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The number of amino acid (AA) mutations in the interferon sensitivity determining region (ISDR) of NS5A is reported to affect the response to interferon (IFN) therapy in patients with chronic hepatitis C (CHC). The aim of this study was to clarify whether host immunity is influenced by the number of AA mutations in the ISDR. Subjects included 44 patients with CHC infected with genotype 1b and high viral load. The number of AA mutations in the ISDR was retrospectively determined using stored serum samples taken immediately before starting therapy. All patients received IFN-alpha 2b or pegylated-IFN (PEG-IFN)-alpha 2b and ribavirin. When serum hepatitis C virus-ribonucleic acid (HCV-RNA) was negative at 4 or 12 weeks after starting therapy, the patient was defined as having rapid viral response (RVR) or early viral response (EVR), respectively. CD4+ T cell (Th1 or Th2) in peripheral blood (PB) before and until day 56 of treatment was analyzed. Rates of RVR and EVR were 0 (0/21) and 14% (3/21), respectively, in patients with one or fewer AA mutations in the ISDR (ISDR0-1), and 30 (7/23), and 74% (17/23), respectively, with two or more AA mutations in the ISDR (ISDR > 2). Although the percentage of PB Th1 cells did not differ between the two groups during the study period, the percentage of PB Th2 cells was significantly lower in the ISDR0-1 group than in the ISDR > 2 group at baseline and on days 3, 7, 14, and 28 of treatment. The number of AA mutations in the ISDR influenced PB Th2 cells before and until day 28, and was associated with higher RVR and EVR rates.

We focused on determining the most accurate and convenient genotyping methods and most appropriate single nucleotide polymorphism (SNP) among four such polymorphisms associated with interleukin-28B (IL-28B) in order to design tailor-made therapy for patients with chronic hepatitis C virus (HCV) patients. First, five different methods (direct sequencing, high-resolution melting analysis [HRM], hybridization probe [HP], the InvaderPlus assay [Invader], and the TaqMan SNP genotyping assay [TaqMan]) were developed for genotyping four SNPs (rs11881222, rs8103142, rs8099917, and rs12979860) associated with IL-28B, and their accuracies were compared for 292 Japanese patients. Next, the four SNPs associated with IL-28B were genotyped by Invader for 416 additional Japanese patients, and the response to pegylated interferon/ribavirin (PEG-IFN/RBV) treatment was evaluated when the four SNPs were not in linkage disequilibrium (LD). HRM failed to genotype one of the four SNPs in five patients. In 2 of 287 patients, the results of genotyping rs8099917 by direct sequencing differed from the results of the other three methods. The HP, TaqMan, and Invader methods were accurate for determination of the SNPs associated with IL-28B. In 10 of the 708 (1.4%) patients, the four SNPs were not in LD. Eight of nine (88.9%) patients whose rs8099917 was homozygous for the major allele were virological responders, even though one or more of the other SNPs were heterozygous. The HP, TaqMan, and Invader methods were suitable to determine the SNPs associated with IL-28B. The rs8099917 polymorphism should be the best predictor for the response to the PEG-IFN/RBV treatment among Japanese chronic hepatitis C patients.

症例は65歳男性，慢性腎不全で加療されていた．2008年4月に原因不明の肝障害が出現し当科紹介，原因検索したが不明のまま血清AST，ALTは自然軽快した．9月に再び肝障害が増悪した際，EBV-VCA IgG抗体価が高値で，ISH法とPCR法により血中，肝組織内のEBV-DNAを確認したことから，慢性活動性EBウイルス感染症（CAEBV）と診断．強力ミノファーゲンC 60 ml /日投与により肝障害は軽快したが，2009年1月に再び肝障害の増悪を認めたためビタラビン600 mg/日静注とプレドニゾロン60 mg/日経口投与を開始したところ肝障害は改善した．しかし，経過中にアスペルギルス，サイトメガロウイルス感染症による重症感染症を併発し永眠された．EBV-VCA IgG抗体価の異常高値が認められた場合，CAEBVを疑い，血中，肝組織内EBV-DNAの存在を証明することは診断確定のために有用と思われた．

症例は66歳女性．全身倦怠感を主訴に近医を受診し，急性B型肝炎重症型と診断され当院に紹介入院となった．第2病日目には脳症II度となり，劇症肝炎急性型と診断した．人工肝補助，抗ウイルス療法やステロイドパルス療法などの集中治療が奏効し肝炎は改善した．しかし，淡い多発性の斑状陰影が両肺にみられ，右腎の腫瘤像も増大するため，腎腫瘤をドレナージ目的で穿刺したところ，アスペルギルスが検出され，侵襲性肺アスペルギルス症（invasive pulmonary aspergillosis：IPA）と診断し，その後から発熱が続き，翌日には自然気胸と脳出血が同時に発生した．一時，回復傾向がみられたが，致命的な両側脳室に穿破するクモ膜下出血が起こり，第75病日に死亡した．アスペルギルスは免疫力が衰えた患者では致命的なIPAを起しうるが，検出の困難な場合が多く，抗真菌治療を行なっても予後不良であるとされており，ハイリスク患者では予防的抗真菌治療が勧められる．

BACKGROUND/AIM: Nearly 20 % of patients with genotype 2 chronic hepatitis C (CHC) do not achieve a sustained virologic response (SVR), even if pegylated-IFN and ribavirin are administered for 24 weeks. The aim of this study was to determine the factors predicting the efficacy of interferon (IFN) -based therapy for patients infected with hepatitis C virus (HCV) genotype 2.PATIENTS AND METHODS: Eighty-seven adults with CHC (M/F: 57/30) due to infection with HCV genotype 2a or 2b were studied. Thirty-six patients were treated with IFN-alpha alone, 30 patients received consensus IFN alone, and 21 were given IFN-alpha 2b plus ribavirin. In all three regimens, IFN was administered daily for 2 weeks, followed by the same dose thrice weekly for a median of 22 weeks (range: 10-46 weeks). A SVR was defined as undetectable (RESULTS: SVR was achieved in 63 patients. The log-10 transformed serum level of HCV-RNA (log HCV-RNA) and log IL-18/IL-10 were factors with an independent influence on SVR on multivariate regression analysis.CONCLUSION: This study provided the first evidence that the baseline serum IL-18/IL-10 ratio levels is an independent prognostic indicator for SVR in patients with CHC genotype 2.

BACKGROUND/AIM: To determine the sustained viral response (SVR) rate and to investigate the baseline host and viral characteristics of chronic hepatitis C (CHC) patients who achieved an SVR with interferon (IFN) alone or IFN plus ribavirin. PATIENTS AND METHODS: One hundred and forty-seven adults with CHC were studied. Baseline serum HCV-RNA was quantified by RT-PCR, and the HCV serotype was classified as S1 and S2. IFN therapy was selected according to the serum HCV-RNA load: IFN-alpha 2b plus ribavirin were given to 63 patients, while the other 84 patients were treated with IFN alone (53 patients received IFN-alpha or -alpha 2b, and 31 patients received consensus IFN). All IFNs were administered daily for 2 weeks, followed by the same dose thrice weekly for a median of 22 weeks (14-94 weeks). Twenty-four weeks after finishing therapy, SVR was defined as negative serum HCV-RNA by a qualitative PCR, and patients with any other outcome were defined as nonresponders. Peripheral blood CD4 positive T cell subsets (Th1 and Th2 cells), NK cells, serum cytokines, and standard liver function tests were measured before starting therapy. RESULTS: An SVR was achieved in 87 patients, while 60 patients were nonresponders. Multiple logistic regression analysis revealed that the serum log 10-transformed HCV-RNA load, serotype, and liver fibrosis were independent factors for SVR. According to univariate logistic regression analysis, serum Log IL-10 and peripheral blood Th1 cells were significant predictors of SVR. CONCLUSION: Our results suggest that an SVR is strongly associated with S2, serum HCV-RNA load, and mild fibrosis, even when therapy is chosen according the serum viral load and serotype. Rec.11/17/2006, Acc.11/27/2006, pp187-193

Recently, an association between hepatitis B virus (HBV) genotype and clinical characteristics has been identified. Of special interest is the recent increase of acute hepatitis B (AHB) genotype A observed in urban areas of Japan. To determine the clinical characteristics associated with AHB genotype A, we compared admission serum levels of alanine aminotransferase, total bilirubin, and HBV markers for patients infected with AHB genotype A (A group) and AHB genotypes B or C (non-A group). Serum level of total bilirubin was significantly higher in the A group than in the non-A group. Serum titers of HBV-DNA and HBe antigen were also significantly higher in the A group, and these may be related to the production of certain types of HBe antigen in genotype A HBV while the other genotypes produce only a single variant of the antigen. Although patients in the non-A group did not develop to chronic hepatitis, 3 of 11 patients in the A group progressed to chronic hepatitis, suggesting that serum HBe antigen promotes immunologic tolerance to persistent viral infection.

