Therapeutic perspectives for hepatitis C

Abstract

OverviewHepatitis C virus (HCV) is represented by a single open reading frame of single-stranded RNA comprising approximately 3000 AA, positioned between 3' and 5' noncoding extremities. Transcription from the 5' end results in a compound polyprotein, generated by structural proteins in the amino-terminal region extremity and by nonstructural proteins in the opposing terminal region. Post-transcription cleavage by viral and host cell proteases generates 10 individual HCV proteins [1]. The HCV cDNA clone was first described in 1989. Subsequently, counter to the expectations of an enormous breakthrough, there was a hiatus in the growth of knowledge regarding the molecular virology of this virus. Only in 1997 was the first functioning and complete HCV cDNA clone described and used in animal models (chimpanzees) for preliminary analyses of the viral expression using biotechnological tools. A milestone in the study of viral molecular biology was the description, in 1999, of a viral culture model in tumor cells (Huh 7) using a HCV 1b subgenomic replicon. Based on this model, despite strict limitations, other viral fragments were used in order to evaluate the dynamics of viral replication in different settings and with exposure to antiviral agents. Nevertheless, the inability to obtain a complete HCV sequence remains an obstacle to be overcome [1].One characteristic of HCV is that is has minimal cytopathic effects, with immunomediated hepatotropic injury. However, it is also found in extrahepatic sites, where it has a short halflife (approximately 3 hours) and high serum turnover [2]. Standard treatment involves the administration of pegylated interferon alpha together with ribavirin. This treatment regimen has had modest success, a little over 50% [3], reaching 71% in cases of dose optimization and full compliance [4]. However, it could be much less, if we consider real life data, as well as characteristics of the host (race, comorbidities, immune state), of the liver disease (level of fibrosis and steatosis), of the medication (dose, interferon type) and of the virus itself. In addition, it is well known that genotype 1 has a lower response rate, and certain viral proteins can subvert the stimulus induced by interferon and ribavirin [3]. Viral kinetics, the evaluation of the decay pattern of the viremia -in terms of intensity and speed -after the initiation of the therapy, has proven to be a useful tool in the management of patients. It demonstrates the interaction among virus, drug, and host, in a relatively simple way: intense, rapid decay indicates a favorable case; insignificant, slow decay indicates cases that are unfavorable, moderate or intermediate. Such kinetic patterns allow patients to be characterized as rapid responders, slow responders, or nonresponders. This approach allows the treatment to be individualized, with ideal doses per weight and shorter, standard, or extended duration. In addition, it allows early prediction of treatment response. Therefore, individualized therapy constitutes the best thera...