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- 저자 : ( Jacqueline O Leary ) (검색결과 1 건)
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Review Article : New Antiviral Therapies for Hepatitis C
( Jacqueline O Leary ),( Raymond T. Chung ) 대한간학회 2003 Clinical and Molecular Hepatology(대한간학회지) Vol.9 No.4
Hepatitis C virus (HCV), originally known as non-A non-B hepatitis, was identified and sequenced in 1989.1 Since its molecular cloning, seroepidemiologic studies have revealed that 170 million people worldwide, and 1.8% of the US population, are chronically infected.2-4 End stage liver disease attributable to chronic HCV infection is the leading indication for liver transplantation worldwide, and is a major risk factor for the development of hepatocellular carcinoma.5 ?Antiviral therapy for HCV has not changed dramatically since the introduction of interferon alfa (IFN) in 1986.6 IFN has protean antiviral effects, both direct and indirect, against a large number of DNA and RNA viruses: (1) It prevents viral entry and uncoating. (2) Through the action of the Jak-Stat kinase signal transduction pathway, it induces a large number of host genes that participate in direct inhibition of viral protein and RNA synthesis. For instance, the protein PKR, potently induced by IFN, inhibits both host and viral protein synthesis by phosphorylating and inactivating the eukaryotic translation initiation factor (eIF-2). (3) It upregulates viral antigen expression at the cell surface, increasing recognition of virally infected cells by cytolytic T lymphocytes. (4) It has immunomodulatory effects on T cell and natural killer cell function. The precise mechanism by which IFN acts against HCV is unknown, but recent evidence from RNA replicon and other cell culture systems demonstrate that IFN can act directly to suppress HCV replication.7,8 ?Unfortunately, clinical trials of IFN monotherapy were met with disappointing rates (5-10%) of sustained virologic response (SVR), defined as clearance of HCV RNA using a sensitive qualitative nucleic acid amplification assay 24 weeks after completion of therapy. Only with addition of ribavirin (RBV), a guanosine nucleoside analogue active against other RNA and DNA viruses, to IFN did SVR rates increase appreciably, to approximately 40%.9-12 Its mechanism of action against HCV remains unclear, but data suggest that RBV acts both as an immunomodulator13 and an RNA mutagen.14 ?Because of pharmacokinetic concerns regarding the loss of antiviral efficacy with conventional IFN dosing (thrice weekly), the most important recent advance in the management of chronic hepatitis C has been a manipulation of the IFN alfa molecule to extend its bioavailability. The covalent addition of a polyethylene glycol (PEG) to either the IFN-alfa 2a [PEG-IFN-alfa-2a (40 kD)] or IFN-alfa 2b [PEG-IFN-alfa-2b (12 kD)] in combination with ribavirin was associated with an increase in overall SVR rates to 54-56%.15,16 Unfortunately, to achieve these SVR rates, patients receiving these regimens must often endure significant side effects for up to 48 weeks. Furthermore, persons harboring genotype 1 HCV infection, the most common genotype in the U.S. (75%), experience less than optimal SVR rates of 42- 45%. In addition, the very populations of patients who are most in need of effective antiviral therapy, including persons with decompensated cirrhosis, recipients of liver transplants, and persons coinfected with HIV, experience yet lower SVR rates and are even less able to tolerate curative doses of these medications. ?In view of these limitations, new therapies with greater efficacy, improved side effect profiles, and broader applicability are desirable. This review will consider new agents for hepatitis C in two groups: (1) modifications of currently available therapies, and (2) agents designed to interrupt specific steps in the life cycle of the virus.
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