Background/Aim: When patients with chronic hepatitis C (CHC) are treated with interferon (IFN)-based therapy, achieving serum HCV-RNA negativity by week 12 (early viral response, EVR) is an important predictor of a sustained virologic response. The aim of this study was to clarify whether changes in IFN-α receptor 2 (IFNAR-2) expression by peripheral blood monocytes (Mo) and the EVR rate differed between patients with genotype 1b and a high viral load showing substitution of amino acid 70 in the core region of HCV (mutant, n = 20) and patients without this substitution (wild, n = 23). Patients and Methods: Forty-three CHC patients were studied, and received pegylated IFN plus ribavirin. IFNAR-2 expression by Mo was determined using flow cytometry to measure the mean fluorescence intensity (MFI) before and up to 28 days after starting therapy. Results: The EVR rate of the mutant group was significantly lower than that of the wild group (35 vs.70%). The MFI of Mo was significantly higher in the wild group than in the mutant group before and also 3, 7, and 28 days after starting therapy. Conclusions: Mutation of HCV was related to lower IFNAR-2 expression by Mo before and after starting therapy.

Tumor necrosis factor (TNF) induces cancer cell-specific apoptosis by binding to a TNF-related apoptosis-inducing ligand. Binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes is also known to induce apoptosis. The aim of this study was to clarify changes of cytokines in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) receiving intra-arterial combination chemotherapy.Twenty-one adult Japanese LC patients with aHCC received intra-arterial combination chemotherapy. The serum levels of TNF-alpha, soluble TNF receptor-I (sTNFr-I), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated.Thirteen of the 21 patients (group R) showed an objective response, while the other eight patients (group N) showed no response. The serum level of TNF-alpha was lower after chemotherapy than before chemotherapy in group N, but there was no difference of serum sTNFr-I levels between before and after chemotherapy and there were also no differences between the two groups. The serum sFas levels were higher after chemotherapy than before chemotherapy in group N, while there was no difference among groups.These results indicate that a high serum TNF-alpha level and a low serum sFas level might be important for successful combined arterial chemotherapy in LC patients with aHCC.

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cells promotes antitumor immunity. However, the immunological features of liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by intra-arterial chemotherapy are still unclear. The aim of this study was to assess the influence of intra-arterial combination chemotherapy on the Th1/Th2 balance in LC patients with aHCC.Twenty-one adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 20 adult Japanese patients with chronic hepatitis C diagnosed from examination of liver biopsy specimens. All control patients were over 55 years old and were stage 1 according to the fibrosis score of Desment.Thirteen of the 21 aHCC patients (group R) showed an objective response, but the other 8 patients (group N) showed no response. There were no significant differences of Th1 cells between group R and group N either before or after chemotherapy. Although there was no significant difference from group R, group N had a significantly higher percentage of Th2 cells than the control group both before and after chemotherapy (p0.05 by Tukey's test).These results indicate that the Th1/Th2 balance might be a useful indicator of the effect of intra-arterial combination chemotherapy in LC patients with aHCC. Inhibition of an increase of Th2 cells might be important for the efficacy of intra-arterial chemotherapy in such patients.

Aim This study was to investigate the immunomodulatory effects of ribavirin combined with interferon (IFN)-alpha 2b (R + IFN) compared with consensus IFN monotherapy (IFN-Con) in chronic hepatitis C (CHC) patients. Patients and methods Thirty-four adult patients with biopsy-proven CHC, who were infected with HCV genotype 2a or 2b, were studied. A 24-week regimen of IFN-alpha 2b (6 MU daily for 2 weeks followed by 6 MU tiw for 22 weeks) and ribavirin (600–800 mg/day for 24 weeks) was given to 17 patients. The other 17 patients were treated with a 24-week regimen of IFN-Con (18 MU daily for 2 weeks followed by 18 MU tiw for 22 weeks). Flow cytometric determination of cytoplasmic IFN-gamma and IL-4 expression in peripheral blood CD4+ T cells was performed, and the percentage of IFN-gamma+ and IL-4− (Th1), IFN-gamma− and IL-4+ (Th2) cells were calculated before and 3, 7, 14, and 28 days after the start of therapy. Results In the R + IFN group, the percentage of Th1 cell peaked on day 3, and then decreased to near baseline by day 14, while the percentage of Th2 cell did not change. In the IFN-Con group, the percentage of Th1 cell peaked on day 14 and the percentage of Th2 cell peaked on day 3, and then decreased to near baseline by day 14. Conclusions Our results suggest that ribavirin induces an early immune response by peripheral blood CD4+ T cells in CHC patients.

To evaluate the time dependence of intra-arterial 5-fluorouracil (5-FU) therapy for advanced hepatocellular carcinoma (aHCC).Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin (CDDP), and leucovorin (LV). The Japan Integrated Staging score (JIS score) of each patient was 3 or more. The patients were divided into two groups, after which the 15 patients in group S were treated with 6-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m2 per 4 h) and the 22 patients in group L were treated with 24-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/ m2 per 22 h). Continuous infusion chemotherapy was performed via the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir.The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S (P0.05).Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.