The clinical significance of core promoter and precore mutations during the natural course and interferon therapy in patients with chronic hepatitis B.

Abstract

We aimed to determine the clinical significance of mutations in core promoter and precore regions in chronic hepatitis B. We investigated changes in these mutations during the natural course and interferon therapy in patients with chronic hepatitis B. A total of 93 patients with hepatitis B virus surface antigen were divided into four groups according to hepatitis B e antigen (HBeAg)/anti-HBe status and serum aminotransferase levels. Group I (n = 16) comprised HBeAg-positive patients with normal aminotransferase levels, group II (n = 31) HBeAg-positive patients with elevated aminotransferase levels, group III (n = 30) anti-HBe-positive patients with normal aminotransferase levels, and group IV (n = 16) anti-HBe-positive patients with elevated aminotransferase levels. All patients of group II and seven of group IV were treated with interferon. Three serial serum samples per untreated patient and eight samples per treated patient were tested for HBV DNA levels and core promoter and precore mutations by polymerase chain reaction combined with restriction fragment length polymorphism, and some were cloned and sequenced. Core promoter mutation was found in 38% of group I, 74% of group II, 97% of group III, and 100% of group IV. Precore mutation was found in 6% of group I, 90% of group II, and 100% of groups III and IV. The HBV DNA levels were significantly higher in groups I, II, IV, and III, in that order. Serial determination of these two mutations and viral levels showed that the core promoter mutation appeared to occur first, followed by a completion of the precore mutation along with a decrease in viral levels in patients who seroconverted to anti-HBe after interferon therapy. Interferon therapy suppressed both precore wild- and mutated-type viral levels equally. However, it did not induce any specific mutations. Core promoter mutation appeared to develop or complete first, followed by completion of the precore mutation, and the virus with these two mutations seemed to be the form to persist in the natural course of chronic hepatitis B. The clinical significance of these mutations appeared to be profoundly associated with the viral levels.