Predictors of hepatitis B e antigen‐negative hepatitis in chronic hepatitis B virus‐infected patients from childhood to adulthood

Abstract

Hepatitis B e antigen (HBeAg)-negative hepatitis is a clinical indicator of poor outcome for chronic hepatitis B viral (HBV) infection. This long-term prospective cohort study aimed to elucidate the predictors of developing HBeAg-negative hepatitis in chronic HBV-infected subjects followed from childhood to adulthood. We followed 434 HBeAgpositive chronic HBV-infected patients from a median age of 7.22 years (interquartile range 4.31-10.21 years). Spontaneous HBeAg seroconversion occurred in 359 subjects at a median age of 13.93 years (interquartile range 8.76-20.59 years), and 75 subjects developed HBeAg seroconversion after antiviral therapy. These patients were followed for a median of 14.40 years (interquartile range 6.14-22.02 years) after HBeAg seroconversion. Clinical data were analyzed to delineate the predictors of developing HBeAgnegative hepatitis. The HBV basal core promoter and precore/core gene sequences were also evaluated in subjects with and without HBeAg-negative hepatitis. The overall annual incidence of HBeAg-negative hepatitis was 0.37% (95% confidence internal 0.35-0.39) in spontaneous HBeAg seroconverters. The overall annual incidence of HBeAg-negative hepatitis increased to 2.64% in lamivudine-treated subjects but did not increase in those treated with interferon-alpha (0.58%). Male gender (hazard ratio 5 3.15), HBV genotype C (hazard ratio 5 4.40), HBeAg seroconversion after 18 years of age (hazard ratio 5 2.46), and lamivudine therapy prior to HBeAg seroconversion (hazard ratio 5 1.42) were predictors of HBeAg-negative hepatitis in HBeAg seroconverters (P < 0.05). HBeAg-negative hepatitis subjects carried more A1762T/G1764A, C2063A, and A2131C HBV gene mutations than those without HBeAg-negative hepatitis. Conclusions: HBeAg seroconversion during childhood predicts a lower risk of HBeAgnegative hepatitis in later life. Interferon-alpha therapy may be an effective antiviral therapy beneficial in chronic HBV-infected children with severe inflammation that facilitates HBeAg seroconversion in earlier life. (HEPATOLOGY 2016;63:74-82)

Hepatitis B cure: From discovery to regulatory approval

“…These patients are considered to be in the “HBeAg‐negative immune‐active” phase, which is characterized by fluctuating HBV DNA and ALT levels. The annual incidence of HBeAg‐negative immune‐active hepatitis among inactive carriers is estimated to be 0.37% . Some patients do not fit into any of these conventional phases.…”

Elevated serum A20 is associated with severity of chronic hepatitis B and A20 inhibits NF-κB-mediated inflammatory response

“…We also find serum A20 level is higher in CHB patients with HBeAg (−) than HBeAg (+). CHB with HBeAg (−) is usually considered with a worse outcome than HBeAg (+) [32]. Thus, this also support that the serum level of A20 might parallel with the severity of this disease.…”

Baseline Level of Hepatitis B Core Antibody Predicts Spontaneous Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg‐Positive Children With a Normal Alanine Aminotransferase Level

“…One of the possible confounding factors is the HBV precore stop variant, G1896A. We had addressed the issue of precore stop variants G1896A during the inflammatory phase on the HBeAg seroconversion and in the inactive phase on HBeAg‐negative hepatitis in our previous studies . We did not check G1896A variants in each case in the HBeAg‐positive normal ALT phase.…”

“…Hepatitis B e antigen (HBeAg) seroconversion is an important indicator of the natural history and treatment response in chronic hepatitis B (CHB) virus (HBV) infection. Spontaneous HBeAg seroconversion in children is often associated with an uneventful disease course and fewer HBeAg‐negative hepatitis events during follow‐up . HBV genotype, interleukin‐10 and interleukin‐12 levels, early puberty onset, and alanine aminotransferase (ALT) level are reportedly predictive of spontaneous HBeAg seroconversion during follow‐up .…”