title: Role of inosine triphosphate pyrophosphatase gene variant on fever incidence during zidovudine antiretroviral therapy.
abstract: Zidovudine, the antiretroviral drug used to treat HIV infection, commonly causes adverse effects, such as systemic fever and gastrointestinal alterations. In the present study, the potential role of inosine triphosphate pyrophosphatase (ITPA) gene variant on the incidence of adverse events during antiretroviral therapy (ART) of HIV with zidovudine was discussed. Individuals from Northeastern Brazil (N = 204) receiving treatment for HIV-1 infection were recruited. Zidovudine-related adverse effects developed during the treatment were registered. The rs1127354 polymorphism in the ITPA gene was genotyped using real-time PCR to assess whether this single nucleotide polymorphism was associated with the occurrence of zidovudine-related adverse effects. We observed a significant association between the ITPA variant genotype and the reported systemic fever (odds ratio = 7.17, 95% confidence interval = 1.19-43.15; P = 0.032). Zidovudine use could indirectly lead to an increase in the levels of inosine monophosphate in an antimetabolite-like manner, which is converted to inosine triphosphate (ITP). The rs1127354 variant caused a decrease in ITPA activity, thereby leading to ITP accumulation. This in turn resulted in cytotoxicity, which was manifested by neutropenia and fever. Therefore, we hypothesized a pharmacogenetic model involving the ITPA variant genotype in multifactorial components that act together to determine the onset of zidovudine-related adverse effects.
authors.affiliation: Departamento de Genética, Universidade Federal de Pernambuco Federal de Pernambuco, Recife, PE, Brasil antonio.victor@ufpe.br.
authors.forename: A V C
authors.initials: AV
authors.lastname: Coelho
authors.affiliation: Programa de Pós-Graduação em Inovação Terapêutica, Universidade Federal de Pernambuco Federal de Pernambuco, Recife, PE, Brasil.
authors.forename: S P S
authors.initials: SP
authors.lastname: Silva
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Zandonà
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stocco
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Decorti
authors.affiliation: Departamento de Genética, Universidade Federal de Pernambuco Federal de Pernambuco, Recife, PE, Brasil.|Institute for Maternal and Child Health, Scientific Institute for Research, Hospitalization and Care Burlo Garofolo, Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Crovella
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001938:Brazil; D005334:Fever / Q000453:epidemiology* / Q000209:etiology*; D005838:Genotype; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D015994:Incidence; D011755:Pyrophosphatases / Q000235:genetics*; D015215:Zidovudine / Q000009:adverse effects* / Q000627:therapeutic use; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D011755:Pyrophosphatases; D015215:Zidovudine; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase