Recent genome-wide association studies report that the SNP rs8099917, located 8.9 kb upstream of the start codon of IL28B, is associated with both disease chronicity and therapeutic response to pegIFN-α and RBV in patients infected with genotype 1 HCV. To determine the effect of rs8099917 variation on the response of HCV to therapy, we genotyped this variant in a cohort of 160 HCV/HIV-1 coinfected patients in our clinic unit who received combined peg-IFN-α/RBV therapy. The rs8099917 T/G or G/G genotypes were observed in 56 patients (35%). Treatment failure occurred in 80% of G-allele carriers versus 48% of non-carriers (P<0.0001). This result reveals that the G allele was strongly associated with treatment failure in this patient cohort. Importantly, a highly significant association was found between the G-allele and response to therapy in HCV genotype 1-infected patients (P<0.0001) but not in HCV genotype 3-infected patients. Multivariate analysis (odds ratio; 95% confidence interval; P value) indicated that the rs8099917 TT genotype was a strong predictor of treatment success (5.83; 1.26–26.92; P = 0.021), independent of baseline plasma HCV-RNA load less than 500 000 IU/ml (4.85; 1.18–19.95; P = 0.025) and absence of advanced liver fibrosis (5.24; 1.20–22.91; P = 0.025). These results reveal the high prevalence of the rs8099917 G allele in HCV/HIV-1 coinfected patients as well as its strong association with treatment failure in HCV genotype 1-infected patients. rs8099917 SNP genotyping may be a valid pre-treatment predictor of which patients are likely to respond to treatment in this group of difficult-to-treat HCV/HIV-infected patients.

A new transiently induced region (interferon-λ 4 protein; IFNL4) harbouring a dinucleotide variant ss469415590 (TT or ΔG), upstream of IFNL3 (IL28B), was recently found to be associated with hepatitis C virus (HCV) clearance. To determine the effect of IFLN4 ss469415590 variation on the HCV response to IFN-based therapy in HCV/HIV-1 coinfected patients, ss469415590 was genotyped in a cohort of 207 patients from our clinic. Treatment failure occurred in 77% of minor ΔG-allele carriers versus 48% of noncarriers, indicating that the ΔG allele was strongly associated with treatment failure. Importantly, multivariate logistic analysis revealed that ss469415590 genotype was a better predictor of treatment failure than rs12979860.

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)-IFN-α 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 3′-untranslated regions. Haplotypes carrying the major alleles at IL28B SNPs were highly associated with sustained virological responses (SVRs) after treatment with peg-IFN-α and RBV [odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.6–4.0, 4.0×10−5]. Three causal SNP genotypes (rs28416813, rs8103142, and rs4803217) displayed the highest association with SVRs (OR = 3.7, 95% CI = 2.0–6.7, p = 1.3×10−5). 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.