Monday, 28 April 2014

A breakthrough in the treatment of hepatitis C virus

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. 
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.
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.

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