Introduction

Although current therapies are effective in more than half of all treated patients, therapy is costly, associated with significant morbidity, requires substantial commitment from the patient and medical staff, and is not suitable for all patients. Thus, there is an important need for more effective therapies, and this remains a priority in terms of continued research endeavours. The lack of an effective cell culture system and small animal model for HCV infection has hampered the development and discovery of alternative effective small molecules or vaccines. Nevertheless, the ideal therapy for patients with chronic hepatitis C would be cost-effective, be orally bioavailable, have an acceptable side effect profile, and be effective in the majority of patients. Such therapies are probably unlikely to be developed in the near future. Therapies in current development and/or in human clinical trials will be discussed.

Adjuvant Agents That May Be Added to Current Regimens

Alternative Interferons or Interferon Inducing Agents

The development of alternative type 1 interferon compounds or methods of delivering longer acting preparations with theoretically different pharmacokinetic profiles may lead to the availability of alternate interferon preparations. Whether these will improve or enhance sustained response rates or side effect profiles in combination with ribavirin or other agents in larger clinical trials is unknown and is currently under early stage clinical investigation. Oral interferon inducing agents are also in pre-clinical trials, and probably phase I human development will occur in late 2002.

IMPDH Inhibitors. The development of compounds which specifically inhibit inosine 5 monophosphate dehydrogenase (IMPDH) may provide an alternative for patients with chronic hepatitis C when combined with interferon. This enzyme, which is also inhibited by ribavirin and mycophenolate, is essential for modulation of host cellular pathways and has antiviral and immunomodulatory effects. Phase I and II clinical trials in patients with chronic hepatitis C have shown one such agent (VX-497) to be safe, but with no observable antiviral effect when given alone. As in the initial ribavirin monotherapy studies, ALT reductions were also noted in some patients. A subsequent phase II, randomized, double-blind study of VX-497 combined with interferon in treatment naïve patients for 4 weeks indicated safety in combination with interferon, but no enhancement of antiviral activity. Further development of more potent and specific IMPDH inhibitors will require randomized controlled clinical trials to determine their efficacy and future place in the management of patients with chronic hepatitis C.

Alternative Ribavirin-Like Drugs. Other agents similar to ribavirin that bias the immune response toward a type 1 profile are in development. These drugs will further test the hypothesis  that a significant component of the benefit of ribavirin is by its action as a type 1 cytokine enhancer. Levovirin, the l-isomer of ribavirin, is associated with lesser degrees of hemolytic anemia, appears safe in animal studies, and has been well tolerated in phase I dose finding studies in healthy volunteers. Viramidine, a ribavirin prodrug, also produces less hemolysis, is converted rapidly to ribavirin in vivo, has a three- to sixfold longer residence time in the liver, and is less concentrated in peripheral blood red cells compared to ribavirin. The safety, utility and future development of these and other similar agents will need to be established in larger-scale clinical trials in combination with alpha interferons.

Other Immunomodulators

Histamine. Histamine dihydrochloride, through binding of H2 receptors on phagocytic cells, disrupts NADPH-oxidase responsible for the production of reactive oxygen species and is also an immunomodulator acting on NK and T cells. This compound has been tested in combination with interferon in certain malignancies and in initial pilot studies in patients with hepatitis C. In two phase II studies where histamine dihydrochloride was administered to patients along with interferon, or in combination with interferon and ribavirin, the data suggest there may be benefit in terms of end of treatment and sustained response rates. An ongoing European, multinational trial is currently evaluating the safety and efficacy of peginterferon plus ribavirin vs. peginterferon plus ribavirin plus histamine injections in hepatitis C patients.

