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Potential future therapeutic options for Hepatitis C
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REVIEW
Chronic hepatitis C and no response to antiviral therapy: potential current and future therapeutic options
G. V. Papatheodoridis and E. Cholongitas
Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
Journal of Viral Hepatitis
Volume 11 Issue 4 - July 2004
EXCERPT
Potential future therapeutic options
The development of new therapeutic agents is critical for further improvement of the management of chronic hepatitis C, as current therapeutic options have rather low efficacy in common subgroups of chronic hepatitis C patients, such as those with HCV genotype 1 or with advanced liver disease, and most probably in nonresponders and relapsers. Moreover, both standard and pegylated IFNa and/or ribavirin are associated with frequent and potentially severe side-effects having a negative impact on patient quality of life and are contraindicated for certain subgroups of chronic hepatitis C patients. New therapeutic approaches currently evaluated in the management of chronic hepatitis C may be classified into agents with mechanism of actions similar to current therapies or agents for combination with current therapies, inhibitors of HCV replication, immunomodulators, and agents for maintenace therapy or antifibrotic agents.
Agents with mechanism of actions similar to current therapies or agents for combination with currrent therapies
Alternative types or new delivery systems of IFN are currently being studied in order to improve the SVR rates and/or the side-effects profile of available IFNa preparations. Omega IFN, a new type 1 interferon active in vitro against DNA, RNA and retroviruses, was tried in chronic hepatitis C patients infected with HCV genotype 1 and achieved normalization of ALT activity and clearance of serum HCV RNA levels in about one-third of cases within the first 4 weeks of therapy. A novel recombinant human albumin-IFNa fusion protein, called Albuferon (Human Genome Sciences Inc., Rockville, MD, USA), was recently evaluated in a phase I study including 34 chronic hepatitis C patients. Albuferon was administered subcutaneously at a single dose of up to 80 g or at two doses 14 days apart and it was reported to be well tolerated and to have an extended half-life of up to 157 h that supports dosing every 2-4 weeks. Alternative strategies for sustained release of IFNa into the circulation might include disposable infusion pumps, controlled release injectables using polymer matrix, polyaminoacid-based oral delivery systems, or encapsulation in liposomes.
Although ribavirin monotherapy is ineffective in the treatment of chronic hepatitis C, the addition of ribavirin to IFNa therapy significantly increases the SVR rates compared with those of IFNa monotherapies. The development of ribavirin-associated haemolysis, however, often results in modification of dose or even discontinuation of ribavirin, which may have an adverse effect on the treatment efficacy. Agents with a ribavirin-like activity but lesser degrees of side-effects such as haemolysis have now been developed. Levovirin is a second-generation l-isomer of ribavirin, while viramidine is a ribavirin prodrug that is converted rapidly to ribavirin and is associated with a longer duration of residence in the liver and less concentration in peripheral red blood cells compared with ribavirin. Both levovirin and viramidine retain the antiviral and immunomodulatory properties of ribavirin. Levovirin was shown to be safe in animals and well tolerated in healthy volunteers without frequent association with haemolysis, while viramidine was also shown to be safe in animal-safety studies.
The inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH), an enzyme that catalyses a rate-limiting step in guanosine triphosphate synthesis, is considered to be important for the antiviral effect of ribavirin and therefore IMPDH inhibitors, such as mycophenolate mophetil and VX-497, are currently evaluated as alternatives to ribavirin for combination with IFNa. Mycophenolate mofetil, a well-known immunosuppressive agent, has been used in combination with pegylated IFNa with or without ribavirin but it has not been shown to increase the probability of SVR. VX-497, an orally bioavailable potent specific inhibitor of IMPDH has been evaluated within phase I and II studies in patients with chronic hepatitis C. Monotherapy with VX-497 was found to be safe and well tolerated and to have an effect only on transaminases but not on HCV viremia levels, similar to that previously observed in studies of ribavirin monotherapy. The combination of VX-497 and IFNa2b given for 4 weeks in 53 naïve chronic hepatitis C patients was reported to be well tolerated and perhaps to have a trend for more potent reduction of serum HCV RNA levels compared with IFNa2b monotherapy..
Inhibitors of HCV replication
The recent advances in our understanding of HCV genome and life cycle as well as of structure and actions of many HCV-specific enzymes has enabled the rational design of agents directed against specific targets in order to inhibit enzymes critical to HCV replication. HCV is a single-stranded RNA virus with a genome of about 10 000 nucleotides in length. HCV RNA is characterized by one long open reading frame that encodes a single polyprotein of approximately 3000 amino acids, which is eventually processed by cellular and viral enzymes into at least 10 discrete polypeptides, the structural and nonstructural (NS) HCV proteins. Translation starts after the formation of a binary complex between the 40S ribosomal subunit and the HCV internal ribosome entry site (IRES), which resides within the 5'-untranslated region (UTR) of HCV genome. The most important HCV-specific targets for new antiviral agent development include the processing of HCV polyprotein by NS3 helicase, NS3 (+NS4A) serine protease, or NS2/NS3 metalloprotease, the HCV replication using NS5B polymerase and NS3 helicase, and the HCV regulatory elements such as the 5'-UTR encoding for IRES or the 3'-UTR used in the generation of both plus and minus strand synthesis. The recent development of cell culture models for HCV, mainly the HCV replicon system, allowed the initial evaluation of several promising antiviral agents before the onset of studies in animals and patients. It should be noted, however, that the in vivo activity of several antiviral agents cannot be always anticipated based on their in vitro efficacy data, as problems of viral resistance or inactivity against different HCV genotypes may arise with the use of such agents within large clinical trials. Therefore, combinations of agents directed against multiple enzyme targets may be required in order to overcome HCV resistance, similar to what has previously been shown in the HIV clinical setting.
