Interferon induced protein 10 remains a useful biomarker of treatment failure in patients stratified for the interleukin-28B rs12979860 Haplotype
Authors: Matthew L. Albert, Armanda Casrouge, Stéphane Chevaliez, Christophe Hézode, Isabelle Rosa, Philippe Renard, Vincent Mallet, Arnaud Fontanet, Jean-Michel Pawlotsky, Stanislas Pol
Journal: Hepatology (2010)

The reporting of three independent genome-wide association studies has heralded a burst of excitement for the use of interleukin-28B (IL-28B) polymorphisms in the prediction of spontaneous or treatment-induced hepatitis C virus (HCV) clearance. In the year following the initial reports,1-3 there were more than 20 publications on the subject. Several studies,4-6 including a recent publication in Hepatology,7 argue that IL-28B genotyping will be of central importance for the management of patients. Although we agree that this discovery holds promise for understanding the variable host responses to interferon-α–based regimens, we believe that there may be some confusion with respect to the difference between odds ratio (OR) and the predictive value of the IL-28B genotype as a standalone biomarker. OR describes the strength of association between an IL-28 single-nucleotide polymorphism and virological response. Tanaka et al.1 reported ORs of 17.7 and 27.1 for rs12980275 and rs8099917 with astronomical P values of 2.84 × 10−27 and 2.68 × 10−32, respectively. Ge et al.3 determined a combined OR of 3.1 for rs12979860, and Suppiah et al.2 found a combined OR of 1.98 for rs809917. It is challenging to ascertain the predictive value of a particular IL-28B allele in the first two studies cited; however, Suppiah et al. were careful to note that "according to a model of dominant inheritance, the rs8099917 G allele predicts non-response with 57% sensitivity and 63% specificity." They also reported a negative predictive value (NPV; i.e., a value indicating the correct prediction of treatment failure) of 64%. We recently reported data from a prospective cohort collected for plasma biomarker discovery.8 Although our cohort was considerably smaller than the populations used for genome-wide association studies, we found that the rs12979860 C/C genotype increased the odds of early virological response (EVR; OR = 2.53) with a positive predictive value (PPV) of 75% (Fig. 1A). Notably, biomarkers are used in the management of chronic patients with the intention of identifying those individuals who will fail to respond to therapy and thus can be directed to alternative treatment options (e.g., the failure to achieve EVR is used in the clinic as a negative predictor of sustained virological response). As such, the important index is the NPV, which was found to be 42% for the patients in our study (Fig. 1A). We thus argue the need for phenotypic markers to complement markers of genetic susceptibility. One plasma biomarker that has received attention is interferon induced protein 10 (IP-10 and also referred to as CXCL10), with higher concentrations predicting treatment failure.9 We confirmed these data and found an NPV of 86% (Fig. 1B). One exciting possibility is the combination of assays; if they are taken together, predictions based on the C/C genotype or a low plasma concentration of CXCL10 yield an NPV of 100% (Fig. 1C). An elevated plasma concentration of CXCL10 is predictive of treatment failure in patients stratified for the IL-28B haplotype. Chronic HCV patients were enrolled in an observational study. Before treatment initiation, plasma was collected. The IL- 28B rs12879860 genotype was assessed with polymerase chain reaction. The CXCL10 concentration was determined with a Clinical Laboratory Improvement Amendments (CLIA) certified Luminex assay. Patients were assessed after 12 weeks of therapy, and those who achieved a 2-log reduction in their serum viral load were classified as early virological responders versus nonresponders. (A) Patients were evaluated for their IL-28B haplotype: C/C (n = 8), C/T (n = 20), or T/T (n = 11). The pie charts indicate responses to therapy in week 12. The PPV, NPV, sensitivity, and specificity are reported for predictions based on the presence of the C/C haplotype or on a model of dominant inheritance for the C allele. (B) The same patients were evaluated for plasma CXCL10. The PPV, NPV, sensitivity, and specificity are reported for predictions based on the presence of a low plasma concentration (<1500 pg/mL). The values are different from those reported by Romero etal.9 and highlight the need for CLIA certified assays. (C) Stratification based on the IL-28B haplotype was performed. The CXCL10 plasma concentration is shown for those patients with the C/T or T/T haplotype. The predictions were based on the presence of the C/C haplotype or a low CXCL10 plasma concentration. (B,C) Mann-Whitney, two-tailed comparisons were performed, and P values are reported. Abbreviation: NR, no response. Our growing knowledge of epigenetics and the impact of environmental factors makes clear that phenotypic markers and/or functional assays (measured with validated assays) will be required to fully exploit the knowledge gained by genetic studies. We conclude that there is a real need to continue the effort to identify predictive biomarkers that will be clinically useful for managing patients with HCV disease. Matthew L. Albert M.D., Ph.D.* , Armanda Casrouge* , Stéphane Chevaliez Ph.D.§ ** , Christophe Hézode M.D., Ph.D.§ ** , Isabelle Rosa M.D§ ** , Philippe Renard M.D , Vincent Mallet M.D., Ph.D.¶ §§ ¶¶, Arnaud Fontanet M.D., Ph.D. , Jean-Michel Pawlotsky M.D., Ph.D.§ ** , Stanislas Pol M.D., Ph.D.¶ §§ ¶¶, * Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, Paris, France, Epidemiology of Emerging Infectious Diseases, Institut Pasteur, Paris, France, Unité 818, Institut National de la Santé et de la Recherche Médicale, Paris, France, § Unité 955, Institut National de la Santé et de la Recherche Médicale, Paris, France, ¶ Unité 1016, Institut National de la Santé et de la Recherche Médicale, Paris, France, ** National Reference Center for Viral Hepatitis B, C, and Delta, Departmentof Virology, Université Paris-Est, Créteil, France, Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France, Department of Gastroenterology and Hepatology, Hôpital Victor Dupouy, Argenteuil, France, §§ Institut Cochin, Université Paris Descartes (Unités Mixtes de Recherche en Santé 1016), Centre National de la Recherche Scientifique (Unités Mixtes de Recherche 8104), Paris, France, ¶¶ Unité d'Hépatologie, Groupe Hospitalier Cochin Saint-Vincent de Paul, Assistance Publique–Hôpitaux de Paris, Paris, France.