title: The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin.
abstract: BACKGROUND
  Hyperbilirubinemia, mild or moderate, is a commonly observed laboratory abnormality in chronic hepatitis C patients treated with simeprevir with pegylated interferon (Peg-IFN) plus ribavirin. In this prospective, multicenter study, we aimed to investigate the clinical features and factors associated with bilirubin increases during the therapy.
  
  
  METHODS
  A total of 192 patients with chronic hepatitis C who were treated with simeprevir with Peg-IFN plus ribavirin were analyzed.
  
  
  RESULTS
  The mean serum bilirubin level increased significantly during the initial 12 weeks of simeprevir administration and peaked at 2 weeks after the administration. Hyperbilirubinemia of more than 2 mg/dl developed in 18% of the patients; in 85% of those patients, the bilirubin levels peaked within 6 weeks and gradually decreased thereafter. A univariable analysis revealed that an increase in serum total bilirubin of 1.0 mg/dl or more from baseline was significantly associated with the sex, red blood cell count, serum hemoglobin level, serum alanine aminotransferase level, serum creatinine level and inosine triphosphate pyrophosphatase (ITPA) genotype. In the multivariable analysis, the ITPA genotype (CC odds ratio 4.990, p = 0.011) was found to be the only independent factor. Consistent with this result, there was a significant correlation between hyperbilirubinemia and the degree of hemolytic anemia.
  
  
  CONCLUSIONS
  Hyperbilirubinemia develops at early time points after simeprevir administration in most cases and is dependent on the ITPA genotype. Careful attention should be paid to hyperbilirubinemia, which occurs at later time points or in patients with an ITPA non-CC genotype so that a diagnosis of liver damage with hyperbilirubinemia is not missed.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tahata
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. hiramatsu@gh.med.osaka-u.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tsugiko
authors.initials: T
authors.lastname: Oze
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Morishita
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yakushijin
authors.affiliation: National Hospital Organization Osaka National Hospital, Osaka, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Mita
authors.affiliation: Kansai Rousai Hospital, Amagasaki, Hyogo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hagiwara
authors.affiliation: Kaizuka City Hospital, Kaizuka, Osaka, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Japan Community Health Care Organization Osaka Hospital, Osaka, Osaka, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ito
authors.affiliation: National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Osaka, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Hijioka
authors.affiliation: Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Inada
authors.affiliation: Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katayama
authors.affiliation: Minoh City Hospital, Minoh, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Osaka Rousai Hospital, Sakai, Osaka, Japan.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Yoshihara
authors.affiliation: Osaka General Medical Center, Osaka, Osaka, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Ikeda Municipal Hospital, Ikeda, Osaka, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Ikeda Municipal Hospital, Ikeda, Osaka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Irishio
authors.affiliation: National Hospital Organization Minami Wakayama Medical Center, Tanabe, Wakayama, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Sakamori
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.affiliation: Department of Innovative Clinical Trials and Data Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Hamasaki
authors.affiliation: Kansai Rousai Hospital, Amagasaki, Hyogo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D006932:Hyperbilirubinemia / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use; D012307:Risk Factors; D000069616:Simeprevir / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D001663:Bilirubin; D006454:Hemoglobins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; D000069616:Simeprevir; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a
keywords: Bilirubin increase; Chronic hepatitis C; Inosine triphosphate pyrophosphatase; Pegylated interferon plus ribavirin; Simeprevir