The good news is that there
is a huge research programme underway looking at new treatments for hepatitis C
and more than 50 candidate drugs are under study in human trials.
Firstly, companies are
looking at new versions of interferon, like Albuferon,
a slow-release formulation that may need only to be injected once a month. But
though this may be more convenient for the patient it does not appear to
achieve higher rates of sustained viral response (SVR). An SVR is the goal of
hepatitis C treatment: it means there has been no reappearance of hepatitis C
by the sixth month after the end of treatment, and is essentially a cure.
The challenge,
therefore, is to develop hepatitis C drugs of new classes. Initially, and for
the foreseeable future, these new drugs would not replace interferon. The
reason is that most of the hepatitis C drugs in development work like HIV
drugs: they prevent the virus replicating but do not clear it. This means that
if they are stopped the virus will reappear, and if too few are taken they will
cause resistance. In contrast interferon creates a stronger immune response to
hepatitis C. So far there have been a couple of animal experiments in which an SVR was achieved without Interferon, using only oral
drugs, but clinical application is probably ten to 15 years away.7
Like HIV therapy, the new hepatitis C drugs
come in a number of classes. The two classes under the most scrutiny are the protease
inhibitors and the polymerase inhibitors. The latter are the equivalent of
reverse transcriptase inhibitors in HIV treatment. Many other classes are under
investigation. Most of them are stop viral replication as described but some have
different modes of action.8
The ones furthest
along in development are the protease
inhibitors. Positive results have come from clinical studies of two drugs, Schering-Plough’s
boceprevir and Vertex Pharmaceuticals’ telaprevir. In several different trials,
these drugs were added to pegylated interferon and ribavirin and given to HIV-negative
patients with genotype 1 of hepatitis C. In both cases an increased proportion
of patients (about 65% instead of 45%) achieved an SVR.9,10
Perhaps just as
importantly, these rates of SVR were achieved in half the length of time of
normal therapy – 24 weeks instead of 48, which is a significant improvement for
anyone trying to put up with often taxing side-effects of interferon and
ribavirin. Even more promisingly, one of the three telaprevir trials targeted
patients who had failed previous pegylated interferon and ribavirin therapy and
achieved SVR rates of 50%, compared with 14% in those taking a placebo - an
unprecedented result in a population that has already experienced interferon
therapy failure.11
Next in line are the nucleoside polymerase inhibitors (NPI). These
appear to be very potent drugs, achieving large reductions in viral load, and active
across a number of different varieties of hepatitis C. The first large phase 2 clinical
trial of an NPI, Roche’s R7128, was announced in April.
Alongside these are the
non-nucleoside polymerase inhibitors. These
have a less potent effect on hepatitis C and are only active against specific
subtypes, but they seem to cause fewer side-effects. The vanguard drug in this
class is Gilead’s GS9190, currently in a phase
2 trial. (Phase 2 trials typically involve several hundred subjects and try to
find out the optimum dose, establish the frequency of side-effects, and so on.
They lead on to phase 3 trials, which may involve thousands of patients and
establish the actual efficacy of a drug in a clinical population.)
A number of other
antiviral classes are in early-stage development, including the NS5a inhibitors, which work against a component of the hepatitis C virus
whose function is uncertain.
There are a number of non-antiviral drugs too. Some of these
are improved formulations of interferon like Albuferon12 and Locteron13
that require less frequent dosing. Others are versions of ribavirin which aim
to be less toxic, like taribavirin, though a trial of this drug last year found
it had relatively few advantages.14
Many more classes of
drugs are in development. Some, as interferon does, work on the machinery of
the human cell which hepatitis C subverts in order to replicate itself, rather
than the virus. These are potentially exciting drugs because they are less
likely to cause resistance than antivirals and may be the best candidates eventually
to replace interferon.
Results from early
studies of two drugs from a class called cyclophilin
inhibitors that stop cells making new hepatitis C viruses were presented
this April. Importantly, one of the drugs, Debio 025, produced significant
viral load drops when given to people with HIV and hepatitis C co-infection who
had previously failed the standard pegylated interferon and ribavirin regimen,15
though it was still only effective when combined with these other two drugs.
Then there are a few
wild cards like nitazoxanide. This
is an antibiotic that was in trials for the AIDS-defining gut illness
cryptosporidiosis. It was serendipitously found to have activity against
hepatitis C infection – no one yet knows why. In one trial the efficacy of pegylated
interferon and ribavirin therapy was increased from 50 to 80% in HIV-negative
patients when they were given one to three months of nitazoxanide before
starting therapy.16
This is by no means a
complete list. Further off, in pre-clinical development, are drugs of many
other classes: TLR agonists, Micro-RNA agents, A3AR agonists,
anti-phospholipids, more thiazolide antibiotics like nitazoxanide, pancaspase
inhibitors, glicosidase Inhibitors…whatever the challenges, it cannot be said
that hepatitis C is not receiving enough attention from the scientific
community.
When looking at the
exciting new developments in hepatitis C treatment, however, we should be
guided by caution. Two particular considerations come to mind.