Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis.

Abstract

Using an oligonucleotide hybridization assay, we studied the clinical implication of wild-type hepatitis B virus (HBV) and a HBV mutant that is unable to secrete hepatitis B e antigen (HBeAg) because of a translational defect due to a stop codon in the pre-C region in 106 hepatitis B surface antigen-positive patients with chronic hepatitis B. Wild-type HBV was detected in 31 of42 (73.8%) HBeAg-positive patients, whereas a mixed viral population was present in 10 (23.8%). Significant differences in the severity and outcome of liver disease were not observed in the two groups of patients. However, the emergence of HBeAg-minus HBV in wild-type HBV carriers was associated with an exacerbation of liver disease and was followed by the presence of antibodies against HBeAg (anti-HBe) in serum in 50% of the cases. In 61 of 64 (95.3%) anti-HBe-positive patients, HBeAg-minus HBV was the predominant virus: HBeAg-minus HBV was detected in 42 patients (65.6%), whereas both wild-type and HBeAg-minus HBV were present in 19 (29.7%). HBeAg-minus HBV was associated with a course of hepatitis characterized by flare-ups of liver cell necrosis interspersed with periods of asymptomatic HBV carriage (P < 0.01). These data support the hypothesis that genetic heterogeneity of HBV significantly influences the course and outcome of chronic hepatitis B. Wild-type HBV secreting HBeAg induces immunologic tolerance and causes chronic infection. HBeAg-minus HBV might be unable to induce chronic infection without the helper function of wildtype HBV, but it appears to be more pathogenic. Once chronic infection is established, HBeAg-minus HBV variants may prevail and displace wild-type virus.Hepatitis B e antigen (HBeAg) is a partially degraded nonparticulate form of hepatitis B nucleocapsid protein secreted into the serum during florid hepatitis B virus (HBV) infection (1-3). HBeAg and polypeptides composing the viral nucleocapsid result from translation of a single open reading frame (C gene) containing two start codons, which identify pre-C and C regions (1-3). Initiation of translation from the first codon (pre-C) yields a secretory protein (HBeAg) with a signal peptide cleaved off during maturation (1-3). In carriers of HBV, disappearance of HBeAg and the presence of antibodies against HBeAg (anti-HBe) in serum is associated with clearance of HBV DNA from serum, hepatitis B core antigen from liver, and the resolution of histological activity (4,5). In areas with high or intermediate HBV endemicity, viral replication and liver damage persist in about 10% of anti-HBe-positive carriers (6-12). HBV mutants unable to secrete HBeAg because of translational defects in the pre-C region have been isolated in these patients (13)(14)(15)(16)(17)(18)(19)(20)(21). In the great majority of them (>90%), an unusual HBV strain was characterized with a G -* A mutation at nucleotide 1896, which generates a stop codon in the pre-C sequence (13-21).In our area, an additional mutation (G --A) at position 1899 was consistently associated with the stop codon...

Hepatitis B-specific T helper cell responses in uninfected infants born to HBsAg+/HBeAg− mothers

“…7,15,16 In neonates born to HBsAg 1 /HBeAg 1 mothers, immune tolerance is further induced by transplacental passage of HBeAg that can result in specific tolerance of T helper cells to both HBeAg and HBcAg because these two antigens are crossreactive. 6,17 However, intrauterine infection and immunoprophylactic failure have also been reported in infants of HBsAg 1 /HBeAg 2 mothers. 7,18 Most studies of neonatal T-cell responses against HBV have focused on the immune responses elicited by HBsAg in vaccinated healthy infants.…”

Different hepatitis b virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion

“…Longitudinal studies found that A1896 emerges or is selected around the time of HBeAg seroconversion. 2,[5][6][7] These findings suggest that A1896 plays an important role in HBeAg clearance. However, not all patients develop A1896 after HBeAg seroconversion; some patients retain wild-type precore sequence, while others have undetectable HBV DNA in serum (by polymerase chain reaction [PCR] assay).…”

“…[1][2][3][4][5][6][7] The predominant mutation involves a G-to-A change at nucleotide 1896 (A1896), which creates a premature stop codon at codon 28 ( Fig. 1).…”

Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine

“…2,3 HBeAg-negative CHB is a potentially severe and progressive form of chronic liver disease with rare spontaneous remissions, frequent progression to cirrhosis, and increased risk of hepatocellular carcinoma (HCC). [4][5][6][7] The management of CHB has improved over the last years with the addition of lamivudine and more recently adefovir dipivoxil (ADV), but it is still suboptimal in achieving sustained off-therapy responses. [8][9][10][11] In particular in HBeAg-negative CHB, interferon-alfa (IFN␣), the first available effective therapeutic option in CHB, is the agent offering the higher chances for sustained-off therapy response ranging between 18% and 30%.…”