Table 1.
Genetic studies on the relationship between IL28 polymorphism and the outcome of HCV infection and therapy
| Study | Cohort | IL28B SNPs | Results |
|---|---|---|---|
| Impact of host genetics on spontaneous resolution of acute and recent HCV infection | |||
| Kamal et al24 | 165 patients with recent exposure to HCV | rs12979860 | IL28B CC genotype, multispecific HCV T-cell responses, rapid decline in ALT, and viral load predict spontaneous clearance and response to acute HCV therapy in genotype 4. IL28B CC genotype correlates with developing early multispecific T-cell responses |
| Tillman et al48 | 90 women from the German anti-D cohort infected with HCV genotype 1b | rs12979860 | Association of rs12979860 with spontaneous clearance of HCV. Women with the C/T or T/T genotype who did not develop jaundice had a lower chance of spontaneous clearance of HCV infection |
| Grebely et al46 | 163 Australians | rs8099917 | Spontaneous clearance in 23%. Among participants with IL28B genotyping, rs8099917 TT homozygosity (versus GT/GG) was the only factor independently predicting time to spontaneous clearance |
| Rauch et al45 | 347 Swiss patients with spontaneous HCV clearance | rs8099917 | The rs8099917 minor allele was associated with progression to chronic HCV infection |
| Thomas et al44 | 388 individuals with spontaneous resolution of HCV/620 individuals with persistent HCV infection | rs12979860 | Association of rs12979860 and spontaneous clearance of HCV viremia. The C/C genotype strongly enhanced resolution of HCV infection in individuals of European or African ancestry |
| Impact of pharmacogenetics on outcome of PEG-IFNα and ribavirin therapy: chronic HCV genotype 1 | |||
| Tanaka et al74 | Japanese patients with chronic HCV | rs12980275, rs8099917, rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668 | Association of SNPs, rs8099917 and rs1298027 with response to PEG-IFNα and ribavirin therapy |
| Ge et al47 | European Americans (n=1,186) African-Americans (n=299) Hispanics (n=130) |
rs12979860 | Genetic polymorphism near the IL28B gene is associated with response to treatment in patients with European or African-American ancestry |
| Suppiah et al75 | 293 Australians with genotype 1 chronic HCV Validation cohort of 555 individuals | rs8099917 | IL28B rs8099917 contributes to viral resistance |
| Thompson et al84 | Chronic HCV patients (1,171 Caucasians, 300 African Americans, 116 Hispanics) | rs12979860 |
IL28B type CC was associated with improved early viral kinetics, RVR, complete EVR, and SVR IL28B type CC was the strongest pretreatment predictor of SVR |
| McCarthy et al85 | 1,021 patients with chronic HCV; 178 Caucasians and 53 African Americans, HCV genotypes 1 (n=186) and 2/3 (n=45) | rs12979860 | rs12979860 genotype CC was found in 40% of Caucasians; rs12979860 genotype CC predicted SVR in Caucasians independent of HCV genotype |
| Rauch et al45 | 1,015 Europeans with chronic hepatitis C | rs8099917 | Association of rs8099917 with failure to respond to therapy, particularly in patients with HCV genotype 1 or 4 |
| Hayes et al86 | 817 Japanese patients with chronic HCV infection | rs12979860, rs8099917 | Association of IL28B rs12979860 genotype CC with SVR Association of rs12979860 CT/TT genotype with nonresponse |
| Stättermayer et al87 | 754 PEG/ribavirin-treated patients (male/female =484/270; Caucasians 98.8%; mean age 42.8 [95% CI 42.0–43.6] years; genotype 1, n=435; genotype 2, n=23; genotype 3, n=185; genotype 4, n=114) | rs12979860, rs8099917 | Of the treated patients, 12.9% had the ss469415590 ΔG/ΔG genotype (IFNL4), 51.3% were heterozygous (TT/ΔG) and 35.8% had TT/TT. IFNL4 polymorphism was independently associated with SVR in genotypes 1 and 4 but not in genotype 3. IFNL4 correlated strongly with rs12979860, but only moderately with rs8099917 |
| Sarrazin et al88 | Chronic HCV genotype 1 patients (n=378), chronic HCV genotype 2/3 (n=267), and healthy controls (n=200) were included | rs8099917, rs12980275, and rs12979860 | rs12979860 genotype CC, younger age, and genotype 2 were significantly associated with SVR in HCV genotype 2/3-infected patients |
| Darling et al77 | 115 nonresponders and 157 sustained responders; African Americans and Caucasian Americans | IL28B genotyping and quantitation of IFNγ-inducible protein-10 | When combining IL28B genotype with pretreatment serum IFNγ-inducible protein-10 measurement, the predictive value for discrimination between SVR and nonresponse was significantly improved, especially in non-CC genotypes |