Molecular Based Therapies

Hepatitis C Specific Viral Enzyme Inhibitors

Based upon current knowledge of the structural biology and actions of HCV specific enzymes during viral replication, many groups are pursuing the development of compounds that specifically inhibit enzymes critical to the HCV life cycle. There are three initial and important virus specific targets for antiviral drug development including the HCV protease, polymerase, and helicase enzymes. The efficacy of these compounds is now being evaluated using the HCV replicon model system, and promising compounds will undergo testing in animals for oral bioavailability and toxicity. The structure of many potential inhibitors has been described, and a number of early phase I trials are being undertaken with HCV specific protease and polymerase inhibitors in chronic hepatitis C patients. Barriers to the development of these agents are numerous, and include the shallow protease binding cleft, viral drug resistance, and the fact that such agents will be required to have activity profiles against a broad range of HCV genotypes. Also, the importance of combination therapy to multiple enzyme targets has been demonstrated in the HIV clinical setting to avoid the selection of resistant viral strains. As such, multiple targets of this class will be required in order to reduce or eliminate drug resistant HCV quasispecies, and assays to detect viral resistance patterns must be established.

Antisense Oligonucleotides

HCV specific antisense oligonucleotides, short sequences of 15–40 nucleotides stabilized to protect these molecules against cellular nuclease degradation, can hybridize to and prevent translation of viral RNA and thus inhibit disease causing protein expression. A 20 nucleotide phosphorothioate oligonucleotide with a sequence complementary to the HCV translation initiation region (ISIS 14803) is currently undergoing phase I and II clinical trials in patients who have failed to respond to available antiviral therapies. Some patients have had viral load ≥ 1 log in HIV RNA after 28 days of therapy.  For unexplained reasons these load changes are sometimes, but not always, associated with asymptomatic but significant ALT elevations. The efficacy and safety of this compound is now being evaluated in phase II studies of 12 weeks’ duration in previous nonresponders to other antiviral therapies.

HCV Specific Ribozymes

Synthetic nuclease resistant ribozymes designed to cleave the hepatitis C virus IRES are currently in phase II clinical trials. These stabilized ribozymes contain modified nucleotides and phosphorothioate linkages and are efficiently taken up by the liver. In preliminary cell culture studies, these ribozymes inhibited viral replication in a dose dependent fashion, and this effect was potentiated by interferon. Phase II trials administering these HCV specific ribozymes, alone or in combination with interferon for 12 weeks’ duration, are currently in progress. While these newer small molecule approaches provide hope and excitement for thetreatment of HCV infected patients, many further studies will be necessary to determine the safety and efficacy of these approaches, their effect on liver histology, and the mechanisms of any antiviral effects, and to evaluate whether such agents will need to be administered in combination with our available antiviral therapies to prevent the development of resistance.

Strategies to Minimize Hepatic Fibrosis

Interferon Gamma. Interferon ã is an antifibrotic cytokine in murine and human hepatic stellate cells, is an immunomodulatory cytokine, and has HCV specific antiviral activity. A phase II randomized, double-blind, multicenter trial to determine the antifibrotic efficacy of interferon gamma 1b is currently underway in patients with hepatic fibrosis due to hepatitis C and compensated cirrhosis, using a histologic primary end point.

Cellular immuno therapy. Cytotoxic T lymphocytes play an important role in viral clearance and immunological memory in chronic hepatitis B, and likewise it is thought that a strong, multispecific directed CTL response contributes to HCV clearance in those individuals who are fortunate enough to spontaneously resolve HCV infection. Various groups have created vaccines containing HCV specific viral epitopes that are recognized by cytotoxic T-cells.

Whether these agents can be successfully used as potential vaccines in the primary prophylaxis setting, or in the setting of a therapeutic vaccine to modify the host immune response in patients with chronic hepatitis C infection is currently unknown. One such agent is currently in early phase human trials.

Conclusion

Although many of these future strategies are currently in development, it will require a number of years before the safety, short- and long-term efficacy, clinical value, and appropriate setting for each of these agents alone and in combination regimens is established. For these reasons, it is unlikely that many of these newer therapies, even if proven to be effective, will be available for routine clinical use within the next 3–5 years.

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