PREDICTIVE VALUE OF PRECORE HEPATITIS-B VIRUS MUTATIONS IN SPONTANEOUS AND INTERFERON-INDUCED HEPATITIS-B E-ANTIGEN CLEARANCE

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 c onducted to determine if the presence of precore mutants affect sponta neous or interferon (IFN)-induced hepatitis B e antigen (HBeAg) cleara nce. Sera from 201 hepatitis B e antigen positive Chinese patients (in cluding 106 who participated in a controlled trial of IFN therapy) wit h chronic hepatitis B virus (HBV) infection were analyzed by direct se quencing of HBV DNA after amplification by polymerase chain reaction ( PCR) assay. Forty-three (21%) patients had M1 (T-1856), and 20 patient s (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 H BeAg (P < .0001). Sustained antiviral response was achieved in 55%, 0% , and 17% of interferon-treated patients who had M2 (A-1896), M1 (T-18 56), and wild-type sequence, respectively, initially (P = .04). Howeve r, patients with M2 (A-1896) were also more likely to have elevated pr etreatment aminotransferase levels (P = .02). In summary, HBeAg-positi ve Chinese patients with M2 (A-1896) were more likely to clear HBeAg, and to do so earlier. Nevertheless, development or selection of M2 (A- 1898) was not a prereqpisite for HBeAg clearance. Interferon therapy d id not increase the rate of HBeAg clearance in patients with M2 (A-189 6) when stratified for aminotransferase levels.