Development of the treatment strategy for HCV-related diseases using ultra-deep sequencing technology.

• Project/Area Number: 24590965
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: University of Yamanashi
• Principal Investigator: MAEKAWA Shinya 山梨大学, 総合研究部, 講師 (70397298)
• Co-Investigator(Renkei-kenkyūsha): ENOMOTO Nobuyuki 山梨大学, 総合研究部, 教授 (20251530) ; MIURA Mika 山梨大学, 総合研究部, 助教 (00436875) ; KOMATSU Nobutoshi 山梨大学, 総合研究部, 助教 (50568003)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HCV / Ultra-deep sequence / DAA / 耐性変異 / Quasispecies / 系統樹 / Ultra-deep sequencing / ３者併用療法

Outline of Final Research Achievements

It has been hard to predict the treatment response of HCV-infected patients to the most advanced DAA-included therapy. Using ultra-deep sequencing technology coupled with phylogenetic analysis, this study was conducted to disclose the role of viral quasispecies in determining the treatment response to DAA-included anti-HCV therapy. As a result, it was disclosed that viral quasispecies changed dynamically and certain viral isolates were selected with the introduction of DAA-based therapy. The result of the study provides better understanding of the mechanism in the appearance of DAA resistance.

Research Products

• [Journal Article] Deep sequencing and phylogenetic analysis of variants resistant to interferon-based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus. (2015)
  • Author(s): Sato M, Maekawa S, Komatsu N, Tatsumi A, Miura M, Muraoka M, Suzuki Y, Amemiya F, Takano S, Fukasawa M, Nakayama Y, Yamaguchi T, Uetake T, Inoue T, Sato T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N.
  • Journal Title: J Virol Volume: 89(11) Issue: 11 Pages: 6105-16
  • DOI: 10.1128/jvi.03127-14
  • Peer Reviewed / Open Access
• [Journal Article] Naturally occurring, resistance-associated hepatitis C virus NS5A variants are linked to IL28B genotype and are sensitive to interferon-based therapy. (2015)
  • Author(s): Itakura J, Kurosaki M, Takada H, Nakakuki N, Matsuda S, Gondou K, Asano Y, Hattori N, Itakura Y, Tamaki N, Yasui Y, Suzuki S, Hosokawa T, Tsuchiya K, Nakanishi H, Takahashi Y, Maekawa S, Enomoto N, Izumi N.
  • Journal Title: Hepatol Res. Volume: [Epub ahead of print] Issue: 10
  • DOI: 10.1111/hepr.12474
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. (2015)
  • Author(s): Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
  • Journal Title: Hum Genet Volume: 134 Issue: 3 Pages: 279-289
  • DOI: 10.1007/s00439-014-1520-7
  • Peer Reviewed / Open Access
• [Journal Article] Hallmarks of hepatitis C virus in equine hepacivirus. (2015)
  • Author(s): Tanaka T, Kasai H, Yamashita A, Okuyama-Dobashi K, Yasumoto J, Maekawa S, Enomoto N, Okamoto T, Matsuura Y, Morimatsu M, Manabe N, Ochiai K, Yamashita K, Moriishi K.
  • Journal Title: J Virol. Volume: 88(22) Issue: 22 Pages: 13352-66
  • DOI: 10.1128/jvi.02280-14
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocellular carcinoma risk assessment using gadoxetic acid-enhanced hepatocyte phase magnetic resonance imaging. (2015)
  • Author(s): Komatsu N, Motosugi U, Maekawa S, Shindo K, Sakamoto M, Sato M, Tatsumi A, Miura M, Amemiya F, Nakayama Y, Inoue T, Fukasawa M, Uetake T, Ohtaka M, Sato T, Asahina Y, Kurosaki M, Izumi N, Ichikawa T, Araki T, Enomoto N.
  • Journal Title: Hepatol Res Volume: - Issue: 13 Pages: 1339-1346
  • DOI: 10.1111/hepr.12309
  • Peer Reviewed
• [Journal Article] Deep sequencing analysis of variants resistant to the non-structural 5A inhibitor daclatasvir in patients with genotype 1b hepatitis C virus infection. (2014)
  • Author(s): Miura M, Maekawa S, Sato M, Komatsu N, Tatsumi A, Takano S, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Enomoto N.