| Urban et al80 | 61 North American patients with chronic HCV | rs12979860 and whole-genome RNA expression in liver biopsies | IL28B-type was associated with SVR. No association was observed between IL28B-type and levels of liver IL28B or IL28A messenger RNA expression. ISG expression was associated with SVR |
| Impact of pharmacogenetics on outcome of chronic HCV non-1 genotype therapy | |||
| Mangia et al81 | 268 chronic HCV Europeans: 213 infected with HCV genotype 2 and 55 infected with genotype 3 | rs12979860 | Association of CC genotype with SVR. Multivariable logistic regression model, IL28B genotype predicted SVR |
| Montes-Cano et al90 | 731 Spanish individuals: 284 were subjects with persistent infection, 69 with spontaneous resolution, 378 noninfected subjects | rs12979860 | CC genotype was overrepresented among patients infected with viral genotypes non-1. An association was demonstrated between the CC genotype and SVR |
| Kawaoka et al91 | 719 Japanese patients with either HCV genotype 2a (n=530) or 2b (n=189) | rs8099917 | Initial viral load and rs8099917 genotype are significant independent predictors of SVR in genotype 2 patients |
| Scherzer et al92 | 71 Caucasians with chronic HCV genotype 3 | rs12979860, rs8099917 | 43 patients had RVR (C/C, 77.8%; C/T or T/T, 50.0%); irrespective of ribavirin dose, the viral load decline was larger than in patients with the T allele. In contrast with HCV genotype 1 patients, no effect on SVR rates was observed in genotype 3 patients |
| Stättermayer et al87 | 208 Caucasians with chronic HCV genotypes 2/3; 102 with HCV genotype 4 | rs12979860, rs8099917 | EVR was more likely among carriers of IL-28 polymorphisms rs12979860 C/C and rs8099917 T/T. RVR was more frequent in patients with the C/C allele. The positive predictive value of rs12979860 C/C for SVR was higher than that of rs8099917 T/T (80.5% versus 71.6%) |
| Impact of pharmacogenetics on outcome of PEG-IFNα + ribavirin + DAA therapy: chronic HCV genotype 1 | |||
| Poordad et al62 | 643 patients, naïve or previously treated. The DAA used was boceprevir | rs12979860 | 80.2% of patients with the CC genotype achieved SVR versus 65.7% of non-CC genotype patients. The CC polymorphism at IL28B rs12979860 was associated with a response to triple therapy and could identify candidates for shorter treatment durations. A $1 log(10) decrease in HCV RNA at week 4 of therapy was the strongest predictor of SVR, regardless of polymorphism in IL28B |
| Pol et al94 | 527 previously treated patients. The DAA used was TPV | rs12979860 | 79% SVR among the CC genotype patients, 60% SVR among CT genotype patients, and 61% SVR among TT genotype. IL28B genotype had a limited impact on SVR rates with TPV-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for TPV-based therapy |
| Furusyo et al99 | 120 Japanese patients. The DAA used was TPV | rs8099917 | About 90% SVR in TT genotype patients, and 41.2%–68.4% SVR in non-TT genotype patients. TPV-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C |
| Jacobson et al61 | 414 naïve patients. The DAA used was TPV | rs12979860 | 88.4% SVR among CC genotype patients and 65.8% SVR among non CC genotype patients |
| Akuta et al97 | 81 Japanese naïve and previously treated patients. The DAA used was TPV | rs8099917 | Genetic variation near the IL28B gene and aa substitution of the core region are predictors of an SVR to triple therapy of TPV/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b |
| Lawitz et al72 | 327 naïve patients. The DAA used was sofosbuvir | A sustained virologic response occurred in 93 of 95 patients (98%) with the CC genotype of IL28B, as compared with 202 of 232 patients (87%) with the non–CC IL28B genotype | |
| Chayama et al95 | 94 Japanese patients: 25 naïve, 44 relapsers, 25 nonresponders The DAA used was TPV | rs8099917 | Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy. 94% SVR among TT genotype patients and 50% SVR among non-TT genotype patients |
| Bronowicki et al96 | 37 treatment-naïve patients from PROVE-2 (TPV) | rs12979860 | SVR: CC 94%, CT 67%, TT 33% SVR (PEG-IFN/ribavirin arm): CC 64%, CT 31%, TT 25% (n=31) |
| Zeusem et al59 | Patients who did not respond (null response) had a partial response or relapsed after treatment with PEG-IFN and ribavirin received simeprevir (100 mg or 150 mg, once daily) for 12, 24, or 48 weeks plus PEG-IFN and ribavirin for 48 weeks (n=396), or placebo plus PEG-IFN and ribavirin for 48 weeks (n=66) | rs12979860 | |
