What does the future hold?

In the near future, trials of SoC plus STAT-C will be initiated in
difficult-to-treat populations (patients with advanced liver
disease, cirrhosis, recipients of liver transplantation or patients
with major comorbidities such as HIV coinfection). It remains to
be seen if there are safer regimens with less drug interactions,
especially with antiretroviral drugs (Seden 2010). As shown in
chapter 1, race is an important determinant of the therapy
response; as a consequence new HCV therapies should be also
studied in Asian, Afro-american and Latino populations in order
to fully characterize their efficacy and safety.
The predictive value of on-treatment viral kinetics will require
re-evaluation for the DAAs and their combinations. Although
evaluation of SVR at 6 months after treatment completion will
remain the gold standard for treatment success, there is growing
evidence indicating that SVR at 12 weeks after treatment
completion may be enough to predict long-term viral clearance.
Searching for new antiviral therapies | 75
Preliminary data show that DAAs induce a more rapid decline in
the VL than the one seen with PegIFN/RBV.
Table 4.3 – The most promising new therapeutical options for CHC
(as of June 2011) *
Category Mechanism Example Manufacturer Phase
BI201335 Boehringer III
TMC435 Medivir/Tibotec III
GS-9256, -9451 Gilead II
Danoprevir Intermune/Roche II
Vaniprevir Merck II
NS3/NS4A
protease
inhibitors
ACH-1625 Achillon Pharm. II
ABT 450 Abbott/Enanta II
BMS-650032 Bristol-Myers Squibb IIa
Mericitabine Roche/Pharmaset II
PSI-7977 Pharmaset II
IDX 184 Idenix II
NS5B polymerase
inhibitors,
nucleoside
analogs
Filibuvir Pfizer II
GS-9190 Gilead II
VX 222 Vertex II
ABT 333, -072 Abbott II
Setrobuvir Anadys Pharm. II
NS5B polymerase
inhibitors,
non-nucleoside
analogs
BMS-790052 Bristol-Myers Squibb II
ABT 267 Abbott II
AZD 7295 AstraZeneca II
Direct-acting
antivirals
NS5A inhibitors
Cyclophilins
inhibitors
Alisporivir Novartis/Debiopharm III
MBL-HCV1
human
monoclonal
antibody
The University of
Massachusetts Medical
School
Virus entry II
inhibitors
ITX 5061 iTherX II
Host
targeting
agents
Bavituximab Peregrine Pharm. II
* For more information, see http://hcvdrugs.com and the manufacturers' web
sites presented at the end of the chapter.
76 | Hepatitis C Treatment
Resistance testing is likely to become a part of the treatment
algorithm with the introduction of DAAs. Extensive knowledge of
the impact of these mutations on the phenotypic characteristics
and on the replicative fitness of the viral population will be
important (Kuntzen 2008) in order to tailor therapeutic decisions
for the management of the HCV infected patient.
It is expected that the HIV model of development of highly
active combined therapies, consisting of at least 3 drugs with
different mechanisms of action will be reproduced for HCV, in an
attempt to obtain effective interferon-free regimens. With such
combinations, HCV may become the first chronic viral infection
to be cured. While sufficient suppression of HIV RNA and HBV
DNA can only be achieved by long-term administration of potent
antiviral drugs, HCV RNA may be completely eradicated from the
infected individual after a limited duration of treatment. This is
foreseeable due to the fact that, unlike HIV (that replicates
through a proviral DNA subsequently integrated into the
lymphocytes nucleus), or HBV (that replicates through a cccDNA
that may integrate into the hepatocyte nucleus), HCV replication
is entirely intra-cytoplasmic and is not accompanied by the
establishment of extrahepatic reservoirs. In a viral kinetic model
for the pharmacokinetics of telaprevir, a rapid decrease in the
second slope of viral decline was found, four fold higher than
with standard interferon therapy. According to these data, a
combination triple therapy administered for 7-10 weeks might
be sufficient to eradicate the virus in fully compliant patients
(Guejd 2011). Patients who ultimately fail to clear the virus with
combination STAT-C regimens may still have improvements in
liver histology that can be further sustained by introduction of a
separate group of anti-fibrotic agents.