  • Journal Title: Hepatol Res. Volume: Feb 25 Issue: 14
  • DOI: 10.1111/hepr.12316
  • Peer Reviewed
• [Journal Article] Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C. (2014)
  • Author(s): Maekawa S, Enomoto N
  • Journal Title: J Gastroenterol. Volume: 49(1) Issue: 12 Pages: 163-164
  • DOI: 10.1371/journal.pone.0082299
  • Peer Reviewed
• [Journal Article] Inhibitory effects of caffeic Acid phenethyl ester derivatives on replication of hepatitis C virus. (2013)
  • Author(s): Shen H, Yamashita A, Nakakoshi M, Yokoe H, Sudo M, Kasai H, Tanaka T, Fujimoto Y, Ikeda M, Kato N, Sakamoto N, Shindo H, Maekawa S, Enomoto N, Tsubuki M, Moriishi K.
  • Journal Title: PLoS One. Volume: 17 Issue: 1 Pages: 163-164
  • DOI: 10.1007/s00535-013-0926-7
  • Peer Reviewed
• [Journal Article] Deep-sequencing analysis of the association between the quasispecies nature of the hepatitis C virus core region and disease progression. (2013)
  • Author(s): Miura M, Maekawa S, Takano S, Komatsu N, Tatsumi A, Asakawa Y, Shindo K, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N.
  • Journal Title: J Virol. Volume: 87(23) Issue: 23 Pages: 12541-12551
  • DOI: 10.1128/jvi.00826-13
  • Peer Reviewed
• [Journal Article] IL-28B (IFN-λ3) and IFN-α synergistically inhibit HCV replication. (2013)
  • Author(s): Shindo H
  • Journal Title: J Viral Hepat. Volume: 20 Issue: 4 Pages: 281-289
  • DOI: 10.1111/j.1365-2893.2012.01649.x
  • Peer Reviewed
• [Journal Article] Serum RANTES level influences the response to pegylated interferon and ribavirin therapy in chronic hepatitis C. (2013)
  • Author(s): Komase K, Maekawa S, Miura M, Sueki R, Kadokura M, Shindo H, Shindo K, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Yamashita A, Moriishi K, Enomoto N
  • Journal Title: Hepatol Res. Volume: 43(8) Issue: 8 Pages: 865-875
  • DOI: 10.1111/hepr.12032
  • NAID: 10031194591
  • Peer Reviewed
• [Journal Article] Correlation between pretreatment viral sequences and the emergence of lamivudine resistance in hepatitis B virus infection. (2012)
  • Author(s): Sueki R
  • Journal Title: J Med Virol. Volume: 84(9) Issue: 9 Pages: 1360-1368
  • DOI: 10.1002/jmv.23314
  • Peer Reviewed
• [Journal Article] Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection. (2012)
  • Author(s): Maekawa S
  • Journal Title: Hepatology. Volume: 56(5) Issue: 5 Pages: 1611-1621
  • DOI: 10.1002/hep.25826
  • Peer Reviewed
• [Presentation] Deep Sequencing Analysis Of Variants Resistant To Ns5a Inhibitors In Patients With Genotype 1b Hepatitis C Virus Infection. (2014)
  • Author(s): S. Maekawa, M. Miura, M. Sato, N. Komatsu, Y. Nakayama, T. Inoue, M. Sakamoto, N.
  • Organizer: AASLD Liver Meeting
  • Place of Presentation: ボストン（米国、マサチューセッツ）
  • Year and Date: 2014-11-08 – 2014-11-13
• [Presentation] Deep-sequenceを用いたnaturally-occurring DAA resistant HCVの検討 (2014)
  • Author(s): 前川伸哉、三浦美香、辰巳明久、小松信俊、佐藤光明、鈴木雄一朗、雨宮史武、中山康弘、井上泰輔、坂本穣、榎本信幸
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京都千代田区）
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 次世代sequencerによるtelaprevir耐性変異の解析 (2014)
  • Author(s): 佐藤光明、三浦美香、前川伸哉、小松信俊、辰巳明久、中山康弘、井上泰輔、坂本穣、榎本信幸
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京都千代田区
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 発癌リスクと治療反応性、薬剤耐性変異を考慮した難治性C型肝炎治療 (2014)
  • Author(s): 坂本穣、前川伸哉、榎本信幸
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京都千代田区
  • Year and Date: 2014-05-29 – 2014-05-30
• [Book] HEPATOLOGY PRACTICE C型肝炎の診療を極める (2014)
  • Author(s): 前川伸哉、榎本信幸
  • Publisher: 文光堂
• [Book] 臨床消化器内科 6月増刊号 C型肝炎のすべて (2014)
  • Author(s): 前川伸哉、榎本信幸
  • Publisher: 診断と治療社