Standard therapeutic treatment against chronic hepatitis C based on the combination of pegyIated alpha interferon and Ribavirin has shown a prolonged viral removal in about 50-60% of the patients.

Limits of the present HCV therapies

HCV genotype 1 and 4 are the most frequent among the non-responding patients, who reveal similar characteristics when compared to genotype 2 and 3. This could explain why these two first groups appear so scarcely reacting to the therapy.

Not only half of the patients’ population does not respond effectively to the present HCV therapies, the half that does respond, still suffers from severe side effects, which often lead to a discontinuation of the therapy. It has become clear that, if not reacting at the first treatment with peg-interferon and Ribavirin, existing long-term therapies are not able to reduce the disease progression in patients with chronic HCV and advanced fibrosis, with or without cirrhosis.

The classic combination approach is compromised by a variety of side effects, for example, anaemia. A solution to the anaemia problem would be reducing the Ribavirin doses, but this will result in a loss of efficacy. Usually, patients who do not respond to a first therapy cycle of combined interferon and Ribavirin, rarely show a positive reaction to a second one. Meanwhile, preclinical studies have evidenced that HCV viruses may quickly create resistance to the more recent class of protease inhibitors.

This means that it will be necessary to combine drugs with different active principles and resistance profiles. In short, we need to develop new pharmaceutical strategies.

Novel approaches to HCV

Various novel approaches to HCV infection are currently available or under development. For instance, protease and polymerase enzyme targets have shown successful results in HIV pharmaceutical treatment.

These agents are particularly important development candidates for HCV. Some clinical studies of selected protease and polymerase inhibitors, have proved to be encouraging.

The standard treatment for HCV was an interferon, subcutaneously injected, but it can often give problematic side effects; consequently, interferon-free combinations of drugs against HCV have been developed.

Viral polymerase is currently considered as one of the more promising drug targets. However, as in HIV, viral RNA polymerase is highly mutation sensitive and as such rapid resistance development is to be expected. It is likely that similar to HAART strategies in HIV, several new combined drugs therapies will have to be developed for an effective cure against HCV.

Latest generation NS5 inhibitors

A development of resistance to HCV is to be expected with such a heavy viral load, speed of replication and mutation rate. It is quite hard to develop inhibitors of viral proteins able to avoid the development of new resistant strains.

The present state of HCV pharmaceutical research concludes that currently no single drug therapy is effective in fighting HCV infection. This also accounts for the recent breakthrough drugs Ledipasvir and Sofosbuvir that target the non structural HCV proteins NS5a and NS5b polymerase essential for viral replication.

Resistance associated mutations have been observed for Ledipasvir in vitro and in humans, as expected from its direct inhibition of a viral protein. So far one mutation has been selected by Sofosbuvir, which leads to reduced susceptibility to the treatment, but increased susceptibility to Ledipasvir. Besides this, so far low resistance has been observed for Sofosbuvir. Nevertheless even Sofosbivir does not target a cellular host factor such as the DDX3 RNA Helicase, and as such, resistance development will likely be inevitable.

It appears clear that a genotype-targeted pharmaceutical strategy will not result cost-effective considering the variety of known HCV genotypes and their big genetic diversity. Thus, research should rather focus on the development of pan-genotyped HCV inhibitors. Such compounds would allow for a vast coverage of genotypes, while at the same time restricting the possibility of resistance development.