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

OBJECTIVE: We aimed to determine the clinical significance of mutations in core promoter and precore regions in chronic hepatitis B. We investigated c hanges in these mutations during the natural course and interferon therapy in patients with chronic hepatitis B. METHODS: A total of 93 patients with hepatitis B virus surface antigen were divided into four groups according to hepatitis B e antigen (HBeAg)/anti-H Be status and serum aminotransferase levels. Group I (n = 16) comprised HBe Ag-positive patients with normal aminotransferase levels, group n (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 i nterferon. Three serial serum samples per untreated patient and eight sampl es per treated patient were tested for HBV DNA levels and core promoter and precore mutations by polymerase chain reaction combined with restriction f ragment length polymorphism, and some were cloned and sequenced. RESULTS: Core promoter mutation was found in 38% of group I, 74% of group I I, 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 le vels were significantly higher in groups I, II, IV, and III, in that order. Serial determination of these two mutations and viral levels showed that t he 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. Howeve r, it did not induce any specific mutations. CONCLUSIONS: Core promoter mutation appeared to develop or complete first, followed by completion of the precore mutation, and the virus with these tw o mutations seemed to be the form to persist in the natural course of chron ic hepatitis B. The clinical significance of these mutations appeared to be profoundly associated with the viral levels. (Am J Gastroenterol 1999;94:2 237-2245. (C) 1999 by Am. Cell. of Gastroenterology).