NS3 serine protease, which is fully activated after the formation of a complex with a cofactor protein NS4A, is currently the target of many novel antiviral agents against HCV. One of these NS3 serine protease inhibitors, BILN 2061, was recently reported to achieve potent inhibition of HCV replication in vitro and to be safe in animals, having a good oral bioavailability. In a recently presented phase I study, BILN 2061 was given orally at a daily dose of 400 mg just for 2 days in eight patients with chronic hepatitis C, all HCV genotype 1 with advanced fibrosis, and found to result in a >1 log10 decrease of serum HCV RNA levels without having any side-effects. Very recently, the succesful development of recombinant human high-affinity antibody fragments against NS3 HCV protein, which achieves complete inhibition of NS3 helicase activity in vitro, was also reported.
Antisense oligonucleotides are short synthetic nucleotide sequences stabilized usually by the addition of phosphorothioates in order to escape degradation from cellular nucleases and improve cellular uptake, stability and hybridization. Antisense oligonucleotides bind an RNA target forming RNA-RNA (antisense RNA) or RNA-DNA (antisense DNA) hybrids, which result in inhibition of RNA translation and/or RNA replication. ISIS 14803, which is an oligonucleotide of 20 nucleotides designed to bind the HCV IRES region, has recently been evaluated within phase I and II trials in chronic hepatitis C patients who had failed to respond to previous courses of standard or pegylated IFNa with or without ribavirin. Treatment with ISIS 14803 at doses of 2-6 mg/kg administered as 2-h intravenous infusions thrice weekly for 4-10 weeks achieved >1 log10 reduction in serum HCV RNA levels in 10 (30%) of 30 patients, while it was associated with frequent (47%) marked elevations of aminotransferase activity (ALT > 8 x ULN) and mild to moderate side-effects.
Ribozymes are synthetic nuclease-resistant catalytic RNA molecules stabilized by the addition of phosphorothioates and modified nucleotides, which are efficiently taken up by the liver where they act by cleavage of specific sequences of HCV RNA. At least one ribozyme against HCV, called Heptazyme (Ribozyme Pharmaceuticals Inc., Boulder, CO, USA), designed to cleave the HCV IRES from the 5'-UTR region of HCV genome, was recently under investigation. In an initial phase I clinical trial including 28 patients with chronic hepatitis C, a single subcutaneous injection of 3-90 mg of Heptazyme was reported to be safe and well tolerated. Similarly, in a phase II clinical trial with 41 patients, Heptazyme at a dose of 50 or 100 mg/m2 given subcutaneously twice daily for 8-13 weeks was also found to be safe and well tolerated but to result in >0.5 log10 decrease in serum HCV RNA levels in a minority (<10%) of cases. At the same time, however, the pharmaceutical company, which developed Heptazyme, announced the discontinuation of further clinical evaluation of this agent due to safety issues in animals.
Immunomodulators
Histamine dihydrochloride is considered to have both immunomodulatory and antioxidant properties because of its activities on the natural killer cells and T lymphocytes and its effect on the production of reactive oxygen species by NADPH-oxidase. The combination of several doses of histamine dihydrochloride with standard IFNa2b, both given for 48 weeks, has been evaluated in a phase II trial including naïve chronic hepatitis C patients and found to be well tolerated achieving SVR rates ranging between 30 and 40%, which seem to be somewhat inferior to those reported with the combination of IFNa2b and ribavirin. The triple combination of IFNa2b, ribavirin and histamine was evaluated in a phase II trial in 18 patients without SVR after a previous course of IFNa monotherapy and achieved virologic ETR at 48 weeks of therapy in approximately 50% of cases. Whether the addition of histamine dihydrochloride may increase the efficacy of the combination of PEG-IFNa2b and ribavirin is currently evaluated within a phase III, multicenter clinical trial.
Thymosin-a1 is a synthetic 28-amino acid peptide that has been shown to have several immunomodulatory activities on T lymphocytes and natural killer cells. Data from three relatively small trials suggest that the combination of thymosin-a1 and IFNa-2a is safe and may be more effective than IFNa monotherapy. The efficacy of the combination of thymosin-a1 plus PEG-IFNa2a for the treatment of cirrhotic and non-cirrhotic patients who did not respond to a previous course of either IFNa alone or IFNa plus ribavirin is currently under evaluation within two large multicentre trials.
