Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C.
OBJECTIVE
The host immune response during the chronic phase of hepatitis C virus infection varies among individuals; some patients have a no interferon (IFN) response in the liver, whereas others have full activation of IFN-stimulated genes (ISGs). Preactivation of this endogenous IFN system is associated with nonresponse to pegylated IFN-α (pegIFN-α) and ribavirin. Genome-wide association studies have associated allelic variants near the IL28B (IFNλ3) gene with treatment response. We investigated whether IL28B genotype determines the constitutive expression of ISGs in the liver and compared the abilities of ISG levels and IL28B genotype to predict treatment outcome.


METHODS
We genotyped 109 patients with chronic hepatitis C for IL28B allelic variants and quantified the hepatic expression of ISGs and of IL28B. Decision tree ensembles, in the form of a random forest classifier, were used to calculate the relative predictive power of these different variables in a multivariate analysis.


RESULTS
The minor IL28B allele was significantly associated with increased expression of ISG. However, stratification of the patients according to treatment response revealed increased ISG expression in nonresponders, irrespective of IL28B genotype. Multivariate analysis of ISG expression, IL28B genotype, and several other factors associated with response to therapy identified ISG expression as the best predictor of treatment response.


CONCLUSIONS
IL28B genotype and hepatic expression of ISGs are independent predictors of response to treatment with pegIFN-α and ribavirin in patients with chronic hepatitis C. The most accurate prediction of response was obtained with a 4-gene classifier comprising IFI27, ISG15, RSAD2, and HTATIP2.
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Michael T
MT
Dill
Francois H T
FH
Duong
Julia E
JE
Vogt
Stéphanie
S
Bibert
Pierre-Yves
PY
Bochud
Luigi
L
Terracciano
Andreas
A
Papassotiropoulos
Volker
V
Roth
Markus H
MH
Heim
D000123:Acetyltransferases / Q000235:genetics; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001706:Biopsy; D016207:Cytokines / Q000235:genetics; D003661:Decision Support Techniques; D003663:Decision Trees; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010641:Phenotype; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013557:Switzerland; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D014452:Ubiquitins / Q000235:genetics; D000095022:Interferon Lambda; D000090123:Viperin Protein
D000123:Acetyltransferases; D000998:Antiviral Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D008565:Membrane Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011092:Polyethylene Glycols; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012254:Ribavirin; D014157:Transcription Factors; D014452:Ubiquitins; C406887:IFI27 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C074034:ISG15 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein; C111246:HTATIP2 protein, human; C100416:peginterferon alfa-2a