Hepatitis C is a dangerous disease. This
week delivered mixed news on novel treatments for it
THE world is full of nasty viruses, but the one that causes
hepatitis C is particularly tricky. Medical science recognized
decades ago that not all cases of hepatitis were caused by
the two viruses (A and B) that had already been identified.
But hepatitis C virus (HCV), which is spread mainly by contaminated
blood from, for example, shared syringes, was not isolated
and identified until 1989.
In 1999, the most recent year for which global figures are
available, HCV was believed to have infected some 170m people
(see chart). Another 3m join their ranks every year. Fewer
than a fifth of those who catch the virus shake it off. In
most cases it settles down to form a chronic infection of
the liver which, over the course of several decades, can lead
to severe forms of liver damage such as cirrhosis and fibrosis,
as well as cancer.
According to the World Health Organization (WHO), hepatitis
C kills around 500,000 people a year. It is less deadly than
AIDS, which claims more than 3m lives annually. However, its
higher prevalence (at the moment, some 42m people are infected
with HIV, the virus that causes AIDS), longer incubation period,
and the absence of effective drugs, mean that it is potentially
a more lethal epidemic.
News of a way to tackle HCV would therefore be welcome. Hence
the enthusiastic headlines which greeted a report published
by researchers from Boehringer Ingelheim, a German drug company,
in this week's online issue of Nature, and also presented
at the annual meeting of the American Association for the
Study of Liver Diseases, in Boston. Daniel Lamarre and his
colleagues have shown that a molecule code-named BILN2061
can block the activity, both in the test tube and in experimental
animals, of an HCV protein called NS3 protease, without which
the virus cannot go about its business. More significantly,
the drug also seems to work in people.
Patients infected with HCV who were given four doses of BILN2061
saw their viral burden plummet to almost undetectable levels
within two days, although there was a slow rebound over the
weeks after the last dose was given.
On the face of it, this is a particularly significant success,
since these patients were infected with a strain of HCV called
genotype I, which is common in Europe and America, but which
the existing therapy is unable to treat well. That therapy
involves two drugs. One is a protein called alpha-interferon
which, as the name suggests, interferes with the virus directly,
as well as stimulating the body's immune system to attack
the invader. The other is ribavirin, which gums up HCV's ability
to replicate.
However, only 40% of those infected with genotype I respond
to this cocktail, for reasons researchers have yet to come
to understand fully.
The bad news is that, whereas BILN2061 looked safe in early
animal testing and clinical trials, further experiments in
monkeys have shown that, at doses many times higher than those
given to patients, the drug can throw the heart seriously
out of whack. That result need not, in turn, kill BILN2061.
After all, it involves a significant overdose. But it does
mean that Boehringer Ingelheim has halted all patient testing,
and has returned to the drawing board to work out why BILN2061
has this effect.
This story illustrates just how difficult it is to come up
with effective new treatments for HCV. Matters are complicated
by the fact that the virus is hard to grow in the laboratory
and, until recently, the only animal "model" of
the human disease was the chimpanzee, a species that it is
impractical (and many would argue immoral) to use for industrial-scale
research. Over the past few years, however, new cell-culture
systems and mouse models have opened the way to further drug
development, the fruits of which were also presented at the
meeting in Boston.
NS3 is a popular target with research groups other than Boehringer
Ingelheim's. Scientists at the Schering-Plough Research Institute,
in New Jersey, for example, are developing their own inhibitor,
and have just begun clinical trials with it. Meanwhile, Vertex
Pharmaceuticals, a biotechnology company based in Cambridge,
Massachusetts, has another anti-NS3 drug in the works. This
substance, called VX-950, has been shown to block its target,
at least in mice. The company hopes to test the drug in people
next year. As John Thomson, the vice-president of research
at Vertex, points out, just because Boehringer Ingelheim's
compound has run into difficulties does not automatically
dim the prospects of other protease inhibitors.
Meanwhile, others are attacking from different angles. Isis
Pharmaceuticals, a biotech company based in Carlsbad, California,
has seen encouraging results in patients given its "antisense"
compound, which binds to the virus's genetic material and
stops it reproducing. Other drugs highlighted in Boston tackle
HCV's outer coat in an attempt to stop it binding to liver
cells in the first stage of infection.
Among these is a compound from XTL Pharmaceuticals, based
in Rehovot, Israel, which has just been tested on 25 chronic
sufferers. The drug is a monoclonal antibody designed to lock
on to, and block, one of HCV's outer features, called the
E2 protein, which it needs to attach to its target cells.
Roughly three-quarters of patients who received the compound
saw a significant drop in their viral levels, with no serious
side-effects. As a result, XTL is testing the drug in HCV-related
liver-transplant patients, in
whom it is hoped that it will prevent the infection of the
transplanted organ by hidden reservoirs of the virus. The
firm hopes to have the results of the trials before the end
of next year.
In practice, it is unlikely that any one medicine will be
enough to beat HCV. Just as with HIV-and, indeed, the existing
interferon/ribavirin approach-a combination of drugs, attacking
the problem from different angles, will probably be the most
potent weapon. And as with AIDS, success in drug making will
bring further difficulties. As Daniel Lavanchy, an infectious-disease
specialist at the WHO, points out, existing treatments already
cost $20,000, which puts them beyond the reach of most of
the world's infected in developing countries. How much more
will shiny new drugs, and the medical care needed to deliver
them, add to the bill? While researchers struggle to find
better ways to combat HCV, politicians will have an equally
tough task-how to find the money to pay for them when they
arrive
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