We aimed to assess the long-term outcomes of e antigen-negative chronic hepatitis B (CHB) infection with low hepatitis B virus (HBV) DNA level (< 200 IU/mL) and persistently normal alanine aminotransferase (PNALT) and to explore the factors associated with the results.

This retrospective cohort study enrolled consecutive baseline CHB patients with PNALT from January 2005 to June 2008. In total, 252 e antigen-negative CHB patients with PNALT and low HBV DNA level (< 200 IU/mL) were enrolled, of whom 188 were eligible for this analysis. Among the 188 patients, 131 were followed up more than twice per year and 57 were followed up at least once per year, with a median follow-up period of 102 (73–123) months.

Of 188 patients, 16 had HBV DNA level of > 200 IU/mL and PNALT, 164 had HBV DNA level of < 200 IU/mL and PNALT and 8 had HBV DNA level of > 200 IU/mL and elevated ALT level, of which 3 used an antiviral drug during follow-up. Twelve of 164 experienced HBsAg loss. Cox regression analysis suggested that baseline HBsAg levels were associated with HBsAg loss in patients after follow-up, especially the baseline HBsAg levels of < 200 IU⁄mL, which is a risk factor for HBsAg loss. The AUC of baseline HbsAg level in the e antigen-negative CHB group was 0.772 (cutoff value 426, P < 0.001). The cumulative probability of HBsAg loss in the HBsAg < 400 IU/L group was 20% (7/35), which ws higher than that in the HBsAg ≥ 400 IU/L group (3.88%; 5/129; X2 = 11.75, P = 0.0006).

The e antigen-negative CHB infection with low HBV DNA level (< 200 IU/mL) and PNALT will progress to chronic hepatitis, although the probability of its occurrence is low. Spontaneous HBsAg loss may not occur frequently because the manifested cumulative probability of HBsAg loss was higher in the HBsAg < 400 IU/L group than in the HBsAg ≥ 400 IU/L group.