今日の臨床サポート

C型肝炎

著者: 竹原徹郎 大阪大学 内科系臨床医学専攻消化器内科学

監修: 金子周一 金沢大学大学院

著者校正済:2021/10/27
現在監修レビュー中
参考ガイドライン:
  1. 日本肝臓学会 肝炎診療ガイドライン作成委員会:C型肝炎治療ガイドライン(第8版)2020年7月
患者向け説明資料

概要・推奨   

  1. C型肝炎に対する治療の基本は抗ウイルス治療によるウイルス排除である(推奨度1)。
  1. 抗ウイルス治療により持続的なウイルス陰性化(SVR)が得られても肝発癌についての定期的な経過観察が必要である(推奨度1)。
  1. ALT値が正常であるか異常であるかは、抗ウイルス治療適応判定の重要な指標ではない(推奨度2)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
竹原徹郎 : 講演料(ギリアド・サイエンシズ株式会社,アッヴィ合同会社,MSD株式会社,あすか製薬株式会社),研究費・助成金など(ギリアド・サイエンシズ株式会社,ヤンセンファーマ株式会社),奨学(奨励)寄付など(アッヴィ,大塚,中外,第一三共,エーザイ,EA,田辺三菱,大日本住友,MSD,武田,アステラス)[2021年]
監修:金子周一 : 研究費・助成金など(バイエル薬品株式会社,株式会社キュービクス,アボットジャパン合同会社,日東電工株式会社,株式会社スギ薬局,株式会社サイトパスファインダー),奨学(奨励)寄付など(小野薬品工業株式会社,エーザイ株式会社,株式会社ツムラ,アッヴィ合同会社,大日本住友製薬株式会社,ゼリア新薬工業株式会社,塩野義製薬株式会社,大塚製薬株式会社,アステラス製薬株式会社,田辺三菱製薬株式会社,マイランEPD合同会社,EAファーマ株式会社,大鵬薬品工業株式会社,中外製薬株式会社,協和キリン株式会社,持田製薬株式会社,日本ケミファ株式会社,LifeScan Japan株式会社)[2021年]

改訂のポイント:
  1. 定期レビューを行い、表の一部修正、語句の変更を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. C型肝炎とは、C型肝炎ウイルス(hepatitis C virus、HCV)によって生じる肝炎である。血液を介して感染する感染症であるが、感染経路の約半数は不明である。1990年までは輸血後約10%の症例で肝炎がみられたが、その後輸血のスクリーニングが導入されて激減した。現在は違法薬物注射の回し打ち、刺青、ピアスなどが原因となっている。家族内感染、性行為感染はまれである。
  1. C型肝炎ウイルス感染により急性肝炎から70%の患者は慢性肝炎に移行、その半数の患者が肝硬変・肝癌へ進展する。
  1. 現在はC型急性肝炎の届け出(5類感染症で届け出義務あり)は年間数十例と少ないが、新規の感染は年間数1.000例存在すると推計されている。HCV持続感染者は1%程度で国内に150万人とされ、低年齢層に少なく高年齢層に多い。
  1. C型肝炎は、感染症法の5類感染症に分類され、診断した医師は、7日以内に最寄りの保健所に届け出る必要がある。
問診・診察のポイント  
問診:
  1. HCV抗体陽性を指摘されて受診した場合、まず輸血歴・手術歴、家族内の肝疾患歴、他人の血液への曝露の可能性(刺青、ピアス、注射器、鍼治療)、過去の肝疾患歴(輸血後肝炎など)を確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: C Conry-Cantilena, M VanRaden, J Gibble, J Melpolder, A O Shakil, L Viladomiu, L Cheung, A DiBisceglie, J Hoofnagle, J W Shih
雑誌名: N Engl J Med. 1996 Jun 27;334(26):1691-6. doi: 10.1056/NEJM199606273342602.
Abstract/Text BACKGROUND: For many people infected with the hepatitis C virus (HCV), the route of exposure, risk of transmission, and severity of associated liver disease are unknown. We studied these variables in people who donated blood voluntarily.
METHODS: Blood donors who tested positive for HCV antibodies on enzyme immunoassay were classified according to whether the results of a confirmatory second-generation recombinant immunoblot assay (RIBA) for HCV were positive, negative, or indeterminate. The evaluations also included an assessment of risk factors, a physical examination, serial determinations of alanine aminotransferase levels and HCV serologic assays, a polymerase-chain-reaction assay for HCV RNA, testing of sexual contacts and family members, and liver biopsies in some participants who were HCV-positive by RIBA.
RESULTS: A total of 481 donors were studied, among whom 248 were positive for HCV by RIBA, 102 had indeterminate results, and 131 were HCV-negative. In a logistic-regression analysis, significant risk factors for HCV infection among the HCV-positive participants were a history of blood transfusion in 66 (27 percent; P < 0.001 for the comparison with RIBA-negative donors), intranasal cocaine use in 169 (68 percent, P < 0.001), intravenous drug use in 103 (42 percent, P = 0.001), sexual promiscuity in 132 (53 percent, P = 0.002), and ear piercing among men (P < 0.05). Nine of 85 sexual partners of HCV-positive donors were anti-HCV-positive; 8 had used intravenous drugs or received transfusions. HCV RNA was found in 213 HCV-positive donors (86 percent), 3 who had indeterminate results by RIBA (2 of these 3 tested positive with a more specific, third-generation RIBA), and none who were HCV-negative. Of the HCV-positive donors, 69 percent had biochemical evidence of chronic liver disease; among 77 donors positive for HCV by RIBA who underwent liver biopsy, 5 had severe chronic hepatitis or cirrhosis, 66 had mild-to-moderate chronic hepatitis, and 6 had no evidence of hepatitis.
CONCLUSIONS: Among volunteer blood donors, prior blood transfusion, intranasal cocaine use, intravenous drug use, sexual promiscuity, and ear piercing in men are risk factors for HCV infection. The high frequency of intravenous drug use was unexpected, because these donors had denied such use when questioned directly at the time of their blood donations.

PMID 8637513  N Engl J Med. 1996 Jun 27;334(26):1691-6. doi: 10.1056/・・・
著者: Pablo Barreiro, Pablo Labarga, José V Fernández-Montero, Eva Poveda, Carmen de Mendoza, Clara Sánchez, Eugenia Vispo, Vincent Soriano
雑誌名: J Clin Virol. 2013 Oct;58(2):391-5. doi: 10.1016/j.jcv.2013.06.031. Epub 2013 Jul 30.
Abstract/Text BACKGROUND: The concentration of circulating viral RNA at baseline and during antiviral therapy predicts response in both HIV infection and chronic hepatitis C.
METHODS: Retrospective review of longitudinal plasma HCV-RNA determinations in untreated chronic hepatitis C patients. As comparison, longitudinal plasma HIV-RNA measurements were performed in untreated HIV individuals.
RESULTS: A total of 3169 HCV-RNA determinations over 43.0±31.6 months were available for 818 chronic hepatitis C patients. For 333 HIV individuals, 1998 HIV-RNA measurements were examined over 27.3±17.5 months. Overall 44% consecutive specimens had >0.5 log variation in HCV-RNA values compared to 23% for HIV-RNA (p<0.001). These rates were 15% and 4%, respectively, for variations >1 log (p<0.001). In multivariate analysis (odds ratio, 95% confidence interval, p), the likelihood of experiencing HCV-RNA variations >0.5 log IU/mL was greater in patients with lower HCV-RNA (0.35 per log[0.26-0.47], 0.001), HIV coinfection (2.57[91.56-4.23], <0.001) and IL28B-CC (1.87[1.28-2.74], 0.001).
CONCLUSIONS: Fluctuation in circulating HCV-RNA may be clinically meaningful in a substantial proportion of chronic hepatitis C patients. It may influence the best time to prescribe antiviral therapy. Moreover, decisions based on early viral kinetics, such as early stopping rules, may require testing of baseline specimens the closest to treatment initiation.

Copyright © 2013 Elsevier B.V. All rights reserved.
PMID 23910933  J Clin Virol. 2013 Oct;58(2):391-5. doi: 10.1016/j.jcv.・・・
著者: L Fanning, E Kenny-Walsh, J Levis, K R Choudhury, B Cannon, M Sheehan, M Whelton, F Shanahan
雑誌名: Hepatology. 2000 Jan;31(1):225-9. doi: 10.1002/hep.510310133.
Abstract/Text The aim of this study was to determine the variation in hepatitis C viral load over an extended period of patient follow up. Serum samples were collected from 49 female individuals who were identified as having been infected from the same source of hepatitis C-contaminated anti-D immunoglobulin during the period from 1977 (May) to 1978 (November). All patients attended the hepatitis C clinic at Cork University Hospital, Cork, Ireland. The study group was homogeneous with respect to gender, hepatitis C virus (HCV) genotype (1b), and duration of infection. None of the patients had received antiviral therapy at the time of completion of study. Viral load quantifications were assessed using the Roche Monitor (F. Hoffmann-La Roche, Ltd., Basel, Switzerland) assay. The mean age of the study group at time of infection was 30.3 years (SD +/- 6.1) with a range from 18.5 to 43 years. The mean time of follow-up was 4. 1 years (SD +/- 1.0) with a range from 1.2 to 5 years. The mean rate of change of viral load per year was 0.23 log(10) viral copies per mL serum for the study group (SD +/- 0.19) with a range of -0.18 to 0.78 that was significantly different from zero, P < 10(-10). The rate of change of viral load per year was negatively correlated with viral load at first determination, r = -.35, P =.01. Age at infection did not correlate with the slope of change of viral load, P =.10. In conclusion, most women infected with HCV 1b will have an increase in viral load over time but a few patients who acquire infection early in adult life will show a decrease in viral load.

PMID 10613750  Hepatology. 2000 Jan;31(1):225-9. doi: 10.1002/hep.5103・・・
著者: Y Arase, K Ikeda, K Chayama, N Murashima, A Tsubota, Y Suzuki, S Saitoh, M Kobayashi, M Kobayashi, F Suzuki, H Kumada
雑誌名: J Gastroenterol. 2000;35(3):221-5.
Abstract/Text The serum level of hepatitis C virus (HCV)-RNA is clinically important as a predictor of the response to interferon (IFN) therapy in patients with chronic hepatitis C. If serum HCV-RNA levels fluctuate during follow-up, and IFN therapy is begun at the time of a low HCV-RNA level, the IFN therapy may be more effective. We evaluated the fluctuation of HCV-RNA serum levels for 2 years in 212 patients with chronic hepatitis C, untreated with IFN who had HCV genotype 1b and an HCV-RNA level of 10 Meq/ml or more at first consultation. The HCV-RNA level was measured monthly for 2 years with an HCV branched DNA probe assay (b DNA probe assay). We classified HCV-RNA patterns into three types by the ratio of maximum HCV-RNA level (a) to minimum HCV-RNA level (b). In pattern 1 (constant type, 151 patients; 71.2%) the a/ b ratio was 1-5. In pattern 2 (slight fluctuation type, 46 patients; 21.7%) the a/b ratio was 5-10. In pattern 3 (severe fluctuation type, 15 patients; 7.1%), the a/b ratio was 10 or more. Next, we evaluated the factors associated with the three patterns. Acute exacerbation of chronic hepatitis was regarded as an increase in serum alanine aminotransferase (ALT) level to more than 250 IU/l. The incidence of acute exacerbation for a 2-year follow-up was 13.9% (21/151) in pattern 1, 19.6% (9/46) in pattern 2, and 53.3% (8/15) in pattern 3. Multivariate analysis showed that acute exacerbation was the most important factor in the manifestation pattern 3. In conclusion, we found that: (1) about 70% of patients had a constant HCV-RNA levels for 2 years. (2) A few patients had severe fluctuation of serum HCV-RNA level after acute exacerbation of chronic hepatitis.

PMID 10755692  J Gastroenterol. 2000;35(3):221-5.
著者: Jacques Fellay, Alexander J Thompson, Dongliang Ge, Curtis E Gumbs, Thomas J Urban, Kevin V Shianna, Latasha D Little, Ping Qiu, Arthur H Bertelsen, Mark Watson, Amelia Warner, Andrew J Muir, Clifford Brass, Janice Albrecht, Mark Sulkowski, John G McHutchison, David B Goldstein
雑誌名: Nature. 2010 Mar 18;464(7287):405-8. doi: 10.1038/nature08825. Epub 2010 Feb 21.
Abstract/Text Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

PMID 20173735  Nature. 2010 Mar 18;464(7287):405-8. doi: 10.1038/natur・・・
著者: Y Murawaki, Y Ikuta, M Koda, H Kawasaki
雑誌名: Hepatology. 1994 Oct;20(4 Pt 1):780-7.
Abstract/Text To assess the clinical value of serum biochemical markers, the aminoterminal peptide of type III procollagen, type IV collagen 7S domain, the central triple-helix of type IV collagen and tissue inhibitor of metalloproteinases, as a marker of hepatic fibrosis, we measured these four serum markers in 132 patients with chronic viral liver disease and compared these serum markers with liver histological findings. Serum levels of these markers increased closely with the progress of liver disease, and the abnormal percentages of type III procollagen peptide, type IV collagen 7S domain, central triple-helix of type IV collagen and tissue inhibitor of metalloproteinases in patients with cirrhosis were 97%, 95%, 83% and 48%, respectively. These four serum markers strongly correlated with the histological degree of periportal with or without bridging hepatocellular necrosis and of liver fibrosis and correlated weakly with the degree of intralobular degeneration and focal necrosis and the degree of portal inflammation. The correlation coefficients of serum type IV collagen 7S domain with periportal with or without bridging hepatocellular necrosis and with liver fibrosis were the highest among these four serum markers, suggesting that serum type IV collagen 7S domain is the most valuable diagnostic marker to assess the degree of liver fibrosis in chronic viral liver disease. When we assessed the ability of each serum marker to detect cirrhosis with a receiver operating curve, the best test was type IV collagen 7S domain, and the second best was type III procollagen peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7927217  Hepatology. 1994 Oct;20(4 Pt 1):780-7.
著者: H Okuda, T Nakanishi, K Takatsu, A Saito, N Hayashi, K Watanabe, N Magario, T Yokoo, T Naraki
雑誌名: Cancer. 1999 Feb 15;85(4):812-8.
Abstract/Text BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a useful tumor marker for hepatocellular carcinoma (HCC). The conventional enzyme immunoassay (EIA) kit for DCP lacks adequate sensitivity to detect small HCC. Thus, a revised EIA kit for DCP has been developed. In this revised DCP kit, the blank value has been reduced, making it now possible to obtain a normal value. The authors used this revised EIA kit for DCP with increased sensitivity and evaluated its usefulness as a tumor marker for HCC.
METHODS: Serum DCP and alpha-fetoprotein (AFP) levels were determined in 60 patients with HCC, 60 with cirrhosis, 57 with chronic hepatitis, and 273 normal subjects. The cutoff value for the revised DCP kit was determined to be 40 mAU/mL, and the values for the conventional DCP kit and AFP were 100 mAU/mL (0.1 AU/mL) and 20 ng/mL, respectively.
RESULTS: The mean DCP value was 17.5 mAU/mL in the normal subjects, and the detection limit was 10 mAU/mL for this revised DCP kit. The positivity rate for DCP in patients with HCC was 60% by the revised DCP kit, in contrast to 40% by the conventional DCP kit. The sensitivity, specificity, and accuracy of the revised kit were 60%, 92.3%, and 81.4%, respectively, whereas those of the conventional kit were 40%, 98.3%, and 78.5%. Thirty-five percent of HCC tumors smaller than 2 cm and 78.1% of those larger than 3 cm were positive for DCP by the revised kit. The corresponding figures were 20% and 56.3% with the conventional kit. Twelve (33.3%) of the 36 HCC patients who were negative for DCP by the conventional kit were positive by the revised kit. When the revised DCP kit was used in combination with AFP, 86.7% of the HCC patients and 78.3% of the patients with solitary HCC were positive for at least 1 of these markers.
CONCLUSIONS: The revised DCP kit is more useful than the conventional DCP kit as a tumor marker for HCC and should be used in combination with AFP.

