title: Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR.
abstract: Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10(-6) for rs1127354 and P = 10(-7) for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10(-11) ). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR.
  
  
  CONCLUSIONS
  Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Rosanna
authors.initials: R
authors.lastname: Santoro
authors.forename: Valeria
authors.initials: V
authors.lastname: Piazzolla
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Clark
authors.forename: Susanna
authors.initials: S
authors.lastname: Naggie
authors.forename: Hans L
authors.initials: HL
authors.lastname: Tillmann
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muir
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mottola
authors.forename: Daniela
authors.initials: D
authors.lastname: Petruzzellis
authors.forename: Mario
authors.initials: M
authors.lastname: Romano
authors.forename: Fernando
authors.initials: F
authors.lastname: Sogari
authors.forename: Domenico
authors.initials: D
authors.lastname: Facciorusso
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangia
mesh_terms: D000328:Adult; D000740:Anemia / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control*; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007558:Italy; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics*; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins; D012189:Retrospective Studies; D012254:Ribavirin / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C417083:peginterferon alfa-2b