The host immune response against HCV, particularly specific cytotoxic T cells, appears to be critical not only for viral clearance during acute infection but also for the development of liver injury during chronic infection. Thus, several groups have developed vaccines containing HCV epitopes recognized by specific cytotoxic T cells, which are planned to be investigated for primary prevention and for therapeutic intervention, but no data in human beings are currently available. Interleukin-12 is a cytokine that stimulates proliferation of activated cytotoxic T cells and natural killer cells and IFNa production. In a phase II, randomized clinical trial including patients without SVR to a previous course of IFNa alone or IFNa plus ribavirin, treatment with recombinant interleukin-12 was found to have rather poor efficacy and substantial toxicity and therefore the trial was discontinued early and the agent was probably withdrawn from further development in the management of chronic hepatitis C.
Indirect evidence suggest that the host humoral response to HCV may also play a role in HCV clearance. Very recently, human monoclonal antibodies against the HCV envelope protein E2 generated from peripheral B cells isolated from patients infected with HCV 1b were reported to be safe and well tolerated and to achieve significant reductions of serum HCV RNA levels in eight of 15 patients with chronic hepatitis C.
Agents for maintenace therapy or antifibrotic agents
Although clearance of HCV from serum and liver is the main therapeutic target in chronic hepatitis C, delay in progression of fibrosis may represent a secondary therapeutic target that could be particularly important in patients with advanced fibrosis who fail to achieve SVR. Several indirect data suggest that IFNa may have antifibrotic properties. Significant improvements in liver histology have been observed not only in patients with SVR, but in all patients who achieve SBR regardless of virologic response as well. Moreover, improvements in both the necroinflammatory activity and the extent of fibrosis have been observed at 6-12 months after the end of therapy in patients with partial virologic response, which are usually included among the nonresponders. It should be kept in mind, however, that the liver biopsy shows the histological lesions at a certain time-point and usually the estimation of histologic changes is attempted within an interval of <2 years, which is quite short for a slowly progressive disease, like chronic hepatitis C. The timing of post-treatment liver biopsy is also very important, as histologic changes usually develop several months after the virologic and biochemical changes. In an analysis of 10 studies with IFNa therapy in chronic hepatitis C, biochemical nonresponders were reported to have some, but not significant, improvement in the necroinflammatory activity and no change in the extent of fibrosis. In another study with IFNa monotherapy, the extent of fibrosis was found to worsen in 22% (19/91) of chronic hepatitis C patients with or without biochemical response compared with 56% (57/102) of untreated controls (P < 0.001). The combination of IFNa plus ribavirin (almost exclusively because of the IFNa activity) has been reported to improve fibrosis in 66% and worsen fibrosis in only 15% of 710 nonresponders. It should be noted, however, that, in all trials, the effects of IFNa on the histologic lesions of non-responders have been evaluated within 6-12 months after the end of therapy and thus there are no data for the actual long-term outcome of this subgroup of chronic hepatitis C patients. IFNa maintenance therapy has been initially evaluated in a randomized study including patients without virologic response, in which liver histological lesions were found to improve after 2.5 years in case of continuous IFNa administration and to worsen in case of stopping IFNa at 6 months of therapy.
Besides its potential beneficial effect on liver histology, IFNa therapy may also be associated with reduction of hepatocellular carcinoma (HCC) incidence. In a meta-analysis including studies with patients with HCV cirrhosis, 6-12 months of IFNa therapy was found to be associated with almost negligible risk of HCC for patients with a sustained response (<1% in 4 years) and significantly lower risk of HCC in patients without sustained response (9%) when compared with untreated patients (21.5%) (OR: 2.7; 95% CI: 1.9-3.9).
The effects of maintenance therapy with PEG-IFNa on the long-term outcome of chronic hepatitis C patients with advanced fibrosis are currently under evaluation within three large randomized-controlled trials, the NIH-funded Hepatitis C Antiviral Long-term Treatment against Cirrhosis, the Colchicine versus Peg-Intron Long-Term, and the Evaluation of Peg-Intron in Control of hepatitis C Cirrhosis trials.
Besides IFNa, ribavirin, interleukin-10 and interferon-gamma have also been suggested as potential antifibrotic agents in chronic hepatitis C. Ribavirin was reported to be associated with some improvement in necroinflammatory activity and prevention of fibrosis progression in nonresponders to IFNa plus ribavirin therapy. In a recent randomized trial, ribavirin monotherapy was shown to maintain biochemical and histological improvements mostly in chronic hepaitits C patients who had a biochemical but not virologic response to IFNa and ribavirin combination therapy. Interleukin-10 was initially suggested to have some antifibrotic activities, but its efficacy did not seem to be maintained with extended follow-up. Interferon-gamma, a cytokine with antifibrotic activities in vitro, is currently under investigation within a phase II double-blind, placebo-controlled trial including patients with advanced fibrosis or compensated cirrhosis and using a histological primary end-point.
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