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).
74 | Hepatitis C Treatment
The majority of DAAs have a low genetic barrier to resistance,
with the possible exception of nucleoside analogs inhibitors of
HCV polymerase.
There is broad cross resistance between drugs in the same
class, as has been shown for the two approved PIs, telaprevir and
boceprevir. Possible exceptions are the non-nucleoside
inhibitors of HCV polymerase that might be administered in
additive or synergistic combinations. The majority of patients
with virologic breakthrough during triple therapy with PIs
presented high-level resistant variants, these emerged more
frequently in the HCV genotype 1a patients (Kuntzen 2008);
predominant mutations were V36M and R155K compared to
A156T in genotype 1b. There is no information regarding the
possible archiving of drug resistant mutants in cellular
sanctuaries, as is the case for HIV. Emergence of resistance may
be limited by optimized pharmacokinetics of the DAAs and by
their use in combinations.