title: ITPA gene polymorphisms significantly affect hemoglobin decline and treatment outcomes in patients coinfected with HIV and HCV.
abstract: Published studies have described a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and ribavirin (RBV)-induced hemolytic anemia in HCV-infected patients receiving pegylated interferon (pegIFN) and RBV. This study sought to evaluate the effect of these polymorphisms on anemia, hemoglobin reduction, HCV kinetics, and treatment outcomes. Sixty-three patients coinfected with HIV and HCV and 58 patients infected with HCV only were treated with pegIFN/RBV were genotyped using the ABI TaqMan allelic discrimination kit for the 2 ITPA SNP variants rs1127354 and rs7270101. A composite variable of ITPA deficiency using both SNPs was created as previously reported. Statistical analysis was performed using Mann-Whitney test or Chi square/Fishers exact test for categorical data and mixed model analysis for multiple variables. Thirty-five patients (30%) were predicted to have reduced ITPA activity. ITPA deficiency was found to be protective against the development of hemoglobin reduction >3 g/dl over the course of treatment. The rates of hemoglobin reduction >3 g/dl decreased in correlation with the severity of ITPA deficiency. ITPA deficiency was associated with slower hemoglobin decline early in treatment (week 4, P = 0.020) and rapid virologic response (RVR) at week 4 (P = 0.017) in patients coinfected with HIV and HCV. ITPA polymorphisms are associated with hemoglobin decline and in patients coinfected with HIV and HCV it is also associated with early virologic outcomes. Determination of ITPA polymorphisms may allow prediction of RBV-induced anemia and earlier initiation of supportive care to ensure optimal therapeutic outcomes.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, USA. osinusia@niaid.nih.gov
authors.forename: Anu
authors.initials: A
authors.lastname: Osinusi
authors.forename: Susanna
authors.initials: S
authors.lastname: Naggie
authors.forename: Seerat
authors.initials: S
authors.lastname: Poonia
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Hu
authors.forename: Emily
authors.initials: E
authors.lastname: Funk
authors.forename: Joerg
authors.initials: J
authors.lastname: Schlaak
authors.forename: Dawn
authors.initials: D
authors.lastname: Fishbein
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.forename: Michael
authors.initials: M
authors.lastname: Polis
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D000740:Anemia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D060085:Coinfection / Q000150:complications / Q000188:drug therapy; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications*; D006454:Hemoglobins / Q000032:analysis; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D007372:Interferons / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics*; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D006454:Hemoglobins; D007372:Interferons; D011755:Pyrophosphatases; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase