Hepatitis C Virus Deletion Mutants Are Found in Individuals Chronically Infected with Genotype 1 Hepatitis C Virus in Association with Age, High Viral Load and Liver Inflammatory Activity.

Hepatitis C virus (HCV) variants characterized by genomic deletions in the structural protein region have been sporadically detected in liver and serum of hepatitis C patients. These defective genomes are capable of autonomous RNA replication and are packaged into infectious viral particles in cells co-infected with the wild-type virus. The prevalence of such forms in the chronically HCV-infected population and the impact on the severity of liver disease or treatment outcome are currently unknown. In order to determine the prevalence of HCV defective variants and to study their association with clinical characteristics, a screening campaign was performed on pre-therapy serum samples from a well-characterized cohort of previously untreated genotype 1 HCV-infected patients who received treatment with PEG-IFNα and RBV. 132 subjects were successfully analyzed for the presence of defective species exploiting a long-distance nested PCR assay. HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%). Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver. While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.

Interleukin 28B genotype and insulin resistance in chronic hepatitis C patients.

BACKGROUND: In patients with chronic HCV infection, an association between IL28B genotype and insulin-resistance (IR), known predictors of sustained virological response (SVR) to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, has been reported. The aim of this study was to investigate the association of IR and IL28B genotype in two cohorts of well-characterized HCV patients. METHODS: A total of 480 non-diabetic HCV patients were analysed: 391 patients who received PEG-IFN/RBV in the MIST study and 89 previously reported patients followed at a metabolic liver diseases centre (Division of Internal Medicine, Fondazione IRCCS Ospedale Maggiore Policlinico, Milan, Italy). All were tested for IL28B rs12979860 single nucleotide polymorphism by real-time PCR and had IR measured by HOMA-IR. Staging of liver disease through liver biopsy was available for all patients. RESULTS: Overall, 164 patients (34%) were IL28B CC. Mean HOMA-IR values (±sd) did not differ according to IL28B genotype, being respectively 1.14 ±0.79 in CC versus 1.14 ±0.78 in CT/TT (P=1.0) in the first, and 2.4 ±1.0 versus 2.5 ±1.0 (P=0.7) in the second cohort. HOMA-IR>2 was not associated with IL28B genotype: 16/132 (12%) CC versus 31/259 (12%) CT/TT (P=1.0) in the first cohort and 16/32 (50%) versus 37/57 (65%; P=0.18) in the second. This held true also when using different HOMA cutoffs (>2.5, >3.0, >3.5 and >4.0). In the MIST cohort, HOMA-IR>2 did not influence treatment outcome, SVR rates being 28/47 (60%) in HOMA-IR>2 versus 214/344 (62%) in HOMA-IR≤2 (P=0.8). IL28B genotype was a strong predictor of SVR: 84% (111/132) in CC versus 51% (131/259) in CT/TT patients (P<0.0001). CONCLUSIONS: In two cohorts of non-diabetic HCV patients where IL28B genotype predicted treatment outcome, we found no association between IL28B genotype and HOMA-IR.