PMID 10091758  Cancer. 1999 Feb 15;85(4):812-8.
著者: Ryosuke Tateishi, Haruhiko Yoshida, Yutaka Matsuyama, Norio Mine, Yuji Kondo, Masao Omata
雑誌名: Hepatol Int. 2008 Mar;2(1):17-30. doi: 10.1007/s12072-007-9038-x. Epub 2007 Dec 29.
Abstract/Text Background and aims The role of alphafetoprotein (AFP) in the diagnosis and surveillance of hepatocellular carcinoma (HCC) is getting smaller owing to the advances in imaging modalities. The aims of this study were to assess the diagnostic accuracy of tumor markers in small HCC and to find the optimal cutoff value of each tumor marker for efficient surveillance. Methods Studies in all languages were identified by searching MEDLINE from 1982 to 2002. Studies were included when they showed sensitivity and specificity for HCCs 5 cm or smaller and recruited only patients with chronic hepatitis or liver cirrhosis as control. We assessed diagnostic odds ratios (DORs) for the evaluation of diagnostic accuracy of tumor markers and positive likelihood ratios (LRs+) to find the optimal cutoff value. DORs and LRs+ were combined according to the random effect model. The summary receiver operating characteristics (ROC) curve was also assessed. Results Seventeen articles on three tumor markers-AFP, des-gamma-carboxyprothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3)-were enrolled after full-text evaluation. AFP was inferior to DCP and AFP-L3 in both DOR (4.50 vs. 8.16 and 10.50) and area under the ROC curve (0.647 vs. 0.688 and 0.695). Optimal cutoff values that provide the best LR+ were 200 ng/ml for AFP, 40 mAU/ml for DCP, and 15% for AFP-L3. Conclusions Diagnostic accuracy of AFP in small HCC was substantially limited. Surveillance including other tumor markers with optimal cutoff value should be conducted to confirm the efficacy of the policy.

PMID 19669276  Hepatol Int. 2008 Mar;2(1):17-30. doi: 10.1007/s12072-0・・・
著者: K Taketa, C Sekiya, M Namiki, K Akamatsu, Y Ohta, Y Endo, K Kosaka
雑誌名: Gastroenterology. 1990 Aug;99(2):508-18.
Abstract/Text Serum alpha-fetoprotein from 146 patients with hepatocellular carcinoma, other malignancies, and benign liver diseases, was fractionated by lectin-affinity electrophoresis coupled with our sensitive detection method of antibody-affinity blotting. Compared with chronic hepatitis and liver cirrhosis, hepatocellular carcinoma was characterized by the increase in proportions of lentil lectin A-reactive alpha-fetoprotein-L3 and erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein-P4; the yolk sac tumor was characterized by the increase of concanavalin A-nonreactive alpha-fetoprotein-C1, lentil lectin-A-weakly reactive alpha-fetoprotein-L2, erythroagglutinating phytohemagglutinin-strongly reactive alpha-fetoprotein-P5, and Allomyrina dichotoma lectin-nonreactive, slow-migrating alpha-fetoprotein-Als; and gastrointestinal tumors were characterized by alpha-fetoprotein-C1, alpha-fetoprotein-L2, alpha-fetoprotein-L3, alpha-fetoprotein-P5 and Allomyrina dichotoma-nonreactive alpha-fetoprotein-A1. By combined evaluation of alpha-fetoprotein-L3 and alpha-fetoprotein-P4, hepatocellular carcinoma was discriminated from chronic hepatitis and liver cirrhosis with a sensitivity of 97% at a specificity of 99.7%. Because the alpha-fetoprotein level of the studied cases ranged from 60-1,500,000 ng/mL (60-1,500,000 micrograms/L), mostly greater than 200 ng/mL (200 micrograms/L), additional patients with lower levels of alpha-fetoprotein [16-177 ng/mL (16-177 micrograms/L) for 16 cases of hepatocellular carcinoma with liver cirrhosis and 28-185 ng/mL (28-185 micrograms/L) for 17 cases of liver cirrhosis alone] were analyzed for alpha-fetoprotein-L3 and alpha-fetoprotein-P4. The resulting sensitivity for combined evaluation was still as high as 88% at the same high specificity of 99.7%, indicating that the simultaneous analysis of alpha-fetoprotein-L3 and alpha-fetoprotein-P4 is effective in monitoring the evolution of hepatocellular carcinoma in cirrhotic patients.

PMID 1694805  Gastroenterology. 1990 Aug;99(2):508-18.
著者: Norio Hayashi, Tetsuo Takehara
雑誌名: J Gastroenterol. 2006 Jan;41(1):17-27. doi: 10.1007/s00535-005-1740-7.
Abstract/Text Antiviral therapy for chronic hepatitis C has dramatically advanced since the discovery of the hepatitis C virus (HCV) in 1989 and the introduction of interferon (IFN) monotherapy in the early 1990s. The current standard therapy uses a combination of pegylated IFN and ribavirin. The duration of therapy and response to therapy are HCV genotype-specific. Genotype 1 patients require 48 weeks of the combination therapy for 50% successful viral elimination, while genotype 2 patients require 24 weeks of therapy for 80% or 90% viral elimination. Early viral kinetics after the initiation of therapy is a useful predictor of the sustained virologic response (SVR), which is formally determined at 24 weeks after completion of the treatment. For example, an early virologic response, which is determined by a 2-log reduction of HCV RNA or viral elimination at 12 weeks after the initiation of therapy, is a strong negative predictor of SVR in genotype 1 patients. In contrast, a rapid virologic response of HCV RNA-negative at 4 weeks after the initiation of therapy identifies genotype 2 "super-responders," who may require a shorter period of therapy. Adherence to therapy is one of the most important factors for successful viral clearance. Hematopoietic growth factors such as epoetin and granulocyte-colony stimulating factor help reduce therapy-mediated cytopenia and improve patient compliance, thereby leading to better viral clearance. New types of anti-HCV agents such as HCV protease and polymerase inhibitors are needed for those patients that do not respond to combination therapy.

PMID 16501853  J Gastroenterol. 2006 Jan;41(1):17-27. doi: 10.1007/s00・・・
著者: Hiromitsu Kumada, Joji Toyota, Takeshi Okanoue, Kazuaki Chayama, Hirohito Tsubouchi, Norio Hayashi
雑誌名: J Hepatol. 2012 Jan;56(1):78-84. doi: 10.1016/j.jhep.2011.07.016. Epub 2011 Aug 7.
Abstract/Text BACKGROUND & AIMS: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C.
METHODS: In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 63 to PEG-IFN and RBV for 48 weeks (Group B).
RESULTS: HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens-Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0 g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p=0.0020).
CONCLUSIONS: Although the triple therapy with telaprevir-based regimen for 24 weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48 weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required.

Copyright © 2011. Published by Elsevier B.V.
PMID 21827730  J Hepatol. 2012 Jan;56(1):78-84. doi: 10.1016/j.jhep.20・・・
著者: Jason Grebely, Kimberly Page, Rachel Sacks-Davis, Maarten Schim van der Loeff, Thomas M Rice, Julie Bruneau, Meghan D Morris, Behzad Hajarizadeh, Janaki Amin, Andrea L Cox, Arthur Y Kim, Barbara H McGovern, Janke Schinkel, Jacob George, Naglaa H Shoukry, Georg M Lauer, Lisa Maher, Andrew R Lloyd, Margaret Hellard, Gregory J Dore, Maria Prins, InC3 Study Group
雑誌名: Hepatology. 2014 Jan;59(1):109-20. doi: 10.1002/hep.26639. Epub 2013 Nov 22.
Abstract/Text UNLABELLED: Although 20%-40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin-28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non-genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males.
CONCLUSIONS: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control.

© 2013 by the American Association for the Study of Liver Diseases.
PMID 23908124  Hepatology. 2014 Jan;59(1):109-20. doi: 10.1002/hep.266・・・
著者: M Yano, H Kumada, M Kage, K Ikeda, K Shimamatsu, O Inoue, E Hashimoto, J H Lefkowitch, J Ludwig, K Okuda
雑誌名: Hepatology. 1996 Jun;23(6):1334-40. doi: 10.1002/hep.510230607.
Abstract/Text Most patients infected with hepatitis C virus (HCV) develop chronic hepatitis. Unfortunately, the pathological evolution of this disease over time is not completely understood. We studied 70 HCV-positive patients, from whom 2 to 10 liver biopsy specimens (mean, 3.9) had been obtained during an interval of 1 to 26 years (mean, 8.8 years). Each biopsy specimen was evaluated independently by four pathologists who each provided a numerical score for the grade of portal/periportal necroinflammation (0-4), grade of lobular necroinflammation (0-4), their sum (final grade), and the stage of fibrosis (1-4). The scores were correlated with progression of disease, if any, and transition to cirrhosis. During follow-up, 35 patients (50%) developed cirrhosis. Cirrhosis developed in all patients with a high final grade (> or = 5) of necroinflammation on initial biopsy who were followed for 10 years and in 96% of patients with an intermediate final grade (3.5-4.9) who were followed for 17 years. Only 30.4% of patients with low final grade (< or = 3.4) on initial biopsy developed cirrhosis after 13 years. All patients with evidence of septal fibrosis with incomplete nodularity (stage 3.0-3.4) in the initial biopsy progressed to unequivocal cirrhosis by 10 years. The rate of progression to cirrhosis was accelerated in patients whose initial biopsies showed high-grade and -stage lesions. This study demonstrates the importance of grading and staging liver biopsy lesions in chronic hepatitis C, particularly for patients with high-grade necroinflammation, septal fibrosis, and regions of modularity on initial biopsy who are at high risk of developing advanced cirrhosis in the ensuing decade.

PMID 8675148  Hepatology. 1996 Jun;23(6):1334-40. doi: 10.1002/hep.51・・・
著者: H Yoshida, Y Shiratori, M Moriyama, Y Arakawa, T Ide, M Sata, O Inoue, M Yano, M Tanaka, S Fujiyama, S Nishiguchi, T Kuroki, F Imazeki, O Yokosuka, S Kinoyama, G Yamada, M Omata
雑誌名: Ann Intern Med. 1999 Aug 3;131(3):174-81.
Abstract/Text BACKGROUND: Previous studies on the effect of interferon therapy on the incidence of hepatocellular carcinoma have not sufficiently assessed degree of liver fibrosis, a major risk factor for hepatocellular carcinoma.
OBJECTIVE: To evaluate the effect of interferon therapy on incidence of hepatocellular carcinoma, adjusting for risk factors, including the degree of liver fibrosis.
DESIGN: Retrospective cohort study.
SETTING: Seven university hospitals and one regional core hospital in Japan.
PATIENTS: 2890 patients with chronic hepatitis C who had undergone liver biopsy since 1986. Of these patients, 2400 received interferon and 490 were untreated.
MEASUREMENTS: The degree of liver fibrosis was assessed from stage F0 (no fibrosis) to stage F4 (cirrhosis). Response to interferon was determined virologically and biochemically. Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years. Effect of interferon therapy on the risk for hepatocellular carcinoma was analyzed by using Cox proportional hazards regression.
RESULTS: Hepatocellular carcinoma developed in 89 interferon-treated patients and in 59 untreated patients. Among untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with stage F4 fibrosis. The cumulative incidence in treated and untreated patients differed significantly for patients with stage F2 fibrosis (P = 0.0128) and for those with stage F3 fibrosis (P = 0.0011). In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma (adjusted risk ratio, 0.516 [95% CI, 0.358 to 0.742]; P < 0.001), especially among patients with sustained virologic response (risk ratio, 0.197 [CI, 0.099 to 0.392]), among those with persistently normal serum alanine aminotransferase levels (risk ratio, 0.197 [CI, 0.104 to 0.375]), and among those with alanine aminotransferase levels less than two times the upper limit of normal (risk ratio, 0.358 [CI, 0.206 to 0.622]).
CONCLUSIONS: Interferon therapy significantly reducesthe risk for hepatocellular carcinoma, especially among virologic or biochemical responders.

