Chronic HCV: Predicting Virological Response to Therapy
Chronic HCV: Predicting Virological Response to Therapy
Background Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue.
Aim To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC).
Methods Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study.
Results Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03–42.6), rs12980275 AA (OR 7.09; 1.97–25.56) and IP-10 (OR 0.04; 0.003–0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR = 0.02; 0.0009–0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44–27.18), age <40 years (OR = 4.79; 1.50–15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03–7.27) in HCV genotype 1 patients and rs12980275 AA (OR = 6.26; 1.98–19.74) and age <40 years (OR 5.37; 1.54–18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06–268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72–46.99) or genotype 3 patients (OR 7.8, 1.43–42.67).
Conclusions In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.
Hepatitis C virus (HCV) infects up to 180 million people worldwide and is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. The current treatment, based on the combination of peginterferon alpha and ribavirin, leads to a sustained virological response (SVR) in ~40–50% in patients with HCV genotype 1 and in ~80% of those with genotype 2 or 3. Several baseline and on-treatment variables affect the likelihood of achieving SVR. Older age, advanced stage of fibrosis, African-American ethnicity and HCV- related factors, including HCV genotype 1 and high viral load at baseline, predict poor response to anti-viral therapy. Furthermore, metabolic factors, such as high body mass index (BMI), presence and severity of liver steatosis and increasing homeostasis model assessment of insulin resistance (HOMA-IR) score have been reported as negative predictors of response. On the other hand, early on-treatment kinetics of HCV RNA, e.g. undetectable HCV RNA at week 4, has a high positive predictive value of SVR.
Among the baseline predictors of response, the pre-treatment activation of IFN-stimulated genes (ISG) and the host genetic polymorphisms have been the subject of recent, major studies. Regarding ISG, it has been shown that low levels of intrahepatic and systemic CXC chemokine IFN-gamma inducible protein 10 kDa (IP-10, or CXCL10), a valid surrogate marker of ISG activation, predict a more pronounced first phase decline of HCV RNA during anti-viral therapy and increased SVR rates. On the other hand, several independent studies have consistently shown that single nucleotide polymorphisms (SNPs) near IL28B, which encodes the type III interferon IFN-λ3 are strongly associated with the response to treatment of chronic hepatitis C. In particular, the homozygous genotypes TT at marker rs8099917, CC at marker rs12979860 and AA at marker rs12980275 are all associated with favourable treatment outcomes. These data have been confirmed in populations of different ancestry and HCV genotypes, and in various clinical scenarios. However, very few studies are available where all these novel pre-treatment variables are analysed together in multivariate models.
We sought to extend our understanding of the impact of these recently reported genetic polymorphisms on treatment outcome by investigating the independent association of candidate genetic (including the rs8099917, rs12979860 and rs12980275 markers), host (including IP-10 levels and HOMA-IR score) and viral factors on virological response in a cohort of treatment-naïve, nondiabetic Caucasian patients with chronic hepatitis C.
Abstract and Introduction
Abstract
Background Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue.
Aim To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC).
Methods Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study.
Results Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03–42.6), rs12980275 AA (OR 7.09; 1.97–25.56) and IP-10 (OR 0.04; 0.003–0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR = 0.02; 0.0009–0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44–27.18), age <40 years (OR = 4.79; 1.50–15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03–7.27) in HCV genotype 1 patients and rs12980275 AA (OR = 6.26; 1.98–19.74) and age <40 years (OR 5.37; 1.54–18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06–268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72–46.99) or genotype 3 patients (OR 7.8, 1.43–42.67).
Conclusions In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.
Introduction
Hepatitis C virus (HCV) infects up to 180 million people worldwide and is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. The current treatment, based on the combination of peginterferon alpha and ribavirin, leads to a sustained virological response (SVR) in ~40–50% in patients with HCV genotype 1 and in ~80% of those with genotype 2 or 3. Several baseline and on-treatment variables affect the likelihood of achieving SVR. Older age, advanced stage of fibrosis, African-American ethnicity and HCV- related factors, including HCV genotype 1 and high viral load at baseline, predict poor response to anti-viral therapy. Furthermore, metabolic factors, such as high body mass index (BMI), presence and severity of liver steatosis and increasing homeostasis model assessment of insulin resistance (HOMA-IR) score have been reported as negative predictors of response. On the other hand, early on-treatment kinetics of HCV RNA, e.g. undetectable HCV RNA at week 4, has a high positive predictive value of SVR.
Among the baseline predictors of response, the pre-treatment activation of IFN-stimulated genes (ISG) and the host genetic polymorphisms have been the subject of recent, major studies. Regarding ISG, it has been shown that low levels of intrahepatic and systemic CXC chemokine IFN-gamma inducible protein 10 kDa (IP-10, or CXCL10), a valid surrogate marker of ISG activation, predict a more pronounced first phase decline of HCV RNA during anti-viral therapy and increased SVR rates. On the other hand, several independent studies have consistently shown that single nucleotide polymorphisms (SNPs) near IL28B, which encodes the type III interferon IFN-λ3 are strongly associated with the response to treatment of chronic hepatitis C. In particular, the homozygous genotypes TT at marker rs8099917, CC at marker rs12979860 and AA at marker rs12980275 are all associated with favourable treatment outcomes. These data have been confirmed in populations of different ancestry and HCV genotypes, and in various clinical scenarios. However, very few studies are available where all these novel pre-treatment variables are analysed together in multivariate models.
We sought to extend our understanding of the impact of these recently reported genetic polymorphisms on treatment outcome by investigating the independent association of candidate genetic (including the rs8099917, rs12979860 and rs12980275 markers), host (including IP-10 levels and HOMA-IR score) and viral factors on virological response in a cohort of treatment-naïve, nondiabetic Caucasian patients with chronic hepatitis C.
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