Hepatitis C virus (HCV) infection affects roughly 3% of the world’s population,^1,2 and is the main indication for liver transplantation in the US and Europe. Therapy for hepatitis C has evolved relatively quickly over the past 16 years. The virus was isolated in 1989, and treatment trials began in the early 1990s. Initially, therapy involved 24 weeks of monotherapy with alpha interferon, and yielded viral clearance rates of less than 10% in genotype ¹, the most common strain in the US. Extending therapy from 24 to 48 weeks improved response rates, but they remained low. The next significant milestone was the use of combination alpha interferon and ribavirin, a nucleoside analogue that improved efficacy to the 30–40% range. Over the past five years, the use of pegylated interferon and ribavirin has increased efficacy to 40–50% in genotype 1.3 More recent data have suggested that extending therapy beyond the standard 48 weeks may yield higher response rates in those individuals who have slower viral clearance.⁴

It has become apparent that the overall efficacy of combination pegylated interferon and ribavirin cannot be improved appreciably with dosing and duration refinements. This has highlighted the need for other therapies. The era of specifically targeted antiviral therapies for hepatitis C virus (STAT-C) compounds is near, but has been hampered by several hurdles. Due to the variability of genetic and structural targets, compounds may have efficacy in vitro, but may be less effective in vivo. This is further complicated by the absence of an inexpensive animal model of HCV. Finally, toxicity and resistance issues have hindered the progression of some compounds into later stages of development. The following is a summary of molecules that have entered at least phase II of clinical development.

Protease Inhibitors
The most promising and well-developed protease inhibitors are inhibitors to the NS3 serine proteinase target, which is involved in post-translational polyprotein processing. The substrate binding site has a shallow cleft, which has been a challenge for the development of a molecule that will effectively bind to it. The first in this class was BILN 2061 (Boehringer Ingelheim, Germany), which was a potent inhibitor of viral replication with a 3 log IU/ml decline after 48 hours of dosing. Unfortunately, development was halted due to significant cardiac toxicity in primates.⁵

The two protease inhibitors that are currently in phase II study are telaprevir (Vertex Pharmaceuticals Inc., Cambridge, MA) and SCH503034 (Schering-Plough, Kenilworth, NJ). Telaprevir 750mg three times daily led to a 4.4 log IU/ml reduction in viral counts after 14 days of dosing. In the early studies with telaprevir, resistance was found to occur within days when using the compound as monotherapy. This led to the realisation that these compounds will not be stand-alone therapies. The combination of pegylated interferon and telaprevir led to a further reduction in viral load.6 This compound is in phase II clinical trials, and is being studied in treatment-naïve genotype-1 HCV patients in combination with pegylated interferon alpha with or without ribavirin. Results of a 12-week treatment regimen were presented at the European Association of the Study of the Liver (EASL) meeting in 2007, and were promising. The 24-week treatment arm will be presented at the American Association for the Study of Liver Disease (AASLD) meeting in November this year. It is also being studied in non-responders and relapsers.

The SCH503034 compound, when combined with pegylated interferon alpha, has shown a mean 2.0 log IU/ml reduction in viral load in previous non-responders to pegylated interferon and ribavirin with 14 days of dosing. The dose of 800mg three times daily has been selected for further study in combination with pegylated interferon and ribavirin.⁷ A phase II, treatment-naïve study is under way.

The GS9132/ACH806 protease inhibitor, a joint effort between Gilead Sciences (Foster City, CA) and Achillion Pharmaceuticals, Inc. (New Haven, CT), has been halted due to renal toxicity. The ITMN-191 (Intermune, Brisbane, CA and Roche, Basel, Switzerland) compound is set to enter phase I development. There are no other protease compounds far enough along in development to report on.

While these compounds hold great promise, long-term toxicity and resistance data are lacking. It is very likely that resistance will be a class effect and may render the virus less susceptible to other protease compounds.

Polymerase Inhibitors
Nucleoside/nucleotide analogues can inhibit the viral polymerase of HCV, which is an RNA-dependent RNA polymerase.⁸ This globular structure is formed by three subdomains with a large binding cleft, and is encoded by the NS5B region of the HCV genome, which is highly conserved across genotypes and is specific to this virus.

The lead compound in development was valopicitabine (Idenix Pharmaceuticals Inc., Cambridge, MA), which was in phase II study. Initial dosing led to gastrointestinal upset at doses of 400mg and higher, and although lower doses in combination with pegylated interferon and ribavirin appeared more tolerable, the compound development was recently halted due to toxicity issues.⁹ Another nucleoside compound, R1626 (Roche), is in phase I study to assess dosing and safety. A non-nucleoside inhibitor of the HCV polymerase, the HCV-796 compound (Wyeth, Madison, NJ), is also in phase II study.

While the polymerase inhibitors do not appear to be as potent as protease inhibitors, they do have antiviral activity, making them attractive adjuvant compounds for use in a multidrug regimen. It may be possible to use nucleoside analogues and non-nucleoside inhibitors of the polymerase protein together to reduce the risk of resistance further.

Other Interferons
Albuferon (Human Genome Sciences, Rockville, MD) – a fusion of interferon alpha and human albumin – is in a phase III registration study in combination with ribavirin for treatment-naïve patients. At both 900 and 1200mg every two weeks, viral decline and adverse effect profile were comparable to pegylated interferon weekly.⁹ It is very likely that this compound will allow twice-monthly dosing.

Consensus interferon, a synthetic type I interferon, had disappointing end-of-treatment results in combination with ribavirin for previous non-responders to pegylated interferon and ribavirin. However, this was tested in a very-difficult-to-treat population, with several negative predictors of response. A second modified study is being planned to evaluate this interferon with ribavirin in the non-responder population.

Ribavirin Analogues
Tarabiviri