PMID 10428733  Ann Intern Med. 1999 Aug 3;131(3):174-81.
著者: Yasuhiro Asahina, Kaoru Tsuchiya, Nobuharu Tamaki, Itsuko Hirayama, Tomohiro Tanaka, Mitsuaki Sato, Yutaka Yasui, Takanori Hosokawa, Ken Ueda, Teiji Kuzuya, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Masayuki Kurosaki, Nobuyuki Enomoto, Namiki Izumi
雑誌名: Hepatology. 2010 Aug;52(2):518-27. doi: 10.1002/hep.23691.
Abstract/Text UNLABELLED: An increase in the aging population is an impending problem. A large cohort study was carried out to determine the influence of aging and other factors on hepatocarcinogenesis in patients treated with interferon. Biopsy-proven 2547 chronic hepatitis C patients registered at our referral center since 1992 were included. Of these, 2166 were treated with interferon-based therapy. Incidences of hepatocellular carcinoma (HCC) associated with interferon were analyzed by Kaplan-Meier and person-years methods for an average follow-up of 7.5 years. Factors associated with HCC risk were determined by Cox proportional hazard analysis. HCC developed in 177 interferon-treated patients. The risk for HCC depended on age at primary biopsy and increased more than 15-fold after 65 years of age. Even when stratified by stage of fibrosis, the cumulative and annual incidences of HCC were significantly higher in older patients than in younger patients (P < 0.001) at the same stage of fibrosis, except for cirrhosis. Progression of fibrosis over time was significantly accelerated in older patients. The impact of viral eradication on HCC prevention was less significant in older patients than in younger patients. Multivariate analysis confirmed that age, gender, liver fibrosis, liver steatosis, total cholesterol level, fasting blood sugar level, baseline and postinterferon alpha-fetoprotein level, and virological response to interferon were independent risk factors associated with HCC. Aging was the strongest risk factor for a nonvirological response to interferon-based antiviral therapy.
CONCLUSION: Elderly patients are at a higher risk for HCC. Hepatitis C viral eradication had a smaller effect on hepatocarcinogenesis in older patients. Patients should therefore be identified at an earlier age and treatment should be initiated.

PMID 20683951  Hepatology. 2010 Aug;52(2):518-27. doi: 10.1002/hep.236・・・
著者: Naoyuki Enokimura, Katsuya Shiraki, Tomoyuki Kawakita, Yukiko Saitou, Hidekazu Inoue, Hiroshi Okano, Norihiko Yamamoto, Masatoshi Deguchi, Takahisa Sakai, Shigeru Ohmori, Katsuhiko Fujikawa, Kazumoto Murata, Yasuo Niki, Takeshi Nakano
雑誌名: Anticancer Res. 2003 Jan-Feb;23(1B):593-6.
Abstract/Text The incidence of hepatocellular carcinoma (HCC) tends to decrease in sustained responders (SR) to interferon (IFN) therapy for chronic hepatitis C rather than in non-responders (NR). However, some SR develop HCC and their details and prognosis are not well-known, so we investigated such cases. Among 462 patients who underwent IFN therapy and were available for follow-up, 142 patients (30.7%) were SR and six of these (4.2%) developed HCCs. The interval between interferon therapy and diagnosis of HCC was 32-99 months (average 59.2 months). Five of the six cases were single HCCs sized 20-125 mm. The remainder was multiple HCCs. After initial treatment, five patients (83.3%) relapsed and three patients (60%) died due to the HCC. The interval between initial treatment and recurrence was 2-14 months (average 5.8 months). Among the three fatal cases, the interval between initial treatment and their death was 11-66 months (average 29.3 months). Though the prognosis of the one patient who did not relapse after initial treatment was good, the other five patients relapsed and three of them died due to the HCC. These results suggest that the prognosis of sustained responders who develop HCC after IFN therapy is not necessarily good, so close follow-up remains necessary, despite their response to IFN therapy.

PMID 12680152  Anticancer Res. 2003 Jan-Feb;23(1B):593-6.
著者: Yoshiaki Iwasaki, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Yasuyuki Araki, Masaharu Ando, Haruhiko Kobashi, Toshitsugu Kobatake, Ryoji Tanaka, Minoru Tomita, Tomonori Senoh, Mitsuhiko Kawaguchi, Toshinari Shimoe, Koji Manabe, Keiji Kita, Junnosuke Shimamura, Kohsaku Sakaguchi, Yasushi Shiratori
雑誌名: Liver Int. 2004 Dec;24(6):603-10. doi: 10.1111/j.1478-3231.2004.0956.x.
Abstract/Text BACKGROUND: Although a variety of papers demonstrated inhibited hepatocarcinogenesis with interferon (IFN) therapy for chronic hepatitis C, a small number of hepatocellular carcinomas (HCCs) were still observed even in sustained virologic responders.
AIMS: To clarify factors affecting the development of HCC, we analyzed the frequency of HCC in sustained virologic responders over a long-term observation period.
METHODS: Seven hundred and ninety-two out of the 2623 IFN-treated hepatitis C patients who had undergone liver biopsy showed sustained virologic response. Screening for development of HCC was performed periodically during an average follow-up of 5.1 years. Fibrosis of the pretreatment liver biopsy sample was graded. Risk factors for HCC were analyzed by using Cox proportional hazards regression.
RESULTS: Of 792 patients, 23 developed HCC. Univariate analysis showed that stage of hepatic fibrosis, age, and alcohol consumption were significantly associated with a risk of HCC (P<0.001). There was a significant difference in the cumulative incidence between patients stratified according to these variables (P<0.001).
CONCLUSIONS: Pretreatment hepatic fibrosis score, age, and alcohol consumption may affect development of HCC even in sustained virologic responders. Thus, patients with these factors should be carefully followed even after eradication of the virus.

PMID 15566511  Liver Int. 2004 Dec;24(6):603-10. doi: 10.1111/j.1478-3・・・
著者: T Okanoue, Y Itoh, M Minami, S Sakamoto, K Yasui, M Sakamoto, K Nishioji, Y Murakami, K Kashima
雑誌名: J Hepatol. 1999 Apr;30(4):653-9.
Abstract/Text BACKGROUND/AIM: Hepatocellular carcinoma frequently develops during the advanced stages of chronic hepatitis C. We examined whether interferon prevents the development of hepatocellular carcinoma in chronic hepatitis C patients.
METHODS: Japanese patients with chronic hepatitis C (n = 1.148; 117 with portal fibrous expansion (F1), 636 with bridging fibrosis (F2), 355 with bridging fibrosis and architectural distortion (F3)) and 40 cirrhotic (F4) patients were treated with interferon. These patients were followed from 1 to 7 years after interferon therapy. Blood tests and image analysis were serially performed to assess response to interferon and to detect hepatocellular carcinoma. Fifty-five cirrhotic type C patients (control F4) not receiving interferon were enrolled in this study.
RESULTS: Sustained (SR: 27.5%) and transient (TR: 23.0%) responders totaled 50.5%, while 49.5% did not respond to interferon. SR showed an improvement in disease stage reflected by increased platelet counts. Fifty-two patients (9 F2, 36 F3, and 7 F4) developed hepatocellular carcinoma in the follow-up period; 3 SR, 8 TR, and 41 non-responders (NR). The cumulative incidence of hepatocellular carcinoma in F2 was significantly lower (p = 0.019) in SR compared with NR, but not in SR in F3 and F4 patients. However, the cumulative incidence of hepatocellular carcinoma was significantly decreased in all SR (p = 0.0001) and TR (p = 0.0397) compared with all NR.
CONCLUSION: These results indicate that interferon therapy in chronic hepatitis C patients lowered the rate of progression of hepatocellular carcinoma in sensitive cases but not in patients in an advanced stage.

PMID 10207807  J Hepatol. 1999 Apr;30(4):653-9.
著者: M Shindo, K Hamada, Y Oda, T Okuno
雑誌名: Hepatology. 2001 May;33(5):1299-302. doi: 10.1053/jhep.2001.24100.
Abstract/Text A proportion of chronic hepatitis C patients who were treated with interferon have a sustained normalization of transaminase levels after interferon therapy without hepatitis C virus (HCV)-RNA clearance. We determined their clinical characteristics and long-term outcome in relation to progression to liver cirrhosis (LC) and the development of hepatocellular carcinoma (HCC). A total of 250 patients with chronic hepatitis C who were treated with interferon were studied for 8 to 11 years' posttherapy. Sixty-seven patients (27%) were complete responders with clearance of HCV RNA. Twenty-six (10%) were biochemical responders who had sustained normal alanine transaminase (ALT) levels without viral clearance. The remaining patients were short-term responders (n = 70) and nonresponders (n = 87). Biochemical responders were older, had higher levels of pretreatment HCV RNA in serum than complete responders, and had less advanced liver histology than nonresponders. Histologic grading scores decreased significantly at the end of therapy, while the staging scores did not change significantly. The annual incidence of cirrhosis was 0% in biochemical and complete responders, which was significantly lower than nonresponders and the controls (P = .0001). The annual incidence of HCC was 0.37% in complete responders and 0.50% in biochemical responders, which was significantly lower than nonresponders (P = .0001 for both). Our findings suggest that biochemical responders had high pretreatment viral levels with less advanced liver histology, and their long-term outcome appeared to be good irrespective of the persistence of the virus.

PMID 11343259  Hepatology. 2001 May;33(5):1299-302. doi: 10.1053/jhep.・・・
著者: Mitsuhiro Takimoto, Shogo Ohkoshi, Takafumi Ichida, Yasuo Takeda, Minoru Nomoto, Hitoshi Asakura, Akira Naito, Shigeki Mori, Kojiro Hata, Kentaro Igarashi, Hidenori Hara, Hironobu Ohta, Kenji Soga, Toshiaki Watanabe, Tomoteru Kamimura
雑誌名: Dig Dis Sci. 2002 Jan;47(1):170-6.
Abstract/Text A retrospective multicenter analysis of 652 patients with chronic hepatitis C who have been treated with interferon (IFN) was performed to assess the effects of IFN on the clinical course and development of HCC. During a mean follow-up of 54.8 months, hepatocellular carcinoma (HCC) developed in 7.0% of the patients. The rate was significantly higher in the patients who did not respond to IFN treatment than in those with sustained virological response and those who obtained a normalization of alanine aminotransferase levels despite the presence of HCV RNA (incomplete response) (P < 0.01). Using multivariate Cox's proportional hazard model, alcohol abuse (P < 0.05) and a higher level of fibrosis (P < 0.05) before treatment were the significant background factors associated with HCC development in the patients who did not respond to IFN. Interestingly, a significant increase in the rate of HCC development occurred in patients who had a histological finding of progressive fibrosis (F3). In addition, patients with low histological staging scores were likely to have an incomplete response, even if a sustained virological response was not obtained. IFN produced an improvement in histological activity and fibrosis stage in the second biopsy specimens irrespective of the clinical outcome when compared against untreated subjects.

PMID 11837720  Dig Dis Sci. 2002 Jan;47(1):170-6.
著者: H Tanaka, H Tsukuma, A Kasahara, N Hayashi, H Yoshihara, M Masuzawa, T Kanda, T Kashiwagi, A Inoue, M Kato, A Oshima, Y Kinoshita, T Kamada
雑誌名: Int J Cancer. 2000 Sep 1;87(5):741-9.
Abstract/Text The effect of interferon on the long-term clinical outcome of patients with chronic hepatitis C remains unclear. This study included 594 patients with chronic hepatitis C who received interferon-alpha therapy (Interferon group) and 144 patients with chronic hepatitis C who did not receive interferon (Control group). The patients in the Interferon group were classified into the following three groups based on the response of the serum aminotransaminase level of the patient during and after completion of the therapy protocol: sustained responders (n = 175), transient responders (n = 165), and non-responders (n = 254). The age, sex, serum aminotransaminase level, platelet count, histological staging, hepatitis C virus (HCV) subtype, and HCV concentration at baseline were adjusted with the Cox proportional hazards model. The length of follow-up for assessment of the risk for developing hepatocellular carcinoma (HCC) was 57.2 +/- 13.9 months in the Interferon group and 67.7 +/- 28.7 months in the Control group. Multivariate analysis showed that interferon therapy decreased the risk for developing HCC by 48% compared with that in the Control group (P = 0.064). The older the age, being male, having a low platelet count, and higher histological stage were independent factors associated with the development of HCC. The hazard rate ratio for development of HCC in the sustained responders, transient responders, and non-responders was 0.16 (95% confidence interval [CI]: 0.04-0.62), 0.27 (95% CI: 0. 09-0.79), and 0.74 (95% CI: 0.37-1.48), respectively. During follow-up, 18 patients in the Interferon group died (10 from liver-related diseases) and 17 patients in the Control group died (10 from liver-related diseases). No sustained responder or transient responder in the Interferon group died of liver-related disease. The cumulative survival rates of the Interferon and Control groups were nearly identical during the first 5 years following diagnosis. Thereafter, the cumulative survival rate of the Control group declined, resulting in an 8-year survival rate in the Interferon and Control groups of 97% and 81%, respectively (P = 0. 061). Similar trends were seen in the survival analysis of those who had died of liver disease: the 8-year survival rates of the Interferon and Control groups were 98% and 88%, respectively (P = 0. 32). Our study demonstrated that interferon therapy significantly lowered the incidence of HCC among patients with chronic hepatitis C who showed sustained normalization and among patients who showed transient normalization of the serum aminotransferase level after completion of interferon therapy. The survival analyses and determination of cause of death suggested that interferon therapy improves the long-term survival of chronic hepatitis C patients who respond to this therapy, possibly by decreasing mortality from liver-related diseases.

Copyright 2000 Wiley-Liss, Inc.
PMID 10925370  Int J Cancer. 2000 Sep 1;87(5):741-9.
著者: A Kasahara, H Tanaka, T Okanoue, Y Imai, H Tsubouchi, K Yoshioka, S Kawata, E Tanaka, K Hino, K Hayashi, S Tamura, Y Itoh, K Kiyosawa, S Kakumu, K Okita, N Hayashi
雑誌名: J Viral Hepat. 2004 Mar;11(2):148-56.
Abstract/Text Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 +/- 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0-3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7-1.1). Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0-30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3-6.9). The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261-0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005-0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004-0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063-0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.

