The current standard of care for hepatitis C is pegylated inter feron (PEG IFN) used in combination with ribavirin

The current standard of care for hepatitis C is
pegylated inter feron (PEG IFN) used in
combination with ribavirin (RBV). Each
genotype responds differently to treatment.
The ideal outcome of treatment is a sustained
virological response (SVR), i.e. undetectable
hepatitis C virus (HCV) six months after
completing treatment. There are several well
known limitations in the effectiveness of IFN
alpha and RBV, and side effects.
A large number of patients have failed prior IFN
treatment. The overall SVR rates in retreated
non-responders are in the region of 20%.
Generally, those who responded to treatment
initially but then experienced a relapse of the
virus respond better than non-responders.
Although the primary goal of treatment remains
eradication of the virus, this goal may require
the advent of new direct antivirals rather than
retreatment with PEG IFN and RBV.
New treatments on the horizon
The limitations of IFN and RBV treatment have
necessitated a continuing search for improved
therapies. Important progress is being made
in the development of new treatments, in
particular new specific inhibitors or direct
antiviral agents active against hepatitis C.
There is an urgent need to develop improved
therapies for patients and to improve the
outcomes in prior non-responders to
treatment. A diverse range of targets are
being exploited for anti-HCV drug development.
Two protease inhibitors are at the most
advanced stage of development.
Protease inhibitors in advanced study:
VX950, (telaprevir) is a peptidomimetic
protease inhibitor. Proteases play a vital role
in the ability of the virus to reproduce. The job
of the protease inhibitor is to inter fere with
this process and can therefore speed up the
process of eradicating the virus, leading to
shorter treatment times. Encouraging results
in phase 2 studies have been reported. Large
phase 3 studies have been completed but not
yet analysed. The combination of telaprevir,
PEG IFN and RBV improves SVR rates
compared to PEG IFN and RBV (69% vs 46 %)
in IFN naïve genotype 1 patients. Telaprevir,
RBV and PEG IFN alpha will likely be dosed for
12 weeks, followed by a combination of PEG
IFN alpha and RBV for a further 12 weeks in
naive patients. A high percentage of patients
(approximately 80%) achieve a rapid viral
response (RVR) i.e. have undetectable HCV
RNA at 4 weeks with a triple combination of
telaprevir, PEG IFN and RBV; more than 90% of
IFN naive genotype 1 patients with
undetectable HCV RNA at week 4 are cured
after 6 months of therapy. RBV remains an
essential component of treatment. Flu-like
syndrome, nausea, diarrhea, pruritus, rash,
headache, insomnia, and anaemia have been
observed in telaprevir treated patients.
Antiviral resistance remains a limitation of the
drug. Dose modifications of RBV are required.
Severe rash has been noted in 5-7% of
telaprevir recipients, and although some
patients may respond to measures such as
topical cor ticosteroids, severe generalised
rash usually necessitates discontinuation of
telaprevir. The pathogenesis of the rash is
unknown, but eosinophilia has been noted. The
median time to onset of moderately severe
rash has been of the order of 7 weeks.
The PROVE 3 trial is a phase 2 study of
telaprevir; 453 previous non-responders
infected with genotype 1 HCV were randomised
to one of 4 treatment arms: 48 weeks of PEG
IFN and RBV (control), 24 weeks of PEG IFN
plus telaprevir (no RBV), 24 weeks of PEG IFN
plus RBV plus telaprevir followed by 24 weeks
of PEG IFN or RBV or 12 weeks of PEG IFN plus
RBV plus telaprevir followed by 12 weeks of
PEG IFN and RBV. 51% of patients treated for
12 weeks and 53% of patients treated with 24
weeks of triple therapy achieved SVR. 69 % of
relapsed patients show an SVR. Patients who
received PEG IFN plus telaprevir without RBV
achieved a relatively poor 24% SVR rate, further
establishing the importance of RBV. The SVR
rate among patients in the control arm of PEG
IFN and RBV was only 14%. (McHutchison JG, et
al. AASLD 2009. Abstract 66).
Several other protease inhibitors are in
development for the treatment of IFN naive and
experienced patients but the data is less
mature at this time.
The ideal duration of treatment remains to be
determined. Response guided therapy, i.e.
lengthening therapy for patients with slower
responses may be the guiding principle
particularly for prior non-responders.
Unfortunately peptidometic protease inhibitors
do not appear to be active against genotype 3
infections and have variable activity against
the remaining genotypes. Initial data indicates
that RBV will remain an essential constituent
of treatment with protease inhibitors for the
time being.
There is nonetheless hope that protease
inhibitors that are about to be licenced in 2011
will provide important changes to therapy and
will be rapidly approved as cost effective in the
UK.
Professor Geoffrey Dusheiko - Royal Free
Hospital and University College London
Medical School