Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response

Abstract

Polymorphisms of IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of Interferon-γ Inducible Protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 non-responders and 157 sustained responders in the VIRAHEP-C cohort, including African Americans (AA) and Caucasian Americans (CA). Mean IP-10 was lower in sustained responders compared to non-responders (460 ± 37 pg/ml vs 697 ± 49 pg/ml, p<0.001), both in AA and CA. The positive predictive value of low IP-10 levels (<600 pg/ml) for SVR was 69% while the negative predictive value of high IP-10 levels (>600 pg/ml) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. CC, CT, or TT genotypes were found in 30%, 49%, and 21%, respectively, with corresponding SVR rates of 87%, 50%, and 39% (p<0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (p< 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT: 48% versus 20%, CC: 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA. Conclusions When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and non-response is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate mechanisms of antiviral response and prospective validation.

Two IL28B polymorphisms are associated with the treatment response of different genotypes of hepatitis C in different racial populations: A meta-analysis

“…As shown in Table I, 16 studies (10,13,21-34) were eligible for examining the association between the IL28B polymorphism rs8099917 and treatment response of hepatitis C, including 3,540 cases with SVR and 2,208 cases with non-SVR. As shown in Table II, 17 studies (4,10,17,21,(27)(28)(29)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) were eligible for examining the association between the IL28B polymorphism rs12979860 and treatment response of hepatitis C, including 2,951 cases with SVR and 2,506 cases with non-SVR.…”

Direct, Interferon-Independent Activation of the CXCL10 Promoter by NF-κB and Interferon Regulatory Factor 3 during Hepatitis C Virus Infection

“…Both of these PRRs also activate mitogen-activated protein (MAP) kinase signaling pathways, which in turn regulate activator protein 1 (AP-1) and CCAAT/enhancer-binding protein ␤ (C/ EBP-␤) activity (12)(13)(14)(15)(16). Putative binding sites for all of these transcription factors have been annotated in the promoter for the proinflammatory chemokine CXCL10 (17), which recruits natural killer (NK) cells, CD4 ϩ T cells, and CD8 ϩ T cells to the HCVinfected liver (18,19) and is associated with the failure of IFNbased antiviral therapy (20)(21)(22).…”

Coinfection with Hepatitis C Virus among HIV-1-Infected Individuals Increases Proinflammatory Cytokines and HIV-1 Disease Severity

“…During HCV infection, hepatocytes produce IP-10 and circulating levels of IP-10 are known to be measurable during chronic HCV infection [37]. High levels of IP-10 levels are known to be associated with reduced rates of sustained virological response during treatment of HCV with pegylated (PEG)-IFN/ribavirin (RBV) [37,[47][48][49] HIV-1/HCV coinfection [38,50] and reduced spontaneous clearance to acute infection [51]. Further, high IP-10 levels have been associated with greater inflammation and liver fibrosis [48,49] even in a cohort of African-American injection drug users with chronic HCV [52].…”