PMID 14996350  J Viral Hepat. 2004 Mar;11(2):148-56.
著者: A Kasahara, N Hayashi, K Mochizuki, M Takayanagi, K Yoshioka, S Kakumu, A Iijima, A Urushihara, K Kiyosawa, M Okuda, K Hino, K Okita
雑誌名: Hepatology. 1998 May;27(5):1394-402. doi: 10.1002/hep.510270529.
Abstract/Text To elucidate the risk factors for liver carcinogenesis and to examine the incidence of hepatocellular carcinoma (HCC) after interferon therapy, 1,022 chronic hepatitis C patients treated with interferon were followed by ultrasonography for 13 to 97 months (median 36 months). Sustained response with prolonged alanine aminotransferase normalization was found in 313 patients, transient response with alanine aminotransferase relapse after therapy in 304, and no response in 405. Forty-six developed HCC, of whom 5 were sustained responders, 9 were transient responders, and 32 were nonresponders. The cumulative incidence of HCC in transient responders was almost equal to that in sustained responders, and it was significantly higher in nonresponders than in sustained and transient responders (P=.0009). The seventh-year cumulative incidence rates of HCC in sustained responders, transient responders, and nonresponders were estimated to be 4.3%, 4.7%, and 26.1%, respectively. However, there was no significant difference in the cumulative incidence of HCC between patients with HCV subtype 1 and 2 (P=.14). Cox regression analysis showed that the risk of HCC development was not elevated in transient responders compared with sustained responders, but that the risk was 7.90-fold higher in nonresponders than in sustained responders (P=.008). Patients > or =55 years of age had a significantly higher risk ratio (4.65) than did those under 55 years of age (P=.006). The risk of HCC development in men was 4.35 times higher than the risk in women (P=.02). However, the degree of fibrosis was not a significant risk factor for the development of HCC (risk ratio, 3.16; P=.052). These results suggest that patients in the high-risk group of HCC after interferon therapy were those who showed no response, those who were older, and those who were male, and that such patients should be carefully followed using ultrasonography.

PMID 9581697  Hepatology. 1998 May;27(5):1394-402. doi: 10.1002/hep.5・・・
著者: Y Imai, S Kawata, S Tamura, I Yabuuchi, S Noda, M Inada, Y Maeda, Y Shirai, T Fukuzaki, I Kaji, H Ishikawa, Y Matsuda, M Nishikawa, K Seki, Y Matsuzawa
雑誌名: Ann Intern Med. 1998 Jul 15;129(2):94-9.
Abstract/Text BACKGROUND: The effect of interferon therapy on the incidence of hepatocellular carcinoma in chronic hepatitis C is poorly defined.
OBJECTIVE: To compare the incidence of hepatocellular carcinoma in interferon-treated patients with chronic hepatitis C to that of historical controls and to examine whether response to therapy is related to incidence of hepatocellular carcinoma in patients with chronic hepatitis C.
DESIGN: Retrospective cohort study.
SETTING: One university hospital and seven university-affiliated hospitals.
PATIENTS: 419 consecutive patients with chronic hepatitis C who started interferon therapy between January 1992 and December 1993 (interferon group) and 144 patients with chronic hepatitis C who had liver biopsy between January 1986 and December 1989 and did not receive interferon (controls).
INTERVENTION: Patients in the interferon group received human lymphoblastoid interferon, recombinant interferon-alpha2a, or recombinant interferon-alpha2b for 6 months.
MEASUREMENTS: The end point was development of hepatocellular carcinoma on abdominal ultrasonography or computed tomography. Sustained response was defined as persistent normalization of alanine aminotransferase (ALT) levels during interferon therapy and follow-up. Relapse was defined as a normal serum ALT level at the end of treatment with an increase to an abnormal level after cessation of treatment. Nonresponse included all other ALT patterns.
RESULTS: Median follow-up in the interferon and control groups was 47.6 and 46.8 months, respectively. During follow-up, hepatocellular carcinoma was found in 28 interferon-treated patients and 19 controls. Cox proportional hazards regression analysis that included all patients revealed that interferon therapy (P=0.041), older age (P=0.003), greater histologic activity (P=0.029), and higher histologic stage (P=0.049) were independent factors associated with the development of hepatocellular carcinoma. The risk ratios for development of hepatocellular carcinoma in patients with sustained response, relapse, and nonresponse were 0.06 (95% CI, 0.01 to 0.46), 0.51 (CI, 0.20 to 1.27), and 0.95 (CI, 0.48 to 1.84), respectively, compared with controls.
CONCLUSIONS: The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.

PMID 9669992  Ann Intern Med. 1998 Jul 15;129(2):94-9.
著者: K Ikeda, S Saitoh, Y Arase, K Chayama, Y Suzuki, M Kobayashi, A Tsubota, I Nakamura, N Murashima, H Kumada, M Kawanishi
雑誌名: Hepatology. 1999 Apr;29(4):1124-30. doi: 10.1002/hep.510290439.
Abstract/Text The activity of interferon (IFN) is not elucidated from the viewpoint of cancer prevention in chronic hepatitis C patients en masse. The hepatocellular carcinogenesis rate was analyzed statistically in 1,643 patients with chronic hepatitis C: 1,191 patients with IFN therapy and 452 without IFN therapy. Hepatocellular carcinogenesis rates in the treated and untreated groups were 2.1% and 4.8% at the end of the 5th year, and 7.6% and 12.4% at the 10th year, respectively (P =.0036). Multivariate analysis showed that IFN slightly decreased the risk of carcinogenesis by 33%, compared with that of untreated patients (P =. 14), adjusting for the confounding effects of age, fibrotic stage, gender, and gamma-glutamyl transpeptidase (GGTP) value. Among 1,191 patients with IFN, 461 patients attained persistent loss of hepatitis C virus (HCV) RNA, and the other 145 patients retained normal alanine transaminase (ALT) values without loss of HCV RNA. The hazard of carcinogenesis in these 606 patients with persistent normal ALT with or without HCV-RNA clearance was significantly lower than that of untreated patients (hazard ratio: 0.32; P =.012) and that of the abnormal aminotransferase group. Among patients with chronic hepatitis C, IFN significantly decreased the hepatocellular carcinogenesis rate in those patients with normal or persistent low ALT values.

PMID 10094956  Hepatology. 1999 Apr;29(4):1124-30. doi: 10.1002/hep.51・・・
著者: Timothy R Morgan, Marc G Ghany, Hae-Young Kim, Kristin K Snow, Mitchell L Shiffman, Jennifer L De Santo, William M Lee, Adrian M Di Bisceglie, Herbert L Bonkovsky, Jules L Dienstag, Chihiro Morishima, Karen L Lindsay, Anna S F Lok, HALT-C Trial Group
雑誌名: Hepatology. 2010 Sep;52(3):833-44. doi: 10.1002/hep.23744.
Abstract/Text UNLABELLED: Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR.
CONCLUSION: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.

PMID 20564351  Hepatology. 2010 Sep;52(3):833-44. doi: 10.1002/hep.237・・・
著者: Tsugiko Oze, Naoki Hiramatsu, Takayuki Yakushijin, Masanori Miyazaki, Akira Yamada, Masahide Oshita, Hideki Hagiwara, Eiji Mita, Toshifumi Ito, Hiroyuki Fukui, Yoshiaki Inui, Taizo Hijioka, Masami Inada, Kazuhiro Katayama, Shinji Tamura, Harumasa Yoshihara, Atsuo Inoue, Yasuharu Imai, Eijiro Hayashi, Michio Kato, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi, Akinori Kasahara, Toshimitsu Hamasaki, Norio Hayashi, Tetsuo Takehara, Osaka Liver Forum
雑誌名: Clin Gastroenterol Hepatol. 2014 Jul;12(7):1186-95. doi: 10.1016/j.cgh.2013.11.033. Epub 2013 Dec 7.
Abstract/Text BACKGROUND & AIMS: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy.
METHODS: We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings.
RESULTS: HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs.
CONCLUSIONS: In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.

Copyright © 2014. Published by Elsevier Inc.
PMID 24321207  Clin Gastroenterol Hepatol. 2014 Jul;12(7):1186-95. doi・・・
著者: K Ikeda, S Saitoh, M Kobayashi, Y Suzuki, F Suzuki, A Tsubota, Y Arase, N Murashima, K Chayama, H Kumada
雑誌名: J Gastroenterol Hepatol. 2001 Apr;16(4):406-15.
Abstract/Text BACKGROUND AND METHODS: In order to elucidate the influence of a long-term administration of interferon on the appearance rates of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-related cirrhosis, we retrospectively analyzed 694 patients with cirrhosis. A total of 113 patients underwent interferon therapy, including 25 patients with a long-term administration of interferon for 1 year or more, and the other 581 patients received no antiviral drugs.
RESULTS: Crude cumulative appearance rates of HCC in the interferon and the untreated groups were 14.1, and 28.4% at the end of the 5th year, and 36.7 and 52.5% at the end of the 10th year, respectively (P = 0.0028). As there was a waiting time between diagnosis and treatment (median 2.0 months, average 21.3 months) in the treated group, Cox proportional hazard analysis using a time-dependent covariate was introduced to evaluate the anticarcinogenic effect of interferon. Although male sex, higher alpha-fetoprotein, older age, lower albumin concentration, and lower platelet count significantly increased the carcinogenesis rate, interferon was not a significant contributing factor to the carcinogenesis rate as a whole (hazard ratio = 0.83, P= 0.32). When the patients with interferon were divided into two groups according to therapy duration, long-term interferon therapy significantly decreased the hepatocellular carcinogenesis rate after an adjustment by significant covariates (hazard ratio = 0.28, P= 0.0048).
CONCLUSION: When interferon is administered for 12 months or longer, effective cancer prevention will be achieved, even in patients with HCV-related cirrhosis.

PMID 11354279  J Gastroenterol Hepatol. 2001 Apr;16(4):406-15.
著者: Anna S Lok, Leonard B Seeff, Timothy R Morgan, Adrian M di Bisceglie, Richard K Sterling, Teresa M Curto, Gregory T Everson, Karen L Lindsay, William M Lee, Herbert L Bonkovsky, Jules L Dienstag, Marc G Ghany, Chihiro Morishima, Zachary D Goodman, HALT-C Trial Group
雑誌名: Gastroenterology. 2009 Jan;136(1):138-48. doi: 10.1053/j.gastro.2008.09.014. Epub 2008 Sep 18.
Abstract/Text BACKGROUND & AIMS: Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors.
METHODS: Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression.
RESULTS: 1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC.
CONCLUSIONS: We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

PMID 18848939  Gastroenterology. 2009 Jan;136(1):138-48. doi: 10.1053/・・・
著者: Jordi Bruix, Thierry Poynard, Massimo Colombo, Eugene Schiff, Kelly Burak, Elizabeth J L Heathcote, Thomas Berg, Jorge-Luis Poo, Carlos Brandao Mello, Rainer Guenther, Claus Niederau, Ruben Terg, Pierre Bedossa, Navdeep Boparai, Louis H Griffel, Margaret Burroughs, Clifford A Brass, Janice K Albrecht, EPIC3 Study Group
雑誌名: Gastroenterology. 2011 Jun;140(7):1990-9. doi: 10.1053/j.gastro.2011.03.010. Epub 2011 Mar 17.
Abstract/Text BACKGROUND & AIMS: Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program.
METHODS: Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event.
RESULTS: There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations.
CONCLUSIONS: Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID 21419770  Gastroenterology. 2011 Jun;140(7):1990-9. doi: 10.1053/・・・
著者: Anna S Lok, James E Everhart, Elizabeth C Wright, Adrian M Di Bisceglie, Hae-Young Kim, Richard K Sterling, Gregory T Everson, Karen L Lindsay, William M Lee, Herbert L Bonkovsky, Jules L Dienstag, Marc G Ghany, Chihiro Morishima, Timothy R Morgan, HALT-C Trial Group
雑誌名: Gastroenterology. 2011 Mar;140(3):840-9; quiz e12. doi: 10.1053/j.gastro.2010.11.050. Epub 2010 Dec 1.
Abstract/Text BACKGROUND & AIMS: Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period.
METHODS: The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores ≥ 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years.
RESULTS: Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a ≥ 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03).
CONCLUSIONS: Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID 21129375  Gastroenterology. 2011 Mar;140(3):840-9; quiz e12. doi:・・・
著者: Adrian M Di Bisceglie, Anne M Stoddard, Jules L Dienstag, Mitchell L Shiffman, Leonard B Seeff, Herbert L Bonkovsky, Chihiro Morishima, Elizabeth C Wright, Kristin K Snow, William M Lee, Robert J Fontana, Timothy R Morgan, Marc G Ghany, HALT-C Trial Group
雑誌名: Hepatology. 2011 Apr;53(4):1100-8. doi: 10.1002/hep.24169.
Abstract/Text UNLABELLED: Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon.
CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.

2011 American Association for the Study of Liver Diseases.
PMID 21480316  Hepatology. 2011 Apr;53(4):1100-8. doi: 10.1002/hep.241・・・
著者: Eiji Kajiwara, Aritune Ooho, Naoki Yamashita
雑誌名: Hepatol Res. 2012 Mar;42(3):254-63. doi: 10.1111/j.1872-034X.2011.00916.x. Epub 2011 Dec 5.
Abstract/Text Aim:  The purpose of this clinical study was to determine the effect of a biweekly low-dosage peginterferon α-2a treatment program on serum alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels. Methods:  Fifty-five patients participated in the study. The inclusion criteria included chronic genotype 1b hepatitis C virus (HCV) infection, liver cirrhosis, or the absence of cirrhosis in subjects 65 years old or above, and interferon therapy naivety or a lack of sustained response to therapy with interferon-plus-ribavirin or peginterferon-plus-ribavirin. Patients were divided into naïve, relapser, and non-responder groups. The median age of the patients was 70 years, and 73% of patients had cirrhosis. All patients were treated with peginterferon α-2a at 90 µg biweekly. Results:  The rates of normalization (≤30 IU/l) of ALT levels at week 24 in the relapser group and the ≥2 log(10) HCV RNA decline group were high (74% and 68%, respectively). However, the ALT and AFP levels decreased significantly in each group, including the non-responder group. The ALT levels decreased significantly even in patients in whom the HCV RNA levels did not decrease. Furthermore, the AFP levels decreased significantly in the patients showing no decline in the ALT and HCV RNA levels. Only three patients discontinued treatment within 48 weeks due to adverse events, and more than 70% of the patients experienced no subjective symptoms during treatment. Conclusion:  A biweekly low-dosage peginterferon α-2a therapy is effective for reducing the serum levels of ALT and AFP and may reduce hepatocarcinogenesis in patients with liver cirrhosis and in the elderly individuals.

