NEW DEVELOPMENTS IN HEPATITIS C TREATMENTS
by: Marcy Coash D.O. and George Y. Wu, M.D., PhD.
Hepatitis C virus infects approximately 250 million people worldwide. It is generally transmitted by contact with infected blood, acquired at birth from HCV infected mothers, and sexual transmission. Since the 1900's, routine screening of blood donors for HCV has greatly decreased the transmission of the virus by transfusion.
After infection with HCV, only about 20% of infected individuals are able to clear the circulating virus on their own without medical treatment. However, 80% of infected individuals will develop chronic infection, of whom about 30% will develop cirrhosis and liver failure within a period of 10-30 years. The risk of contracting liver cancer increases with the development of cirrhosis.
Hepatitis C virus has been classified into types 1-7, which do not all respond similarly to standard treatment. In the US, genotype 1 is the most common, followed by genotypes 2 and 3.
Current standard antiviral therapy for hepatitis C consists of an injectable medication called pegylated interferon given once weekly in combination with doses of an oral medication called ribavirin. Unfortunately, these agents are not successful in approximately 50% of genotype 1 patients. In addition, the medications have many side effects. Therefore, much effort is being applied towards the development of new agents for the treatment of HCV.
Future treatment options
Insights into the way the hepatitis C virus behaves have allowed pharmaceutical companies to develop compounds to target certain steps that are essential in the life cycle of HCV. The hepatitis C virus particle is composed of a single strand of RNA made up of individual pieces termed nucleotides. The RNA strand is surrounded by a core of proteins called capsid proteins. The interaction of the capsid proteins and the RNA form the nucleocapsid. The entire structure is then surrounded by an envelope composed of membrane. The RNA within the hepatitis C virus particle makes up its genetic code. Unlike human genes which are separated from each other by stop signals, one HCV gene runs right into the neighboring ones without any separation. As a result, the HCV code produces a single very long protein, which must be cut into separate functional pieces. To accomplish this, the virus makes its own special type of protein (an enzyme) called a protease, which cuts at exactly the right places to form active viral proteins. Because humans don't have such a protease, this has been considered a potential target to interfere with HCV without causing damage to humans. Another attractive target is an enzyme known as a polymerase. This is the enzyme that is made, and used by the virus to reproduce its genetic code. Like the protease, this is a desirible drug target because it is not found in humans.
Because of the specific antiviral design, these classes of agents have been called "specifically targeted antiviral therapies for hepatitis C" (STAT-C). The most promising of these STAT-C compounds are called protease inhibitors, because they target the HCV protease as described above. Of the many protease inhibitors that have been, and are currently under investigation, telaprevir and boceprevir are at the most advanced stage of clinical trials, and are the closest to FDA approval. However early studies have shown that these agents cannot be administered successfully by themselves because of the tendency for rapid development of virus that is resistant to those agents. Therefore, these drugs must be given in combination with standard therapy of interferon and ribavirin.
Treatment of telaprevir in combination with standard of care medications for 24 weeks resulted in sustained response in 61% of patients with HCV genotype 1 who had not previously been treated. When treatment was extended to 48 weeks, 67% achieved sustained response compared to 48% with interferon and ribavirin alone, A second trial with telaprevir showed a 68% and 62% sustained viral response for 12 and 24 week comibination therapy, respectively. Based on these results, 24 week treatment with triple therapy appears to be significantly better than conventional treatment for 48 weeks.
Another protease inhibitor, boceprevir, administered in combination with standard therapy in treatment - naive, genotype 1 patients for 24 and 48 weeks showed sustained responses of 54% and 67% respectively, which were significantly higher than standard of care sustained viral of 38%. When pretreated with pegylated interferon and ribavirin for 4 weeks prior to the addition of boceprevir, their sustained response reached 56% and 75% in the 24 and 48 week treatment groups, respectively.
Another class of STAT-C compounds called polymerase inhibitors consists of two types, nucleoside and non-nucleoside, both of which target a certain area of the polymerase enzyme preventing reproduction of the HCV genetic code. These are in early clinical development. However, some compounds have been shown to have adverse effects on gastrointestinal system and cause toxicity of the liver.
Nitazoxanide is a medication that has suppressive activity against viruses, bacteria and parasites. It is currently being studied in combination with standard treatment for use against HCV, and is in an advanced stage in clinical trials.
Cyclosporin A is a drug that has been used for immune suppression after organ transplantation, and in the treatment of various autoimmune deiseases and inflammatory diseases. Several studies have shown that cyclosporine can inhibit intracellular HCV replication. Debio 025, a non-immunosuppresive cyclosporine analog, has also been tested with similar results when used in combination with pegylated interferon.
The global epidemic of HCV infection and the frequency of chronicity leading to the development of cirrhosis and often liver cancer, make effective treatment of this viral infection of great importance. Unfortunately, a large fraction of genotype 1 patients fail to achieve a sustained response with standard therapy. Significant research is underway to develop new treatment modalities. The data indicate that these new agents are more potent than our current drugs, and will offer significantly higher success rates for the treatment of HCV.