Comparison of Use of Interferons Combined with Ribavirin for Hepatitis C vs DAAs

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.

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 has 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 2a and 2b. Pegylation is the addition of polythene glycol to the protein. This is significant as it prolongs the half-life (the average half-life of 2a and 2b is 4.6 hours and 50 hours.) and 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 four main classes of DAAs and these are classified according to their target: NS3/4A protease inhibitors, NS5B nucleoside polymerase inhibitors, NS5B non-nucleoside polymerase inhibitors and NS5A inhibitors. NS34A protease inhibitors The first DAAs were mainly NS3/4A protease inhibitors such as Telaprevir and Boceprevir. 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. Simeprevir is another example of this class which was approved to treat genotypes 1&4 in 2013. However, some problems have been associated with these drugs.

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. NS5 Nucleoside polymerase inhibitors This class is one of the most significant DAAs because it inhibits non-structural protein 5B.

This is an RNA dependent polymerase that replicates the genome via the formation of a negative strand RNA which then serves as a template strand for the synthesis of positive strand HCV RNA. An example is Sofobuvir; according to the NEUTRINO phase 3 trial, this drug has been found to cause a sustained viral response (SVR) of 91% when given in addition to PEG-IFN and Ribavirin and SVR of 81% in those who already had underlying cirrhosis.