© 2011 The Japan Society of Hepatology.
PMID 22136198  Hepatol Res. 2012 Mar;42(3):254-63. doi: 10.1111/j.1872・・・
著者: Tadashi Ikegami, Yasushi Matsuzaki
雑誌名: Hepatol Res. 2008;38(2):123-31. doi: 10.1111/j.1872-034X.2007.00297.x. Epub 2007 Nov 23.
Abstract/Text Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, gallstone dissolution, and for patients with hepatitis C virus infection to ameliorate elevated alanine aminotransferase levels. The efficacy of UDCA treatment has been debated and the mechanisms of action in humans have still not defined. Suggested mechanisms include the improvement of bile acid transport and/or detoxification, cytoprotection, and anti-apoptotic effects. In this review, we summarize the proposed molecular mechanisms for the action of UDCA, especially in hepatocytes, and also discuss the putative future clinical usage of this unique drug.

PMID 18034825  Hepatol Res. 2008;38(2):123-31. doi: 10.1111/j.1872-034・・・
著者: S Takano, Y Ito, O Yokosuka, M Ohto, K Uchiumi, K Hirota, M Omata
雑誌名: Hepatology. 1994 Sep;20(3):558-64.
Abstract/Text The effect of ursodeoxycholic acid on liver function tests and on bile acid metabolism was investigated in a multi-center randomized controlled dose study for chronic hepatitis C. Twenty, 18 and 19 patients were administered 150, 600 and 900 mg/day, respectively of ursodeoxycholic acid every day for 16 wk. Serum liver parameters and bile acid composition in the treatment groups were compared with 17 control patients. A similarly significant decrease of serum alanine aminotransferase and serum gamma-glutamyltransferase was observed in patients administered 600 and 900 mg of ursodeoxycholic acid. Serum bile acid composition was determined by high-performance liquid chromatography. At entry, the relative proportions of major bile acids were similar to those observed in normal individuals. Maximal concentrations of total ursodeoxycholic acid were 0.30 mumol/L, 5.59 mumol/L, 21.42 mumol/L and 14.73 mumol/L in the control, 150, 600 and 900 mg/day groups, respectively. The fraction of the total ursodeoxycholic acid increased in a dose-dependent manner, and it was significantly higher than in controls (p < 0.001). The hydrophobicity index of bile acids was calculated by the method of Heuman, and its correlation with serum parameter levels was analyzed. In the 600 and 900 mg/day dose groups, serum alanine aminotransferase decreased in the cases in which hydrophobicity index significantly decreased during treatment. The same correlation was observed between the hydrophobicity index and serum gamma = glutamyltransferase in these two groups. There was no correlation between these parameters in the control and 150-mg groups. There was no correlation between reduction rate of serum alanine aminotransferase and initial liver histology.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7521313  Hepatology. 1994 Sep;20(3):558-64.
著者: Masao Omata, Haruhiko Yoshida, Joji Toyota, Eiichi Tomita, Shuhei Nishiguchi, Norio Hayashi, Shiro Iino, Isao Makino, Kiwamu Okita, Gotaro Toda, Kyuichi Tanikawa, Hiromitsu Kumada, Japanese C-Viral Hepatitis Network
雑誌名: Gut. 2007 Dec;56(12):1747-53. doi: 10.1136/gut.2007.120956. Epub 2007 Jun 15.
Abstract/Text BACKGROUND: Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH-C) therapy; however, sustained virological response is achieved in only about half of the patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon non-responders.
METHODS: CH-C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200) or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) were assessed. This study is registered at ClinicalTrial.gov, identifier NCT00200343.
RESULTS: ALT, AST and GGT decreased at week 4 and then remained constant during drug administration. The median changes (150, 600 and 900 mg/day, respectively) were: ALT, -15.3, -29.2 and -36.2%; AST, -13.6, -25.0 and -29.8%; GGT, -22.4, -41.0 and -50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/l. Serum HCV-RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups.
CONCLUSIONS: A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH-C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.

PMID 17573387  Gut. 2007 Dec;56(12):1747-53. doi: 10.1136/gut.2007.120・・・
著者: Kazuo Tarao, Shigetoshi Fujiyama, Shinichi Ohkawa, Kaoru Miyakawa, Setsuo Tamai, Satoru Hirokawa, Takahiro Masaki, Katsuaki Tanaka
雑誌名: Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):164-9.
Abstract/Text In a previous study of patients with hepatitis C virus (HCV)-associated liver cirrhosis (HCV-LC), we showed that increased liver inflammation, as assessed by higher serum alanine aminotransferase (ALT), was associated with increased risk for the development of hepatocellular carcinoma (HCC). This suggested that suppression of inflammation might inhibit HCC development in HCV-LC. Several agents have been suggested to possess chemopreventive potential against the development of HCC in chronic HCV-associated liver disease, including herbal medicines, such as Stronger-Neo-Minophagen C (glycyrrhizin) and Sho-saiko-to (TJ-9). Ursodiol [ursodeoxycholic acid (UDCA)], a bile acid widely used to treat cholestatic liver diseases, also possesses anti-inflammatory properties in liver disease. We hypothesized that suppression of liver inflammation, as assessed by decreases in serum ALT, might inhibit HCC occurrence in patients with HCV-LC. In this study, the preventive effect of UDCA on HCC was examined in patients with early-stage HCV-LC. One hundred two patients with HCV-LC (Child stage A) were treated with anti-inflammatory drugs, Stronger-Neo-Minophagen C,Sho-saiko-to, or UDCA, with the goal of lowering the average serum ALT level to <80 IU. Iftheaverage ALT level did not remain <80 IU after treatment with one agent, multiagent therapy was initiated. The patients were followed up for >5 years and were retrospectively subdivided into two groups: 56 UDCA users (group A) and 46 UDCA nonusers (group B). The mean +/- SD dosage of UDCA administered in group A was 473.7 +/- 183.0 mg/d. The average duration of UDCA administration in group A was 37.3 +/- 15.9 months over the 5-year study period. The cumulative incidence of HCC was recorded. The 5-year incidence of HCC in group A was 17.9% (10 of 56) and was significantly lower than that in group B (39.1%, 18 of 46; P = 0.025). The risk for HCC incidence, calculated by a logistic regression model, showed that the administration of UDCA significantly decreased hepatocarcinogenesis (P = 0.036). The herbal medicines used were comparable in dosage and treatment duration in the UDCA and non-UDCA groups. In conclusion, UDCA might prevent HCC development in HCV-LC. Interestingly, because the serum ALT trends over time were nearly the same in both groups, the chemopreventive effectiveness of UDCA was not accompanied by greater reductions in ALT compared with the UDCA nonusers.

PMID 15668491  Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):164-9.・・・
著者: S Iino, T Tango, T Matsushima, G Toda, K Miyake, K Hino, H Kumada, K Yasuda, T Kuroki, C Hirayama, H Suzuki
雑誌名: Hepatol Res. 2001 Jan 1;19(1):31-40.
Abstract/Text Stronger neo-minophagen C (SNMC), a glycyrrhizin (GL) preparation, has been extensively used with considerable success in Japan for the treatment of chronic hepatitis. The aim of the present study was to elucidate the efficacy of administering massive doses of 100 ml/day to patients in whom standard administration (40 ml/day) for 2 weeks did not show sufficient improvement. A comparative study was conducted by dividing at random 100 cases (56.2%), out of a total of 178 enrolled, into two groups, one for the administration of 100 ml/day for 3 weeks (group A) and the other for administration of 40 ml/day for 3 weeks (group B). Cases were rated 'markedly improved'or 'improved' according to their ALT levels (defined respectively as <1.2 times and 1.2-1.5 times the normal upper level 3 weeks after treatment). Except those who dropped out or were otherwise not eligible for analysis, 44 and 46 cases were analyzed. In group A, 23 of 44 cases (52.3%) were rated 'improved' or better whereas only 12 of 46 (26.1%) in group B were 'improved' or better. Group A showed significant improvement compared to group B (P=0.017), thus documenting the greater efficacy of administering SNMC at 100 ml/day compared to only 40 ml/day.

PMID 11137478  Hepatol Res. 2001 Jan 1;19(1):31-40.
著者: Kazuhiko Miyake, Toshiro Tango, Yasuhiko Ota, Keiji Mitamura, Makoto Yoshiba, Makoto Kako, Shigeki Hayashi, Yusei Ikeda, Norimasa Hayashida, Shogo Iwabuchi, Yuzuru Sato, Toshiaki Tomi, Naoya Funaki, Naoaki Hashimoto, Tomoyuki Umeda, Jun Miyazaki, Katsuaki Tanaka, Yasuo Endo, Hiroshi Suzuki
雑誌名: J Gastroenterol Hepatol. 2002 Nov;17(11):1198-204.
Abstract/Text BACKGROUND: A daily injection of glycyrrhizin (Stronger Neo-Minophagen C (SNMC) containing 40 mg glycyrrhizin in a 20 mL ampoule) lowers alanine aminotransferase (ALT) levels in patients with chronic viral hepatitis.
METHODS: The therapeutic effects of intermittent administration of SNMC three times a week for 12 weeks were evaluated and compared between two doses (40 and 100 mL) in a randomized clinical trial.
RESULTS: Overall, the therapeutic response was better in the 53 patients allocated 100 mL than the 59 who were allocated to have 40 mL SNMC (P = 0.0243). At the completion of SNMC treatment, ALT levels decreased more extensively in the patients on 100 mL than those on 40 mL SNMC (-29 vs-50% in comparison with the baseline value, P = 0.0002). Minor side-effects occurred in both the patients on 100 mL (20%) and those on 40 mL (12%), but they did not require any therapies.
CONCLUSIONS: Intermittent SNMC would be efficient in suppressing ALT levels in patients with chronic viral hepatitis in a dose-dependent manner. Taken along with infrequent and very mild side-effects, long-term intermittent SNMC would benefit patients with chronic hepatitis by maintaining their quality of life with easier compliance.

Copyright 2002 Blackwell Publishing Asia Pty Ltd
PMID 12453280  J Gastroenterol Hepatol. 2002 Nov;17(11):1198-204.
著者: Kenji Ikeda, Yasuji Arase, Masahiro Kobayashi, Satoshi Saitoh, Takashi Someya, Tetsuya Hosaka, Hitomi Sezaki, Norio Akuta, Yoshiyuki Suzuki, Fumitaka Suzuki, Hiromitsu Kumada
雑誌名: Dig Dis Sci. 2006 Mar;51(3):603-9. doi: 10.1007/s10620-006-3177-0.
Abstract/Text To elucidate the influence of a glycyrrhizin therapy on hepatocarcinogenesis rate in interferon (IFN)-resistant hepatitis C, we retrospectively analyzed 1249 patients with chronic hepatitis with or without cirrhosis. Among 346 patients with high alanine transaminase value (twice or more of upper limit of normal), 244 patients received intravenous glycyrrhizin injection and 102 patients did not, after judgment of IFN resistance. Crude carcinogenesis rates in the treated and untreated group were 13.3%, 26.0% at the 5th year, and 21.5% and 35.5% at the 10th year, respectively (P = .0210). Proportional hazard analysis using time-dependent covariates disclosed that glycyrrhizin treatment significantly decreased the hepatocarcinogenesis rate (hazard ratio 0.49, 95% confidence interval 0.27-0.86, P = .014) after adjusting the background features with significant covariates. Glycyrrhizin injection therapy significantly decreased the incidence of hepatocellular carcinoma in patients with IFN-resistant active chronic hepatitis C, whose average aminotransferase value was twice or more of upper limit of normal after interferon.

PMID 16614974  Dig Dis Sci. 2006 Mar;51(3):603-9. doi: 10.1007/s10620-・・・
著者: H Hayashi, T Takikawa, N Nishimura, M Yano, T Isomura, N Sakamoto
雑誌名: Am J Gastroenterol. 1994 Jul;89(7):986-8.
Abstract/Text OBJECTIVES: Iron metabolism may be altered in patients with chronic active hepatitis C. In an attempt to evaluate whether excess iron contributes to liver injury, we used phlebotomy for removal of iron from patients with chronic hepatitis C.
METHODS: All 10 patients had histochemically detectable iron in the liver and underwent an initial period of weekly or monthly phlebotomy of 200 or 400 ml. A serum ferritin level of 10 ng/ml or less was chosen as the endpoint, and maintenance phlebotomy was performed if the level rebounded.
RESULTS: The treatment reduced mean serum alanine aminotransferase activity from 152 +/- 49 to 55 +/- 32 IU/L; this level became normal in five of the 10 patients. Anti-HCV antibodies could be detected in all patients throughout the study. Histologic abnormalities of the liver were unchanged except for disappearance of iron deposits from seven of the patients studied.
CONCLUSIONS: Our findings suggest that iron removal may be beneficial for patients with chronic active hepatitis C and histochemical iron in the liver.

