Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance

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Abstract
We previously reported two mutually exclusive mutations in the precore region of hepatitis B virus: M1 (T-1856, proline-serine substitution at codon 15) and M2 (A-1896, stop codon at codon 28). This study was conducted to determine if the presence of precore mutants affect spontaneous or interferon (IFN)-induced hepatitis B e antigen (HBeAg) clearance. Sera from 201 hepatitis B e antigen posititis B virus (HBV) infection were analyzed by direct sequencing of HBV DNA after amplification by polymerase chain reaction (PCR) assay. Forty-three (21%) patients had M1 (T-1856), and 20 patients (10%) had M2 (A-1896). During a follow-up period of 1 to 7 years, 75%, 28%, and 26% of those with M2 (A-1896), M1 (T-1856), and wild type sequence respectively, cleared HBeAg (P<.0001). Eighteen (67%) of 27 patients with wild-type sequence but none of 10 patients who had M1 (T-1856) in their initial samples developed M2 (A-1896) after loss of HBeAg (P<.0001). Sustained antiviral response was achieved in 55%, 0%, and 17% of interferontreated patients who had M2 (A-1896), M1 (T-1856), and wild-type sequence, respectively, initially (P = 0.04). However, patients with M2 (A-1896) were also more likely to have elevated pretreatment aminotransferase levels (P = 0.02). In summary, HBeAg-positive Chinese patients with M2 (A-1896) were more likely to clear HBeAg, and to do so earlier. Neverthless, development or selection of M2 (A-1896) was not a prerequisite for HBeAg clearance. Interferon therapy did not increase the rate of HBeAg clearance in patients with M2 (A-1896) when stratified for aminotransferase levels. (Hepatology 1995;21:19-24).