At any time, between two and three percent of the world's population (140-170 million people) are infected with the hepatitis C virus (HCV). Chronic hepatitis C infection is often asymptomatic, but patients with untreated or ineffectively treated long-term infection carry a significant risk of developing serious liver disease, including hepato-cellular carcinoma. Chronic HCV infection is the cause of about 50% of cases of primary hepatocellular carcinoma in the developed world. Improving HCV treatments and increasing the proportion of cases in which the virus is cleared would, therefore, lead to a significant decrease in the prevalence of this aggressive tumour.

Current treatments for HCV infection, however, are inadequate. The current standard of care consists of a combination of a form of interferon, most often pegylated interferon (pegIFN), combined with ribavarin. Neither of these drugs is specific for HCV infection; all interferons must be given by injection; side effects can be severe and often lead to termination of therapy, and the combination regimen is expensive. There is therefore an urgent need for novel drug treatments for this disease. Fortunately, there are now a large number of anti-HCV drugs in development, targeting a wide range of viral proteins and mechanisms. Michael Gilman and Jeffrey Glenn from Stanford University School of Medicine, Stanford, CA, USA, have now surveyed the development status of a number of these specific targeted antiviral therapies for HCV (STAT-C agents), looking ahead to the most promising future strategies for control of the virus¹. Within each class, the review focuses where possible on drugs already in clinical trials.

The hepatitis C virus is an RNA virus from the family Flaviviridae, with a single-stranded genome that encodes at least ten proteins. Its complex life cycle has been extensively and recently reviewed (see e.g.²). Many hepatitis C proteins have become targets for drugs in development against the disease. Targets being investigated include the virus' protease, its RNA polymerase, the protein NS4B which binds RNA and the multi-functional protein NS5A. HCV, like many viruses, can develop resistance to any drug very easily, and both individual drugs and drug regimens must be designed with the aim of minimising that resistance. Gelman and Glenn outline strategies through which both clinicians and drug developers can aim to minimise resistance. These include using "cocktails" of at least four drugs with different targets (along the lines of the HAART therapy used successfully for HIV/AIDS); targeting aspects of the host biochemistry that are used by the virus; and developing drugs or drug combinations that decrease the viral replication rate below the threshold needed for mutations to emerge. The authors then described the drugs that are in development against each viral target in turn.

The development of drugs targeting the protease and polymerase is being helped by the availability of structural data and the precedence of inhibitors of these proteins as successful drugs for other viral diseases. There are currently two drugs that target the protease in Phase III clinical trials, telaprevir and boceprevir, and several others are in earlier stages of clinical development. The two most advanced drugs have different, fairly severe major toxicities and similar resistance profiles. A number of inhibitors of the catalytic subunit of HCV's RNA-dependent RNA polymerase are in Phase I and Phase II clinical trials. Natural products called silibinins, obtained from a milk thistle extract and under development as HCV polymerase inhibitors, may be particularly interesting because milk thistle extracts are often taken as over-the-counter medications for hepatitis C.

Other HCV proteins that are targets for drugs in development include NS4B, which binds RNA and is involved in forming the web-like viral replication platform. One compound found to inhibit this protein in an in vitro screen, clemizole, is in clinical use as an anti-histamine. The anti-HCV activity of this compound demonstrates strong synergy with boceprevir and telaprevir, and no cross-resistance has yet been observed between these compounds. Phase I trials of clemizole are underway in HCV-infected populations with different genotypes. Inhibitors of the multi-functional protein NS5A have been identified using high throughput in vitro screens, and there are a number in Phase I trials and in late pre-clinical development.

The viral genome also contains a gene coding for a small protein, p7, which assembles in the viral membrane to form an ion channel. Other anti-virals that target ion channels, such as the adamantanes, have been tested against HCV and one of these, amantadine (once used as an anti-influenza drug), is showing promise particularly in patients who do not respond to the current standard of care. Cyclophilin inhibitors have also attracted some attention as potential anti-HCV agents, and several of these, including alisporivir, have shown promising results in Phase I clinical trials.

If HCV infection is to become chronic (and therefore form a risk factor for serious liver disease) the virus must evade the host's immune system, and it has developed a number of mechanisms to do this. Some of these mechanisms are also drug development targets. Potential anti-HCV agents in this class target interactions with both the innate and the adaptive immune systems. Drugs in the first category include nitazoxanide, which is clinical use as an anti-protozoal and in clinical trials for HCV, and agonists at the toll-like receptor. Adaptive immune system modulators are less well developed, although there is at least one human monoclonal antibody in early clinical trials. Therapeutic vaccination and agents that might interfere with host lipid metabolism or with the initiation of viral polyprotein translation are also under consideration as anti-HCV strategies.

Gelman and Glenn conclude by discussing likely future developments in the standard of care, distinguishing between those that are likely in the short term and those that are further in the future. Already, genetic tests are able to predict which patients are most likely to respond to the current drugs. The first STAT-C drugs are likely to enter the clinic within a few years. Initially, the best strategy will be a triple therapy involving the addition of one targeted drug to interferon and ribavarin. However, resistance to a third drug is likely to develop in many patients given this combination who are non-responders to the standard drugs. It is likely that further drugs will become available within 5-10 years, and the authors propose that further into the future drug regimens for HCV will consist only of a number of orally available targeted agents. They expect these regimens to be easier to administer and more tolerable than the current ones, and patients will be prescribed the optimum combination of agents based on their genotype.

Reference

1. Gelman, M.A. and Glenn, J.S. Mixing the right hepatitis C inhibitor cocktail Trends Mol. Med. 17(1), 34-46 doi:10.1016/j.molmed.2010.10.005 (2011)

2. Rehermann, B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence J. Clin. Invest. 119, 1745–1754 (2009)