PMID 8017395  Am J Gastroenterol. 1994 Jul;89(7):986-8.
著者: Motoyoshi Yano, Hisao Hayashi, Kentaro Yoshioka, Yutaka Kohgo, Hiroyuki Saito, Yoshiro Niitsu, Junji Kato, Shiro Iino, Hiroshi Yotsuyanagi, Yoshimasa Kobayashi, Kinya Kawamura, Shinichi Kakumu, Masahiko Kaito, Jiro Ikoma, Shinya Wakusawa, Takeshi Okanoue, Yoshio Sumida, Fumiaki Kimura, Eiji Kajiwara, Michio Sata, Kei Ogata
雑誌名: J Gastroenterol. 2004 Jun;39(6):570-4. doi: 10.1007/s00535-003-1344-z.
Abstract/Text BACKGROUND: Increasing evidence indicates that iron cytotoxicity plays an important role in the pathogenesis of chronic hepatitis C (CHC). However, the biochemical effects of iron reduction therapy on CHC remain to be confirmed in a controlled study. This study aimed to test whether iron removal by repeated phlebotomy improves serum alanine aminotransferase (ALT) levels in patients with CHC.
METHODS: Patients were randomly assigned to an iron reduction therapy or control group. The patients in the treatment group received 3-month iron reduction therapy by biweekly phlebotomy, while the patients in the control group were followed up for 3 months with regular blood tests alone.
RESULTS: Thirty-three patients completed the 3-month treatment, while 29 patients received the complete follow-up. The serum ALT levels were reduced from 118 +/- 79 to 73 +/- 39 IU/L in the treatment group, but did not change in the control group (106 +/- 45 versus 107 +/- 48 IU/L). Posttreatment enzyme activity was decreased significantly from the baseline. Furthermore, it was significantly lower than the 3-month control level. Although 5 patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required them to discontinue the treatment.
CONCLUSIONS: This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.

PMID 15235875  J Gastroenterol. 2004 Jun;39(6):570-4. doi: 10.1007/s00・・・
著者: Junji Kato, Koji Miyanishi, Masayoshi Kobune, Tokiko Nakamura, Kohichi Takada, Rishu Takimoto, Yutaka Kawano, Sho Takahashi, Minoru Takahashi, Yasushi Sato, Tetsuji Takayama, Yoshiro Niitsu
雑誌名: J Gastroenterol. 2007 Oct;42(10):830-6. doi: 10.1007/s00535-007-2095-z. Epub 2007 Oct 15.
Abstract/Text BACKGROUND: We have previously demonstrated that in patients with chronic hepatitis C (CHC), iron depletion improves serum alanine aminotransferase (ALT) levels as well as hepatic oxidative DNA damage. However, it has not been determined whether continuation of iron depletion therapy for CHC favorably influences its progression to hepatocellular carcinoma (HCC).
METHODS: We conducted a cohort study on biopsy-proven CHC patients with moderate or severe liver fibrosis who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN is contradicted. Patients were divided into two groups: subjects in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44-144 months (median, 107 months), and they were advised to consume a low-iron diet (5-7 mg iron/day); group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy.
RESULTS: In group A, during the maintenance phase, serum ALT levels decreased to less than 60 IU/l in all patients and normalized (<40 IU/l) in 24 patients (69%), whereas in group B no spontaneous decrease in serum ALT occurred. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively. Multivariate analysis revealed that iron depletion therapy significantly lowered the risk of HCC (odds ratio, 0.57) compared with that of untreated patients (P = 0.0337).
CONCLUSIONS: Long-term iron depletion for CHC patients is a promising modality for lowering the risk of progression to HCC.

PMID 17940836  J Gastroenterol. 2007 Oct;42(10):830-6. doi: 10.1007/s0・・・
著者: H Hagiwara, N Hayashi, E Mita, K Ueda, T Takehara, A Kasahara, H Fusamoto, T Kamada
雑誌名: Hepatology. 1992 Jan;15(1):37-41.
Abstract/Text We tested serial serum samples for hepatitis C virus RNA from patients undergoing treatment for chronic hepatitis C with interferon-alpha using an assay that combined reverse transcription and polymerase chain reaction. The subjects studied were 20 patients with chronic hepatitis who had serum antibody to hepatitis C virus (anti-C100-3). Before therapy, hepatitis C virus RNA was detected in 18 (90%) and 20 (100%) patients using primer sets derived from the NS3 region or the 5'-noncoding region of hepatitis C virus, respectively. Hepatitis C virus RNA became undetectable in all patients whose ALT level fell into the normal range during therapy. However, hepatitis C virus RNA reappeared in all patients whose ALT levels rose again after therapy, usually before the relapse. In patients whose ALT levels did not become normal, hepatitis C virus RNA did not disappear during therapy. Thus therapy with interferon-alpha appears to be beneficial in chronic hepatitis C because of its suppressive effects on hepatitis C virus replication. Detection of hepatitis C virus RNA in serum is useful for evaluating the antiviral effect of interferon.

PMID 1370161  Hepatology. 1992 Jan;15(1):37-41.
著者: Ana-Carolina Cardoso, Rami Moucari, Claudio Figueiredo-Mendes, Marie-Pierre Ripault, Nathalie Giuily, Corinne Castelnau, Nathalie Boyer, Tarik Asselah, Michelle Martinot-Peignoux, Sarah Maylin, Roberto J Carvalho-Filho, Dominique Valla, Pierre Bedossa, Patrick Marcellin
雑誌名: J Hepatol. 2010 May;52(5):652-7. doi: 10.1016/j.jhep.2009.12.028. Epub 2010 Mar 4.
Abstract/Text BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) currently represents the major cause of liver-related death in patients with hepatitis C virus (HCV)-related cirrhosis. We assessed the influence of combination therapy on the risk of HCC, liver-related complications (ascites, variceal bleeding), and liver-related death (or liver transplantation).
METHODS: Three hundred seven chronic hepatitis C patients with bridging fibrosis (n=127) or cirrhosis (n=180) were evaluated by Cox regression analysis. Sustained virological response (SVR) was defined as undetectable serum HCV RNA at 24 weeks after treatment.
RESULTS: SVR developed in 33% of patients. The SVR rates were not different between patients with bridging fibrosis (37%) and those with cirrhosis (30%), p=0.186. During a median follow-up of 3.5 years (range 1-18 years) after the last treatment, the incidence rates per 100 person-years of HCC, liver-related complications, and liver-related death, were 1.24, 0.62, and 0.61 among SVR patients, respectively, and 5.85, 4.16, and 3.76 among non-SVR patients, respectively (log-rank test, p<0.001). According to multivariate analysis, non-SVR was an independent predictor of HCC (HR 3.06; 95% CI=1.12-8.39), liver-related complications (HR 4.73; 95% CI: 1.09-20.57), and liver-related death (HR 3.71; 95% CI=1.05-13.05).
CONCLUSIONS: SVR is achieved in one-third of patients with HCV-related cirrhosis treated with peginterferon and ribavirin. SVR has a strong independent positive influence on the incidence of HCC and on the prognosis of these patients.

Copyright (c) 2010. Published by Elsevier B.V.
PMID 20346533  J Hepatol. 2010 May;52(5):652-7. doi: 10.1016/j.jhep.20・・・
著者: Stefan Zeuzem, Moisés Diago, Edward Gane, K Rajender Reddy, Paul Pockros, Daniele Prati, Mitchell Shiffman, Patrizia Farci, Norman Gitlin, Christopher B O'Brien, François Lamour, Pilar Lardelli, PEGASYS Study NR16071 Investigator Group
雑誌名: Gastroenterology. 2004 Dec;127(6):1724-32.
Abstract/Text BACKGROUND & AIMS: Patients with chronic hepatitis C and persistently normal alanine aminotransferase (ALT) levels have been routinely excluded from large randomized treatment trials; consequently, the efficacy and safety of antiviral therapy in this population are unknown.
METHODS: Patients with at least 3 normal ALT values over an 18-month period were randomized (3:3:1) to treatment with peginterferon alfa-2a 180 mug/wk plus ribavirin 800 mg/day for 24 weeks (212 patients), the same combination for 48 weeks (210 patients), or no treatment (69 patients) in a multinational study. All patients were monitored for 72 weeks. The primary measure of efficacy was sustained virologic response (SVR), defined as undetectable serum hepatitis C virus (HCV) RNA by qualitative polymerase chain reaction at the end of 24 weeks of untreated follow-up.
RESULTS: No patient cleared HCV RNA in the untreated control group. SVR rates of 30% and 52% were obtained in the 24- and 48-week treatment groups, respectively. In patients infected with HCV genotype 1, SVR rates of 13% and 40% were obtained with 24 and 48 weeks of treatment, respectively (P < .0001). In patients infected with genotypes 2 or 3, SVR rates were 72% and 78% with 24 and 48 weeks of treatment, respectively (P = .452). Treatment-related flares in ALT activity were not observed.
CONCLUSIONS: The efficacy and safety of peginterferon alfa-2a and ribavirin combination therapy in patients with chronic hepatitis C and persistently normal ALT levels are similar to that in patients with elevated ALT levels. The indication for treatment of hepatitis C can be evaluated independently from baseline ALT activity.

PMID 15578510  Gastroenterology. 2004 Dec;127(6):1724-32.
著者: Doris B Strader, Teresa Wright, David L Thomas, Leonard B Seeff, American Association for the Study of Liver Diseases
雑誌名: Hepatology. 2004 Apr;39(4):1147-71. doi: 10.1002/hep.20119.
Abstract/Text
PMID 15057920  Hepatology. 2004 Apr;39(4):1147-71. doi: 10.1002/hep.20・・・
著者: Takeshi Okanoue, Yoshito Itoh, Masahito Minami, Hiroaki Hashimoto, Kohichiro Yasui, Hiroshi Yotsuyanagi, Tetsuo Takehara, Takashi Kumada, Eiji Tanaka, Shuhei Nishiguchi, Namiki Izumi, Michio Sata, Morikazu Onji, Gotaro Yamada, Kiwamu Okita, Hiromitsu Kumada
雑誌名: Hepatol Res. 2008 Jan;38(1):27-36. doi: 10.1111/j.1872-034X.2007.00217.x.
Abstract/Text Aim: We aimed to identify the candidates for antiviral therapy, among patients who are hepatitis C virus (HCV) carriers with normal serum aminotransferase (ALT), focused on the inhibition of hepatocellular carcinoma (HCC). Methods: Four hundred and sixty-four HCV carriers with normal serum ALT and 129 HCV carriers with persistently normal ALT (PNALT) and platelet (PLT) counts >/=150 000/muL who received liver biopsies were enrolled. HCV carriers with normal serum ALT were divided into four groups according to their ALT levels (/=150 000/muL or <150 000/muL). Results: In 129 HCV carriers with PNALT, the rate of progression of fibrosis stage was 0.05/year and no HCC was detected during the follow up for 10 years. Approximately 20% of patients with ALT /=150 000/muLwere at stage F2-3; however, approximately 50% of patients with ALT /=31 U/L when we focus on the inhibition of the development of HCC.

PMID 18039201  Hepatol Res. 2008 Jan;38(1):27-36. doi: 10.1111/j.1872-・・・
著者: Takeshi Okanoue, Akiko Makiyama, Mika Nakayama, Yoshio Sumida, Hironori Mitsuyoshi, Tomoki Nakajima, Kohichiroh Yasui, Masahito Minami, Yoshito Itoh
雑誌名: J Hepatol. 2005 Oct;43(4):599-605. doi: 10.1016/j.jhep.2005.04.008.
Abstract/Text BACKGROUND/AIMS: Long-term follow-up study was performed to identify the candidates for antiviral therapy for hepatitis C virus (HCV) infection among carriers with persistently normal aminotransferase (ALT< or = 30 U/L) levels (PNAL).
METHODS: One hundred and twenty-nine HCV carriers with PNAL who underwent liver biopsy and had platelet count over 150,000/microl were entered and 69 were followed for over 5 years. Thirty-five patients underwent serial liver biopsies. Serum ferritin and thioredoxin levels were also determined.
RESULTS: Seventeen patients had normal liver histology, 10 had moderate chronic hepatitis and the remainder 102 had mild hepatitis. Serum ferritin and thioredoxin levels were normal. The mean follow-up period for the 69 patients was 8.5 years. Of these 69 patients, 10 had persistently normal ALT levels (group A), 39 had transient elevation of ALT (group B), and 20 changed to symptomatic chronic hepatitis (group C). The rate of progression of fibrosis for groups A, B, and C were 0.05, 0.04, and 0.08, respectively. Hepatocellular carcinoma was not diagnosed in any of the patients.
CONCLUSIONS: Around 90% of HCV carriers with PNAL have normal to mild liver histology. This long-term follow-up study demonstrated that 30% of such carriers became candidates for antiviral therapy within 5 years.

PMID 16024129  J Hepatol. 2005 Oct;43(4):599-605. doi: 10.1016/j.jhep.・・・
著者: Namiki Izumi, Yasuhiro Asahina, Masayuki Kurosaki, Gotaro Yamada, Tsutomu Kawai, Eiji Kajiwara, Yukishige Okamura, Takayuki Takeuchi, Osamu Yokosuka, Kazuya Kariyama, Joji Toyoda, Mie Inao, Eiji Tanaka, Hisataka Moriwaki, Hiroshi Adachi, Shinji Katsushima, Masatoshi Kudo, Kouichi Takaguchi, Yoichi Hiasa, Kazuaki Chayama, Hiroshi Yatsuhashi, Makoto Oketani, Hiromitsu Kumada
雑誌名: J Gastroenterol. 2013 Mar;48(3):382-90. doi: 10.1007/s00535-012-0641-9. Epub 2012 Aug 9.
Abstract/Text BACKGROUND: We investigated whether the administration of maintenance doses of interferon prevented hepatocellular carcinoma (HCC) in patients with chronic hepatitis C.
METHODS: Study 1: A multicenter, retrospective, cooperative study was carried out to determine whether long-term administration of low-dose peginterferon alpha-2a (PegIFNα-2a) prevented HCC development in patients with chronic hepatitis C. In total, 594 chronic hepatitis C patients without a history of HCC were enrolled and treated with 90 μg PegIFNα-2a administered weekly or bi-weekly for at least 1 year. Study 2: HCC developed in 16 of 99 additional patients without PegIFNα-2a treatment during 3.8 years of observation. A propensity-matched control study was then carried out to compare the incidence of HCC between the 59 patients who received low-dose PegIFNα-2a (PegIFNα-2a group) and 59 patients who did not receive PegIFNα-2a treatment (control group), matched for sex, age, platelet count, and total bilirubin levels.
RESULTS: Study 1: HCC developed in 49 patients. The risk of HCC was lower in patients with undetectable hepatitis C virus RNA, ≤40 IU/L alanine aminotransferase (ALT), or ≤10 ng/L alpha-fetoprotein (AFP) 24 weeks after the start of therapy. Study 2: The incidence of HCC was significantly lower in the PegIFNα-2a group than in the control group.
CONCLUSIONS: Low-dose and long-term maintenance administration of PegIFNα-2a decreased the incidence of HCC in patients with normalized ALT and AFP levels at 24 weeks compared with patients without normal ALT and AFP levels.

