Page 72 - The Flying Publisher Guide to Hepatitis C Treatment

72 | Hepatitis C Treatment

allosteric inhibition. HCV polymerase has at least four allosteric
binding pockets for nonnucleosidic inhibitors, unlike the HIV
reverse transcriptase where there is only a single one. Therefore,
if patients do not respond to one non-nucleoside inhibitor, there
is enough differentiation between the binding sites to allow the
use of a different drug within the class. Several non-nucleoside
HCV polymerase inhibitors are in clinical development. Most of
these investigational agents are active only against HCV
genotypes 1a and 1b and show a relatively high rate of
resistance, as well as an increased frequency of specific side-
effects. These observations suggest that their use could be
limited to combination with other DAAs (Table 4.2). Such an
approach was investigated for a low potent non-nucleoside
polymerase inhibitor (tegobuvir, formerly known as GS-9190) in
combination with a protease inhibitor (GS-9256) in treatment-
naive G1 HCV patients. The combination alone, without SoC was
not effective due to virologic rebound and selection of dual
resistance mutations that existed before treatment. Addition of
RBV alone significantly reduced the virologic breakthrough
rates.

Table 4.2 – Combinations of DAAs tested with or without PegIFN/RBV
Company DAA combination Phase
Vertex Telaprevir (PI*) + VX-222 (NNI†) II
Boehringer Ingelheim BI 201335 (PI) + BI 207127 (NNI) IIb
Bristol-Myers-Squibb BMS-650032 (PI) II
+ BMS-790052 (NS5A inhibitor)
Gilead GS-9256 (PI) + GS-9190 (NNI) II
Hoffmann-La Roche Danoprevir (R7227) (PI) + R7128 (NI‡) I
* PI: protease inhibitor
† NNI: non-nucleoside (polymerase) inhibitor
‡ NI: nucleoside (polymerase) inhibitor

NS5A inhibitors
NS5A is a membrane-associated phosphoprotein involved in
both the formation of the replication complex and in the virus
assembly. The most potent HCV NS5A inhibitor reported to date