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

Abstract

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.

Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance

“…Two smaller studies compared rs4803217 to rs12979860, a variant that is in strong LD with rs4803217 and which is associated with HCV clearance less strongly than IFNL4- ΔG/TT [4, 10]. Among 197 HCV/HIV-1 co-infected patients from Barcelona, associations for response to treatment with pegylated IFN-α plus ribavirin were comparable for rs4803217 and rs12979860 genotypes [27]. Those findings are consistent with the data from EA individuals in our study.…”

Prevalence ofIFNL3rs4803217 single nucleotide polymorphism and clinical course of chronic hepatitis C

“…In turn, the relation between rs4803217 and SVR in HCV-infected individuals was analyzed only in several studies. All of them confirmed that rs4803217C allele is strongly associated with SVR after IFN-based therapy[22-25]. Only in one study this association was weak, due to a small number of patients enrolled ( n = 23, 7 vs 16) and the fact that no individual possessed the favorable homozygous genotype[24].…”

PharmGKB summary

“…The association between the IFNL3 genotype and PEG-IFN-α/RBV therapy outcome has been consistently demonstrated across studies in subgroup analyses of HIV patients coinfected with HCV genotypes 1 and 4, but not in patients with HCV genotypes 3 and 4 [79,84]. Several studies have shown an association between the favorable IFNL3 genotypes (rs12979860 CC or rs8099917 TT) and higher SVR rates [79,84,93–95], although one study that compared the two SNPs found that rs12979860 was a better predictor of response [96]. IFNL3 genotyping may also be useful in patients coinfected with HIV and HCV genotype 1 or 4 who had undergone previously failed PEG-IFN-α/RBV therapy, to identify nonresponders who would likely benefit from retreatment [84,97].…”