Overview Of The Development Of Treatments For Hepatitis C Virus

Introduction

Hepatitis C is a virus which is being extensively researched due to its prevalence in developing countries such as Egypt and link to liver cirrhosis and other disease. This bloodborne virus, which has infected around 170 million people worldwide and has caused chronic hepatitis C infection in approximately 71 million people, is transmitted primarily via reuse of medical equipment and injecting equipment in intravenous drug users. Treatment of HCV has proved to be difficult due to the genetic variation that the virus possesses. There are seven different genotypes and almost 70 different sub types. The most common genotype is genotype 1 making up 83. 4 million cases worldwide followed by genotype 3 at 54. 3 million. This means that while some therapies act successfully on some genotypes, they remain ineffective with others. Currently, there is no vaccine for the treatment of Hepatitis C. Instead, treatment plans rely on interferons combined with the drug ribavirin, as well as direct-acting antivirals.

Use of Interferons and Ribavirin

Interferon alpha is a cytokine which acts by binding to receptors on the surface of target cells. This leads to a phosphorylation cascade which eventually results in production of a transcription factor that is able to cause the production of antiviral proteins. For the treatment of Hepatitis C, a combination of interferon and ribavirin was most commonly used for 24-48 weeks as it had been found to cause a sustained viral response in 35-40% of patients according to a randomised trial conducted in 1998. However, there are limitations to this treatment. The biological effect of standard interferon does not last long due to its short absorption half-life of about 2. 3 hours. This factor, in addition to the high replication rate (1012 new virons are produced daily) the Hepatitis C virus means that HCV RNA is able to increase back to its original value in 24-48 hours. As a result, the drug must be administered three times weekly according to the Hep C trust. Standard interferon also can cause side effects in the form of flu-like symptoms. Due to the aforementioned reasons, there has been a shift from the use of standard interferon towards pegylated interferon a2a and a2b. Pegylation is the addition of polythene glycol to the protein. This is significant as it prolongs the half-life of the drug- the average half-life of a2a and a2b is 4. 6 hours and 50 hours. It also reduces the probability of eliciting an immune response, thus causing a sustained viral response of 54-63%. This prolonged half-life means that treatment can be taken once a week in comparison to three with unmodified interferon.

Ribavirin also plays an important role in this therapy targeting HCV. It is said to operate in 4 ways, although it is not known which pathway dominates. The drug is able to control the interferon signalling pathway, as well as competitively inhibit IMPDH (inosine monophosphate dehydrogenase), usually involved in the synthesis of guanine nucleotides. By doing this, it is able to deplete intracellular guanosine triphosphate levels (GTP), which leads to a decrease in viral protein synthesis and replication. Ribavirin is also thought to contribute to RNA mutagenesis. Once ribavirin enters the hepatocyte, it is converted into ribavirin triphosphate (RTP) which is then integrated into the HCV viral genome, pairing with bases cytosine and uracil. This increases the rate of mutations, resulting in the formation of ‘less fit’ virus (known as error catastrophe). The other two mechanisms include inhibition of HCV RNA polymerase and immunomodulation. This drug inhibits RNA polymerase as RTP binds to nucleotide binding sites instead of the usual bases, reducing replication. In terms of immunomodulation, ribavirin enhances a Th1 response. It does this by increasing production of interferon-gamma and tumour necrosis factor alpha in individuals with chronic hepatitis C.

Direct Acting Antivirals (DAAs)

This development is a more recent one which has changed the treatment plan of HCV considerably. These direct acting antivirals act on the non-structural proteins of the virus (NS2-NS5). There are three main classes of DAAs which are classified according to their target: NS3/4A protease inhibitors, NS5B nucleoside polymerase inhibitors, NS5B non-nucleoside polymerase inhibitors. A summary of these classes and their mechanisms is shown in the table below. By inhibiting this protease, they are able to inhibit the cleavage of the polyprotein that the genome encodes in four places. This blockage is extremely important as it will prevent replication of the virus.

Telaprevir Boceprevir Simeprevir NS5 Nucleoside polymerase inhibitors

These inhibit non-structural protein 5B. This is an RNA dependent polymerase that replicates the genome via the formation of a negative strand RNA. This negative strand then serves as a template strand for the synthesis of positive strand HCV RNA. [8] Sofobuvir Non-nucleoside polymerase inhibitors Non-nucleoside polymerase inhibitors act similarly to nucleoside polymerase inhibitors; however, they are non-competitive. These drugs bind to the RNA dependent RNA polymerase and prevent the structural modifications required for viral replication to occur.

Dasabuvir Limitations of DAAs

Some DAAs have been found to show variants of resistance. A study in 2011 showed that variants of resistance were detected in two of 14 patients on telaprevir and 4 of 14 on boceprevir after being followed up for 4. 2 years. Although a small number, it suggests that this antiviral may not be as effective as others and uncovers the possibility that other DAAs may also have this issue. Additionally, the price of DAAs varies significantly between developed and developing countries from approximately £75 to £30000 per course. This poses a problem as developing countries such as Egypt and Pakistan, where prevalence is higher, may not be able to afford to implement this strategy. An example of this is Egypt in 2014, when a small supply of Sofobuvir costed $900 for a 12-week course.

IFN-Ribavirin vs DAAs

Generally, DAAs tend to show a better SVR in comparison to IFN- Ribavirin treatment. For example, Sofobuvir monotherapy has been shown to have an SVR of 60%. However, the drug has been found to be even more effective when paired with PEG-IFN and Ribavirin. This is shown in the phase 3 NEUTRINO trials, where this combination has been found to cause a sustained viral response (SVR) of 91% and an SVR of 81% in those who already had underlying cirrhosis. With DAAs, there are also fewer known side effects than interferons and duration of treatment is shorter. DAAs are taken orally for 8-24 weeks, whereas interferons are taken from 24-48 weeks. On the contrary, DAAs are a much more recent and costly development, therefore, most research surrounding this area has been done in vitro and so there are limitations in the clinically available data to evaluate how effective they really are.

Conclusion

Treatment of HCV has developed significantly over the years, from the use of interferons to DAAs. Both drugs are best used in combinations with each other. It is difficult to determine which is more effective as both therapies have their advantages and disadvantages. It is important to note that every patient responds in a different way, highlighting the need for personalised medicine, to achieve what is best for each patient.