NS3 genetic variability in HCV genotype-1b isolates from liver specimens and blood samples of treatment-naive patients with chronic hepatitis C

Background: Two distinct inhibitors of the HCV protease have been approved for the treatment of patients infected with HCV genotype-1. These drugs are highly efficient in suppressing HCV replication; however, their use is limited by the emergence of viral mutants resistant to them after a very short time of treatment. By analysing blood samples, it was shown that viral strains resistant to protease inhibitors (PIs) may exist prior to treatment. The aim of this study was to investigate the presence of viral variants resistant to PIs in isolates from liver and blood of HCV patients naive to any antiviral therapy. Methods: Liver and blood HCV genotype-1b isolates from 10 patients with chronic hepatitis were analysed by cloning and sequencing procedures. Results: The analyses of 10-15 clones from liver isolates of each patient showed that 7/10 cases had single or multiple mutations potentially conferring resistance to PIs. However, the analysis of the corresponding blood samples excluded the presence of these mutations in all cases but one, which had the Q80R mutation in all clones from both liver and plasma samples. No PI-resistant variants were detected in isolates from either liver or plasma samples of three patients. Conclusions: Naturally occurring HCV variants resistant to PIs are commonly present at the intrahepatic level and this clearly explains their usual, very early emergence under treatment; however, the identification of these variants as circulating viral populations is not unusual in untreated patients.