VIRAL HEPATITIS Variation in genes encoding for interferon k-3 and k-4 in the prediction of HCV-1 treatment-induced viral clearance Orazio Palmieri 1 , Antonio M. Ippolito 1 , Maurizio Margaglione 2 , Maria R. Valvano 1 , Domenica Gioffreda 1 , Massimo Fasano 3 , Giovanna D’Andrea 2 , Giuseppe Corritore 1 , Michele Milella 4 , Nicola Andriulli 5 , Filomena Morisco 6 , Lydia Giannitrapani 7 , Anna Latiano 1 , Rosanna Fontana 1 , Pietro Gatti 8 , Paolo Tundo 9 , Michele Barone 10 , Raffaele Cozzolongo 11 , Teresa Santantonio 3 and Angelo Andriulli 1 1 Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy 2 Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy 3 Clinic of Infectious Diseases, University of Foggia, Foggia, Italy 4 Clinic of Infectious Diseases, University of Bari, Bari, Italy 5 Department of Chemical Pharmaceutics, University La Sapienza, Rome, Italy 6 Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples ‘Federico II’, Naples, Italy 7 Dipartimento Biomedico di Medicina Interna e Specialistica (DiBiMIS), Universit a di Palermo, Palermo, Italy 8 DIMO Medical Oncology, University of Bari, Bari, Italy 9 Division of Infectious Diseases, S. Caterina Novella Hospital, Galatina, Italy 10 Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy 11 Division of Gastroenterology, ‘S. de Bellis’ Hospital, IRCCS, Castellana Grotte, Italy Keywords chronic hepatitis – HCV – IL28B/interferon lambda-3 gene – interferon lambda-4 gene – peg-interferon/ribavirin Abbreviations CI, confidence interval; DAAs, direct-acting antivirals; EOT, undetectable serum HCV RNA at the end of treatment; HCV, hepatitis C virus; HWE, Hardy–Weinberg equilibrium; IFN k-3, interferon Lambda 3; IFN k-4, interferon Lambda 4; IL28B, interleukin-28B; LD, linkage disequilibrium; non-SVR, non sustained virological response; OR, odds ratio; PCR, polymerase chain reaction; Peg-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virological response; SNP, single- nucleotide polymorphism; SVR, sustained virological response. Correspondence Angelo Andriulli, Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, IRCCS, viale Cappuccini 1, San Giovanni Rotondo, Italy Tel: +39 0882 410263 Fax: +39 0882 835411 e-mail: a.andriulli@operapadrepio.it Received 10 September 2013 Accepted 16 November 2013 DOI:10.1111/liv.12411 Abstract Background & Aims: In patients with chronic HCV-1 infection, recent evi- dences indicate that determination of a dinucleotide polymorphism (ss469415590, DG/TT) of a new gene, designated IFN k-4, might be more accurate than the 12979860CC type of the IL28B locus in predicting sus- tained virological response (SVR) following peg-interferon and ribavirin. In addition, combined genotyping of different SNPs of the IL28B locus was shown to help dissect patients most prone to SVR among those with rs12979860CT. We examined whether single or combined genotyping of two IL28B SNPs, rs12979860 and rs8099917, and ss469415590 variation might improve the prediction of SVR. Results: In the study cohort of 539 patients, 38% had SVR. The SNPs 12979860CC, rs8099917TT, and rs469415590TT/TT correlated significantly with SVR (68%, 50%, and 67%). Carriers of either the triplotype rs12979860CC_ss469415590TT/ TT_rs8099917TT or the diplotype rs12979860CC_ss469415590TT/TT had the highest SVR rate (72%). In carriers of the rs12979860 T allele, neither the rs8099917 nor the ss469415590 improved the response prediction. After pooling this finding with data from previous studies, in rs12979860 T hetero- zygous individuals the co-presence of the rs8099917TT SNP was associated with improved response prediction. Conclusion: In HCV-1 patients, the rs12979860 polymorphism appeared as the hit SNP better predicting response following peg-interferon and ribavirin treatment. Additional ss469415590 or rs8099917 genotyping had no added benefit for response pre- diction. In the subset of carriers of the rs12979860 T allele, genotyping of the rs8099917 SNP was unhelpful in the present investigation, but may inform clinical prediction of treatment response when our data were pooled with previous investigations. Evidence has accumulated suggesting that the individ- ual ability to clear HCV infection in the context of therapy with peg-interferon (Peg-IFN) and ribavirin (RBV) partly reflects differences in the genetic make- up of the human host. Since the landmark discovery that variants on chromosome 19 located within a Liver International (2013) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1 Liver International ISSN 1478-3223