title: An IL28B genotype-based clinical prediction model for treatment of chronic hepatitis C.
abstract: BACKGROUND
  Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.
  
  
  METHODS
  HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).
  
  
  RESULTS
  Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.
  
  
  CONCLUSIONS
  A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America. obrient@mail.nih.gov
authors.forename: Thomas R
authors.initials: TR
authors.lastname: O'Brien
authors.forename: James E
authors.initials: JE
authors.lastname: Everhart
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.forename: Anna S
authors.initials: AS
authors.lastname: Lok
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Yongwu
authors.initials: Y
authors.lastname: Shao
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Shiffman
authors.forename: Myhanh
authors.initials: M
authors.lastname: Dotrang
authors.forename: John J
authors.initials: JJ
authors.lastname: Sninsky
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D003710:Demography; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda