HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease

Background&Aims: Hepatocellular carcinoma (HCC) is a main cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) due to chronic hepatitis C and who have achieved sustained virologic response (SVR). We elaborated risk stratification algorithms for de-novo-HCC-development after SVR and validated them in an independent cohort. Methods: Derivation cohort: 527 patients with pre-treatment ACLD and SVR to interferon-free therapy were evaluated for de-novo-HCC-development. Among others, alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. Validation cohort: 1500 patients with compensated ACLD (cACLD) from other European centers. Results: During a median follow-up (FU) of 41 months, 22/475 cACLD (4.6%) (1.45/100patient-years)vs.12/52 decompensated patients (23.1%, 7.00/100patient-years, p<0.001) developed de-novo-HCC. Since decompensated patients were at substantial HCC-risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de-novo-HCC-development during FU than pre-treatment-values or absolute/relative changes. Models based on post-treatment AFP≥4.6ngxmL-1-3points, alcohol consumption (males:>30g/d/females:>20g/d)-2points (optional), age≥59year-2points, LSM≥19.0kPa-1point, and albumin<42gxL-1-1point, accurately predicted de-novo-HCC-development (bootstrapped Harrel’s C with and without considering alcohol:0.893 and 0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low-(0-3points; ≈2/3 of patients) and high-risk (≥4points; ≈1/3) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk:0%vs.16.5%) and validation (3.3%/17.5%) cohorts. An alternative approach based on age/alcohol (optional)/FU-LSM/FU-albumin (i.e., without FU-AFP) also showed a robust performance. Conclusions: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol, accurately stratified de-novo-HCC-risk in cACLD patients with SVR. Approximately 2/3 were identified as having an HCC-risk <1%/y in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC-surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately 2/3) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound

Impact of IL-28B polymorphisms on pegylated interferon plus ribavirin treatment response in children and adolescents infected with HCV genotypes 1 and 4

IL-28B polymorphisms are predictors of response to therapy in adults infected with hepatitis C. We do not know whether they are markers of response to therapy in children and adolescents. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the IL-28B gene could influence the probability of response to therapy compared with other known baseline prognostic factors and correlate with clinical findings in pediatric patients infected with hepatitis C virus (HCV) genotypes 1 or 4. We determined three SNPs of IL-28B (rs12979860, rs12980275, and rs8099917) in 82 patients with chronic HCV infection treated with pegylated interferon alpha and ribavirin (peg-IFNα/RBV). Treatment response and clinical data were analyzed. Overall, sustained virological response (SVR) was achieved by 45 % of patients infected with difficult-to-treat HCV genotypes 1 and 4. Except for IL-28B polymorphisms, there was no association of SVR with any other clinical data. IL-28B rs12979860 CC [odds ratio (OR), 6.81; p = 0.001] and rs8099917 TT (OR, 3.14; p = 0.013) genotypes were associated with higher SVR rates. IL-28B rs12980275 was not significantly associated with SVR ( p = 0.058). Only the distribution between CC and CT-TT genotypes of rs12979860 significantly differentiated patients achieving early virological response (EVR) (OR, 10.0; p = 0.011). Children with the rs12979860 CC genotype had significantly higher baseline viral load compared with CT-TT patients ( p = 0.010). In children and adolescents chronically infected with HCV genotypes 1 and 4, IL-28B rs12979860 and rs8099917 polymorphisms were the only predictors of response to peg-IFN/RBV

IL28B SNP rs12979860 Is a Critical Predictor for On-Treatment and Sustained Virologic Response in Patients with Hepatitis C Virus Genotype-1 Infection

