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Abstract and Introduction
Abstract
Genetic factors can influence the outcome of antiviral therapy in chronic hepatitis C (HCV). We evaluated the role of interleukin-28B single nucleotide polymorphisms (SNPs) and inosine triphosphatase (ITPA) gene variants in HCV cirrhosis treated with Peg-Interferon and ribavirin. A prospective cohort of 233 patients with compensated cirrhosis received 1–1.5 μg/kg/week of Peg-Interferon alpha-2b plus 1000–1200 mg/day of RBV for 48 weeks. A sustained virologic response (SVR) was achieved in 27% of patients. On multivariate logistic analysis, the absence of oesophageal varices (OR 3.64 CI 95% 1.27–10.44 P = 0.016), infection with genotype 2 or 3 (OR 4.06, CI 95% 1.08–15.26, P = 0.038), C/C alleles of rs12979860 SNP (OR 7.04, CI 95% 2.40–20.72, P < 0.001) and rapid virologic response (RVR) (OR 78.29, CI 95% 16.07–381.29, P < 0.001) were independently associated with SVR. Patients who experienced post-treatment relapse received lower total doses of Peg-Interferon (52.0 ± 15.8 μg/kg vs 65.7 ± 13.3 μg/kg, P < 0.001) and lower total dose of RBV (3829 ± 1210 mg vs 4709 ± 954 mg, P < 0.001) than patients who achieved an SVR. ITPA variants predictive of high ITPase activity were associated with reduction of haemoglobin ≥3 g/dL in the first 4 weeks (P < 0.001), and with reduction of haemoglobin <10 g/dL (P = 0.03) on treatment. In conclusion, combination therapy with Peg-Interferon and RBV in patients with HCV cirrhosis must be guided by virus genotype, severity of portal hypertension, favourable IL-28B polymorphisms and ITPA variants, and RVR on treatment.
Introduction
The prevalence of hepatitis C virus (HCV) cirrhosis and the incidence of its complications have increased recently in several countries because of the long-term persistence of HCV infection. Identification and treatment of patients with HCV cirrhosis can reduce the number of cases of decompensation and hepatocellular carcinoma (HCC). There are few data on the efficacy and safety of combination therapy with Peg-Interferon (Peg-IFN) and ribavirin (RBV), in cirrhosis with portal hypertension, because these patients have been excluded from randomized controlled trials. Host factors such as age, gender, staging of liver fibrosis and steatosis, HCV genotypes, baseline HCV RNA levels and rapid disappearance of serum HCV RNA can influence the rate of sustained virologic response (SVR).
Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) located in and near the interleukin-28B (IL-28B) locus, which encodes for IFN-λ3 and is associated with a higher rate of SVR. Two genetic variants of rs1127354 and rs7270101 SNPs in the inosine triphosphatase (ITPA) gene, which encode a protein that hydrolyses inosine triphosphate (ITP), have been found to be associated with anaemia in patients treated with Peg-IFN and RBV.
As patients with cirrhosis have a low SVR rate and frequently have adverse events, it may be relevant to identify factors associated with higher probability of viral clearance, and to assess a patient's likelihood of SVR.
We studied a large prospective cohort of patients with compensated HCV cirrhosis to assess the safety and the efficacy of Peg-IFN and RBV, and to evaluate the association between virus-, genetic- and disease-related factors and SVR and the incidence of adverse events.
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