PMID 22875473  J Gastroenterol. 2013 Mar;48(3):382-90. doi: 10.1007/s0・・・
著者: Adrian M Di Bisceglie, Mitchell L Shiffman, Gregory T Everson, Karen L Lindsay, James E Everhart, Elizabeth C Wright, William M Lee, Anna S Lok, Herbert L Bonkovsky, Timothy R Morgan, Marc G Ghany, Chihiro Morishima, Kristin K Snow, Jules L Dienstag, HALT-C Trial Investigators
雑誌名: N Engl J Med. 2008 Dec 4;359(23):2429-41. doi: 10.1056/NEJMoa0707615.
Abstract/Text BACKGROUND: In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.
METHODS: We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.
RESULTS: We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).
CONCLUSIONS: Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)

2008 Massachusetts Medical Society
PMID 19052125  N Engl J Med. 2008 Dec 4;359(23):2429-41. doi: 10.1056/・・・
著者: Alejandro Soza, James E Everhart, Marc G Ghany, Edward Doo, Theo Heller, Kittichai Promrat, Yoon Park, T Jake Liang, Jay H Hoofnagle
雑誌名: Hepatology. 2002 Nov;36(5):1273-9. doi: 10.1053/jhep.2002.36502.
Abstract/Text Interferon therapy of hepatitis C causes a decrease in neutrophil counts, and neutropenia is a common reason for dose adjustment or early discontinuation. However, it is unclear whether neutropenia caused by interferon is associated with an increased rate of infection. In this study, we assessed factors associated and clinical consequences of neutropenia before and during interferon therapy of chronic hepatitis C. A total of 119 patients with chronic hepatitis C treated with the combination of interferon alfa and ribavirin were analyzed. In these studies, neutropenia was not used as an exclusion or dose modification criterion. In multivariate analysis, only black race was associated with baseline neutropenia. During treatment, neutrophil counts decreased by an average of 34%. Among 3 blacks with baseline neutropenia without cirrhosis or splenomegaly, there was little or no decrease in neutrophil counts (despite typical decreases in platelet and lymphocyte counts). Documented or suspected bacterial infections developed in 22 patients (18%), but in no patient with neutropenia. United States population estimates suggest that 76,000 blacks with hepatitis C have neutrophil counts below 1,500 cells/microL and might be denied therapy if this exclusion criterion was generally applied. In conclusion, neutropenia is frequent during treatment of hepatitis C with interferon and ribavirin, but it is not usually associated with infection. Constitutional neutropenia, which is common among blacks, should not exclude patients from therapy with interferon as these patients usually have minimal further decreases in neutrophil counts on therapy and are not excessively prone to bacterial infections.

PMID 12395340  Hepatology. 2002 Nov;36(5):1273-9. doi: 10.1053/jhep.20・・・
著者: Charles L Raison, Marina Demetrashvili, Lucile Capuron, Andrew H Miller
雑誌名: CNS Drugs. 2005;19(2):105-23.
Abstract/Text Recombinant preparations of the cytokine interferon (IFN)-alpha are increasingly used to treat a number of medical conditions, including chronic viral hepatitis and several malignancies. Although frequently effective, IFN alpha induces a variety of neuropsychiatric adverse effects, including an acute confusional state that develops rapidly after initiation of high-dose IFN alpha, a depressive syndrome that develops more slowly over weeks to months of treatment, and manic conditions most often characterised by extreme irritability and agitation, but also occasionally by euphoria. Acute IFN alpha-induced confusional states are typically characterised by disorientation, lethargy, somnolence, psychomotor retardation, difficulties with speaking and writing, parkinsonism and psychotic symptoms. Strategies for managing delirium should be employed, including treatment of contributing medical conditions, use of either typical or atypical antipsychotic agents and avoidance of medications likely to worsen mental status. Significant depressive symptoms occur in 21-58% of patients receiving IFN alpha, with symptoms typically manifesting over the first several months of treatment. The most replicated risk factor for developing depression is the presence of mood and anxiety symptoms prior to treatment. Other potential, but less frequently replicated, risk factors include a past history of major depression, being female and increasing IFN alpha dosage and treatment duration. The available data support two approaches to the pharmacological management of IFN alpha-induced depression: antidepressant pretreatment or symptomatic treatment once IFN alpha has been initiated. Pretreatment might be best reserved for patients already receiving antidepressants or for patients who endorse depression or anxiety symptoms of mild or greater severity prior to therapy. Several recent studies demonstrate that antidepressants effectively treat IFN alpha-induced depression once it has developed, allowing the vast majority of subjects to complete treatment successfully. Recent data suggest that IFN alpha-induced depression may be composed of two overlapping syndromes: a depression-specific syndrome characterised by mood, anxiety and cognitive complaints, and a neurovegetative syndrome characterised by fatigue, anorexia, pain and psychomotor slowing. Depression-specific symptoms are highly responsive to serotonergic antidepressants, whereas neurovegetative symptoms are significantly less responsive to these agents. These symptoms may be more effectively treated by agents that modulate catecholaminergic functioning, such as combined serotonin-noradrenaline (norepinephrine) antidepressants, bupropion, psychostimulants or modafinil. Additional factors to consider in selecting an antidepressant include potential drug-drug interactions and adverse effect profile. Finally, IFN alpha appears capable of inducing manic symptoms. Mania, especially when severe, is a clinical emergency. When this occurs, IFN alpha and antidepressants should be stopped, an emergency psychiatric consultation should be obtained, and treatment with a mood stabilizer should be initiated.

PMID 15697325  CNS Drugs. 2005;19(2):105-23.
著者: V Bocci
雑誌名: Cancer Drug Deliv. 1985 Fall;2(4):313-8.
Abstract/Text
PMID 2415233  Cancer Drug Deliv. 1985 Fall;2(4):313-8.
著者: H C Bodenheimer, K L Lindsay, G L Davis, J H Lewis, S N Thung, L B Seeff
雑誌名: Hepatology. 1997 Aug;26(2):473-7. doi: 10.1002/hep.510260231.
Abstract/Text Hepatitis C is a common cause of chronic liver disease that may progress to cirrhosis. We conducted a multicenter double-blind placebo-controlled trial of ribavirin 600 mg given orally twice daily for 36 weeks with follow-up off therapy for an additional 16 weeks. Fifty-nine patients with compensated chronic hepatitis C were entered. Efficacy was measured at the end of therapy and after follow-up by normalization of alanine aminotransferase (ALT), improvement in liver histology, reduction in hepatitis C virus (HCV) RNA level and improvement of symptoms. Among the ribavirin recipients, 12 of 29 (41.4%) had normal ALT values at 36 weeks compared with only 1 of 30 (3.3%) placebo recipients (P < .001). No patient maintained a normal ALT when therapy was stopped. No significant decrease in level of HCV RNA was observed during the study. Histological improvement among subjects who normalized ALT (-1.67 Knodell index) was significantly greater than that in other treated patients (+0.33 Knodell index; P < .05). Fatigue improved in 19.2% of ribavirin-treated subjects and in 8.3% of placebo recipients whereas no worsening of fatigue was reported by ribavirin recipients compared with 16.7% of controls. This difference in fatigue was significant at weeks 36 and 52 (P < .05; .02, respectively). Adverse events were generally comparable between treatment groups except for a reversible hemolytic anemia experienced by ribavirin recipients. Chest pain was noted in four patients on ribavirin. Ribavirin was well tolerated and improved aminotransferase values and reduced fatigue in patients with hepatitis C viral infection while treatment was being administered. Because this action was produced without change in viral level, the mechanism of action of this agent requires further investigation.

PMID 9252161  Hepatology. 1997 Aug;26(2):473-7. doi: 10.1002/hep.5102・・・
著者: G Dusheiko, J Main, H Thomas, O Reichard, C Lee, A Dhillon, S Rassam, A Fryden, H Reesink, M Bassendine, G Norkrans, T Cuypers, N Lelie, P Telfer, J Watson, C Weegink, P Sillikens, O Weiland
雑誌名: J Hepatol. 1996 Nov;25(5):591-8.
Abstract/Text BACKGROUND/AIMS: Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo.
METHODS: A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo.
RESULTS: Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001).
CONCLUSIONS: These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

PMID 8938532  J Hepatol. 1996 Nov;25(5):591-8.
著者: O Reichard, J Andersson, R Schvarcz, O Weiland
雑誌名: Lancet. 1991 May 4;337(8749):1058-61.
Abstract/Text We evaluated oral ribavirin as therapy for chronic hepatitis C infection in a pilot study including 10 patients. Patients (7 men, 3 women; mean age 40 years, range 23-54) all had biopsy-proven chronic non-A, non-B hepatitis and were repeatedly positive for antibodies to hepatitis C virus. Treatment was with oral ribavirin 1000-1200 mg per day in two divided doses for 12 weeks. The median serum alanine aminotransferase concentration for all patients at enrollment was 3.15 mu kat/l (range 1.22-7.79) and decreased significantly (p less than 0.005) to 1.25 mu kat/l (0.78-2.04) after 12 weeks of treatment. Within 6 weeks of the end of treatment the median serum alanine aminotransferase concentration was not significantly different from that before treatment. Side-effects were mild and fully reversible after cessation of therapy. We conclude that ribavirin is the first drug to offer a potentially effective oral treatment for chronic hepatitis C. It should be further evaluated in controlled trials, possibly in combination with interferon alpha.

PMID 1673493  Lancet. 1991 May 4;337(8749):1058-61.
著者: Akira Doi, Ryotaro Sakamori, Yuki Tahata, Ayako Urabe, Naoki Morishita, Ryoko Yamada, Kunimaro Furuta, Takahiro Kodama, Hayato Hikita, Takayuki Yakushijin, Kazuyoshi Ohkawa, Akira Kaneko, Yasuharu Imai, Tomohide Tatsumi, Tetsuo Takehara
雑誌名: Hepatol Res. 2017 Dec;47(13):1438-1444. doi: 10.1111/hepr.12919. Epub 2017 Aug 1.
Abstract/Text AIM: Several case reports have shown that hepatitis B virus (HBV) reactivation developed in hepatitis C patients with a current or previous HBV infection during direct-acting antiviral (DAA) treatment, which led to severe hepatitis or death in some cases. However, its precise frequency and risk factors are not entirely clear. We analyzed a prospective cohort.
METHODS: We analyzed HBV reactivation in 461 consecutive hepatitis C patients who received 12 weeks of ledipasvir/sofosbuvir for genotype 1 or sofosbuvir plus ribavirin for genotype 2 at multiple centers.
RESULTS: By the examination of the preserved sera at baseline, 159 patients (34%) were identified as seropositive for HBV core antibody (anti-HBc) and were included in the subsequent analysis; 4 patients were positive for HBV surface antigen (HBsAg), and the others were negative. Serum HBV DNA was undetectable or was detectable but <20 IU/mL at baseline for all patients. Serial measurement of HBV DNA at 4 weeks and 12 weeks in the preserved serum samples was available in 147 patients and identified HBV reactivation (defined as the appearance of serum HBV DNA ≥20 IU/mL) in 2 HBsAg-positive and 3 HBsAg-negative patients. No patient developed HBV-associated hepatitis. Patients who developed HBV reactivation had significantly lower anti-HBs titers and higher serum alanine transferase levels before treatment.
CONCLUSION: Hepatitis B virus reactivation during direct-acting antiviral therapies occurs in 3.4% (5/147) of patients who are positive for anti-HBc. A low titer of anti-HBs and a high serum alanine transferase level prior to treatment are associated with reactivation in this patient group.

© 2017 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society of Hepatology.
PMID 28585404  Hepatol Res. 2017 Dec;47(13):1438-1444. doi: 10.1111/he・・・
著者: Masao Omata, Shuhei Nishiguchi, Yoshiyuki Ueno, Hitoshi Mochizuki, Namiki Izumi, Fusao Ikeda, Hidenori Toyoda, Osamu Yokosuka, Kazushige Nirei, Takuya Genda, Takeji Umemura, Tetsuo Takehara, Naoya Sakamoto, Yoichi Nishigaki, Kunio Nakane, Nobuo Toda, Tatsuya Ide, Mikio Yanase, Keisuke Hino, Bing Gao, Kimberly L Garrison, Hadas Dvory-Sobol, Akinobu Ishizaki, Masa Omote, Diana Brainard, Steven Knox, William T Symonds, John G McHutchison, Hiroshi Yatsuhashi, Masashi Mizokami
雑誌名: J Viral Hepat. 2014 Nov;21(11):762-8. doi: 10.1111/jvh.12312. Epub 2014 Sep 8.
Abstract/Text Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.

