Deciphering the Interleukin 28B Variants That Better Predict Response to Pegylated Interferon-α and Ribavirin Therapy in HCV/HIV-1 Coinfected Patients

et al. (2012) Deciphering the Interleukin 28B Variants That Better Predict Response to Pegylated Interferon-a and Ribavirin Therapy in HCV/HIV-1 Coinfected Patients. PLoS ONE 7(2): e31016. doi:10.1371/journal.pone.0031016 Deciphering the Interleukin 28B Variants That Better Predict Response to Pegylated Interferon-a and Ribavirin Therapy in HCV/HIV-1 Coinfected Patients Montserrat de Castellarnau 0 Ester Aparicio 0 Mariona Parera 0 Sandra Franco 0 Cristina Tural 0 Bonaventura Clotet 0 Miguel Angel Martnez 0 Aftab A. Ansari, Emory University School of Medicine, United States of America 0 1 Fundacio irsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona (UAB) , Badalona, Barcelona, Spain, 2 Fundacio de la Lluita contra la Sida , Hospital Universitari Germans Trias i Pujol , Badalona , Spain Previous works have documented the contribution of different IL28B-associated SNPs to spontaneous HCV clearance. This study investigated the effect of different interleukin (IL) 28B genetic variants on interferon (IFN)-based therapy response. We genotyped eight IL28B single-nucleotide polymorphisms (SNPs) in a cohort of 197 hepatitis C virus (HCV)/human immunodeficiency virus type 1 (HIV-1) coinfected patients from our clinic unit who received combined pegylated (peg)-IFNa and ribavirin (RBV) therapy. This analysis included the two strongest tag predictors for HCV clearance, rs8099917 and rs12979860, and four causal variants (rs4803219, rs28416813, rs8103142, and rs4803217) located in the IL28B promoter, coding, and 39-untranslated regions. Haplotypes carrying the major alleles at IL28B SNPs were highly associated with sustained virological responses (SVRs) after treatment with peg-IFN-a and RBV [odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.6-4.0, 4.061025]. Three causal SNP genotypes (rs28416813, rs8103142, and rs4803217) displayed the highest association with SVRs (OR = 3.7, 95% CI = 2.0-6.7, p = 1.361025). All four causal variants were in high linkage disequilibrium, both among themselves (r2$0.94) and with the rs12979860 variant (r2$0.92). In contrast, rs8099917 was in low linkage disequilibrium with the four causal variants (r2#0.45) and with the rs12979860 variant (r2 = 0.45). These results demonstrate that rs12979860, compared to rs8099917, may be a better predictor of response to the peg-IFN/RBV treatment among HCV/ HIV-1 coinfected patients. Moreover, causal IL28B variants are strongly associated with treatment SVRs. - Funding: This study was supported by grants from the Spanish Ministry of Science and Innovation (BFU2010-15194 and SAF2010-21617). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The combination of pegylated interferon alpha (peg-IFN-a) with ribavirin (RBV) has been used to treat hepatitis C virus (HCV) infection. However, a sustained virological response (SVR; a negative hepatitis C polymerase chain reaction (PCR) test 6 months after cessation of therapy) for individuals infected with HCV genotypes 1 or 4 ranges between 40% and 50%. Patients infected with HCV genotypes 2 or 3 typically achieve SVRs of nearly 75% after only 6 months of therapy [1,2,3,4]. HCV genotype has been the most important predictive factor regarding the treatment response of HCV-infected patients. Nevertheless, host factors such as age, sex, race, liver fibrosis, and obesity have also been associated with peg-IFN-a/RBV therapy outcome [5,6]. Four genome-wide association studies have demonstrated that several highly-correlated, common, single nucleotide polymorphisms (SNPs) located near the interleukin 28B gene (IL28B) strongly predict an SVR to peg-IFN-a/RBV therapy [7,8,9,10]. Il28B polymorphisms have been also strongly associated with SVR in HCV/HIV-1 coinfected patients [11,12,13,14,15,16]. Two SNPs in particular (rs12979860 and rs8099917, located 3 and 7.5 kb upstream of the IL28B gene, respectively) were the strongest predictors for HCV clearance. The recent approval of direct-acting antiviral (DAA) molecules, the NS3 protease inhibitors telaprevir and bocebrevir, active on HCV will represent a major breakthrough for HCV infected patients. Because of the low genetic resistance of first-generation protease inhibitors most failures to a triple combination of peg-IFN-a/RBV and either telaprevir o boceprevir will be due to a poor response to peg-IFNa and RBV. Predictors of SVR to former triple combination will be also included the IL28B genotype. To determine the best SNP to predict a response to peg-IFN-a/RBV treatment, we studied the effect of different IL28B genetic variants on IFN-based therapy response. Not only will this data refine IL28b based predictions of treatment response, it may also inform studies of IL28b mechanism in HCV response. Although the rs12979860 and rs8099917 genotypes have been independently associated with HCV treatment outcome, whether these SNPs play a causal role or are merely tagging other unknown causal variants remains to be elucidated. IL28B (which encodes IFN-l3) up-regulates interferon-stimulated genes, similar to IFN-a and IFN-b, but via a different receptor. There is also evidence that IFN-l 3 affects the adaptive immune response [17,18]. Moreover, IFN-l molecules inhibit HCV replication in vitro, and trials of IFN-l1 in HCV-infected patients have demonstrated promising results that suggest a mechanistic link between IL28B variants and HCV treatment outcome [19]. Recently, four SNPs located in the promoter (rs4803219 and rs28416813), coding (rs8103142), and 39-untranslated (rs4803217) regions of IL28B have been shown to be highly associated with spontaneous HCV clearance [20]. Therefore, we assessed the influence of four causal IL28B variants (rs4803219, rs28416813, rs8103142, and rs4803217) on SVR to IFN-based therapies, and compared the relationships of these four causal SNPs with the tag IL28B variants rs12979860 and rs8099917. We previously established the strong relationships between the rs8099917 G allele and treatment failure in our cohort of HCV/ HIV-1 coinfected patients [21]. In the present study, was examined the effect of eight different IL28B genetic variants on IFN-based therapeutic response in these patients. In a recent study, four causal SNPs (rs4803219, rs28416813, rs8103142, and rs4803217) were associated with the two tagging SNPs that were most strongly associated with spontaneous HCV clearance (rs12979860 and rs8099917) [20]. In this study, the four causal SNPs and two tagged SNPs were genotyped along with two additional SNPs, rs11881222 and rs8113007, which are located in the second IL28B intron and 7.5 kb upstream of the IL28B gene, respectively (Figure 1). These eight SNPs were genotyped in a cohort of 197 HCV/HIV-1 coinfected patients from our clinic unit who received standard combined peg-IFN-a/RBV therapy. (...truncated)