TREATMENT OF HEPATITIS C IN 2011

Abstract

New knowledge on the treatment of Hepatitis C is accruing at an extraordinarily rapid rate and my
aim in this editorial based on a talk I gave at the Pakistan Society of Gastroenterology Annual
International Congress this year, is to outline how patients may be treated both currently and over
the next two to three years.
One aspect is certain, namely, that careful
documentation is essential in determining the optimal
course of therapy for an individual patient. The first
key event to be documented in a patient being given
treatment is whether a rapid virological response
(RVR) is obtained with a negative HCV RNA at 4
weeks. Seen in around 20% only of genotype I
infections, frequencies are considerably higher with
genotype II and III. A RVR predicts an 80-90%
chance of obtaining a sustained virological response
(SVR) which is the ultimate goal of treatment. The
next key measurement is at 12 weeks -the early
virological response (EVR). A complete EVR with
RNA negativity is also highly predictive of an SVR
whereas with a partial EVR will achieve this. No
response makes later clearance of the virus very
unlikely and in clinical practice is usually taken as an
indication for discontinuing therapy. Slow and nonresponders with either some or no reduction in viral
load at 24 weeks are also important to define as even a
partial response to antiviral therapy may lead to
improvement in histological appearances and to
reduced frequency in later life of HCC.1
Being able to confidently predict the chances of,
or of not, obtaining an SVR before starting on treatment
with all the attendant side effects, would represent a major
advance. Distinct gene signatures in liver tissue and
blood have been reported and there are many papers
currently on IL-28B gene polymorphisms involved in
regulation of the host's innate immune responses. The
chances of an SVR are much higher for the CC genotype
than for CT and TT genotypes.2 Response rates are even
less with the combination of an unfavourable IL-28B and
a high serum level of interferon gamma inducible protein
which interferes with Interferon signalling pathways in
the liver. Such pre-treatment prediction may still be
helpful with the higher responses obtainable from the new
protease and polymerase inhibitor drugs.
Whether IFN alpha-2a or 2b is used marks little
difference. What is important in the current standard of
care treatment regime is an adequate dosage of Ribavirin
as this agent has a major influence in preventing relapse
after cessation of treatment. Overall SVR's in genotype I
naive patients are around 50-55%, but when there is a
RVR as well as a low level of viraemia (<600,000 IU/ml)
pre-treatment, SVR's as high as 80% can be
obtained and the period of treatment shortened
from 48 to 24 weeks. Similarly for genotypes II
and III -with overall SVR's higher at 70% to
90%, when an RVR is obtained, treatment can be
shortened -from 24 weeks to 12 weeks. If risk
factors for impaired responsiveness, namely,
obesity and severe fibrosis/cirrhosis are present,
the duration of the first course of treatment should
be extended from 24 to 48 weeks. For slow
responders extending the duration of treatment
from 48 to 72 weeks gave a substantial increase in
SVR from 19% to 38% consequent on a marked
reduction in relapses from 59% to 20%.3
A difficult question is whether
retreatment is of value in genotype I nonresponders or relapsers. Identifiable reasons for
the initial failure of treatment may be correctable
such as inadequate Ribavirin dosage and
interruptions in therapy. Weight reduction in the
obese should be attempted but is often difficult to
achieve and in one trial of subjects weighing >85
Kg, increasing the dose of Ribavirin to 1600mg
daily gave an improvement in SVR of 28% to
47%.4 In the EPIC 3 retreatment trial, SVR's were
38% for the relapsers and 14% for nonresponders.5 In the REPEAT trial, treatment
duration was extended from 48 to 72 weeks with a
doubling of SVR in non-responders -8% to
16%.6 Both the EPIC 3 and the REPEAT trials
had a high percentage of cirrhotics -the hardest
to treat category which emphasises the need for
early diagnosis and treatment of chronic hepatitis
C infection. Both trials showed that further
treatment was pointless if there was no EVR at 12
weeks.
The new and encouragingly potent
antiviral drugs, namely, Telaprevir and
Boceprevir specifically inhibit protease activity of
the virus. Late 2011 is the projected date for
release onto the market. Early trials of Telaprevir
as monotherapy showed that a rapid fall in viral
titre over the first week was followed by a high
breakthrough rate from development of viral
resistance. This could be prevented by giving
J Ayub Med Coll Abbottabad 2010;22(3)
2 http://www.ayubmed.edu.pk/JAMC/PAST/22-3/Roger.pdf
additional PegIFN and Ribavirin with Telaprevir being
discontinued after 12 weeks and the PegIFN/Ribavirin
continued for a further 12 weeks. The PROVE phase 2b
trials of this triple therapy regime in genotype I naive
subjects showed over 80% achieving a RVR giving an
SVR rate of 61% at 24 weeks versus 41% in the control
arm of PegIFN/Ribavirin given for 48 weeks.7 Thus not
only is a higher SVR obtainable with Telaprevir but
treatment duration is shortened. In the PROVE 3 trial of
non-responders and prior relapsers, SVR's of 39% and
69% were obtained compared with 9% and 20%
respectively in control arms. Viral breakthrough in the
non responders was high at 22% which is not surprising
as these patients were essentially on Telaprevir
monotherapy. Side-effects of rash and anaemia lead to a
discontinuation rate for severe adverse events of around
20%. The drug has to be given in tds dosage at exactly 8
hour intervals and as it is metabolised through the P450
enzyme system, drug interactions may occur with the
commonly used statins.
Boceprevir similarly has significant side effects
including anaemia requiring Epoetin support,
gastrointestinal disturbances and unpleasant taste in the
mouth (dysgeusia) with discontinuation of therapy in
around 25% of cases. In contrast to Telaprevir, the drug is
started after a lead in period of Peg IFN/Ribavirin for 4
weeks. By obtaining steady state concentrations prior to
the start of Boceprevir, the emergence of resistant
mutations to the drug is reduced. Depending on level of
RNA reduction during the lead in period, Boceprevir is
given for a further 24 or 44 weeks along with
PegIFN/Ribavirin. In the Sprint-I phase 2 study, the SVR
was nearly double that in the control arm -75% vs 39%.8
With a RVR achieved in nearly two thirds of the cases,
the SVR was 82% and treatment duration can be
shortened.
There is progress too in what we are all hoping
for, namely, an antiviral regime without Interferon and
based on oral medication only. Gane et al, reported at the
AASLD Meeting in 2009 that combining the protease
inhibitor drug Danoprevir with a polymerase inhibitor
R7128 resulted in rapid viral suppression over 14 days
without the emergence of resistance to either compound,
and confirmatory results of this approach were published
recently.9 Targeting different steps of viral replication
concurrently, as we have learnt from HIV infection, may
prevent or delay the emergence of drug resistance.
Many other compounds targeting different areas
of the virus and with potentially less severe side effects
are in Phase 1-2 trials and the reader is referred to
the abstract book of the recent EASL meeting in
Berlin. One can but hope that the lead time in their
introduction to clinical practice will be less than
the 10 years interval between introduction of
current standard of care -PegIFN & Ribavirin
and release of the new Protease inhibitors.