title: Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.
abstract: BACKGROUND
  A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients.
  
  
  METHODS
  DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rs1127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia.
  
  
  RESULTS
  A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR.
  
  
  CONCLUSIONS
  This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina, USA. susanna.naggie@duke.edu
authors.forename: Susanna
authors.initials: S
authors.lastname: Naggie
authors.forename: Norma I
authors.initials: NI
authors.lastname: Rallon
authors.forename: José M
authors.initials: JM
authors.lastname: Benito
authors.forename: Judith
authors.initials: J
authors.lastname: Morello
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez-Novoa
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Clark
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Eugenia
authors.initials: E
authors.lastname: Vispo
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Vincent
authors.initials: V
authors.lastname: Soriano
mesh_terms: D000328:Adult; D000743:Anemia, Hemolytic / Q000139:chemically induced*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D011755:Pyrophosphatases; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase