Analysis of HCV drug resistance associated variants treated with direct-acting antiviral (DAA) failure and genetic factors predict of HCC development after SVR.

• Project/Area Number: 17K15960
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Nagoya City University
• Principal Investigator: IIO ETSUKO 名古屋市立大学, 医薬学総合研究院(医学), 助教 (20543797)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: HCV / DAA / SVR後発癌 / TLL1 / SVR後肝発癌 / NS5B / ウイルス / 臨床

Outline of Final Research Achievements

The eradication of HCV by IFN-free DAAs treatment is effective at reducing the risk of HCC. However, there is still a risk of HCC after eradicating HCV. We envestigated the host genetic risk factors of SVR-HCC. More than 1100 patients achieved SVR with IFN free DAAs treatment were enrolled. The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group . Higher levels of a-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC. Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA. Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA. The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. We reported these results with J Gastroenterol. 2019 Apr;54(4):339-346.

Academic Significance and Societal Importance of the Research Achievements

HCVはIFNフリーDAA治療の進歩により、ごく一部の難治症例を除き、ほぼ全例ウイルス排除（SVR）ができる時代になり、SVR後の肝発癌高リスク群の囲い込みが重要になっている。IFN治療時代から言われていた肝硬変、高齢といった因子だけでなく、ヒトの遺伝子要因としてTLL1遺伝子多型が関与することを明らかにした。AFPやFIb4といった従来の発癌リスク因子に加えて、遺伝的要因を加味することで、多数のSVR症例の中から、発癌高リスク群の囲い込みに寄与すると思われる。今後の日常臨床において、SVR後フォローに関する重要な知見が得られたと思われる。

Research Products

• [Journal Article] TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy. (2019)
  • Author(s): Iio E, Matsuura K (co-first author), Shimada N, Atsukawa M, Itokawa N, Abe H, Kato K, Takaguchi K, Senoh T, Eguchi Y, Nomura H, Yoshizawa K, Kang JH, Matsui T, Hirashima N, Kusakabe A, Miyaki T, Fujiwara K, Matsunami K, Tsutsumi S, Iwakiri K, Tanaka Y.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 4 Pages: 339-346
  • DOI: 10.1007/s00535-018-1526-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Direct-acting antivirals in East Asian hepatitis C patients: real-world experience from the REAL-C Consortium. (2019)
  • Author(s): Huang CF, Iio E, Nguyen MH; et al.
  • Journal Title: Hepatol Int. 2019 Sep;13(5):587-598 Volume: 13 Issue: 5 Pages: 587-598
  • DOI: 10.1007/s12072-019-09974-z
  • Peer Reviewed / Int'l Joint Research
• [Presentation] C型慢性肝疾患におけるDAA治療後初発肝発癌のリスク因子検討 (2019)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] C型慢性肝疾患IFNフリーDAA治療不成功例における薬剤耐性変異からみた再治療の検討 (2019)
  • Author(s): 飯尾悦子、島田紀朋、田中靖人
  • Organizer: 第5５回日本肝臓学会総会
• [Presentation] Predictors of hepatocellular carcinoma development after eradication of hepatitis C virus based on TLL1 variant, AFP and Fib 4 index (2019)
  • Author(s): Etsuko Iio, Kentaro Matsuura, Noritomo Shimada, Masanori Atsukawa, Koichi Takaguchi, Yuichiro Eguchi, Hideyuki Nomura, Noboru Hirashima, Atsunori Kusakabe, Tomokatsu Miyaki, Kei Fujiwara, and Yasuhito Tanaka
  • Organizer: AASLD2019
  • Int'l Joint Research
• [Presentation] C型慢性肝疾患におけるDAA治療後予後因子の検討 (2019)
  • Author(s): 飯尾悦子、島田紀朋、田中靖人
  • Organizer: 第43回日本肝臓学会西部会
• [Presentation] C型慢性肝疾患におけるDAA治療後肝発癌のリスク因子検討 (2018)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] C型慢性肝疾患におけるDAA再治療、治療後発癌および肝線維化の検討 (2018)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] C型慢性肝疾患におけるDAA治療後肝発癌及び線維化改善とTLL1遺伝子多型の関連性 (2018)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: JDDW2018
• [Presentation] Association of TLL1 variant with development of hepatocellular carcinoma and fibrosis after eradication of hepatitis C virus (2018)
  • Author(s): Etsuko Iio, Kentaro Matsuura, Noritomo Shimada, Masanori Atsukawa, Koichi Takaguchi, Yuichiro Eguchi, Hideyuki Nomura, Noboru Hirashima, Atsunori Kusakabe, Tomokatsu Miyaki, Shunsuke Nojiri, Kayoko Matsunami, Kei Fujiwara, and Yasuhito Tanaka
  • Organizer: AASLD2018
  • Int'l Joint Research
• [Presentation] C型慢性肝疾患に対するIFN-free治療非著効例の宿主因子、薬剤耐性変異の検討 (2017)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: JDDW2017
• [Presentation] Investigating the association of TLL1 variant with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free regimens (2017)
  • Author(s): Etsuko Iio, Noritomo Shimada, Yasuhito Tanaka
  • Organizer: AASLD2017
• [Presentation] C型慢性肝疾患に対するIFNフリー治療成績及び治療後発癌に寄与する宿主因子の同定 (2017)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第42回日本肝臓学会西部会
• [Presentation] C型慢性肝疾患に対するSofosbuvir/Ledipasvir併用療法における 非著効例の検討 (2017)
  • Author(s): 飯尾悦子, 島田紀朋, 高口浩一, 妹尾知典, 江口有一郎, 厚川正則, 坪田昭人, 安部宏, 加藤慶三, 日下部篤宣, 宮木知克, 松浦健太郎,野尻俊輔, 藤原圭, 松波加代子, 田中靖人
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] C型慢性肝疾患genotype1に対するSofosbuvir/Ledipasvir併用療法非著効例における薬剤耐性変異検討 (2017)
  • Author(s): 飯尾悦子、島田紀朋、松浦健太郎、松波加代子、野尻俊輔、田中靖人
  • Organizer: 第2７回抗ウイルス療法学会総会