Report from EASL; The European Association for the Study of the Liver Conference, Rotterdam, April 28-May 3, 2000 - Report 13
Primer & New Drugs in Development
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.
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
Drugs in Development for HCV
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.
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.
an antiviral that are in an initial clinical trial in HCV uninfected.
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.
for Antiviral therapy include:
potential targets are being explored and screening for potential drug candidates
are likely in progress or planned.