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Hepatitis C virus (HCV) RNA serum concentration, quasispecies complexity, and sequence and phylogenetic analysis of the nonstructural 5A gene (NS5A) interferon sensitivity determining region (ISDR) were determined in pretreatment serum samples from 47 patients with chronic hepatitis C (36 infected by HCV genotype 1b and 11 by 3a). Among HCV genotype 1b-infected patients, virus load was lower (P = .003) and the number of NS5A-ISDR amino acid changes was higher (P = .001) in long-term responders than in non-long-term responders, but there were no differences in quasispecies complexity. Multivariate analysis showed a close association between response to interferon and NS5A-ISDR phenotype. Phylogenetic analysis showed that isolates from non-long-term responders clustered apart from the majority of isolates from long-term responders. There was no association between virologic features and therapeutic response in HCV genotype 3a-infected patients. In conclusion, low virus load and mutant NS5A-ISDR phenotype are closely associated with long-term response to interferon in HCV genotype 1b- but probably not in 3a-infected patients.

In patients with chronic hepatitis C, the influence of the genetic heterogeneity of the hepatitis C virus (HCV) on the progression of liver disease and on the responsiveness to interferon therapy is a matter of controversy. In this study we evaluated the genetic complexity of HCV by singlestrand conformation polymorphism (SSCP) analysis of amplicons from the hypervariable region 1 (HVR1) in 168 patients with chronic genotype 1b HCV infection, of whom 122 received a single course of interferon therapy (3 MU, three times weekly for 6 months). No correlation was observed between the degree of genetic complexity of HCV (indicated by the number of bands in the SSCP assay) and patient age, serum alanine aminotransferase activity, or serum HCV-RNA concentration, measured by competitive polymerase chain reaction. HCV genomic complexity was not related to gender nor to the presumed source of infection. The number of SSCP bands detected in serum samples from patients with chronic hepatitis, either mild (8.1 ؎ 3.9), moderate (8.0 ؎ 3.3), or severe (9.2 ؎ 3.3), and in patients with liver cirrhosis, either compensated (8.0 ؎ 2.9), decompensated (6.3 ؎ 2.9), or with superimposed hepatocellular carcinoma (9.5 ؎ 2.9), was similar. The number of SSCP bands detected in patients with sustained response (7.5 ؎ 3.9), transient response (8.3 ؎ 2.9), or no response (8.2 ؎ 3.6) to interferon administration was similar as well. These observations suggest that the genetic complexity of hypervariable region (HVR1) of HCV, as estimated by SSCP analysis, is not related to the severity of liver injury nor to the type of response to interferon therapy. The hepatitis C virus (HCV) is an RNA virus that replicates with a high rate of mutation, 1 which is particularly evident in the hypervariable region 1 (HVR1) of the N-amino terminal region of the second envelope domain of the viral genome. 2,3 Under the influence of environmental factors, continuous viral mutation gives raise to a mixed and changing population of mutants, which is known as quasispecies. 4 As in infections with other RNA viruses, the quasispecies nature of HCV 5 may have important biological implications concerning viral persistence, pathogenicity, and resistance to antiviral agents. However, attempts aimed to define the relationship between clinical aspects of chronic HCV infection and the genetic heterogeneity of the infecting virus have provided conflicting results.By sequence analysis of HVR1, greater nucleotide sequence diversity between HCV variants was shown in isolates from patients with more advanced liver disease, 6 but this finding has not been confirmed by others. 7 Studies based on singlestrand conformational polymorphism (SSCP) analysis of HVR1 derived amplicons have also provided controversial data. In 1995, Koizumi et al. 8 found that the viral populations were more heterogeneous in patients with hepatic cirrhosis or hepatocellular carcinoma than in those with chronic hepatitis, but other studies did not disclose a clear association between the degree of HCV qu...

Chronic hepatitis C virus infection is a global problem worldwide due to the lack of an effective therapy (the current standard of care treatment is effective in about 40-50% of the cases), and the difficulties in developing a protective vaccine. Chronic infection progresses to end-stage liver disease and liver failure in a considerable number of infected individuals. Once liver function is compromised, the only reliable therapeutic intervention is liver transplantation. Unfortunately, re-infection of the graft is unavoidable, and a new chronic hepatitis is early established in transplant recipients, that can result in graft loss. Thus, there is an urgent need for new, specifically targeted therapies for the treatment of HCV chronic infection. Among the viral proteins, the NS3/4A protease and the NS5b RNA-dependent RNA-polymerase, essential for the virus life cycle, have concentrated the efforts in the development of new antivirals, and some promising ones have already entered clinical trials. In particular, inhibitors of the HCV NS3/4A protease are the most advanced in clinical development. This review summarizes the available data for the most important HCV NS3/4A protease inhibitors in development, the most recent patents of these type of compounds, the envisioned options for future HCV therapies, and the eventual impact of HCV genetic variability on resistance to new NS3/4A protease inhibitors.

The effect of hepatitis C virus (HCV) genetic heterogeneity on clinical features of post-transplantation hepatitis C is controversial. Different regions of the HCV genome have been associated with apoptosis, fibrosis, and other pathways leading to liver damage in chronic HCV infection. Besides, differences in immunodominant regions, such as NS3, may influence HCV-specific immune responses and disease outcome. In the liver transplant setting, a recent study has reported a positive association between HCV-1b Core region genetic relatedness 5-year post-transplantation and histological severity of recurrent hepatitis C. We have compared nucleotide sequences of HCV Core, NS3 and NS5b regions in HCV-1b-infected patients 3 years post-transplantation (n = 22). A cohort of nontransplanted patients (n = 22) was used as control of natural chronic HCV-1b infection. Histological evaluation was used to define the rate of fibrosis progression. Molecular variance analysis did not show significant differences in HCV sequences between transplanted and nontransplanted patients, or between those with fast or slow fibrosis progression. The same results were obtained when analysing phylogenetic trees for Core, NS3 and NS5b regions. A more appropriate clustering method (using minimum spanning networks) revealed a significant positive relationship between HCV genetic similarity in Core (r = 0.550, P < 0.01) and NS5b regions (r = 0.847, P < 0.01) and the yearly rate of fibrosis progression in nontransplanted patients which, in contrast, was not observed in transplanted patients. Our results indicate that some strains of HCV-1b might be more pathogenic in the natural course of chronic infection by this virus subtype. In the liver transplant setting, when the immune response is severely compromised, other mechanisms are probably more important in determining hepatitis C progression.

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