Single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) have received considerable interest for their association with sustained virological response (SVR) when treating patients of genotype-1 hepatitis C virus (GT1-HCV) chronic infection with pegylated interferon and ribavirin (PegIFN/RBV). This study was to investigate the predictive power of IL28B SNPs for on-treatment responses and SVR in treatment-naïve patients with GT1-HCV chronic infection.We analyzed ten SNPs of IL28B in 191 treatment-naïve patients with GT1-HCV chronic infection who received PegIFN/RBV. In these patients, rapid virological response (RVR), early virological response (EVR) and SVR were achieved in 69.6%, 95.8% and 68.6% of the patients, respectively. Multivariate analysis (odds ratio; 95% confidence interval; P value) indicated age (0.96; 0.93-0.99; 0.012), low baseline viral load (4.65; 2.23-9.66; <0.001) and CC genotype of rs12979860 (7.74; 2.55-23.53; <0.001) but no other SNPs were independent predictors for SVR. In addition, none of the ten SNPs examined were associated with baseline viral load and stages of liver fibrosis. Regarding RVR, low baseline viral load (2.83; 1.40-5.73; 0.004) and CC genotype of rs12979860 (10.52; 3.45-32.04; <0.001) were two critical predictors. As for EVR, only CC genotype of rs12979860 (36.21; 6.68-196.38; <0.001) was the predictor. Similarly, for end of treatment response (ETR), CC genotype of rs12979860 (15.42; 4.62-51.18; <0.001) was the only predictor. For patients with RVR, only low baseline viral load (3.90; 1.57-9.68; 0.003) could predict the SVR. For patients without RVR, only rs12979860 (4.60; 1.13-18.65; 0.033) was the predictor for SVR.rs12979860 is the critical predictor for RVR, EVR, ETR and SVR in treatment-naïve patients of GT1-HCV chronic infection. Furthermore, this SNP is the only predictor for SVR in patients without RVR. These results have provided evidence that rs12979860 is the ideal IL28B SNP for genetic testing in treating patients of GT1-HCV chronic infection

Relation of IL28B Gene Polymorphism with Biochemical and Histological Features in Hepatitis C Virus-Induced Liver Disease

BACKGROUND/AIMS: Polymorphism at the IL28B gene may modify the course of hepatitis C virus (HCV) chronic infection. Our aim was to study the influence of IL28B rs12979860 gene polymorphism on the biochemistry and pathology of HCV-induced disease in the clinical course from mild chronic hepatitis C to hepatocellular carcinoma. METHODS: We have determined the rs12979860 single nucleotide polymorphism (SNP) upstream IL28B gene in two groups of patients with HCV-induced chronic liver disease: 1) 268 patients (159 men) with biopsy-proven chronic hepatitis C, to analyse its relation with biochemical, virological and histological features; and 2) 134 patients (97 men) with HCV-related hepatocellular carcinoma. The distribution of the analysed SNP in hepatocellular carcinoma patients was compared with that found in untreated chronic hepatitis C patients. All patients were white and most were Spaniards. RESULTS: In multivariate analysis ALT values were higher (P = 0.001) and GGT values were lower (P<0.001) in chronic hepatitis C patients homozygotes for the major rs12979860C allele as compared with carriers of the mutated rs12979860T allele. Steatosis was more frequent (Odds ratio = 1.764, 95% C.I. 1.053-2.955) and severe (P = 0.026) in carriers of the rs12979860T allele. No relation was found between the analysed SNP and METAVIR scores for necroinflammation and fibrosis, and there were no differences in the distribution of the analysed SNP between hepatocellular carcinoma and untreated chronic hepatitis C patients. CONCLUSION: The IL28B rs12979860 polymorphism correlates with the biochemical activity and the presence and severity of liver steatosis in chronic hepatitis C

The Impact of Host Factors on Management of Hepatitis C Virus

The Seventh Edition of Fundamentals of Modern Property Law retains the highly successful problem method that has long characterized this landmark casebook: students take on the role of the lawyer in fact-rich hypothetical problems (Assignments) with multiple legal issues. Each Assignment builds students\u27 lawyering skills of analysis and problem solving, as they master the fundamental principles and doctrines of property law. In addition, many Assignments are ideal for instructor-designed simulations of other professional skills, such as client interviewing and counseling, negotiation, oral advocacy, drafting, and objective and persuasive writing. The Seventh Edition continues the book\u27s emphasis on emerging issues of environmental sustainability. The Seventh Edition also provides a comprehensive introduction to Intellectual Property law and emphasizes the art of planning to avoid controversy, in contrast to the typical first year curricular focus on resolving existing controversies