title: Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.
abstract: OBJECTIVE
  The response rate to treatment of chronic hepatitis C virus-genotype 1 and 4 infections was recently found to be strongly influenced by many polymorphisms. The aim of our study was to carry out an integrated analysis of the effects of polymorphisms and ribavirin (RBV) plasma exposure on outcome.
  
  
  METHODS
  The retrospective analysis included 174 patients. IL28B, CYP27B1, SLC29A1, SLC28A3, and SLC28A2 polymorphisms were genotyped and tested for association with sustained virological response. The impact of RBV plasma exposure during the first 3 months of therapy on outcome was also investigated.
  
  
  RESULTS
  Considering patients infected by hepatitis C virus-1/4, 3 polymorphisms (IL28B rs8099917TT, CYP27B1 rs4646536TT, and CNT2 rs11854484TT) were associated with sustained virological response. The number of negative variant allele and low RBV exposure were correlated to percentage increasing to therapy failure, suggesting some degree of cumulative effect of the 4 factors. A cutoff of 2.5 μg/mL of RBV was found to be associated with outcome (area under ROC [AUROC] curve = 0.64, sensitivity = 55.0%, and specificity = 71.2%, P = 0.020). In multivariate logistic regression analyses, each variant allele and RBV plasma exposure cutoff were independently associated with outcome.
  
  
  CONCLUSIONS
  In this study, we found that additional polymorphisms and RBV plasma exposure are also able to influence the achievement of response. Regardless of the magnitude of RBV pharmacokinetic exposure, the negative predictive value of the polymorphisms here investigated is much stronger than the positive one.
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy. antonio.davolio@unito.it
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Alessia
authors.initials: A
authors.lastname: Ciancio
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Antonina
authors.initials: A
authors.lastname: Smedile
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.forename: Lorena
authors.initials: L
authors.lastname: Baietto
authors.forename: Diego
authors.initials: D
authors.lastname: Aguilar Marucco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cariti
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez de Requena
authors.forename: Mauro
authors.initials: M
authors.lastname: Sciandra
authors.forename: Giulia
authors.initials: G
authors.lastname: Troshina
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Caviglia
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: Mario
authors.initials: M
authors.lastname: Rizzetto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D016903:Drug Monitoring; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D056726:Genetic Association Studies; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D007558:Italy; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000095022:Interferon Lambda
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D026901:Membrane Transport Proteins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C065171:cif nucleoside transporter; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a