Predictive value of interferon-lambda gene polymorphisms for treatment response in chronic hepatitis C.
BACKGROUND
IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.


METHODS
Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.


RESULTS
Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20-35% vs. 46-47%) this was also true for ss469415590 TT/TT (20-35% vs. 45-47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71-96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.


CONCLUSIONS
IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71-96%.
Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
Simone
S
Susser
Institute of Biostatistics and Mathematical Modeling, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
Eva
E
Herrmann
Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
Christian
C
Lange
Department of Pharmacology and Toxicology, German University in Cairo, Cairo, Egypt.
Nabila
N
Hamdi
Clinic for Gastroenterology, Section Hepatology, University Hospital Leipzig, Leipzig, Germany.
Tobias
T
Müller
Clinic for Gastroenterology, Section Hepatology, University Hospital Leipzig, Leipzig, Germany.
Thomas
T
Berg
Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
Dany
D
Perner
Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
Stefan
S
Zeuzem
Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany.
Christoph
C
Sarrazin
D000998:Antiviral Agents / Q000627:therapeutic use*; D016903:Drug Monitoring; D005786:Gene Expression Regulation; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D009842:Oligopeptides / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D015398:Signal Transduction; D016896:Treatment Outcome; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D009842:Oligopeptides; D011092:Polyethylene Glycols; D011392:Proline; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C100416:peginterferon alfa-2a