Predictors of Sustained Virological Response After Antiviral Therapy for Chronic Hepatitis C In Patients with Hemophilia: The Role of the Interleukin-28B (IL28B) Polymorphism

Chronic hepatitis C is the main cause of morbidity and mortality in patients with hemophilia. HCV eradication is the only approach that can halt disease progression and it may be attempted by using antiviral therapy, the standard of care being represented by the combination of pegylated interferon (Peg-IFN) plus ribavirin. Sustained virologic response (SVR) is defined by undetectable HCV-RNA in serum 6 months after therapy completion. The likelihood of a SVR depends on various host and viral factors, as sex, stage of liver fibrosis, HCV genotype and viral kinetics during treatment, being the rapid virologic response (RVR; undetectable HCV-RNA in serum after 4 weeks of therapy) a strong predictor of SVR. Recently, it has been reported that a single-nucleotide polymorphism (SNP) near the IL28B gene, named rs12979860, is a predictor of response to therapy in non-hemophiliacs. This SNP may be genotyped as CC, CT or TT and the CC variant has been associated with higher rates of SVR and with higher rates of spontaneous viral clearance after acute infection. Methods and Results: the SNP was determined by Polymerase Chain Reaction in 189 patients with hemophilia aged 37–54 years (median: 44) infected with HCV. Fifty-five patients (29%) were HIV and 10 (5%) HBV co-infected. HCV genotype 1 was the most prevalent (n=124, 73%) and the IL28B SNP was CC in 70 (37%), CT in 104 (55%) and TT in 15 (8%). The median duration of HCV infection was 34 years (IQR: 28–39) and the median age at antiviral treatment 38 years (IQR: 31–46). Clinical signs of cirrhosis were present in 22 patients (12%). Fifteen patients (8%) had spontaneous clearance of viral infection and 134 (71%) of those with chronic infection underwent antiviral therapy that was Peg-IFN plus ribavirin in 114 (85%). Overall SVR rate was 49% (37% in patients with HCV genotype 1 and 70% in those with HCV genotype 2 or 3). Rapid, early and sustained virologic response were more frequent in patients carrying the CC SNP than in those carrying a non-CC SNP (59 vs 17%, 90 vs 71% and 67 vs 39%, respectively; p<0.05). By stratifying patients by HCV genotype, the presence of the CC variant was associated with higher RVR rate in patients with HCV type 1 (40 vs 9%; p<0.01), while no difference was observed in patients with HCV type 2 or 3. By univariate logistic regression HCV genotype 2 or 3, the CC IL28B SNP, the absence of cirrhosis and RVR were predictors of SVR (Odds Ratio 4.0, 3.1, 4.5 and 10.2, respectively). By multivariate analysis, only RVR was confirmed as independent predictor of SVR (Adjusted Odds Ratio 7.2; 95%CI 2.2–23.8). Moreover, the presence of the CC IL28B SNP was more prevalent among patients who had a spontaneous clearance of HCV infection (60% vs 35% in those who have chronic hepatitis C). Conclusions: The IL28B SNP may serve as pre-treatment predictor of IFN-based therapies outcome in patients with hemophilia and chronic hepatitis C, since the CC variant is associated with a higher chance of SVR. Our data also confirm that on-treatment viral kinetics has a key role and a stronger impact on the final outcome, since the achievement of RVR was the only independent predictor of SVR. However, due to the higher chances of SVR, the presence of a CC IL28B SNP should encourage the attempt at eradicating HCV infection in patients with genotype 1 by using the standard of care instead of waiting for new antiviral drugs that may increase therapy-related side effects.

No relevant conflicts of interest to declare.