Page 65 - The Flying Publisher Guide to Hepatitis C Treatment

Searching for new antiviral therapies | 65

combination therapies including DAAs (most of which are also
associated with a certain degree of anemia) remains to be seen.

Direct-Acting Antivirals (DAAs)

Direct-acting antivirals (DAAs), also known as “specifically
targeted antiviral therapy for hepatitis C” (STAT-C), are the most
important new therapeutical options for CHC. In May 2011, two
HCV protease inhibitors Telaprevir (Incivek™) and Boceprevir
(Victrelis™) have been approved by the FDA. For the first time,
we have now drugs with specific anti-HCV activity. Several other
DAAs are at various stages of clinical development, the most
advanced being alternative protease inhibitors and nucleoside
and non-nucleoside polymerase inhibitors. Other tentative
approaches include inhibitors of host cyclophilins, alpha-
glucosidase inhibitors, oligonucleotides and immune modulators
(Soriano 2009).

Protease inhibitors (PIs)
A clear understanding of the key sites of action for the newer
antiviral compounds in development is of outmost importance.
HCV is a positive-sense single-stranded RNA virus, meaning that
its genome can function directly as a template for viral protein
synthesis. Consequently, after entering into hepatocytes, HCV
starts its replication by direct translation of the genome into a
large polypeptide that is further processed by the virus NS3
protease. This enzyme has dual activity of serine protease and of
helicase (unwinding the single-strand viral RNA). Together with
the NS4A cofactor, the NS3 protease is responsible for
proteolytic cleavage of its downstream nonstructural proteins
that in turn are critical in forming the replicative complex from
which viral synthesis occurs. Additionally, NS3 protease may
directly impair host IFN responses through the inhibition of
phosphorylation of IFN regulatory factor-3, and administration
of PIs may restore interferon responsiveness.