Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment

Ther Drug Monit. 2012 Dec;34(6):722-8. doi: 10.1097/FTD.0b013e318272e55a.

Abstract

Objectives: 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.

Publication types

  • Multicenter Study

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / genetics*
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / metabolism
  • Adult
  • Antiviral Agents / blood
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / therapeutic use
  • Drug Interactions
  • Drug Monitoring
  • Drug Resistance
  • Drug Therapy, Combination
  • Female
  • Genetic Association Studies
  • Hepacivirus / drug effects
  • Hepatitis C / blood
  • Hepatitis C / drug therapy*
  • Hepatitis C / metabolism
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / therapeutic use
  • Interferons
  • Interleukins / genetics*
  • Interleukins / metabolism
  • Italy
  • Male
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Middle Aged
  • Polyethylene Glycols / therapeutic use
  • Polymorphism, Single Nucleotide*
  • Recombinant Proteins / therapeutic use
  • Retrospective Studies
  • Ribavirin / blood
  • Ribavirin / pharmacokinetics*
  • Ribavirin / therapeutic use

Substances

  • Antiviral Agents
  • interferon-lambda, human
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukins
  • Membrane Transport Proteins
  • Recombinant Proteins
  • cif nucleoside transporter
  • Polyethylene Glycols
  • Ribavirin
  • Interferons
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • peginterferon alfa-2b
  • peginterferon alfa-2a