Page 73 - The Flying Publisher Guide to Hepatitis C Treatment

Searching for new antiviral therapies | 73

is BMS-790052, currently in phase II clinical trial in combination
with SoC. It was also used in combination with a protease
inhibitor (BMS-650032) for retreatment of previous non-
responders to SoC with good results, but only in association with
PegIFN/RBV. Exclusion of SoC from the therapeutic regimen
resulted in high rates of viral breakthrough through week 12.

Host cyclophilins inhibitors
Another interesting therapeutic approach is directed at host
factors important in the viral life cycle. The most promising
target are cyclophilins, a family of highly conserved cellular
peptidyl-prolyl isomerases (PPIase) involved in many cellular
processes such as protein folding and trafficking. Cyclophilin
inhibitors block the interaction of cyclophilins with HCV
proteins and hence the formation of a functional viral
replication complex. Currently, several non-immunosuppressive
cyclosporin analogs are being tested. The most potent seems to
be Alisporivir (Debio-025), tested in both HCV monoinfected
and HIV/HCV coinfected patients with promising results. The
combination of Debio 025 and PegIFN-ɑ2a showed a significant
VL reduction after 28 days in patients infected with genotypes 1,
3 and 4 (Flisiak 2009). Such host protein-targeting compounds
have the advantage of higher genetic barriers to resistance and
could be instrumental in future IFN-free regimens (Table 4.3).

Emergence of drug resistant mutations
High levels of baseline drug resistance mutations in the NS3
protease or NS5B polymerase were identified in a significant
number of viral isolates from treatment-naive patients.
Moreover, there seem to be differences between HCV
genotypes/subtypes in terms of the frequencies of baseline
mutations and natural polymorphisms which can translate into
distinct susceptibility to DAAs. An overlap of immune escape and
drug resistance profiles has also been reported (Gaudieri 2009).