© 2014 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.
PMID 25196837  J Viral Hepat. 2014 Nov;21(11):762-8. doi: 10.1111/jvh.・・・
著者: Helen Payne, Nonhlanhla Mkhize, Kennedy Otwombe, Joanna Lewis, Ravindre Panchia, Robin Callard, Lynn Morris, Abdel Babiker, Avy Violari, Mark F Cotton, Nigel J Klein, Diana M Gibb
雑誌名: Lancet Infect Dis. 2015 Jul;15(7):803-9. doi: 10.1016/S1473-3099(15)00087-0. Epub 2015 Jun 1.
Abstract/Text BACKGROUND: Early antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART.
METHODS: We compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5·7-12·0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen-antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960.
FINDINGS: The median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90·6-93·4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0·0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0·0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 μg/μL [IQR 133-13 129]) than in the ART-Def group (6870 μg/μL [1706-53 645]; p<0·0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13·7 times (95% CI 3·1-60·2; p=0·001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG concentrations (coefficient 0·54; p<0·0001) and increased odds of seropositivity (odds ratio 1·59 [95% CI 1·1-2·3]) adjusted for ART initiation age.
INTERPRETATION: About half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests.
FUNDING: Wellcome Trust, Medical Research Council, and National Institutes of Health.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26043884  Lancet Infect Dis. 2015 Jul;15(7):803-9. doi: 10.1016/S・・・
著者: Nezam Afdhal, Stefan Zeuzem, Paul Kwo, Mario Chojkier, Norman Gitlin, Massimo Puoti, Manuel Romero-Gomez, Jean-Pierre Zarski, Kosh Agarwal, Peter Buggisch, Graham R Foster, Norbert Bräu, Maria Buti, Ira M Jacobson, G Mani Subramanian, Xiao Ding, Hongmei Mo, Jenny C Yang, Phillip S Pang, William T Symonds, John G McHutchison, Andrew J Muir, Alessandra Mangia, Patrick Marcellin, ION-1 Investigators
雑誌名: N Engl J Med. 2014 May 15;370(20):1889-98. doi: 10.1056/NEJMoa1402454. Epub 2014 Apr 11.
Abstract/Text BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection.
METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea.
CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

PMID 24725239  N Engl J Med. 2014 May 15;370(20):1889-98. doi: 10.1056・・・
著者: Hiromitsu Kumada, Yoshiyuki Suzuki, Yoshiyasu Karino, Kazuaki Chayama, Norifumi Kawada, Takeshi Okanoue, Yoshito Itoh, Satoshi Mochida, Hidenori Toyoda, Hitoshi Yoshiji, Shintaro Takaki, Naoyoshi Yatsuzuka, Etsuo Yodoya, Takashi Iwasa, Go Fujimoto, Michael N Robertson, Stuart Black, Luzelena Caro, Janice Wahl
雑誌名: J Gastroenterol. 2017 Apr;52(4):520-533. doi: 10.1007/s00535-016-1285-y. Epub 2016 Nov 21.
Abstract/Text BACKGROUND: Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis.
METHODS: The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment.
RESULTS: In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment.
CONCLUSION: Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. CLINICALTRIALS.
GOV IDENTIFIER: NCT02203149.

PMID 27873094  J Gastroenterol. 2017 Apr;52(4):520-533. doi: 10.1007/s・・・
著者: Alma Halilbasić, Enisa Mesic, Elmir Cikusić, Aida Arnautović
雑誌名: Med Arh. 2006;60(6 Suppl 2):78-83.
Abstract/Text INTRODUCTION: NHL are the group of lymphoproliferative neoplasms which incidence is in constant increase. The aim of the paper is the analysis of the immunophenotypes, clinical distribution and ways of primary presentation and biological aggressiveness of NHL in the North-East Bosnia. It especially illustrates the post war period from 1998 to 2002.
METHODS: Two hundred and twenty-eight patients with pathohistologically proved NHL are analysed in the paper. The tested group consisted of 142 patients with diagnosed NHL in the period between 1998 and 2002, and the control group consisted of 86 patients whose NHL was proved in the period between 1987 and 1991. These factors were analysed: immunophenotype NHL by immunohistochemical method of indirect three-stage immunoperoxidase with streptovidin, the type of NHL, the degree of biological aggressiveness of NHL, the way of primary presentation and the clinical phases of distribution of the disease according to the age, sex, profession and the habitat (urban or rural) of the patients. The prevalence and the incidence of the disease in the region of the North-East Bosnia was determined. The statistical analyses of the date was performed by the average values, standard deviations and chi2 test.
RESULTS: The total number of patients with NHL in the North-East Bosnia was quite bigger in the test group than in the control group with the incidence of 2.6/100,000 inhabitants in 1989, and 6.91/100,000 inhabitants in 2002. There were 80 men (56%) and 62 women (44%) in the test group, and 55 men (64%) and 31 women (36%) in the control group. The average age of the patients was 55.78 +/- -15.1 years. Statistically significant decrease of patients was noticed in the groups of industrial and agricultural workers in the test group comparing with the control group (9% against 15% and 4% against 19%, p < 0.005). At the same time the significant increase of the number of patients was found in the test group from the industrial regions of Lukavac (15 against 4 patients, p < 0.005), Tuzla (49 against 19 patients, p < 0.005) and Zivinice (14 against 3 patients, p < 0.005). Diffuse Large Cell Lymphoma (DLCL) was dominant in the test group with total of 73 patients (51%), and Small Cell Lymphoma was dominant in the control group with total of 33 patients (38%). Statistically significant increase of both DLCL and MALT lymphoma is found in the test group (p < 0.025), and the most frequent were patients with IV-B (18%), I-AE (15%) and II-BE (12%) clinical stadium, while in the control group the most frequent number of patients was in the clinical studia III-B (19%), II-B (14%) and IV-B (14%). The most prevalent stadium in both groups was B fenotype with 94% of cases in the test and 93% in the control group. The aggressive lymphomas are predominant in the test group (62%) while the indolent ones are predominant in the control group (64%). In both groups the most of the patients were with nodal primary presentation (51%). In the test group there was a significant increase of aggressive lymphoma in both men and women (p < 0.01).
DISCUSSION: In recent years, all NHL studies have shown an increase of the incidence in patients, especially in older age while the increase is not found only in infants. In our study the highest percentage of the incidence of NHL occurs in patients who are 55 and older that exactly matches the literature date. There is an increase of extranodal primary presentation (28%) in test group in comparison with the control group (18%). The distribution of the patients is not significantly different from the findings of the European Oncology Association from 2003 where it says that there are 54% of patients with primary nodal presentation, 34% of them with primary extranodal presentation and 12% combination of the two presentations. Recently, the most frequent presentation worldwide is in stomach, which is also proven in our research. In the test group the number of MALT and DLCL lymphoma located in stomach is in increase. In the last few years the dominant type of NHL worldwide is DLCL. Therefore the significant increase of the patients with this disease is noticed in our test group. The continuous increase of patients with aggressive NHL in the recent years has been noticed especially Lukavac, Tuzla and Zivinice. These are the regions where the electric plant and the chemical industry factories are located.
CONCLUSION: The incidence of NHL in the region of the North East Bosnia follows the world trend of the general increase of the NHL incidence including the significant increase in number of aggressive lymphoma. The frequency of DLCL and MALT lymphoma is evidently in increase. The significant changes in primary presentation of the disease have not been noticed. B phenotype of NHL is predominant in both periods of testing.

PMID 18172989  Med Arh. 2006;60(6 Suppl 2):78-83.
著者: Y Arase, K Ikeda, N Murashima, K Chayama, A Tsubota, I Koida, Y Suzuki, S Saitoh, M Kobayashi, H Kumada
雑誌名: Cancer. 1997 Apr 15;79(8):1494-500.
Abstract/Text BACKGROUND: Hepatocellular carcinoma (HCC) occurs in patients with hepatitis C virus-RNA positive chronic liver disease. It is important to prevent HCC with drug administration.
METHODS: A retrospective study was undertaken to evaluate the long term preventive effect of Stronger Neo-Minophagen C (SNMC) on HCC development. SNMC is a Japanese medicine that is commonly administered to patients with chronic hepatitis C to improve the serum alanine aminotransferase (ALT) level. Of 453 patients diagnosed with chronic hepatitis C retrospectively in the study hospital between January 1979 and April 1984, 84 patients (Group A) had been treated with SNMC; SNMC was given at a dose of 100 mL daily for 8 weeks, then 2-7 times a week for 2-16 years (median, 10.1 years). Another group of 109 patients (Group B) could not be treated with SNMC or interferon for a long period of time (median, 9.2 years) and were given other herbal medicine (such as vitamin K). The patients were retrospectively monitored, and the cumulative incidence of HCC and risk factors for HCC were examined.
RESULTS: The 10th-year rates of cumulative HCC incidence for Groups A and B were 7% and 12%, respectively, and the 15th-year rates were 12% and 25%. By Cox regression analysis, the relative risk of HCC incidence in patients not treated with SNMC (Group B) was 2.49 compared with that of patients treated with SNMC (Group A).
CONCLUSIONS: In this study, long term administration of SNMC in the treatment of chronic hepatitis C was effective in preventing liver carcinogenesis.

PMID 9118029  Cancer. 1997 Apr 15;79(8):1494-500.
著者: Y Benhamou, M Bochet, V Di Martino, F Charlotte, F Azria, A Coutellier, M Vidaud, F Bricaire, P Opolon, C Katlama, T Poynard
雑誌名: Hepatology. 1999 Oct;30(4):1054-8. doi: 10.1002/hep.510300409.
Abstract/Text The natural history of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients has never been studied according to the concept of liver fibrosis progression. The aim of this work was to assess the fibrosis progression rate in HIV-HCV coinfected patients and in patients infected by HCV only. A cohort of 122 HIV-HCV coinfected patients was compared with a control group of 122 HIV-negative HCV-infected patients. Groups were matched according to age, sex, daily alcohol consumption, age at HCV infection, and duration and route of HCV infection. The fibrosis progression rate was defined as the ratio between fibrosis stage (METAVIR scoring system) and the HCV duration. The prevalence of extensive liver fibrosis (METAVIR fibrosis scores 2, 3, and 4) and moderate or severe activity were higher in HIV-infected patients (60% and 54%, respectively) than in control patients (47% and 30%, respectively; P <.05 and P <.001, respectively). The median fibrosis progression rate in coinfected patients and in control patients was 0.153 (95% confidence interval [CI], 0.117-0.181) and 0.106 (95% CI, 0.084-0.125) fibrosis units per year, respectively (P <.0001). HIV seropositivity (P <.0001), alcohol consumption (>50 g/d, P =.0002), age at HCV infection (<25 years old, P <.0001), and severe immunosuppression (CD4 count 50 g/d), CD4 count (
PMID 10498659  Hepatology. 1999 Oct;30(4):1054-8. doi: 10.1002/hep.510・・・
著者: Kerry Townsend, Tess Petersen, Lori A Gordon, Anita Kohli, Amy Nelson, Cassie Seamon, Chloe Gross, Lydia Tang, Anu Osinusi, Michael A Polis, Henry Masur, Shyam Kottilil
雑誌名: AIDS. 2016 Jan;30(2):261-6. doi: 10.1097/QAD.0000000000000903.
Abstract/Text OBJECTIVE: As the treatment of hepatitis C virus (HCV) infection has evolved to directly acting antiviral agents, the impact of these directly acting antiviral-only regimens on improving adherence to HCV treatment in HIV/HCV coinfected populations has not been evaluated. The study compared adherence to ledipasvir/sofosbuvir (LDV/SOF) in HCV monoinfected and HIV/HCV coinfected individuals.
DESIGN: Adherence was measured from participants in two phase 2 open-label studies (NCT01805882 and NCT01878799).
METHODS: HCV treatment-naive, genotype 1 study individuals [HCV monoinfected participants (N = 20) and HIV/HCV coinfected participants, antiretroviral untreated (N = 13) or on combination antiretroviral therapy (N = 37)] were treated with LDV (90 mg) and SOF (400 mg) administered as one tablet once daily for 12 weeks. Adherence was measured using three tools: medication event monitoring system cap, pill count, and patient report.
RESULTS: Participants were predominately African American (83%) and male (73%), with a median age of 59 years. Participants had prompt HCV viral load decline and high adherence rates (97 ± 0.5% by medication event monitoring system). Participant adherence decreased significantly from early (baseline week 4) as compared with late (weeks 8-12) in therapy in all three groups - HCV monoinfected (P = 0.01), HIV/HCV antiretroviral untreated (P = 0.02), and HIV/HCV antiretroviral treated participants (P = 0.01).
CONCLUSION: Adherence to LDV/SOF in this urban population was high and comparable between HCV monoinfected and HIV/HCV coinfected participants regardless of antiretroviral use.

PMID 26691547  AIDS. 2016 Jan;30(2):261-6. doi: 10.1097/QAD.0000000000・・・
著者: Mark S Sulkowski, Susanna Naggie, Jacob Lalezari, Walford Jeffrey Fessel, Karam Mounzer, Margaret Shuhart, Anne F Luetkemeyer, David Asmuth, Anuj Gaggar, Liyun Ni, Evguenia Svarovskaia, Diana M Brainard, William T Symonds, G Mani Subramanian, John G McHutchison, Maribel Rodriguez-Torres, Douglas Dieterich, PHOTON-1 Investigators
雑誌名: JAMA. 2014 Jul 23-30;312(4):353-61. doi: 10.1001/jama.2014.7734.
Abstract/Text IMPORTANCE: Treatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon.
OBJECTIVE: To determine the rates of HCV eradication (sustained virologic response [SVR]) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment.
DESIGN, SETTING, AND PARTICIPANTS: Open-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants.
INTERVENTIONS: Treatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks.
MAIN OUTCOMES AND MEASURES: The primary study outcome was the proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks (SVR12) after cessation of HCV therapy.
RESULTS: Among treatment-naive participants, 87 patients (76%) of 114 (95% CI, 67%-84%) with genotype 1, 23 patients (88%) of 26 with genotype 2 (95% CI, 70%-985), and 28 patients (67%) of 42 with genotype 3 (95% CI, 51%-80%) achieved SVR12. Among treatment-experienced participants, 22 patients (92%) of 24 with genotype 2 (95% CI, 73%-99%) and 16 patients (94%) of 17 (95% CI, 71%-100%) achieved SVR12. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed.
CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12. Further studies of this oral regimen in diverse populations of coinfected patients are warranted.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01667731.

PMID 25038354  JAMA. 2014 Jul 23-30;312(4):353-61. doi: 10.1001/jama.2・・・

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