title: Pharmacogenetics of efficacy and safety of HCV treatment in HCV-HIV coinfected patients: significant associations with IL28B and SOCS3 gene variants.
abstract: OBJECTIVE
  This was a safety and efficacy pharmacogenetic study of a previously performed randomized trial which compared the effectiveness of treatment of hepatitis C virus infection with pegylated interferon alpha (pegIFNα) 2a vs. 2b, both with ribavirin, for 48 weeks, in HCV-HIV coinfected patients.
  
  
  METHODS
  The study groups were made of 99 patients (efficacy pharmacogenetic substudy) and of 114 patients (safety pharmacogenetic substudy). Polymorphisms in the following candidate genes IL28B, IL6, IL10, TNFα, IFNγ, CCL5, MxA, OAS1, SOCS3, CTLA4 and ITPA were assessed. Genotyping was carried out using Sequenom iPLEX-Gold, a single-base extension polymerase chain reaction. Efficacy end-points assessed were: rapid, early and sustained virological response (RVR, EVR and SVR, respectively). Safety end-points assessed were: anemia, neutropenia, thrombocytopenia, flu-like syndrome, gastrointestinal disturbances and depression. Chi square test, Student's T test, Mann-Whitney U test and logistic regression were used for statistic analyses.
  
  
  RESULTS
  As efficacy is concerned, IL28B and CTLA4 gene polymorphisms were associated with RVR (p<0.05 for both comparisons). Nevertheless, only polymorphism in the IL28B gene was associated with SVR (p = 0.004). In the multivariate analysis, the only gene independently associated with SVR was IL28B (OR 2.61, 95%CI 1.2-5.6, p = 0.01). With respect to safety, there were no significant associations between flu-like syndrome or depression and the genetic variants studied. Gastrointestinal disturbances were associated with ITPA gene polymorphism (p = 0.04). Anemia was associated with OAS1 and CTLA4 gene polymorphisms (p = 0.049 and p = 0.045, respectively), neutropenia and thromobocytopenia were associated with SOCS3 gene polymorphism (p = 0.02 and p = 0.002, respectively). In the multivariate analysis, the associations of the SOCS3 gene polymorphism with neutropenia (OR 0.26, 95%CI 0.09-0.75, p = 0.01) and thrombocytopenia (OR 0.07, 95%CI 0.008-0.57, p = 0.01) remained significant.
  
  
  CONCLUSIONS
  In HCV-HIV coinfected patients treated with PegIFNα and ribavirin, SVR is associated with IL28B rs8099917 polymorphism. HCV treatment-induced neutropenia and thrombocytopenia are associated with SOCS3 rs4969170 polymorphism.
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain. fvidalmarsal.hj23.ics@gencat.cat
authors.forename: Francesc
authors.initials: F
authors.lastname: Vidal
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Dupla
authors.forename: Montserrat
authors.initials: M
authors.lastname: Laguno
authors.forename: Sergi
authors.initials: S
authors.lastname: Veloso
authors.forename: Josep
authors.initials: J
authors.lastname: Mallolas
authors.forename: Javier
authors.initials: J
authors.lastname: Murillas
authors.forename: Carmen
authors.initials: C
authors.lastname: Cifuentes
authors.forename: Lluis
authors.initials: L
authors.lastname: Gallart
authors.forename: Teresa
authors.initials: T
authors.lastname: Auguet
authors.forename: Gloria
authors.initials: G
authors.lastname: Sampériz
authors.forename: Antoni
authors.initials: A
authors.lastname: Payeras
authors.forename: Pilar
authors.initials: P
authors.lastname: Hernandez
authors.forename: Mireia
authors.initials: M
authors.lastname: Arnedo
authors.forename: Josep Ma
authors.initials: JM
authors.lastname: Gatell
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Richart
mesh_terms: D000328:Adult; D005260:Female; D015967:Gene Expression Regulation, Viral; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis*; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012254:Ribavirin / Q000494:pharmacology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012254:Ribavirin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C106644:SOCS3 protein, human