The hepatitis C virus (HCV) is the major cause of chronic addition, we recently reported a close correlation be-non-A, non-B hepatitis, a disease that seldom resolves spontween the number of mutations in amino acid sequences taneously and that can progress to cirrhosis and hepatocellu-2209 to 2248 of the nonstructual protein 5A gene lar carcinoma over several decades. 1 The development of ef-(NS5A2209-2248) of HCV-1b and the response to IFN-a. fective treatments to eradicate HCV infection is of great In the present study, we analyzed these viral factors in medical importance. relation to the efficacy to IFN-b, another type I IFN. TheInterferon alfa (IFN-a) a type I IFN, has been used to treat pretreatment sera of 40 patients treated with IFN-b in-chronic hepatitis C throughout the world since the first report travenously at 6 MU daily for 42 days were studied. HCV of its beneficial effects in 1986. 2 IFN-b is also a type I IFN genotypes, serum HCV-RNA levels, and the amino acid that is commonly used in the treatment of acute and chronic sequence of NS5A2209-2248 in HCV-1b were determined. hepatitis C in Japan. [3][4][5] It has been believed that type I IFNs A sustained complete response to IFN therapy occurred bind to the same receptor; however, recent evidence suggests in none of the ten patients with the wild-type HCV-1b the existence of a second receptor-associated protein that is who had an NS5A2209-2248 sequence identical to the involved specifically in the IFN-b signaling pathway. 6 Inprototype HCV-1b and in none of the six patients with deed, in vitro experiments have shown that different type I the intermediate-type HCV-1b that had 1 mutation. In IFNs induce different biological responses. 7,8 Thus, IFN-a contrast, complete responses occurred in the following: and IFN-b may exhibit different characteristics in the treat-4 of 6 patients with the mutant-type HCV-1b that had ment of chronic hepatitis C. five to ten mutations; 6 of 13 patients with genotype 2aThe majority of clinical trials in hepatitis C have employed of HCV (HCV-2a); and 2 of 5 patients with genotype 2b recombinant or natural IFN-a and have shown that HCV of HCV (HCV-2b). Among patients with the mutant-type genotypes and serum HCV-RNA levels correlate with long-HCV-1b or genotype 2 of HCV (HCV-2) the rate of com-term beneficial responses to IFN-a. Thus, genotype 1b of HCV plete response was significantly higher (12 of 24 vs. 0 of (HCV-1b) has been found to be more resistant to IFN-a than 16 patients, P õ .001) and HCV-RNA levels were signifi-was genotype 2 of HCV (HCV-2), and patients with high cantly lower (4.5 [4.0-6.5] vs. 6 [4.5-6.5] log copies/mL, me-HCV-RNA levels were found to be more resistant to IFN-a dian [range]; P õ .001) compared with patients with the than were those with low HCV-RNA levels. 9-17 Furthermore, wild-or the intermediate-type HCV-1b. Patients with the we reported recently that the sensitivity to IFN-a in HCVmutant-type HCV-1b or HCV-2 whose HCV-RNA levels 1b correlates closely with the number of mutations in the ...

The core promoter region of hepatitis B virus genomes regulates transcription of the precore and pregenomic mRNAs encoding hepatitis B e antigen (HBeAg) and core antigen that contain target epitopes for cytotoxic T lymphocytes. The prevalence and clinical significance of mutations in this region were investigated. DNA was extracted from six asymptomatic carriers positive for HBeAg, eight asymptomatic carriers positive for an anti-HBe antibody, and 24 patients with chronic liver disease. The core promoter and precore regions of hepatitis B virus genomes were amplified by polymerase chain reaction, and predominant sequences were determined by direct sequencing. Mutations were found in none of the HBeAg-positive asymptomatic carriers but in all of the anti-HBe-positive asymptomatic carriers and the patients with chronic liver disease. Especially, A to T mutations at nucleotide 1762 and G to A mutations at nucleotide 1764 were found in five anti-HBe-positive asymptomatic carriers, and 22 patients with chronic liver disease. These two mutation hot spots were located within binding sites of the nuclear factors, and nucleotide 1762 was also involved in the A, T rich sequence that is located 28 base pairs upstream of the precore mRNA initiation site. Serum HBeAg and DNA polymerase levels were significantly lower in patients with these mutations than those without these mutations, and five individuals with these mutations were positive for anti-HBe despite the absence of the precore stop codon mutation. These mutants may be selected by host immune response to HBeAg and/or core antigen.

No abstract

The core promoter region of hepatitis B virus genomes regulates transcription of the precore and pregenomic mRNAs encoding hepatitis B e antigen (HBeAg) and core antigen that contain target epitopes for cytotoxic T lymphocytes. The prevalence and clinical significance of mutations in this region were investigated. DNA was extracted from six asymptomatic carriers positive for HBeAg, eight asymptomatic carriers positive for an anti-HBe antibody, and 24 patients with chronic liver disease. The core promoter and precore regions of hepatitis B virus genomes were amplified by polymerase chain reaction, and predominant sequences were determined by direct sequencing. Mutations were found in none of the HBeAg-positive asymptomatic carriers but in all of the anti-HBe-positive asymptomatic carriers and the patients with chronic liver disease. Especially, A to T mutations at nucleotide 1762 and G to A mutations at nucleotide 1764 were found in five anti-HBe-positive asymptomatic carriers, and 22 patients with chronic liver disease. These two mutation hot spots were located within binding sites of the nuclear factors, and nucleotide 1762 was also involved in the A, T rich sequence that is located 28 base pairs upstream of the precore mRNA initiation site. Serum HBeAg and DNA polymerase levels were significantly lower in patients with these mutations than those without these mutations, and five individuals with these mutations were positive for anti-HBe despite the absence of the precore stop codon mutation. These mutants may be selected by host immune response to HBeAg and/or core antigen.

A 32-year-old woman with asymptomatic primary biliary cirrhosis had autoimmune hemolytic anemia associated with reticulocytopenia and thrombocytopenia despite an intensely erythroid bone marrow. Her anemia was successfully treated with oral prednisolone and intravenous pulse methylprednisolone, with a rapid response of reticulocytosis and sustained erythrocytosis. Tiopronin therapy was later initiated and resulted in fever, rash, exacerbation of the liver disease, and positive direct and indirect antiglobulin tests.