A₁₈₉₆ variant was found exclusively in patients infected with HBV genotypes C and D. Thus, the A₁₈₉₆ variant is uncommon in the United States. The activity of liver disease appears to be more closely related to the level of HBV replication than the presence of mutations at nucleotide 1896 in the genome.