title: Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirin and peginterferon in hepatitis C treatment.
abstract: BACKGROUND
  Anaemia is a common side-effect of ribavirin (RBV) use that overwhelms management of hepatitis C when protease inhibitors are added.
  
  
  OBJECTIVE
  To assess the pharmacogenomic impact of candidate genes SLC28A2, SLC28A3 and ITPA on anaemia in patients receiving triple therapy.
  
  
  METHODS
  Patients (n=161) with chronic hepatitis C genotype 1 treated with telaprevir (n=95) or boceprevir (n=66) were included. Using RT-PCR we genotyped ITPA (rs1127354, rs7270101) and SLC28A3 (rs56350726, rs10868138) and SLC28A2 (rs11854484). Clinically significant anaemia (CSA) was diagnosed when at least one of the following criteria was observed: (a) haemoglobin <8.5g/dL during treatment; (b) blood transfusion required; (c) erythropoietin administered.
  
  
  RESULTS
  CSA occurred in 44% (69/157) of patients and was associated with SLC28A2 rs11854484 [CC/CT genotypes: 33% (26/78) vs. TT genotype: 56% (36/64); p=0.006]. Further, the needed for blood transfusion was related to genotype [CC: 0% (0/18) vs. CT: 13% (8/61) vs. TT: 27% (17/64); p=0.016]. Similarly, ITPA rs1127354 genotypes [AA/AC: 19% (3/16) vs. CC: 45% (61/135; p=0.060] were linked to CSA. In multivariate analysis, SLC28A2 rs11854484 TT genotype (OR:2.33;95%CI:1.10-4.95; p=0.027), female sex (OR:2.54;95% CI:1.13-5.71;p=0.024) and Hb drop at week 4) OR: 1.36; 95CI%: 1.11-1.67; p=0.003) were independently associated with CSA. Similarly, ITPA rs1127354 genotypes [AA/AC: 16% (3/19) vs. CC: 63% (85/134); p=0.0001] and ITPA rs6051702 genotypes [CC/CA: 46% (26/57) vs. CC: 65% (60/93); p=0.023] were related to Hb drop of >3g/dL at week 4.
  
  
  CONCLUSIONS
  In patients receiving first generation protease inhibitors, genotype SLC28A2 rs11854484 predicts CSA, and helps to identify a subgroup of patients with better tolerance of triple therapy.
authors.affiliation: Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ampuero
authors.affiliation: Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Del Campo
authors.affiliation: Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rojas
authors.affiliation: Digestive Department, Puerta de Hierro Hospital, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Calleja
authors.affiliation: Digestive Department, Hospital Marqués de Valdecilla, Santander, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Cabezas
authors.affiliation: Hepatology Unit, Hospital Clinic and IDIBAPS & CIBERehd, Barcelona, Spain.
authors.forename: Sabela
authors.initials: S
authors.lastname: Lens
authors.affiliation: Digestive Department, Hospital Marqués de Valdecilla, Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo
authors.affiliation: Hepatology Unit, Hospital Clinic and IDIBAPS & CIBERehd, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
authors.affiliation: Digestive Unit, Hospital Virgen de la Victoria & CIBERehd, Málaga, Spain.
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
authors.affiliation: Hepatology Unit, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Fernández
authors.affiliation: Hepatology Unit, Hospital Vall d'Hebron & CIBERehd, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Buti
authors.affiliation: Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Millán
authors.affiliation: Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gómez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011755:Pyrophosphatases / Q000235:genetics*; D012254:Ribavirin / Q000009:adverse effects* / Q000627:therapeutic use; D018570:Risk Assessment; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D026901:Membrane Transport Proteins; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011755:Pyrophosphatases; D012254:Ribavirin; C065171:cif nucleoside transporter; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase
keywords: Adverse event; Anaemia; Boceprevir; Hepatitis C; ITPA; Lead-in-phase; Pharmacogenomics; Polymorphism; SLC28; Telaprevir