| Impact of IL28B on outcome of IFN-free regimen | |||
| Marcellin et al66 | 83 chronic HCVpatients assigned to mericitabine (500 or 1,000 mg twice daily) plus danoprevir (100 or 200 mg, every 8 hours, or 600 or 900 mg twice daily) or placebo | rs12979860 | At day 14 (the end of IFN-free treatment), the mean reduction in serum HCV RNA level was slightly greater in patients with the CC polymorphism (5.01 log10 IU/mL) than in those without Patients with CC also had a better on-treatment response, suggesting that the IL28B genotype has a positive influence on early viral kinetics in patients with chronic HCV receiving IFN-free treatment |
| Impact of pharmacogenetics on outcome of chronic HCV/HIV infection and therapy | |||
| De Araujo et al101 | 26 HCV/HIV coinfected patients from South America, HCV genotypes 1 and 3 | rs12979860 | PEG-IFNα-2a was more effective in rs12979860 CC genotype carriers than in those with the TT/TC genotype. The first phase viral decline was greater in rs12979860 CC genotype than in TT/TC genotype. The second slower phase viral decline was greater in rs12979860 genotype CC than in genotype TT/TC in HCV genotype 1 patients |
| Rivero-Juarez et al102 | 260 Europeans patients coinfected with HIV/HCV genotype 1 and naïve to PEG-IFNα-2a and ribavirin (PEG-IFNα-2a/ribavirin) | rs12979860 | No differences were found between HCV-1 subtypes in terms of HCV viral decline or rapid virological response rate. The effect of the IL28B CC genotype on HCV viral decline was observed only among patients infected with HCV-1b at all time points analyzed |
| Clausen et al103 | 206 Europeans with HIV and recent HCV infection | rs8103142, rs12979860, rs11881222 | 23% cleared HCV, 77% had chronic HCV IL28B polymorphism. HCV genotype and the host’s genetic background affected the outcome of HCV infection. Association between IL28B SNP (rs8103142 CT, rs12979860 CT and rs11881222 AG) and decreased clearance rates of HCV |
| Rallón et al104 | 650 Europeans (Spanish) | rs12979860 | Association between rs12979860 and treatment outcome in HCV genotypes 1 and 4 patients coinfected with HIV |
| Aparicio et al105 | 160 Europeans coinfected with HIV and HCV genotype 1 | rs8099917 | rs8099917 G allele is highly prevalent in HCV/HIV patients. rs8099917 G allele is associated with treatment failure. rs8099917 genotyping is a good predictor of treatment outcome. |
| Medrano et al106 | 159 HIV-HCV coinfected Spanish patients | rs12979860 | rs12979860 SNP, liver stiffness, genotype, and viral load are good predictors of SVR in HCV/HIV coinfected patients |
| Pineda et al107 | 154 HIV-HCV coinfected Spanish patients | rs12979860 | IL28B polymorphisms are good predictors of SVR in HIV/HCV coinfected patients |
| Nattermann et al108 | 254 HIV-HCV coinfected Caucasians | rs12979860 | In HIV patients with acute HCV, IL28B genotype was associated with serum levels of hepatitis C virus RNA, GGT, and CD4 cell count. In HIV patients with chronic HCV, the IL28B genotype was not associated with treatment response rates in patients with acute HCV infection |
| Impact of pharmacogenetics on outcome of antiviral therapy after liver transplantation | |||
| Fukuhara et al110 | 67 Japanese liver recipients and 41 Japanese donors | rs8099917 | IL28B mutations are predictors of SVR in the event of recurrent HCV infection after liver transplantation |
| Lange et al111 | 91 Europeans with liver graft reinfection (only 47 on treatment with PEG-IFNα and ribavirin) | rs12979860 | Association between IL28B genetic background of the donor and treatment response in liver graft reinfection patients. The IL28B genetic background of the recipient does not greatly influence treatment response in liver graft reinfection patients. Association between donor IL28B rs12979860 CC and RVR, complete EVR, and SVR HCV RNA serum concentration and peak ALT in patients with donor IL28B rs12979860 CC is higher than patients with TT/CT genotype |
Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PEG-IFNα, PEGylated interferon alpha; DAAs, direct-acting antiviral agents; SVR, sustained virologic response; TPV, teleprevir; RVR, rapid virologic response; EVR, early virologic response; IL28B, interleukin-28B; IFN, interferon; SNP, single nucleotide polymorphism; ISG, interferon-stimulated gene; GGT, gammaglutamyl transferase.