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Published studies have shown that peginterferon-alpha alone results in "sustained response" rates of 30% to almost 40%. The side effect profile is similar to unmodified interferon-alpha. Preliminary data show that addition of oral ribavirin to pegylated interferon-alpha results in "sustained response" rates of approximately 50%. Hence, pegylation enhances the efficacy of interferon-alpha for the treatment of chronic hepatitis C.
The United States Food and Drug Administration (FDA) has recently approved peginterferon-alpha-2b (Peg-Intron, Schering-Plough) for the treatment of chronic hepatitis C. Peginterferon-alpha-2a (Pegasys, Hoffmann La Roche) will likely be approved in the near future. Within a year, the FDA will likely approve the combination of peginterferon-alphas with ribavirin. Clinical trials of peginterferon-alpha with a compound called VX-497 (Vertex Pharmaceuticals) are also in progress. VX-497 has some features similar to ribavirin and inhibits a cellular enzyme know as inosine monophosphate dehydrogenase that may responsible for some of its effects.
An even longer acting form on interferon-alpha is currently in early stage clinical testing. This is a fusion protein between albumin and interferon alpha (Albuferon, Human Genome Sciences). Data on its clinical efficacy are not yet available. It is also probable that other long acting preparations of interferon-alpha will be developed in the next few years.
Therapeutic vaccines are also being developed to enhance the immune response against the hepatitis C virus. In contrast to a preventive vaccine, which is likely to be a very long way off for hepatitis C, a therapeutic vaccine is administered to already-infected individuals to stimulate the immune system to fight the infection. Several therapeutic vaccines are in preclinical development for hepatitis C. The most promising of these are DNA vaccines involving injection of DNA copies of the hepatitis C virus's RNA genome, which are taken up by certain immune system cells. These cells then express viral proteins, stimulating an immune response against the virus. These theoretically appealing therapeutic vaccine for hepatitis C remain to be shown effective in human subjects
Three favorite targets of the hepatitis C virus for pharmaceutical chemists are its N3S RNA polymerase, NS3 RNA helicase and NS5B RNA polymerase. Compounds directed against these targets are in various stages of preclinical development. The targets are all enzymes (proteins that catalyze chemical reactions) essential for hepatitis C virus replication. They are expressed in cells infected with the virus but not in mature viral particles themselves. Armed with knowledge of the three-dimensional structures of these enzymes deduced using X-ray crystallography, scientists can identify molecules that inhibit their activities.
NS3 has two parts with distinct enzymatic activities. One part is a protease that cuts a larger precursor protein encoded by the hepatitis C virus RNA into smaller functional proteins. Inhibition of NS3 would result in a failure of the virus to make the smaller proteins necessary for its replication. The other part of NS3 is a RNA helicase that unwinds the hepatitis C viral RNA. RNA unwinding is necessary for its efficient replication and translation into protein. Specific inhibitors of NS3's enzymatic activities would theoretically not influence critical host cell functions, limiting the side effect profiles. NS5B of the hepatitis C virus is an essential RNA-dependent RNA polymerase that copies the virus's RNA genome. Animal cells do not copy RNA; they make RNA copies from DNA. Therefore, specific inhibitors of the NS5B should not affect host cell processes.
Of course, one cannot accurately predict the adverse event profile of a given drug until it is tested in human. Drugs designed as best as possible against specific viral targets may still prove to have side effects. However, well-designed drugs directed against the hepatitis C virus RNA, NS3 protease, NS3 RNA helicase and NS5AB RNA polymerase are very likely to be more effective and better tolerated than currently available treatments for hepatitis C. The timeline from the laboratory to the clinic is likely to be several years.
Very little is known about why the liver becomes fibrotic in response to chronic inflammation. Furthermore, it is not known why some individuals infected with the hepatitis C virus develop significant fibrosis or cirrhosis while others never do. Some drugs that may prevent liver fibrosis and cirrhosis are in early clinical trials. IP-501 (Interneuron Pharmaceuticals) is an orally administered anti-fibrotic compound being tested for the treatment of including alcoholic and hepatitis C-induced cirrhosis. Animal models suggest that IP-501 is effective in preventing the development of alcohol-induced cirrhosis, however the exact mechanism by which this compound works is not fully understood. Clinical trials of IP-501 in alcohol-induced liver disease and chronic hepatitis C are underway. Preliminary studies in humans have also shown that interleukin-10 (Schering-Plough) may prevent liver fibrosis in chronic hepatitis C. Clinical trials of interleukin-10 need to be carried out on a larger scale to demonstrate safety and efficacy. Increasing scientific effort is being devoted to the study of liver fibrosis in response to injury and exciting new drugs to prevent it will hopefully be available someday.
Pharmacogenomics is the science of understanding the correlation between an individual patient's genetic make-up and response to a drug. The discipline is evolving rapidly as a result of the extensive work recently completed on sequencing the entire human genome. Phamacogenomics aims to identify genetic markers that predict response to a drug. The genetic markers commonly assessed are known a single nucleotide polymorphisms (SNPs) and haplotypes. SNPs are changes at a single base of DNA between individuals. Haplotypes are linear arrays of slightly different forms of particular genes on a chromosome. By studying populations of patients and their responses to a drug, inheritance of a collection of SNPs or different haplotypes can be correlated with successful treatment, unsuccessful treatment or development of side effects. This knowledge can them be used to "customize" drug therapy for a particular patient based on first examining their DNA. Click here to return to Diseases of the Liver home page.