A staggering 130-150 million people are estimated to have chronic hepatitis C virus (HCV) infection
worldwide, that’s approximately 5 times the number of people that are infected with HIV.
HCV can be divided into 11 major genotypes, based on divergence of the genetic
material that makes up the virus. Of the global total for HCV infections,
genotype 1 constitutes 60% of these infections.
Even though HCV is a global problem,
treatment for infection is sorely lacking, especially for genotype 1. Until
recently, up to 48 weeks worth of ribavirin and interferon injections were the
only option. Neither of these treatments specifically targets the virus, and both cause significant side effects. Interferons are proteins produced by our bodies
in response to infection and are responsible for the associated general
symptoms; fever, chills, headache, malaise, nausea and so on. Ribavirin, on the
other hand, is a drug that partially mimics a building block of RNA. This
incomplete mimicry means ribavirin can interfere with production of RNA; a
process essential for replication of the RNA genome of HCV. This is how ribavirin is thought to work, however, it has never been proved, and its full
function isn’t know. Similarly to interferon, ribavirin can cause fever, chills
etc., but can also cause many more serious side effects such as depression and
problems with vision.
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| Hepatitis C virus particles under an electron microscope |
Due to the problems
associated with HCV therapy, many patients opt out, choosing to live with
chronic infection. Indeed, in the UK, only 3% of patients receive treatment.
Opting out may seem rational since the vast majority of chronic infections are
completely asymptomatic, why take treatment that will make you feel appalling,
when you feel fine without it? Combine that with the knowledge that only 50-60%
of patients infected with genotype 1 viruses will achieve a sustained virologic
response (defined as having no virus in the blood for 24 weeks following the
treatment, essentially a cure), and you can appreciate why many people opt out.
However, chronic HCV infection will inevitably lead to complications in the
liver, including cirrhosis, failure and cancer. HCV is the most common cause of
liver transplantation in the US, for example, and is responsible for
300,000-500,000 deaths per year globally.
With all that said, things
are starting to improve for HCV patients with many new, HCV specific, drugs
starting to enter the market. HCV was only classified in 1989 and, following
much research, the essential proteins the virus makes were identified and their
structures defined just before the turn of the millennium. Knowing these
structures allowed for drugs to be designed that could specifically interfere
with their functions, and now, finally, we are starting to see the outcome of
these research programs. Currently, four HCV specific drugs have been approved
for clinical use, while many others are in phase 2 and 3 clinical trials. Phase
3 clinical trials are essentially the final stage of testing any new drug and where
its efficacy is tested in a large number of patients, if it proves to be
effective, and safe, it can then be approved for general use.
This leads me into the
topic of this blog post, the results of a phase 3 trial published earlier this
month in the New England Journal of Medicine showing remarkable promise for the
treatment of HCV genotype 1. The treatment is a single, orally administered,
pill combining two drugs named Ledipasvir and Sofosbuvir. Ledipasvir
interferes with the function of the viral protein NS5A, which plays many key
functions for HCV infection, the most well characterized being modulation of the immune response against the virus. While
Sofosbuvir inhibits the function of the viral RNA polymerase, blocking the
production of new HCV genomes, and by extension, virus particles.
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| A schematic of the hepatitis C virus genome, and the proteins it encodes |
The study treated 865
patients, chronically infected with HCV genotype 1. These individuals were evenly
divided into four groups. Two groups received Ledipasvir and Sofosbuvir for 12
or 24 weeks, while the remaining two groups received Ledipasvir and Sofosbuvir
along with ribavirin for the same time periods. In all four groups, the
percentage of sustained virologic response (essentially a cure) was over 95%.
This is an incredible increase from the current efficacy of HCV genotype 1 treatment, and
was reported in a wonderfully understated manner, a direct quote from the manuscript; “the rates of sustained
virologic response in all four treatment groups were superior to the historical
rate of 60%. The rates of sustained virologic response 12 weeks after the end
of treatment were as follows… 99%… 97%… 95%… 99%.” Modest reporting of a
fantastic result.
Furthermore, the inclusion
of ribavirin had no impact on the percentage of patients that attained
sustained viriologic response, suggesting it can be dropped from the therapy,
along with it’s associated side effects. The difference between 12 and 24 weeks
was also negligible, with both being around 98% effective. The treatment with
Ledipasvir and Sofosbuvir proved to be extremely effective, and also proved to
be safe, with only mild side effects being reported. Indeed, the majority of
reported adverse reactions were from the group receiving ribavirin, and most of
those reactions were known to be associated with ribavirin itself.
It’s worth noting three cases of virologic failure, patients who cleared the virus but
then had detectable levels within 12 weeks of cessation of treatment. In one
case, the patient had undetectable levels of metabolites from the drugs,
suggesting non-adherence to the regimen. The other two cases were patients who
had relapse of the virus, even though they had adhered to the treatment
regimen. Importantly, both of these patients were found to have viruses with
mutations to NS5A that made the protein resistant to Ledipasvir, before the
trial. This was concluded to be the cause of the relapse and in future clinical
situations it would be easy to remove Ledipasvir and use an alternative drug
that targets another protein of the virus.
Another point to note is
that this study was not designed to look at any long-term effect. Chronic HCV
infection causes damage of the liver that can result in complications such as
cirrhosis and cancer. It is not known if the clearance of the virus with
Ledipasvir and Sofosbuvir will have any effect on reducing the occurance of
these issues. However, I would speculate that the liver, an organ highly adept
at repairing itself (as anyone who has ever had a hangover will indirectly
know), would become healthy again once the virus has been removed.
Hepatitis C virus infection
has been historically difficult to treat, particularly genotype 1. Until
recently, the only available treatments were a combination of ribavirin and
interferon, both of which come with substantial side effects and only work
about 50-60% of the time. However, following a huge amount of research on HCV
in labs around the world, numerous drugs have been developed to specifically
stop HCV replication. Many of these drugs are finally starting to reach the
point of being clinically available. Ledipasvir and Sofosbuvir seem to be
incredibly promising for the treatment of HCV having a nearly perfect rate of
sustained virologic response and only minimal side effects. I imagine it won’t
be long before the single pill of these two drugs reaches patients around the
world.
