Report from EASL; The European Association for the Study of the Liver Conference, Rotterdam, April 28-May 3, 2000 - Report 13

HCV Primer & New Drugs in Development

HCV, like HIV, does not generally clear from a person like HBV. About of those 85% HCV infected develop persistant or chronic HCV. Why? It's possible that the immune system is unable to adequately recognize or respond to HCV. An immune response seen in other diseases where CTLs (cytotoxic T lymphocytes) can recognize an invader may not be able to be mounted in HCV. Infected cells  may not be less likely to be recognized by virus-specific CTLs. Like in HIV HCV has been found to be genetically diverse with individual distinct sequences. I think it appears uncertain whether viral persistance permits such evolution or if this evolution encourages viral persistance by an ineffective immune response. Because there is considerable genetic diversity among different strains of HCV, development of an HCV vaccine may become more challenging. It's possible that HCV, like other virsuses, may have evolved specific mechanism sfor evasion of the host immune system. It appears HIV accomplishes this by invading the CD4 cells, the very cells that might assist in mounting an effective immune response. It's been suggested that HCV could interfere with the host immune response which could stimulate a natural interferon by a person's immune system. Interferon exists naturally in people. HCV may create a cellular environment within which interferon antiviral responses may be rendered ineffective.  There may be several causes for viral persistance not just one cause.

How does interferon work. Although it has a clear antiviral effect, I think it's unclear whether this is due direct suppression of viral replication or enhanced immunologic suppression of viral replication due to immunomodulatory action of interferon. Even if a person does not achieve full viral suppression at least a transient improvement in fibrosis and reduction in hepatic inflammation appears to occur. This suggests that interferon, I think, may have a significant effect on disease progression even if viral load response is limited. I think it remains uncertain if there is a long term clinical benefit of apparent improved fibrosis. For example, can this improvement without a viral response (complete non-response or partial response or relapse) translate into reduced incidence of decompensated cirrhosis and HCC? The mechanism of action for ribavirin remains uncertain as several theories have been offered. There is a difference of opinion on whether ribavirin exerts influence in early therapy or around 24 weeks.

New Drugs in Development for HCV

The benefit of interferon monotherapy was limited and so the addition of ribavirin improved viral response. Data on pegylated interferon shows it offers an improvement in virologic response to regular interferon. It's assumed this will translate into clinical long term improvement. Small clinical trials have shown individuals out to 10 years still have undetectable HCV-RNA after achieving undetectable HCV-RNA 6 months after cessation of therapy. However, its generally agreed that new treatments are needed to further improve treatment. A number of research efforts are focusing on the following potential new therapies.

Maxima appears to be an immune therapy. Preliminary studies of Maxima+interferon in HCV infected individuals suggest it may offer a new therapeutic approach.

…        Antisense is in a small clinical trial in HCV infected.

…        Ribozymes are an antiviral that are in an initial clinical trial in HCV uninfected.

…        VX-497 works similarly to ribavirin and Vertex says it may be more potent and have less side effects than ribavirin. VX-497 is in human clinical trials.

Targets for Antiviral therapy include:

…        NS3 protease

…        NS3 helicase

…        NS5B Polymerase

…        IRES

These potential targets are being explored and screening for potential drug candidates are likely in progress or planned.